CVD, DKA and LLA were captured using linkage to national ...



The Effect of Dapagliflozin on Glycaemic Control and other Cardiovascular Disease Risk factors in type 2 diabetes mellitus patients: a real-world observational studyAuthors: Stuart J McGurnaghan1, Liam Brierley1, Thomas M Caparrotta1, Paul M McKeigue2, Luke AK Blackbourn1, Sarah H Wild2, Graham P Leese4, Rory J McCrimmon4, John A McKnight2, Ewan R Pearson4, John R Petrie5, Naveed Sattar5, Helen M Colhoun1, on behalf of Scottish Diabetes Research Network Epidemiology Group.1MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.2Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.4Ninewells Hospital and Medical School, Dundee, DD1 9SY5Institute of Cardiovascular and Medical Sciences, University of Glasgow, G12 8TAWord count: 4,000 main text, 326 abstractFigures: 1, Tables: 3, ESM Tables: 7, ESM Figures: 1.No. references: 36Corresponding author: Professor Helen ColhounMRC Institute of Genetics & Molecular MedicineThe University of EdinburghWestern General HospitalCrewe Road, Edinburgh EH4 2XUhelen.colhoun@igmm.ed.ac.uk /Tel:+44 1316518770AbstractAimsDapagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), is indicated for improving glycaemic control in type 2 diabetes mellitus. Whether its effects on HbA1c and other parameters, including safety outcomes, in clinical trials are obtained in real-world practice needs to be established. MethodsWe used data from the comprehensive national diabetes register, the Scottish Care Information-Diabetes (SCI-Diabetes) collaboration database, available from 2004-mid-2016. Data within this database were linked to mortality data from the General Registrar available from the Information Services Division (ISD) of the NHS in Scotland. We calculated crude within-person differences between pre- and post-drug-initiation values of HbA1c, BMI, weight, SBP and estimated glomerular filtration rate (eGFR). We used mixed-effects-regression models to adjust for within-person time trajectories in these measures. For completeness we evaluated safety outcomes, cardiovascular disease (CVD) events, lower-limb amputation (LLA) and diabetic ketoacidosis (DKA) focusing on cumulative-exposure effects, using Cox proportional hazard models though power to detect such effects was limited. ResultsAmong 8566 people exposed to dapagliflozin over a median of 210 days the crude within-person change in HbA1c was -10.41 mmol/mol (-0.95%) after three-months’ exposure. The crude change after 12-months was -12.99 mmol/mol (-1.19%) but considering the expected rise over time in HbA1c gave a dapagliflozin-exposure-effect estimate of -15.14 mmol/mol (-1.39%) (95% confidence interval (CI) -14.41, -15.87) at 12-months that was maintained thereafter. A drop in SBP of -4.32mmHg (95% CI -4.84, -3.79) on exposure within the first 3-months was also maintained thereafter. Reductions in BMI and weight stabilised by 6-months at -0.82kg/m2 (95% CI -0.87, -0.77) and -2.20kg (95% CI -2.34, -2.06) and were maintained thereafter. eGFR declined initially by -1.81 ml min-1 1.73m-2 (95% CI -2.10, -1.52) at 3-months but varied thereafter. There were no significant effects of cumulative drug-exposure on safety outcomes.ConclusionsDapagliflozin-exposure was associated with reductions in HbA1c, SBP, weight and BMI that were at least as large as in clinical trials. Dapagliflozin also prevented the expected rise in HbA1c and SBP over this time period. Keywords: Dapagliflozin, type 2 diabetes, glycaemic controlAbbreviations: CVD- cardiovascular disease; SBP- systolic blood pressure; SGLT2- sodium glucose transporter-2.Research in context What is already known about this subject? (maximum of 3 bullet points) Dapagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a class of drugs used for controlling glycaemia in type 2 diabetes mellitus patients. In clinical trials dapagliflozin improved glycaemic control, as measured by HbA1c, and reduced body mass index, weight and blood pressure; the reported effects on HbA1c, available from documents submitted to the drug licensing authorities, ranged from 0.7 to 0.9% units (about 7-10 mmol/mol). Data from clinical trials and adverse event reporting systems suggest that some SGLT-2 inhibitors may be associated with a decreased risk of CVD events and an increased risk of lower limb amputation and diabetic ketoacidosis but it remains unclear if these effects apply to all drugs in this class. What is the key question? (one bullet point only)Is the treatment effectiveness of dapagliflozin on HbA1c and other clinical continuous and event outcomes observed in clinical trials/adverse event reporting systems seen in real-world practice?What are the new findings? (maximum of 3 bullet points)This large study of actual use, including those with both on and off licence use allowed us to establish that dapagliflozin usage was associated with substantial improvements in HbA1c and avoidance of worsening of HbA1c over time. Reductions in weight, body mass index and systolic blood pressure were also found; effects were at least as large as in clinical trials both in licenced and non-licenced users. There were no significant effects of cumulative drug-exposure on safety outcomes but power to detect such effects was limited.How might this impact on clinical practice in the foreseeable future? (one bullet point only)Reassuringly, the beneficial effects of dapagliflozin on HbA1c, body weight, BMI and SBP found in trials do seem to be obtained in the actual real-world setting.IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2i) block SGLT2 within the proximal renal tubule, reducing glucose and sodium reabsorption and increasing glycosuria and fluid-loss. Dapagliflozin is a new SGLT2i indicated alongside diet and exercise in improving glycaemic control in adults with type 2 diabetes (T2DM), licensed in the EU (2012) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a2h80l30ca1","properties":{"formattedCitation":"[1]","plainCitation":"[1]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/dGSY580Q","uris":[""],"uri":[""],"itemData":{"id":522,"type":"webpage","title":"European Medicines Agency - Forxiga (dapagliflozin)","URL":"","accessed":{"date-parts":[["2017",9,8]]}}}],"schema":""} [1], and the US (2014) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a1tbrovin48","properties":{"formattedCitation":"[2]","plainCitation":"[2]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/T4hM3qw8","uris":[""],"uri":[""],"itemData":{"id":531,"type":"article","title":"Summary Review for Regulatory Action - Farxiga (dapagliflozin)","publisher":"FDA","issued":{"date-parts":[["2014"]]}}}],"schema":""} [2]. Dapagliflozin improves glycaemic control in randomised controlled trials (RCTs) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"rhlL3hbA","properties":{"formattedCitation":"[3\\uc0\\u8211{}10]","plainCitation":"[3–10]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/PB7nItij","uris":[""],"uri":[""],"itemData":{"id":321,"type":"article-journal","title":"Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes","container-title":"Diabetes Care","page":"650–657","volume":"32","issue":"4","source":"Google Scholar","author":[{"family":"List","given":"James F."},{"family":"Woo","given":"Vincent"},{"family":"Morales","given":"Enrique"},{"family":"Tang","given":"Weihua"},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009"]]}}},{"id":"TeVZF1gX/3Ux5XT12","uris":[""],"uri":[""],"itemData":{"id":317,"type":"article-journal","title":"Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin - a randomized trial","container-title":"Annals of internal medicine","page":"405–415","volume":"156","issue":"6","source":"Google Scholar","author":[{"family":"Wilding","given":"John PH"},{"family":"Woo","given":"Vincent"},{"family":"Soler","given":"Norman G."},{"family":"Pahor","given":"Andrea"},{"family":"Sugg","given":"Jennifer"},{"family":"Rohwedder","given":"Katja"},{"family":"Parikh","given":"Shamik"}],"issued":{"date-parts":[["2012"]]}}},{"id":"TeVZF1gX/3nckOKvE","uris":[""],"uri":[""],"itemData":{"id":320,"type":"article-journal","title":"Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial","container-title":"Diabetes Care","page":"2217-2224","volume":"33","issue":"10","source":"CrossRef","DOI":"10.2337/dc10-0612","ISSN":"0149-5992, 1935-5548","shortTitle":"Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise","language":"en","author":[{"family":"Ferrannini","given":"E."},{"family":"Ramos","given":"S. J."},{"family":"Salsali","given":"A."},{"family":"Tang","given":"W."},{"family":"List","given":"J. F."}],"issued":{"date-parts":[["2010",10,1]]}}},{"id":"TeVZF1gX/1BYwyWkC","uris":[""],"uri":[""],"itemData":{"id":486,"type":"article-journal","title":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial","container-title":"The Lancet","page":"2223–2233","volume":"375","issue":"9733","source":"Google Scholar","shortTitle":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin","author":[{"family":"Bailey","given":"Clifford J."},{"family":"Gross","given":"Jorge L."},{"family":"Pieters","given":"Anne"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."}],"issued":{"date-parts":[["2010"]]}}},{"id":"TeVZF1gX/Y9689ec5","uris":[""],"uri":[""],"itemData":{"id":487,"type":"article-journal","title":"Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy","container-title":"Diabetes Care","page":"1473-1478","volume":"35","issue":"7","source":"CrossRef","DOI":"10.2337/dc11-1693","ISSN":"0149-5992, 1935-5548","language":"en","author":[{"family":"Rosenstock","given":"J."},{"family":"Vico","given":"M."},{"family":"Wei","given":"L."},{"family":"Salsali","given":"A."},{"family":"List","given":"J. F."}],"issued":{"date-parts":[["2012",7,1]]}}},{"id":"TeVZF1gX/KOX4ll5F","uris":[""],"uri":[""],"itemData":{"id":318,"type":"article-journal","title":"Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin","container-title":"Diabetes Obes Metab","page":"159–169","volume":"16","issue":"2","source":"Google Scholar","author":[{"family":"Bolinder","given":"J."},{"family":"Ljunggren","given":"?sten"},{"family":"Johansson","given":"L."},{"family":"Wilding","given":"J."},{"family":"Langkilde","given":"A. M."},{"family":"Sj?str?m","given":"C. D."},{"family":"Sugg","given":"J."},{"family":"Parikh","given":"S."}],"issued":{"date-parts":[["2014"]]}}},{"id":"TeVZF1gX/S2XFvjOK","uris":[""],"uri":[""],"itemData":{"id":485,"type":"article-journal","title":"Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin","container-title":"Diabetes, Obesity and Metabolism","page":"1111–1120","volume":"16","issue":"11","source":"Google Scholar","author":[{"family":"Nauck","given":"M. A."},{"family":"Del Prato","given":"S."},{"family":"Durán-García","given":"S."},{"family":"Rohwedder","given":"K."},{"family":"Langkilde","given":"A. M."},{"family":"Sugg","given":"J."},{"family":"Parikh","given":"S. J."}],"issued":{"date-parts":[["2014"]]}}},{"id":"TeVZF1gX/sfDTQFS1","uris":[""],"uri":[""],"itemData":{"id":484,"type":"article-journal","title":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment","container-title":"Diabetes Care","page":"1656-1662","volume":"32","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).\nRESEARCH DESIGN AND METHODS: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).\nRESULTS: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C > or =0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.\nCONCLUSIONS: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.","DOI":"10.2337/dc09-0517","ISSN":"1935-5548","note":"PMID: 19528367\nPMCID: PMC2732143","shortTitle":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers","journalAbbreviation":"Diabetes Care","language":"eng","author":[{"family":"Wilding","given":"John P. H."},{"family":"Norwood","given":"Paul"},{"family":"T'joen","given":"Caroline"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009",9]]}}}],"schema":""} [3–10], with mean difference in glycated-haemoglobin (HbA1c) compared to controls of ~0.52% (5.5 mmol/mol) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a151v2tsvme","properties":{"formattedCitation":"[11, 12]","plainCitation":"[11, 12]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/7uArmvvt","uris":[""],"uri":[""],"itemData":{"id":348,"type":"article-journal","title":"Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials","container-title":"Diabetes/Metabolism Research and Reviews","page":"204-221","volume":"30","issue":"3","source":"PubMed","abstract":"CONTEXT: Type 2 diabetes has reached epidemic proportions and places a heavy burden on society. Dapagliflozin is a novel treatment choice for type 2 diabetes.\nOBJECTIVE: A meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of dapagliflozin treatment.\nDATA SOURCES: Medline (via PubMed), Embase (via OVID) and the Cochrane Library (up to August 2012) were searched, and RCTs were collected.\nSTUDY SELECTION: Studies included type 2 diabetic subjects, who had been treated with dapagliflozin, and recorded HbA1c as outcomes.\nDATA EXTRACTION: Two reviewers independently assessed articles and study quality. Patient characteristics, interventions and outcomes were collected.\nDATA SYNTHESIS: Ten RCTs were included. Risk of bias for outcomes was low. Fixed or random effects models were used to pool the results. Dapagliflozin treatment was associated with a reduction in HbA1c [weighted mean difference (WMD): -0.53%; 95% confidence interval (CI): -0.58% to -0.47%; p?<?0.00001], fasting plasma glucose (WMD: -1.06?mmol/L; 95% CI: -1.20, -0.92; p?<?0.00001), and body weight (WMD: -1.63?kg; 95% CI: -1.83, -1.43; p?<?0.00001). Dapagliflozin monotherapy did not lead to hypoglycaemia [relative risk (RR): 1.44; 95% CI: 0. 86, 2.41; p?=?0.17], although hypoglycaemic risk increased (RR: 1.16; 95% CI: 1.05, 1.29; p?=?0.005) when dapagliflozin was combined with other hypoglycaemic drugs. Dapagliflozin increased urinary glucose excretion (WMD: 26.98; 95% CI: 21.72, 32.24; p?<?0.00001) and was associated with an increased risk of urinary tract infections (RR: 1.33; 95% CI: 1.10, 1.60; p?=?0.004) and genital tract infections (RR: 3.23; 95% CI: 2.50, 4.18; p?=?0.00001).\nCONCLUSIONS: Dapagliflozin appears to be an effective treatment for type 2 diabetes, although it may increase the risk of urinary tract infections and genital tract infections.","DOI":"10.1002/dmrr.2479","ISSN":"1520-7560","note":"PMID: 24115369","shortTitle":"Dapagliflozin treatment for type 2 diabetes","journalAbbreviation":"Diabetes Metab. Res. Rev.","language":"eng","author":[{"family":"Zhang","given":"Mei"},{"family":"Zhang","given":"Lin"},{"family":"Wu","given":"Bin"},{"family":"Song","given":"Haolan"},{"family":"An","given":"Zhenmei"},{"family":"Li","given":"Shuangqing"}],"issued":{"date-parts":[["2014",3]]}}},{"id":"TeVZF1gX/efMdflC8","uris":[""],"uri":[""],"itemData":{"id":495,"type":"article-journal","title":"The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus: meta-analysis of randomised controlled trials","container-title":"BMJ open","page":"e004619","volume":"4","issue":"4","source":"PubMed","abstract":"OBJECTIVES: This meta-analysis aimed to evaluate whether dapagliflozin is synergistic with other antidiabetic drugs without body weight gain.\nSETTING: Randomised controlled trial (RCT) reports were retrieved from PubMed, Cochrane Library, EMBASE, , Google Scholar and Google. Eligible RCTs were selected according to the criteria (including types of participants, intervention, outcomes) and assessed by the Cochrane risk of bias tool and GRADEpro software for evidential quality. Meta-analysis on the eligible RCTs was performed with the random effects model. The RCTs of low-quality and interim stages were excluded for further sensitivity analysis. Meta-regression was conducted on the follow-up durations. Publication bias was evaluated with funnel plots and the Egger's regression test and adjusted using the trim-and-fill procedure. Heterogeneity was assessed with the I(2) statistics.\nPARTICIPANTS: Adult patients with type 2 diabetes mellitus (T2DM).\nINTERVENTIONS: Dapagliflozin combined with conventional antidiabetic drugs.\nPRIMARY AND SECONDARY OUTCOME MEASURES: Glycaemic level (measured by glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG)) and body weight.\nRESULTS: 12 RCTs were eligible for quantitative synthesis and meta-analysis. The overall effect size of HbA1c calculated from mean difference was -0.52% (Z=-13.56, p<0.001) with 95% CI (-0.60 to -0.45). The effect size of FPG was -1.13 mmol/L (Z=-11.12, p<0.001) with 95% CI (-1.33 to -0.93). The effect size of body weight was -2.10 kg (Z=-18.77, p<0.001) with 95% CI (-2.32 to -1.88). Exclusions of low quality and interim RCTs changed the overall mean differences respectively to -0.56%, -1.11 mmol/L, 2.23 kg and -0.50%, -1.08 mmol/L, -2.08 kg. The sensitivity analysis indicated good robustness of the meta-analysis on HbA1c, FPG and body weight.\nCONCLUSIONS: The meta-analysis showed that dapagliflozin as an add-on drug to conventional antidiabetic drugs improved the glycaemic control in T2DM participants without significant body weight gain.\nTRIAL REGISTRATION NUMBER: CRD42013005034.","DOI":"10.1136/bmjopen-2013-004619","ISSN":"2044-6055","note":"PMID: 24710132\nPMCID: PMC3987716","shortTitle":"The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus","journalAbbreviation":"BMJ Open","language":"eng","author":[{"family":"Sun","given":"Yu-Nan"},{"family":"Zhou","given":"Yi"},{"family":"Chen","given":"Xi"},{"family":"Che","given":"Weng-Si"},{"family":"Leung","given":"Siu-Wai"}],"issued":{"date-parts":[["2014",4,7]]}}}],"schema":""} [11, 12]. Although not an indication for use, RCTs of dapagliflozin have demonstrated weight loss and improved systolic blood pressure (SBP) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a1b09a613j1","properties":{"formattedCitation":"[3, 5, 6, 9, 10, 13]","plainCitation":"[3, 5, 6, 9, 10, 13]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/PB7nItij","uris":[""],"uri":[""],"itemData":{"id":321,"type":"article-journal","title":"Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes","container-title":"Diabetes Care","page":"650–657","volume":"32","issue":"4","source":"Google Scholar","author":[{"family":"List","given":"James F."},{"family":"Woo","given":"Vincent"},{"family":"Morales","given":"Enrique"},{"family":"Tang","given":"Weihua"},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009"]]}}},{"id":"TeVZF1gX/sfDTQFS1","uris":[""],"uri":[""],"itemData":{"id":484,"type":"article-journal","title":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment","container-title":"Diabetes Care","page":"1656-1662","volume":"32","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).\nRESEARCH DESIGN AND METHODS: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).\nRESULTS: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C > or =0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.\nCONCLUSIONS: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.","DOI":"10.2337/dc09-0517","ISSN":"1935-5548","note":"PMID: 19528367\nPMCID: PMC2732143","shortTitle":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers","journalAbbreviation":"Diabetes Care","language":"eng","author":[{"family":"Wilding","given":"John P. H."},{"family":"Norwood","given":"Paul"},{"family":"T'joen","given":"Caroline"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009",9]]}}},{"id":"TeVZF1gX/3nckOKvE","uris":[""],"uri":[""],"itemData":{"id":320,"type":"article-journal","title":"Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial","container-title":"Diabetes Care","page":"2217-2224","volume":"33","issue":"10","source":"CrossRef","DOI":"10.2337/dc10-0612","ISSN":"0149-5992, 1935-5548","shortTitle":"Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise","language":"en","author":[{"family":"Ferrannini","given":"E."},{"family":"Ramos","given":"S. J."},{"family":"Salsali","given":"A."},{"family":"Tang","given":"W."},{"family":"List","given":"J. F."}],"issued":{"date-parts":[["2010",10,1]]}}},{"id":"TeVZF1gX/1BYwyWkC","uris":[""],"uri":[""],"itemData":{"id":486,"type":"article-journal","title":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial","container-title":"The Lancet","page":"2223–2233","volume":"375","issue":"9733","source":"Google Scholar","shortTitle":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin","author":[{"family":"Bailey","given":"Clifford J."},{"family":"Gross","given":"Jorge L."},{"family":"Pieters","given":"Anne"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."}],"issued":{"date-parts":[["2010"]]}}},{"id":"TeVZF1gX/pWw41kY3","uris":[""],"uri":[""],"itemData":{"id":488,"type":"article-journal","title":"Effects of Dapagliflozin on Body Weight, Total Fat Mass, and Regional Adipose Tissue Distribution in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Metformin","container-title":"The Journal of Clinical Endocrinology & Metabolism","page":"1020-1031","volume":"97","issue":"3","source":"CrossRef","DOI":"10.1210/jc.2011-2260","ISSN":"0021-972X, 1945-7197","language":"en","author":[{"family":"Bolinder","given":"Jan"},{"family":"Ljunggren","given":"?sten"},{"family":"Kullberg","given":"Joel"},{"family":"Johansson","given":"Lars"},{"family":"Wilding","given":"John"},{"family":"Langkilde","given":"Anna Maria"},{"family":"Sugg","given":"Jennifer"},{"family":"Parikh","given":"Shamik"}],"issued":{"date-parts":[["2012",3]]}}},{"id":"TeVZF1gX/S2XFvjOK","uris":[""],"uri":[""],"itemData":{"id":485,"type":"article-journal","title":"Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin","container-title":"Diabetes, Obesity and Metabolism","page":"1111–1120","volume":"16","issue":"11","source":"Google Scholar","author":[{"family":"Nauck","given":"M. A."},{"family":"Del Prato","given":"S."},{"family":"Durán-García","given":"S."},{"family":"Rohwedder","given":"K."},{"family":"Langkilde","given":"A. M."},{"family":"Sugg","given":"J."},{"family":"Parikh","given":"S. J."}],"issued":{"date-parts":[["2014"]]}}}],"schema":""} [3, 5, 6, 9, 10, 13]. In large-scale placebo-controlled cardiovascular disease (CVD) outcome trials (CVOT), other SGLT2i’s (empagliflozin ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vFhxVltf","properties":{"formattedCitation":"[14]","plainCitation":"[14]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/msur5mdd","uris":[""],"uri":[""],"itemData":{"id":332,"type":"article-journal","title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","container-title":"NEJM","page":"2117-2128","volume":"373","issue":"22","source":"Taylor and Francis+NEJM","abstract":"In this study, the addition of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, to standard care reduced cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk.","DOI":"10.1056/NEJMoa1504720","ISSN":"0028-4793","note":"PMID: 26378978","author":[{"family":"Zinman","given":"Bernard"},{"family":"Wanner","given":"Christoph"},{"family":"Lachin","given":"John M."},{"family":"Fitchett","given":"David"},{"family":"Bluhmki","given":"Erich"},{"family":"Hantel","given":"Stefan"},{"family":"Mattheus","given":"Michaela"},{"family":"Devins","given":"Theresa"},{"family":"Johansen","given":"Odd Erik"},{"family":"Woerle","given":"Hans J."},{"family":"Broedl","given":"Uli C."},{"family":"Inzucchi","given":"Silvio E."}],"issued":{"date-parts":[["2015",11,26]]}}}],"schema":""} [14] and canagliflozin ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ISycFkG3","properties":{"formattedCitation":"[15]","plainCitation":"[15]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/PWd30Rat","uris":[""],"uri":[""],"itemData":{"id":333,"type":"article-journal","title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","container-title":"NEJM","page":"644-657","volume":"377","issue":"7","source":"Taylor and Francis+NEJM","abstract":"In this report of two randomized trials, patients with type 2 diabetes at risk for cardiovascular disease received the sodium–glucose cotransporter 2 inhibitor canagliflozin or placebo and were followed for 188 weeks. Canagliflozin reduced the risk of cardiovascular events.","DOI":"10.1056/NEJMoa1611925","ISSN":"0028-4793","note":"PMID: 28605608","author":[{"family":"Neal","given":"Bruce"},{"family":"Perkovic","given":"Vlado"},{"family":"Mahaffey","given":"Kenneth W."},{"family":"Zeeuw","given":"Dick","non-dropping-particle":"de"},{"family":"Fulcher","given":"Greg"},{"family":"Erondu","given":"Ngozi"},{"family":"Shaw","given":"Wayne"},{"family":"Law","given":"Gordon"},{"family":"Desai","given":"Mehul"},{"family":"Matthews","given":"David R."}],"issued":{"date-parts":[["2017",8,17]]}}}],"schema":""} [15]) were shown to reduce major CVD events. Although the results for the dapagliflozin DECLARE CVOT have not yet been published it has been reported that the primary safety endpoint of non-inferiority for major adverse cardiovascular events was met and that there was a significant reduction in one of two primary efficacy CVD endpoints ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"68dS3XDy","properties":{"formattedCitation":"[16]","plainCitation":"[16]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/AZVR69iz","uris":[""],"uri":[""],"itemData":{"id":1386,"type":"article-journal","title":"DECLARE-TIMI 58: Participants’ baseline characteristics","container-title":"Diabetes, Obesity and Metabolism","page":"1102-1110","volume":"20","issue":"5","source":"Wiley Online Library","abstract":"Aim To describe the baseline characteristics of participants randomized in the Dapagliflozin Effect on CardiovascuLAR Events (DECLARE-TIMI 58) trial, the pivotal study conducted to assess cardiovascular (CV) outcomes with dapagliflozin. Methods The DECLARE-TIMI 58 trial will analyse 17 160 patients with type 2 diabetes randomized to treatment with dapagliflozin (10 mg/d) or matching placebo. We analysed their baseline characteristics. Results The participants’ mean ± SD age was 63.8 ± 6.8 years, 62.6% were male, and their mean ± SD diabetes duration was 11.8 ± 7.8 years, glycated haemoglobin 8.3% ± 1.2% (67 mmol/mol ± 9.7 mmol/mol) and body mass index 32.1 ± 6.0 kg/m2. Randomization included 6971 (40.6%) patients with atherosclerotic CV disease (CVD), and 10 189 (59.4%) patients with multiple risk factors (MRF) for CVD (defined as men age ≥ 55 years or women ≥60 years, with at least one of dyslipidaemia, hypertension or smoking). Patients with CVD compared with patients with MRF were younger (62.5 ± 8.1 vs 64.7 ± 5.6 years), more frequently male (72.1% vs 56.1%), less often used metformin (74.6% vs 81.2%), more often used insulin (44.2% vs 36.4%), and more frequently used statins, aspirin, clopidogrel and β-blockers (82.2%, 71.1%, 24.7% and 66.6% vs 63.7%, 39.1%, 1.5% and 32.3%, respectively). Conclusion The DECLARE-TIMI 58 trial is expected to provide conclusive data on the effect of treatment with dapagliflozin in addition to standard of care, on CV outcomes in a broad patient population with type 2 diabetes and CVD or MRF for CVD.","DOI":"10.1111/dom.13217","ISSN":"1463-1326","shortTitle":"DECLARE-TIMI 58","language":"en","author":[{"family":"Raz","given":"Itamar"},{"family":"Mosenzon","given":"Ofri"},{"family":"Bonaca","given":"Marc P."},{"family":"Cahn","given":"Avivit"},{"family":"Kato","given":"Eri T."},{"family":"Silverman","given":"Michael G."},{"family":"Bhatt","given":"Deepak L."},{"family":"Leiter","given":"Lawrence A."},{"family":"McGuire","given":"Darren K."},{"family":"Wilding","given":"John P. H."},{"family":"Gause‐Nilsson","given":"Ingrid A. M."},{"family":"Langkilde","given":"Anna M."},{"family":"Johansson","given":"Peter A."},{"family":"Sabatine","given":"Marc S."},{"family":"Wiviott","given":"Stephen D."}],"issued":{"date-parts":[["2018",5,1]]}}}],"schema":""} [16] ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"H1phH7rX","properties":{"formattedCitation":"[17]","plainCitation":"[17]","noteIndex":0},"citationItems":[{"id":2,"uris":[""],"uri":[""],"itemData":{"id":2,"type":"webpage","title":"Farxiga achieved a positive result in the Phase III DECLARE-TIMI 58 trial, a large cardiovascular outcomes trial in 17,000 patients with type-2 diabetes","URL":"","language":"en","accessed":{"date-parts":[["2018",9,24]]}}}],"schema":""} [17]. Over three years of real-world observational data are available for dapagliflozin-users in a large national electronic healthcare record-derived dataset of individuals with T2DM in Scotland, allowing effects on continuously distributed outcomes HbA1c, BMI, body weight, SBP, kidney function (as estimated glomerular filtration rate; eGFR) to be evaluated. First, we aimed to determine whether the effects of dapagliflozin on HbA1c and other parameters in RCTs are obtained in real-world practice. Second, we aimed to undertake safety-event outcome analyses, since safety concerns about SGLT2i exist, to establish if an increased rate of these could be observed in dapagliflozin-users. Specifically, the Canagliflozin Cardiovascular Assessment Study Programme demonstrated an unexpected increased risk of lower limb amputation (LLA) in patients treated with canagliflozin ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"jPy9DZ1A","properties":{"formattedCitation":"[15]","plainCitation":"[15]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/PWd30Rat","uris":[""],"uri":[""],"itemData":{"id":333,"type":"article-journal","title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","container-title":"NEJM","page":"644-657","volume":"377","issue":"7","source":"Taylor and Francis+NEJM","abstract":"In this report of two randomized trials, patients with type 2 diabetes at risk for cardiovascular disease received the sodium–glucose cotransporter 2 inhibitor canagliflozin or placebo and were followed for 188 weeks. Canagliflozin reduced the risk of cardiovascular events.","DOI":"10.1056/NEJMoa1611925","ISSN":"0028-4793","note":"PMID: 28605608","author":[{"family":"Neal","given":"Bruce"},{"family":"Perkovic","given":"Vlado"},{"family":"Mahaffey","given":"Kenneth W."},{"family":"Zeeuw","given":"Dick","non-dropping-particle":"de"},{"family":"Fulcher","given":"Greg"},{"family":"Erondu","given":"Ngozi"},{"family":"Shaw","given":"Wayne"},{"family":"Law","given":"Gordon"},{"family":"Desai","given":"Mehul"},{"family":"Matthews","given":"David R."}],"issued":{"date-parts":[["2017",8,17]]}}}],"schema":""} [15] and the FDA’s Adverse Reporting System showed a disproportionately increased reporting ratio for canagliflozin and LLA. It is unclear if increased LLA risk is an SGLT-2i-class effect, is restricted to canagliflozin or is a chance effect ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"llpHDVTM","properties":{"formattedCitation":"[18]","plainCitation":"[18]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/hdhAge0f","uris":[""],"uri":[""],"itemData":{"id":343,"type":"article-journal","title":"SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System","container-title":"The Lancet Diabetes & Endocrinology","page":"680-681","volume":"5","issue":"9","source":"","DOI":"10.1016/S2213-8587(17)30257-7","ISSN":"2213-8587, 2213-8595","note":"PMID: 28733172, 28733172","journalAbbreviation":"The Lancet Diabetes & Endocrinology","language":"English","author":[{"family":"Fadini","given":"Gian Paolo"},{"family":"Avogaro","given":"Angelo"}],"issued":{"date-parts":[["2017",9,1]]}}}],"schema":""} [18]. Case-reports exist detailing the development of (often euglycaemic) diabetic ketoacidosis (DKA) in T2DM patients following initiation of SGLT-2i, with increased disproportionality signalling in both EMA and FDA pharmacovigilance databases ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"o2WsRhtr","properties":{"formattedCitation":"[19, 20]","plainCitation":"[19, 20]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/TmVEDf6K","uris":[""],"uri":[""],"itemData":{"id":325,"type":"article-journal","title":"Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors","container-title":"Diabetes Care","page":"1638-1642","volume":"38","issue":"9","source":"care.","abstract":"Recently, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication that warns of an increased risk of diabetic ketoacidosis (DKA) with uncharacteristically mild to moderate glucose elevations (euglycemic DKA [euDKA]) associated with the use of all the approved sodium–glucose cotransporter 2 (SGLT2) inhibitors (1). This Communication was based on 20 clinical cases requiring hospitalization captured between March 2013 and June 2014 in the FDA Adverse Event Reporting System database. The scarce clinical data provided suggested that most of the DKA cases were reported in patients with type 2 diabetes (T2D), for whom this class of agents is indicated; most likely, however, they were insulin-treated patients, some with type 1 diabetes (T1D). The FDA also identified potential triggering factors such as intercurrent illness, reduced food and fluid intake, reduced insulin doses, and history of alcohol intake. The following month, at the request of the European Commission, the European Medicines Agency (EMA) announced on 12 June 2015 that the Pharmacovigilance Risk Assessment Committee has started a review of all of the three approved SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin) to evaluate the risk of DKA in T2D (2). The EMA announcement claimed that as of May 2015 a total of 101 cases of DKA have been reported worldwide in EudraVigilance in T2D patients treated with SGLT2 inhibitors, with an estimated exposure over 0.5 million patient-years. No clinical details were provided except for the mention that “all cases were serious and some required hospitalisation. Although [DKA] is usually accompanied by high blood sugar levels, in a number of these reports blood sugar levels were only moderately increased” (2).\n\nWith this background, it is very timely that in this issue of Diabetes Care there are two articles on this subject. Erondu et al. (3) report cases of DKA in T2D …","DOI":"10.2337/dc15-1380","ISSN":"0149-5992, 1935-5548","note":"PMID: 26294774","shortTitle":"Euglycemic Diabetic Ketoacidosis","language":"en","author":[{"family":"Rosenstock","given":"Julio"},{"family":"Ferrannini","given":"Ele"}],"issued":{"date-parts":[["2015",9,1]]}}},{"id":"TeVZF1gX/c2SlKCqW","uris":[""],"uri":[""],"itemData":{"id":324,"type":"webpage","title":"Safety Alerts for Human Medical Products - SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood","container-title":"Office of the Commissioner","genre":"WebContent","abstract":"High levels of blood acids called ketones may require hospitalization. Posted 05/15/2015","URL":"","shortTitle":"Safety Alerts for Human Medical Products - SGLT2 inhibitors","language":"en","accessed":{"date-parts":[["2017",10,28]]}}}],"schema":""} [19, 20]. It is unclear if this is a true drug effect.It is important to understand the extent to which drug-effects in RCTs are achieved in real clinical recipients who may have a wider range of characteristics ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a1oh8154oh7","properties":{"formattedCitation":"[21]","plainCitation":"[21]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/gzKu6zcq","uris":[""],"uri":[""],"itemData":{"id":292,"type":"article-journal","title":"External validity of randomised controlled trials: “To whom do the results of this trial apply?”","container-title":"Lancet","page":"82-93","volume":"365","issue":"9453","source":"ScienceDirect","abstract":"Summary\nIn making treatment decisions, doctors and patients must take into account relevant randomised controlled trials (RCTs) and systematic reviews. Relevance depends on external validity (or generalisability)—ie, whether the results can be reasonably applied to a definable group of patients in a particular clinical setting in routine practice. There is concern among clinicians that external validity is often poor, particularly for some pharmaceutical industry trials, a perception that has led to underuse of treatments that are effective. Yet researchers, funding agencies, ethics committees, the pharmaceutical industry, medical journals, and governmental regulators alike all neglect external validity, leaving clinicians to make judgments. However, reporting of the determinants of external validity in trial publications and systematic reviews is usually inadequate. This review discusses those determinants, presents a checklist for clinicians, and makes recommendations for greater consideration of external validity in the design and reporting of RCTs.","DOI":"10.1016/S0140-6736(04)17670-8","ISSN":"0140-6736","shortTitle":"External validity of randomised controlled trials","journalAbbreviation":"Lancet","author":[{"family":"Rothwell","given":"Peter M"}],"issued":{"date-parts":[["2005",1,1]]}}}],"schema":""} [21], ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a2887vs9f13","properties":{"formattedCitation":"[22]","plainCitation":"[22]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/vkPlTMtE","uris":[""],"uri":[""],"itemData":{"id":483,"type":"article-journal","title":"Real-World Evidence — What Is It and What Can It Tell Us?","container-title":"New England Journal of Medicine","page":"2293-2297","volume":"375","issue":"23","source":"Taylor and Francis+NEJM","abstract":"The term “real-world evidence” is widely used by those who develop medical products or who study, deliver, or pay for health care, but its specific meaning is elusive. We believe it refers to information on health care that is derived from multiple sources outside typical clinical research settings, including electronic health records (EHRs), claims and billing data, product and disease registries, and data gathered through personal devices and health applications.1,2 Key to understanding the usefulness of real-world evidence is an appreciation of its potential for complementing the knowledge gained from traditional clinical trials, whose well-known limitations make it difficult . . .","DOI":"10.1056/NEJMsb1609216","ISSN":"0028-4793","note":"PMID: 27959688","author":[{"family":"Sherman","given":"Rachel E."},{"family":"Anderson","given":"Steven A."},{"family":"Dal Pan","given":"Gerald J."},{"family":"Gray","given":"Gerry W."},{"family":"Gross","given":"Thomas"},{"family":"Hunter","given":"Nina L."},{"family":"LaVange","given":"Lisa"},{"family":"Marinac-Dabic","given":"Danica"},{"family":"Marks","given":"Peter W."},{"family":"Robb","given":"Melissa A."},{"family":"Shuren","given":"Jeffrey"},{"family":"Temple","given":"Robert"},{"family":"Woodcock","given":"Janet"},{"family":"Yue","given":"Lilly Q."},{"family":"Califf","given":"Robert M."}],"issued":{"date-parts":[["2016",12,8]]}}}],"schema":""} [22]. Dapagliflozin is licensed for those between 18–75 years-of-age, with an eGFR ≥ 60 ml min-1 1.73m-2 and not receiving pioglitazone or loop diuretics. Some patients not meeting these criteria are nevertheless prescribed the drug. We focus on dapagliflozin in Scotland, as there are sufficient dapagliflozin-users to adequately power our analyses (8566 dapagliflozin-users, 1782 canagliflozin-users and 2385 empagliflozin-users in current data extract). As data accrues other SGLT2i’s will be evaluated. Materials and MethodsData sourcesAnonymised data were obtained via extraction from the Scottish Care Information-Diabetes (SCI-Diabetes) collaboration database, which has been described in detail previously ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a17osrdmlc0","properties":{"formattedCitation":"[23, 24]","plainCitation":"[23, 24]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/6dHpVmKz","uris":[""],"uri":[""],"itemData":{"id":347,"type":"article-journal","title":"Assessment of the under-reporting of diabetes in hospital admission data: a study from the Scottish Diabetes Research Network Epidemiology Group","container-title":"Diabetic medicine : a journal of the British Diabetic Association","page":"1514-1519","volume":"28","issue":"12","source":"PubMed Central","abstract":"Aims\nGood quality data are required to plan and evaluate diabetes services and to assess progress against targets for reducing hospital admissions and bed days. The aim of this study was to assess the completeness of recording of diabetes in hospital admissions using recent national data for Scotland.\n\nMethods\nData derived from linkage of the Scottish national diabetes register and hospital admissions data were analysed to assess the completeness of coding of diabetes in hospital inpatient admissions between 2000 and 2007 for patients identified with diabetes prior to hospital admission.\n\nResults\nIn 2007 only 59% of hospital inpatient admissions for people previously diagnosed with diabetes mentioned diabetes, whereas over 99% of people with a mention of diabetes on hospital records were included in the diabetes register. The completeness of diabetes recording varied from 44% to 82% among mainland NHS Boards and from 34% to 89% among large general hospitals. Completeness of recording of diabetes as a co-morbidity also varied by primary diagnosis: 70% and 41% of admissions with coronary heart disease and cancer as the primary diagnosis mentioned co-existing diabetes respectively.\n\nConclusion\nThere is wide variation in the completeness of recording of diabetes in hospital admission data. Hospital data alone considerably underestimate the number of admissions and bed days but overestimate length of stay for people with diabetes. Linkage of diabetes register data to hospital admissions data provides a more accurate source for measuring hospital admissions among people diagnosed with diabetes than hospital admissions data.","DOI":"10.1111/j.1464-5491.2011.03432.x","ISSN":"0742-3071","note":"PMID: 21883441\nPMCID: PMC4215191","shortTitle":"Assessment of the under-reporting of diabetes in hospital admission data","journalAbbreviation":"Diabet Med","author":[{"family":"Anwar","given":"H"},{"family":"Fischbacher","given":"CM"},{"family":"Leese","given":"G"},{"family":"Lindsay","given":"R"},{"family":"McKnight","given":"J"},{"family":"Wild","given":"Sarah"}],"issued":{"date-parts":[["2011",12]]}}},{"id":"TeVZF1gX/mLpaNLRn","uris":[""],"uri":[""],"itemData":{"id":482,"type":"article-journal","title":"Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013","container-title":"Diabetologia","page":"2106-2113","volume":"59","issue":"10","source":"link.","abstract":"Aims/hypothesisThe relative contribution of increasing incidence and declining mortality to increasing prevalence of type 2 diabetes in Scotland is unclear. Trends in incidence and mortality rates are described for type 2 diabetes in Scotland between 2004 and 2013 by age, sex and socioeconomic deprivation.MethodsData for incident and prevalent cases of type 2 diabetes were obtained from the Scottish national diabetes register with number of deaths identified from linkage to mortality records. Population size and death data for Scotland by age, sex and socioeconomic deprivation were obtained from National Records of Scotland. Age- and sex-specific incidence and mortality rates stratified by year and deciles of socioeconomic status were calculated using Poisson models.ResultsThere were 180,290 incident cases of type 2 diabetes in Scotland between 2004 and 2013. Overall, incidence of type 2 diabetes remained stable over time and was 4.88 (95% CI 4.84, 4.90) and 3.33 (3.28, 3.32) per 1000 in men and women, respectively. However, incidence increased among young men, remained stable in young women, and declined in older men and women. Incidence rates declined in all socioeconomic groups but increased after 2008 in the most deprived groups. Standardised mortality ratios associated with diabetes, adjusted for age and socioeconomic group, were 1.38 (1.36, 1.41) in men and 1.49 (1.45, 1.52) in women, and remained constant over time.Conclusions/interpretationIncidence of type 2 diabetes has stabilised in recent years suggesting that increasing prevalence may be primarily attributed to declining mortality. Prevention of type 2 diabetes remains important, particularly among socioeconomically deprived populations.","DOI":"10.1007/s00125-016-4054-9","ISSN":"0012-186X, 1432-0428","journalAbbreviation":"Diabetologia","language":"en","author":[{"family":"Read","given":"Stephanie H."},{"family":"Kerssens","given":"Joannes J."},{"family":"McAllister","given":"David A."},{"family":"Colhoun","given":"Helen M."},{"family":"Fischbacher","given":"Colin M."},{"family":"Lindsay","given":"Robert S."},{"family":"McCrimmon","given":"Rory J."},{"family":"McKnight","given":"John A."},{"family":"Petrie","given":"John R."},{"family":"Sattar","given":"Naveed"},{"family":"Wild","given":"Sarah H."},{"family":"Group","given":"On behalf of the Scottish Diabetes Research Network Epidemiology"}],"issued":{"date-parts":[["2016",10,1]]}}}],"schema":""} [23, 24] but in brief comprises a nationwide-register of e-health-records containing extensive clinical and issued prescriptions, for 99% of Scottish diabetes patients. These data are linked using the Community Health Index, an identifier used in all Scottish records, to mortality data from the General Registrar and hospitalisation records available from the ISD of the NHS in Scotland. Study period and population Data were available from 2004 till mid-2016 for all analyses. Those eligible for inclusion into the study i) alive with a diagnosis of T2DM at any time since the introduction of dapagliflozin, ii) had no diagnosis of type 1 diabetes, iii) were aged 18-80 upon study entry. For the safety analyses, since we focus on cumulative drug effect, a further criterion was imposed that persons had to be fully-evaluable for drug-exposure since the date-of-introduction of dapagliflozin or date-of-onset of diabetes, whichever was later. For both analyses, individuals’ contributed person-time to the study upon the latest of: study-start-date, date-of-diagnosis of T2DM, or becoming observable within the dataset. Individuals ceased contributing person-time to the study upon the earliest of: death, becoming unobservable within the dataset (i.e. lost due to emigration) or study-end-date. For the safety analysis, individuals were censored following exposure to other SGLT-2i.Drug exposure Issued prescription data were used to define drug-exposures. All prescriptions were assigned Anatomical Therapeutic Chemical Classification System (ATC) codes. For dapagliflozin defined as ATC code A10BX09/A10BK01 as dapagliflozin-exposure. Dapagliflozin ever-users were those with any initiation of dapagliflozin between November 2012 (the first date-of-dapagliflozin-availability) and study-end-date. Drug-exposure-start-date was defined as the date-of-initial-prescription, and drug-exposure-end-dates were extrapolated based on dosage, frequency and directions. Dapagliflozin-users were stratified to those receiving dapagliflozin ‘on-licence’, (defined as: aged between 18-75, eGFR ≥60 ml min-1 1.73m-2, not receiving pioglitazone and not receiving loop diuretics); and ‘off-licence’ for individuals not fulfilling these criteria. Never-users were those who never received a prescription for dapagliflozin throughout the study period. Clinical measures including outcome measures The SCI-Diabetes database contains demographic data, captures all HbA1c, serum creatinine, other biochemical results, as well as all routine clinical measures such as BP, height and weight. For baseline comparisons of demographic and clinical characteristics of dapagliflozin-users versus never-users, measurements for users were taken as those closest to (but no earlier than 24-months before) dapagliflozin initiation. For never-users, equivalent measurements were taken as their closest to (but no earlier than 24-months’ before) the median-initiation-date among users. CVD, DKA and LLA were captured using linkage to national hospitalisation records and death data. ICD-10 codes for cause of admission and operative codes for amputations and revascularisation surgeries were used to define events. CVD codes included chronic ischemic heart disease, cerebrovascular disease, heart failure, cardiac arrhythmia or coronary revascularisation. See ESM Table 1.Statistical methodsSimple descriptive statistics and linear- or logistic-regressions adjusted for age, sex and diabetes duration were used to compare characteristics of users and never-users. To evaluate the effect of dapagliflozin on continuous clinical outcomes of interest, we first described the distribution of within-person absolute and percentage changes following dapagliflozin initiation at regular three-month intervals throughout follow-up among users. For this analysis clinical outcomes were assigned to time windows by applying a caliper of ±1.5 months (e.g. the 3-month-time-point contained measurements observed between 1.5- and 4.5-months). For continuous variable analyses, person-time was right censored when dapagliflozin was ceased, a diabetes drug that was co-prescribed at dapagliflozin initiation was ceased, or a new diabetes drug that was not already being received at the dapagliflozin-initiation-date was initiated. Where another diabetes drug was dropped at the time-of-initiation of dapagliflozin the record was included since that will be conservative with respect to the apparent dapagliflozin effect. For analyses with outcomes of SBP and for CVD events, person-time was also right-censored upon initiating a new CVD drug (all drugs with first-level ATC code C) that was not received at dapagliflozin initiation or ceasing a CVD drug that was co-prescribed at dapagliflozin initiation. Mixed-effects-regression models of continuous outcomesSimple analyses of pre/post-drug-initiation comparisons in clinical outcomes in observational studies can provide misleading estimates of apparent long-term efficacy if the underlying trend in that outcome in the absence of drug exposure is not considered. Therefore to assess the change in clinical outcomes of interest following dapagliflozin-exposure whilst taking into consideration the underlying calendar time trend, we constructed linear mixed-effects-regression models (ESM Methods) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a1vhq0nghhf","properties":{"formattedCitation":"[25]","plainCitation":"[25]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/jexxzldv","uris":[""],"uri":[""],"itemData":{"id":481,"type":"article-journal","title":"Random-effects models for longitudinal data","container-title":"Biometrics","page":"963-974","volume":"38","issue":"4","source":"PubMed","abstract":"Models for the analysis of longitudinal data must recognize the relationship between serial observations on the same unit. Multivariate models with general covariance structure are often difficult to apply to highly unbalanced data, whereas two-stage random-effects models can be used easily. In two-stage models, the probability distributions for the response vectors of different individuals belong to a single family, but some random-effects parameters vary across individuals, with a distribution specified at the second stage. A general family of models is discussed, which includes both growth models and repeated-measures models as special cases. A unified approach to fitting these models, based on a combination of empirical Bayes and maximum likelihood estimation of model parameters and using the EM algorithm, is discussed. Two examples are taken from a current epidemiological study of the health effects of air pollution.","ISSN":"0006-341X","note":"PMID: 7168798","journalAbbreviation":"Biometrics","language":"eng","author":[{"family":"Laird","given":"N. M."},{"family":"Ware","given":"J. H."}],"issued":{"date-parts":[["1982",12]]}}}],"schema":""} [25] that utilise pre-exposure data to control for the expected within-person trajectories in the outcome of interest in the absence of the drug. Clinical measurements up to 24-months’ before dapagliflozin initiation, and measurements throughout entire follow-up time until right-censoring were used. To examine the likely magnitude of regression-to-the-mean effects we constructed mixed-regression-models of the deviation of within person observed HbA1c from the expected HbA1c at the time-of-drug-initiation. For this analysis, we used data up to a maximum of 3 years prior to dapagliflozin initiation. Fixed-effects were specified as age, gender, duration of diabetes, number of diabetes drug classes, and month-of-observation. Random effects and autocorrelation structure were specified as for the primary analysis. Cox regression models for event outcomesAs we have described in detail elsewhere detecting drug effects on events is subject to allocation bias if simple comparisons of event rates in those ever versus never exposed are made. Such bias is not removed by adjustment for differences in observed risk factors for the events between ever and never-users. We have argued that for CVD evaluation of cumulative effects on outcomes is a more valid way to infer causality ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"cqYkBFmL","properties":{"formattedCitation":"[26]","plainCitation":"[26]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/XBloPEeN","uris":[""],"uri":[""],"itemData":{"id":314,"type":"article-journal","title":"Modelling cumulative exposure for inference about drug effects in observational studies","container-title":"Pharmacoepidemiology and Drug Safety","source":"Wiley Online Library","abstract":"Purpose\n\nTo demonstrate a modelling approach that controls for time-invariant allocation bias in estimation of associations of outcome with drug exposure.\n\n\nMethods\n\nWe show that in a model that includes terms for both ever-exposure versus never-exposure and cumulative exposure, the parameter for ever-exposure represents the effect of time-invariant allocation bias, and the parameter for cumulative exposure represents the effect of the drug after adjustment for this unmeasured confounding. This assumes no stepwise effect of the drug on the event rate, no reverse causation, and no unmeasured time-varying confounders. We demonstrated this by modelling the effect of statins on cardiovascular disease, for which the true effect has been well characterised in randomised trials, using time-updated Cox regression models in a national cohort of Type 2 diabetes patients.\n\n\nResults\n\nThe crude hazard ratio associated with ever-use of statins was 1.13 in a standard cohort analysis comparing exposed with unexposed person-time intervals. When ever-never use and cumulative exposure are modelled jointly, the effect of statins can be estimated from the cumulative exposure parameter (hazard ratio 0.97 per year of exposure, 95% CI 0.97 to 0.98). The ever-exposed term (hazard ratio 1.20, 1.16 to 1.23) in this model can be interpreted as estimating the allocation bias.\n\n\nConclusions\n\nWhere stepwise effects on the risk of adverse events are unlikely, as for instance for effects on risk of cancer, joint modelling of ever-never and cumulative exposure can be used to study the effects of multiple drugs and to distinguish causal effects from confounding by allocation.","URL":"","DOI":"10.1002/pds.4327 [epub ahead of print]","ISSN":"1099-1557","journalAbbreviation":"Pharmacoepidemiol Drug Saf","language":"en","author":[{"family":"Farran","given":"Bassam"},{"family":"McGurnaghan","given":"Stuart"},{"family":"Looker","given":"Helen C."},{"family":"Livingstone","given":"Shona"},{"family":"Lahnsteiner","given":"Eva"},{"family":"Colhoun","given":"Helen M."},{"family":"McKeigue","given":"Paul M."}],"accessed":{"date-parts":[["2017",10,18]]}}}],"schema":""} [26]. More specifically Cox regression models for time-to-event were specified to include a time-updated term for ever-exposure versus never-exposure and this term in fact captures the allocation bias and also to include a term for cumulative-exposure. Person time was split into 28 day intervals and each interval updated for exposure. Models were constructed with and without adjustment for baseline clinical risk factors. Imputation was used where risk factor data were missing as shown in ESM Table 2. For events such as DKA it might be argued that sudden rather than cumulative drug effects may occur then this effect would be captured in the ever versus never term but it cannot be differentiated from allocation bias effects. ResultsCohort descriptive statisticsIn total, 8566 dapagliflozin-users (of which 7231 were considered ‘on-licence’) and 230310 never-users met inclusion criteria for this analysis (Table 1, ESM Table 3). In total, 2782 users (32.48%) had ceased dapagliflozin before their last follow-up, and mean within-person persistence (i.e. proportion of all available follow-up time in which dapagliflozin continued to be received) was 0.81 (SD: 0.32). During their observable follow-up, 2576 users (30.17%) initiated at least one additional diabetes drug they were not receiving at dapagliflozin initiation (median time until additional diabetes’-drug-initiation: 214 days, IQR: 103 – 381 days), and 1963 users (22.92%) ceased a non-dapagliflozin diabetes drug they continued to receive when dapagliflozin had been initiated (median time until cessation of concurrent diabetes drug: 265 days, IQR: 141 – 453 days). 32% of users dropped another diabetes drug at time-of-initiation of dapagliflozin and their inclusion here is conservative with regard to estimating the effect of dapagliflozin. Altogether there were 6674 person-years of follow-up time available post-initiation for evaluating treatment effects and the median observation time post-initiation, i.e. follow-up time, was 210 days (IQR: 91 – 421 days). Dapagliflozin was prescribed mostly via add-on therapy on top of existing monotherapy or dual therapy (Table 1). Baseline characteristics adjusted for age, gender, and diabetes duration differed considerably between users and non-users (Table 1). Crude within-person absolute changes in clinical measures with dapagliflozin-exposureThe mean number of measurements per user pre-initiation were as follows. Mean (SD); HbA1c: 4.92 (1.99), BMI: 3.58 (2.81), weight: 3.44 (2.81), SBP: 5.44 (3.28), eGFR: 5.07 (3.62). The mean number of measurements per user post-initiation were as follows (SD); HbA1c: 2.42 (1.71), BMI: 2.13 (1.77), weight: 2.06 (1.70), SBP: 2.68 (2.27), eGFR: 2.94 (3.12). Crude within-person absolute changes in clinical outcomes throughout follow-up are shown in Table 2 (with % changes in ESM Table 4). Note that unlike in a clinical trial where all measurements will occur at the same regularly spaced intervals, our real-world observational dataset reflects whatever clinical measures were made. Thus different individuals contribute data within different 3-month windows being evaluated and there are of course fewer persons observed at increasingly longer durations of follow-up. With these caveats in mind at 3-months the mean change HbA1c was -10.41 mmol/mol (-0.95%) with the largest change observed at 12-months where it was -12.99 mmol/mol (-1.19%) and with the change from baseline generally persisting above -10 mmol/mol (-0.91%) throughout follow up (Table 2). In terms of target achievement by six-months from initiation 26.0% of users reached HbA1c ≤ 58 mmol/mol (7.5%) and 13.1% reached HbA1c ≤ 53mmol/mol (7.0%) compared to 5.4% and 2.3% of users at baseline respectively. For SBP, BMI, and weight, these fell by 3-months post-initiation (crude within person changes of -4.32 mmHg, -0.74 kg/m2and -2.1 kg) respectively and these changes persisted thereafter. Variability in effects by 24-months’ exposure and effects of baseline characteristicsHbA1c was reduced in the majority of dapagliflozin recipients but as shown in the quadrant plot (ESM Figure 1), the magnitude of effect varied considerably. Using the most recently available treatment measure up to 24-months’ post-initiation, much larger mean within-person absolute reductions were observed for users in the highest two tertiles for baseline values of HbA1c (ESM Table 5). Mean within-person HbA1c reductions were also marginally more pronounced for users with a higher baseline kidney function and shorter duration of diabetes. No clear gender difference was observed. Similarly, those in the top tertile for weight BMI and SBP had the highest absolute decline in these outcomes. All observed subgroup effects persisted when within-person changes were examined on a proportional scale.Crude effects by on-licence statusMean within-person changes in the 84.4% of users considered on-licence were similar to the overall effect. Comparing off and on-licence-users, effects on HbA1c in the 15.6% of off-licence-users were clearly observed and substantial, but were slightly lower than in on-licence-users (see ESM Tables 5 and 6).Effects from mixed-effects-regression modelsAs shown in Table 2, crude absolute changes in clinical outcomes compared to baseline were fairly stable over follow-up time. Fitted mean trajectories of clinical outcomes from final covariate-adjusted mixed-regression models suggested that before initiating dapagliflozin, HbA1c was increasing by 0.40%/year (Table 3), SBP was increasing by 0.59 mmHg/year, BMI was decreasing by 0.03 kg/m2/year, weight was decreasing by 0.12kg/year, and eGFR was decreasing by 1.21 ml/min/1.73m2/year in these users. However, there was substantial individual random variation around these mean slopes.In a mixed-regression model taking account of time trends in the clinical outcomes the estimates for the apparent dapagliflozin effect on HbA1c at 3-months was similar to the simple crude comparisons but the effect sizes yielded by the model were greater than the crude estimates at longer follow up. Thus the crude effect on HbA1c at 12-months was -12.99 mmol/mol (-1.19%) whereas the estimate from the model taking into consideration the upward change in HbA1c that would have been expected in the absence of the drug at that time-point was -15.14 mmol/mol (-1.39%) (95% CI -15.87, -14.41), (Table 3, Figure 1A). Model effect estimates for BMI and weight (Figure 1B, 1C) showed stabilisation by 6-months at changes of -0.82kg/m2 (95% CI -0.87, -0.77) and -2.20kg (95% CI -2.34, -2.06). For SBP, dapagliflozin was associated with a decrease of -4.32mmHg (95% CI -4.84, -3.79) within the first 3-months’ use (Figure 1D), that at least persisted throughout follow up. The pattern of apparent effect of dapagliflozin upon kidney function was less clear. An initial decline in eGFR of -1.81 ml min-1 1.73m-2 (95% CI -2.10, -1.52) was observed within the first 3-months’ use (Figure 1E), but by 12-months was no greater than the expected decline in eGFR the absence of drug. Estimates of treatment effects were consistent when mixed-regression model procedures were repeated restricting data to on-licence-users only (data not shown).Estimating potential magnitude of regression-to-the-mean on apparent drug-associated changes Residual values from mixed-regression models showed that the closest prior measurements to dapagliflozin initiation appeared systematically greater than expected given the respective individual HbA1c trajectories. This difference was approximately 10% on average but with considerable variability in this estimate. Thus, of the change in HbA1c at 12-months of -15.14 mmol/mol (-1.39%) approximately 1.5 mmol/mol (2.29%) might be attributable to this bias. Safety-event AnalysisESM table 2 shows the results of fitting Cox proportional hazards models for CVD, DKA and LLA. As shown with this duration of follow up there were very few cases of CVD (n=111) and even fewer for DKA (n=13) and LLA (n=28) in the exposed subgroup such that power to detect effects is limited. Power is further limited for cumulative effects analysis in that duration of exposure is short overall. Nonetheless we show these data for completeness, and have right censored for exposure to other SGLT-2i to ensure no negative confounding effect balancing the non-significant effect observed in the dapagliflozin-exposed group. As shown there was no significant effect of cumulative exposure on any of these outcomes. In the comparison of ever versus never-users there is a significantly lower rate of CVD (HR=0.71, p=0.02) that is unchanged by adjustment for additional clinical covariates for CVD events. Whilst this is consistent with a protective effect of drug it is not proof of this since this effect could also be due to allocation bias. DiscussionWe describe usage trends of dapagliflozin in individuals with T2DM in Scotland. Almost all (84.4%) of those prescribed dapagliflozin were on-licence-users. Dapagliflozin was largely prescribed as add-on therapy on top of one or two drugs, and was continued throughout follow-up for the majority of patients. As expected, dapagliflozin appeared to be preferentially prescribed for younger individuals with poorer glycaemic control, longer duration of diabetes and on >1 additional oral anti-diabetes medication. Dapagliflozin use was associated with substantial improvements in HbA1c and with slight improvements in BMI, weight and SBP. Based on follow-up values, the greatest absolute improvements in glycaemic control were observed for users with poorer baseline glycaemic control, as well as users with shorter duration of diabetes and higher kidney function. As well as an initial reduction in these outcomes, dapagliflozin appeared to stabilise HbA1c and SBP so that expected rises in these through time were prevented across this median of 210 days of follow up. Real-world evidence can help corroborate findings from RCTs by testing the generalisability of their reported treatment effects and conclusions within a broader and more heterogeneous population who are less supervised in their healthcare management. At 3- to 6-months the crude and the modelled estimated treatment effects on HbA1c were slightly higher than the effect sizes observed in previous RCTs. For example, at 3- and 6-months, the observed crude mean reduction in HbA1c from baseline was 10-12 mmol/mol (or -1.0 to -1.1 % units), compared to RCT estimates of -0.61% to -0.85% at 3-months, and -0.5% to -1.4% at 6-months, subject to dosage and additional drug therapies ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"ansigsslk6","properties":{"formattedCitation":"[3, 6, 27\\uc0\\u8211{}31]","plainCitation":"[3, 6, 27–31]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/IQ1rrguk","uris":[""],"uri":[""],"itemData":{"id":534,"type":"article-journal","title":"Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial","container-title":"Diabetes Care","page":"365-372","volume":"38","issue":"3","source":"CrossRef","DOI":"10.2337/dc14-0666","ISSN":"0149-5992, 1935-5548","shortTitle":"Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea","language":"en","author":[{"family":"Matthaei","given":"Stephan"},{"family":"Bowering","given":"Keith"},{"family":"Rohwedder","given":"Katja"},{"family":"Grohl","given":"Anke"},{"family":"Parikh","given":"Shamik"}],"issued":{"date-parts":[["2015",3]]}}},{"id":"TeVZF1gX/nnqJL2Cc","uris":[""],"uri":[""],"itemData":{"id":535,"type":"article-journal","title":"Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes","container-title":"Diabetes Care","page":"2009-2017","volume":"38","issue":"11","source":"CrossRef","DOI":"10.2337/dc15-0779","ISSN":"0149-5992, 1935-5548","language":"en","author":[{"family":"Mathieu","given":"Chantal"},{"family":"Ranetti","given":"Aurelian Emil"},{"family":"Li","given":"Danshi"},{"family":"Ekholm","given":"Ella"},{"family":"Cook","given":"William"},{"family":"Hirshberg","given":"Boaz"},{"family":"Chen","given":"Hungta"},{"family":"Hansen","given":"Lars"},{"family":"Iqbal","given":"Nayyar"}],"issued":{"date-parts":[["2015",11]]}}},{"id":"TeVZF1gX/a8099kR2","uris":[""],"uri":[""],"itemData":{"id":537,"type":"article-journal","title":"Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study","container-title":"Diabetes Care","page":"740–750","volume":"37","issue":"3","source":"Google Scholar","shortTitle":"Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin","author":[{"family":"Jabbour","given":"Serge A."},{"family":"Hardy","given":"Elise"},{"family":"Sugg","given":"Jennifer"},{"family":"Parikh","given":"Shamik"},{"family":"Group","given":"Study 10"},{"literal":"others"}],"issued":{"date-parts":[["2014"]]}}},{"id":"TeVZF1gX/1BYwyWkC","uris":[""],"uri":[""],"itemData":{"id":486,"type":"article-journal","title":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial","container-title":"The Lancet","page":"2223–2233","volume":"375","issue":"9733","source":"Google Scholar","shortTitle":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin","author":[{"family":"Bailey","given":"Clifford J."},{"family":"Gross","given":"Jorge L."},{"family":"Pieters","given":"Anne"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."}],"issued":{"date-parts":[["2010"]]}}},{"id":"TeVZF1gX/PB7nItij","uris":[""],"uri":[""],"itemData":{"id":321,"type":"article-journal","title":"Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes","container-title":"Diabetes Care","page":"650–657","volume":"32","issue":"4","source":"Google Scholar","author":[{"family":"List","given":"James F."},{"family":"Woo","given":"Vincent"},{"family":"Morales","given":"Enrique"},{"family":"Tang","given":"Weihua"},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009"]]}}},{"id":"TeVZF1gX/wWnO5uOy","uris":[""],"uri":[""],"itemData":{"id":533,"type":"article-journal","title":"Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study","container-title":"The Lancet Diabetes & Endocrinology","page":"211–220","volume":"4","issue":"3","source":"Google Scholar","shortTitle":"Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy","author":[{"family":"Weber","given":"Michael A."},{"family":"Mansfield","given":"Traci A."},{"family":"Cain","given":"Valerie A."},{"family":"Iqbal","given":"Nayyar"},{"family":"Parikh","given":"Shamik"},{"family":"Ptaszynska","given":"Agata"}],"issued":{"date-parts":[["2016"]]}}},{"id":"TeVZF1gX/dhgZtaqT","uris":[""],"uri":[""],"itemData":{"id":536,"type":"article-journal","title":"Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial","container-title":"The Lancet Diabetes & Endocrinology","page":"1004–1016","volume":"4","issue":"12","source":"Google Scholar","shortTitle":"Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8)","author":[{"family":"Frías","given":"Juan P."},{"family":"Guja","given":"Cristian"},{"family":"Hardy","given":"Elise"},{"family":"Ahmed","given":"Azazuddin"},{"family":"Dong","given":"Fang"},{"family":"?hman","given":"Peter"},{"family":"Jabbour","given":"Serge A."}],"issued":{"date-parts":[["2016"]]}}}],"schema":""} [3, 6, 27–31]. The FDA estimates the treatment effect of dapagliflozin on HbA1c to be in the range -0.40% to -0.84% which is smaller than our findings ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a1al8h8fpij","properties":{"formattedCitation":"[2, 32]","plainCitation":"[2, 32]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/7ecfwj6j","uris":[""],"uri":[""],"itemData":{"id":378,"type":"article","title":"Clinical Review - Farxiga (dapagliflozin)","publisher":"FDA","author":[{"family":"Pucino","given":"Frank"}],"issued":{"date-parts":[["2013"]]}}},{"id":"TeVZF1gX/T4hM3qw8","uris":[""],"uri":[""],"itemData":{"id":531,"type":"article","title":"Summary Review for Regulatory Action - Farxiga (dapagliflozin)","publisher":"FDA","issued":{"date-parts":[["2014"]]}}}],"schema":""} [2, 32]. The National Institute for Clinical Excellence (NICE) in the United Kingdom estimates the same to be -0.39% to -0.84%, which is also smaller than our findings but like the FDA estimate ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a2i47halmf5","properties":{"formattedCitation":"[33]","plainCitation":"[33]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/A7kdGtI8","uris":[""],"uri":[""],"itemData":{"id":528,"type":"article","title":"Final Appraisal Determination : Dapagliflozin in Combination Therapy for Treating Type 2 Diabetes","publisher":"National Institute for Health and Care Excellence"}}],"schema":""} [33]. However, estimated effects of dapagliflozin upon HbA1c at 3- to 6-months were consistent with reported follow-up values from a recent UK-wide real-world retrospective study ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a1o6ap1qeto","properties":{"formattedCitation":"[34]","plainCitation":"[34]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/GyE19aHK","uris":[""],"uri":[""],"itemData":{"id":380,"type":"article-journal","title":"Dapagliflozin therapy for type 2 diabetes in primary care: Changes in HbA1c, weight and blood pressure over 2 years follow-up","container-title":"Primary Care Diabetes","source":"PubMed","abstract":"AIMS: To investigate prescribing patterns and effect of dapagliflozin among individuals with T2DM using UK primary care data.\nMETHODS: Adult patients with T2DM initiating dapagliflozin treatment were identified from the Clinical Practice Research Datalink. Changes in HbA1c, body weight and systolic blood pressure were assessed in subgroups defined by glucose lowering treatment at baseline and compliance with the Summary of Product Characteristics. Logistic regression examined the association of baseline characteristics with achievement of target HbA1c (≤53mmol/mol) and weight reduction (by ≥3.0%).\nRESULTS: Among 5828 eligible individuals, HbA1c was reduced from a baseline mean of 80.0mmol/mol (SD 17.6) by -12.8 (95% CI -13.8, -11.8)mmol/mol at >12-24 months. The corresponding value for weight reduction (baseline mean 101.7kg) was -5.0 (-5.4, -4.5)kg, and for systolic blood pressure reduction (baseline mean 134.1mmHg) was -3.1 (-4.0, -2.2) mmHg. Lower baseline HbA1c values (<69; 69-85 versus ≥86mmol/mol) were positively associated with achievement of target HbA1c <53mmol/mol.\nCONCLUSIONS: Treatment with dapagliflozin in T2DM was associated with reductions in HbA1c, weight and systolic blood pressure over time periods up to 2 years. Changes in these parameters were consistent with those reported in RCTs.","DOI":"10.1016/j.pcd.2017.04.004","ISSN":"1878-0210","note":"PMID: 28583425","shortTitle":"Dapagliflozin therapy for type 2 diabetes in primary care","journalAbbreviation":"Prim Care Diabetes","language":"eng","author":[{"family":"Wilding","given":"J."},{"family":"Bailey","given":"C."},{"family":"Rigney","given":"U."},{"family":"Blak","given":"B."},{"family":"Kok","given":"M."},{"family":"Emmas","given":"C."}],"issued":{"date-parts":[["2017",6,2]]}}}],"schema":""} [34]. One potential reason for apparently higher treatment effects in an observational study is regression-to-the-mean. Where there is considerable short-term within-person variation (or ‘noise’) in clinical measures whether due to true short term biological variability or to measurement error, a new drug is more likely to be prescribed in response to extreme or outlying clinical observations such as unusually high HbA1c for the respective individual. Even where a drug is ineffective pre/post-initiation, comparisons of data might show an apparent treatment effect, as after a given extreme observation subsequent measurements might be expected to regress to the mean. It is also the case that true biological worsening of the clinical measure such as HbA1c will also precede new drug intervention. The combined effect of these two phenomena is HbA1c at the time-of-drug-initiation is likely to be systematically higher than expected given an individual’s prior measurements, their current characteristics of age, sex diabetes duration and other characteristics relevant to expected HbA1c. Precisely how much of the observed treatment effect is attributable to regression-to-the-mean effects is not directly estimable. By examining the residuals of the last prior measurements to dapagliflozin initiation in a model of pre-initiation trajectories, we have provided a crude estimate of the magnitude of such effects as being an apparent reduction of about 10% of the apparent treatment effect. The treatment effects we observed on HbA1c at 3- to 6-months were 0.15-0.30% units higher than in clinical trials but half of this difference from trial effects might be explained by regression-to-the-mean. Another potential reason for apparently higher effects could be because changes in lifestyle that reduce HbA1c could co-occur with drug-initiation. Our observed treatment effects at 3- to 6-months upon BMI, weight and SBP were highly consistent with those from RCTs where ranges from RCTs; effect on weight have been -1.50kg to -3.2 kg and effect on SBP have been -2.19mmHg to -3.9 mmHg ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a2bh1hpktt5","properties":{"formattedCitation":"[3, 5, 6, 27\\uc0\\u8211{}29, 31]","plainCitation":"[3, 5, 6, 27–29, 31]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/IQ1rrguk","uris":[""],"uri":[""],"itemData":{"id":534,"type":"article-journal","title":"Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial","container-title":"Diabetes Care","page":"365-372","volume":"38","issue":"3","source":"CrossRef","DOI":"10.2337/dc14-0666","ISSN":"0149-5992, 1935-5548","shortTitle":"Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea","language":"en","author":[{"family":"Matthaei","given":"Stephan"},{"family":"Bowering","given":"Keith"},{"family":"Rohwedder","given":"Katja"},{"family":"Grohl","given":"Anke"},{"family":"Parikh","given":"Shamik"}],"issued":{"date-parts":[["2015",3]]}}},{"id":"TeVZF1gX/nnqJL2Cc","uris":[""],"uri":[""],"itemData":{"id":535,"type":"article-journal","title":"Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes","container-title":"Diabetes Care","page":"2009-2017","volume":"38","issue":"11","source":"CrossRef","DOI":"10.2337/dc15-0779","ISSN":"0149-5992, 1935-5548","language":"en","author":[{"family":"Mathieu","given":"Chantal"},{"family":"Ranetti","given":"Aurelian Emil"},{"family":"Li","given":"Danshi"},{"family":"Ekholm","given":"Ella"},{"family":"Cook","given":"William"},{"family":"Hirshberg","given":"Boaz"},{"family":"Chen","given":"Hungta"},{"family":"Hansen","given":"Lars"},{"family":"Iqbal","given":"Nayyar"}],"issued":{"date-parts":[["2015",11]]}}},{"id":"TeVZF1gX/a8099kR2","uris":[""],"uri":[""],"itemData":{"id":537,"type":"article-journal","title":"Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study","container-title":"Diabetes Care","page":"740–750","volume":"37","issue":"3","source":"Google Scholar","shortTitle":"Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin","author":[{"family":"Jabbour","given":"Serge A."},{"family":"Hardy","given":"Elise"},{"family":"Sugg","given":"Jennifer"},{"family":"Parikh","given":"Shamik"},{"family":"Group","given":"Study 10"},{"literal":"others"}],"issued":{"date-parts":[["2014"]]}}},{"id":"TeVZF1gX/1BYwyWkC","uris":[""],"uri":[""],"itemData":{"id":486,"type":"article-journal","title":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial","container-title":"The Lancet","page":"2223–2233","volume":"375","issue":"9733","source":"Google Scholar","shortTitle":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin","author":[{"family":"Bailey","given":"Clifford J."},{"family":"Gross","given":"Jorge L."},{"family":"Pieters","given":"Anne"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."}],"issued":{"date-parts":[["2010"]]}}},{"id":"TeVZF1gX/3nckOKvE","uris":[""],"uri":[""],"itemData":{"id":320,"type":"article-journal","title":"Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial","container-title":"Diabetes Care","page":"2217-2224","volume":"33","issue":"10","source":"CrossRef","DOI":"10.2337/dc10-0612","ISSN":"0149-5992, 1935-5548","shortTitle":"Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise","language":"en","author":[{"family":"Ferrannini","given":"E."},{"family":"Ramos","given":"S. J."},{"family":"Salsali","given":"A."},{"family":"Tang","given":"W."},{"family":"List","given":"J. F."}],"issued":{"date-parts":[["2010",10,1]]}}},{"id":"TeVZF1gX/PB7nItij","uris":[""],"uri":[""],"itemData":{"id":321,"type":"article-journal","title":"Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes","container-title":"Diabetes Care","page":"650–657","volume":"32","issue":"4","source":"Google Scholar","author":[{"family":"List","given":"James F."},{"family":"Woo","given":"Vincent"},{"family":"Morales","given":"Enrique"},{"family":"Tang","given":"Weihua"},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009"]]}}},{"id":"TeVZF1gX/dhgZtaqT","uris":[""],"uri":[""],"itemData":{"id":536,"type":"article-journal","title":"Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial","container-title":"The Lancet Diabetes & Endocrinology","page":"1004–1016","volume":"4","issue":"12","source":"Google Scholar","shortTitle":"Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8)","author":[{"family":"Frías","given":"Juan P."},{"family":"Guja","given":"Cristian"},{"family":"Hardy","given":"Elise"},{"family":"Ahmed","given":"Azazuddin"},{"family":"Dong","given":"Fang"},{"family":"?hman","given":"Peter"},{"family":"Jabbour","given":"Serge A."}],"issued":{"date-parts":[["2016"]]}}}],"schema":""} [3, 5, 6, 27–29, 31]. These effects on SBP are consistent with the mechanisms of the action of the drug which encourages renal sodium and glucose loss.An important aspect of our analyses is the persistence of the apparent drug effect. Since HbA1c and SBP tend to worsen over time in diabetes in the absence of drug-exposure, a stable absolute difference from baseline over longer follow up is consistent not only with the drug improving the HbA1c and SBP but also preventing their worsening over time. This is illustrated in the mixed model where a much larger net effect of dapagliflozin on HbA1c of -16 mmol/mol (-1.47%) given its underlying time trend was estimated at 24-months’ exposure. The vast majority of people receiving dapagliflozin showed response to the drug but there was considerable variation in the magnitude of the response. We are not able to evaluate in this study to what extent such variation reflects true biological variation in response versus differences in compliance. Some of the variation on an absolute scale reflects that the largest reductions in HbA1c during follow-up were seen for those users in the highest tertile for baseline HbA1c (ESM Table 5). Individuals also generally exhibited wide variation in responses in clinical trials (SD for HbA1c effect ranging from 0.61% to 0.92%), though the wider variation seen here may reflect the broader diversity of patient characteristics in our real-world dataset as well as more diverse compliance ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"as7okcvm7e","properties":{"formattedCitation":"[3\\uc0\\u8211{}7, 10]","plainCitation":"[3–7, 10]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/PB7nItij","uris":[""],"uri":[""],"itemData":{"id":321,"type":"article-journal","title":"Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes","container-title":"Diabetes Care","page":"650–657","volume":"32","issue":"4","source":"Google Scholar","author":[{"family":"List","given":"James F."},{"family":"Woo","given":"Vincent"},{"family":"Morales","given":"Enrique"},{"family":"Tang","given":"Weihua"},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009"]]}}},{"id":"TeVZF1gX/sfDTQFS1","uris":[""],"uri":[""],"itemData":{"id":484,"type":"article-journal","title":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment","container-title":"Diabetes Care","page":"1656-1662","volume":"32","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).\nRESEARCH DESIGN AND METHODS: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).\nRESULTS: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C > or =0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.\nCONCLUSIONS: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.","DOI":"10.2337/dc09-0517","ISSN":"1935-5548","note":"PMID: 19528367\nPMCID: PMC2732143","shortTitle":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers","journalAbbreviation":"Diabetes Care","language":"eng","author":[{"family":"Wilding","given":"John P. H."},{"family":"Norwood","given":"Paul"},{"family":"T'joen","given":"Caroline"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009",9]]}}},{"id":"TeVZF1gX/3nckOKvE","uris":[""],"uri":[""],"itemData":{"id":320,"type":"article-journal","title":"Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial","container-title":"Diabetes Care","page":"2217-2224","volume":"33","issue":"10","source":"CrossRef","DOI":"10.2337/dc10-0612","ISSN":"0149-5992, 1935-5548","shortTitle":"Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise","language":"en","author":[{"family":"Ferrannini","given":"E."},{"family":"Ramos","given":"S. J."},{"family":"Salsali","given":"A."},{"family":"Tang","given":"W."},{"family":"List","given":"J. F."}],"issued":{"date-parts":[["2010",10,1]]}}},{"id":"TeVZF1gX/1BYwyWkC","uris":[""],"uri":[""],"itemData":{"id":486,"type":"article-journal","title":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial","container-title":"The Lancet","page":"2223–2233","volume":"375","issue":"9733","source":"Google Scholar","shortTitle":"Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin","author":[{"family":"Bailey","given":"Clifford J."},{"family":"Gross","given":"Jorge L."},{"family":"Pieters","given":"Anne"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."}],"issued":{"date-parts":[["2010"]]}}},{"id":"TeVZF1gX/Y9689ec5","uris":[""],"uri":[""],"itemData":{"id":487,"type":"article-journal","title":"Effects of Dapagliflozin, an SGLT2 Inhibitor, on HbA1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy","container-title":"Diabetes Care","page":"1473-1478","volume":"35","issue":"7","source":"CrossRef","DOI":"10.2337/dc11-1693","ISSN":"0149-5992, 1935-5548","language":"en","author":[{"family":"Rosenstock","given":"J."},{"family":"Vico","given":"M."},{"family":"Wei","given":"L."},{"family":"Salsali","given":"A."},{"family":"List","given":"J. F."}],"issued":{"date-parts":[["2012",7,1]]}}},{"id":"TeVZF1gX/3Ux5XT12","uris":[""],"uri":[""],"itemData":{"id":317,"type":"article-journal","title":"Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin - a randomized trial","container-title":"Annals of internal medicine","page":"405–415","volume":"156","issue":"6","source":"Google Scholar","author":[{"family":"Wilding","given":"John PH"},{"family":"Woo","given":"Vincent"},{"family":"Soler","given":"Norman G."},{"family":"Pahor","given":"Andrea"},{"family":"Sugg","given":"Jennifer"},{"family":"Rohwedder","given":"Katja"},{"family":"Parikh","given":"Shamik"}],"issued":{"date-parts":[["2012"]]}}}],"schema":""} [3–7, 10]. Currently, the most common reported adverse effect following RCTs of dapagliflozin is a higher risk of urinary and genital tract infections ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KZVKddf6","properties":{"formattedCitation":"[9, 10, 35]","plainCitation":"[9, 10, 35]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/sfDTQFS1","uris":[""],"uri":[""],"itemData":{"id":484,"type":"article-journal","title":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment","container-title":"Diabetes Care","page":"1656-1662","volume":"32","issue":"9","source":"PubMed","abstract":"OBJECTIVE: To determine whether dapagliflozin, which selectively inhibits renal glucose reabsorption, lowers hyperglycemia in patients with type 2 diabetes that is poorly controlled with high insulin doses plus oral antidiabetic agents (OADs).\nRESEARCH DESIGN AND METHODS: This was a randomized, double-blind, three-arm parallel-group, placebo-controlled, 26-center trial (U.S. and Canada). Based on data from an insulin dose-adjustment setting cohort (n = 4), patients in the treatment cohort (n = 71) were randomly assigned 1:1:1 to placebo, 10 mg dapagliflozin, or 20 mg dapagliflozin, plus OAD(s) and 50% of their daily insulin dose. The primary outcome was change from baseline in A1C at week 12 (dapagliflozin vs. placebo, last observation carried forward [LOCF]).\nRESULTS: At week 12 (LOCF), the 10- and 20-mg dapagliflozin groups demonstrated -0.70 and -0.78% mean differences in A1C change from baseline versus placebo. In both dapagliflozin groups, 65.2% of patients achieved a decrease from baseline in A1C > or =0.5% versus 15.8% in the placebo group. Mean changes from baseline in fasting plasma glucose (FPG) were +17.8, +2.4, and -9.6 mg/dl (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin, respectively). Postprandial glucose (PPG) reductions with dapagliflozin also showed dose dependence. Mean changes in total body weight were -1.9, -4.5, and -4.3 kg (placebo, 10 mg dapagliflozin, and 20 mg dapagliflozin). Overall, adverse events were balanced across all groups, although more genital infections occurred in the 20-mg dapagliflozin group than in the placebo group.\nCONCLUSIONS: In patients receiving high insulin doses plus insulin sensitizers who had their baseline insulin reduced by 50%, dapagliflozin decreased A1C, produced better FPG and PPG levels, and lowered weight more than placebo.","DOI":"10.2337/dc09-0517","ISSN":"1935-5548","note":"PMID: 19528367\nPMCID: PMC2732143","shortTitle":"A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers","journalAbbreviation":"Diabetes Care","language":"eng","author":[{"family":"Wilding","given":"John P. H."},{"family":"Norwood","given":"Paul"},{"family":"T'joen","given":"Caroline"},{"family":"Bastien","given":"Arnaud"},{"family":"List","given":"James F."},{"family":"Fiedorek","given":"Fred T."}],"issued":{"date-parts":[["2009",9]]}}},{"id":"TeVZF1gX/S2XFvjOK","uris":[""],"uri":[""],"itemData":{"id":485,"type":"article-journal","title":"Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin","container-title":"Diabetes, Obesity and Metabolism","page":"1111–1120","volume":"16","issue":"11","source":"Google Scholar","author":[{"family":"Nauck","given":"M. A."},{"family":"Del Prato","given":"S."},{"family":"Durán-García","given":"S."},{"family":"Rohwedder","given":"K."},{"family":"Langkilde","given":"A. M."},{"family":"Sugg","given":"J."},{"family":"Parikh","given":"S. J."}],"issued":{"date-parts":[["2014"]]}}},{"id":"TeVZF1gX/5l97035P","uris":[""],"uri":[""],"itemData":{"id":379,"type":"article-journal","title":"Urinary tract infections in patients with diabetes treated with dapagliflozin","container-title":"Journal of Diabetes and Its Complications","page":"473-478","volume":"27","issue":"5","source":"PubMed","abstract":"AIMS: Urinary tract infection is common in patients with type 2 diabetes. Possible causative factors include glucosuria, which is a result of treatment with sodium glucose cotransporter 2 (SGLT2) inhibitors. Dapagliflozin is an investigative SGLT2 inhibitor with demonstrated glycemic benefits in patients with diabetes. Data from dapagliflozin multi-trial safety data were analyzed to clarify the association between glucosuria and urinary tract infection.\nMETHODS: Safety data from 12 randomized, placebo-controlled trials were pooled to evaluate the relationship between glucosuria and urinary tract infection in patients with inadequately controlled diabetes (HbA1c >6.5%-12%). Patients were treated with dapagliflozin (2.5, 5, or 10mg) or placebo once daily, either as monotherapy or add-on to metformin, insulin, sulfonylurea, or thiazolidinedione for 12-24weeks. The incidence of clinical diagnoses and events suggestive of urinary tract infection were quantified.\nRESULTS: This analysis included 3152 patients who received once-daily dapagliflozin (2.5mg [n=814], 5mg [n=1145], or 10mg [n=1193]) as monotherapy or add-on treatment, and 1393 placebo-treated patients. For dapagliflozin 2.5mg, 5mg, 10mg, and placebo, diagnosed infections were reported in 3.6%, 5.7%, 4.3%, and 3.7%, respectively. Urinary glucose levels, but not the incidence of urinary tract infection, increased progressively with dapagliflozin dosage. Most identified infections were those considered typical for patients with diabetes. Discontinuations due to urinary tract infection were rare: 8 (0.3%) dapagliflozin-treated patients and 1 (0.1%) placebo-treated patient. Most diagnosed infections were mild to moderate and responded to standard antimicrobial treatment.\nCONCLUSIONS: Treatment of type 2 diabetes with once-daily dapagliflozin 5 or 10mg is accompanied by a slightly increased risk of urinary tract infection. Infections were generally mild to moderate and clinically manageable. This analysis did not demonstrate a definitive dose relationship between glucosuria and urinary tract infection.","DOI":"10.1016/j.jdiacomp.2013.05.004","ISSN":"1873-460X","note":"PMID: 23849632","journalAbbreviation":"J. Diabetes Complicat.","language":"eng","author":[{"family":"Johnsson","given":"Kristina M."},{"family":"Ptaszynska","given":"Agata"},{"family":"Schmitz","given":"Bridget"},{"family":"Sugg","given":"Jennifer"},{"family":"Parikh","given":"Shamik J."},{"family":"List","given":"James F."}],"issued":{"date-parts":[["2013",10]]}}}],"schema":""} [9, 10, 35]. There is also some evidence that dapagliflozin is associated with a risk of decline in kidney function, though this association did not persist in subgroups with long-term (>24 month) treatment, consistent with our observation of an initial decline in eGFR that by 12-months was consistent with the annual decline expected in the absence of drug (Figure 1E) ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a2h7sfnch00","properties":{"formattedCitation":"[36]","plainCitation":"[36]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/c1M6Xlxs","uris":[""],"uri":[""],"itemData":{"id":514,"type":"article-journal","title":"Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials","container-title":"Diabetes, Obesity & Metabolism","page":"1106-1115","volume":"19","issue":"8","source":"PubMed","abstract":"AIM: To compare the associations of individual sodium-glucose co-transporter-2 (SGLT2) inhibitors with adverse renal outcomes in patients with type 2 diabetes mellitus (T2DM).\nMETHODS: PubMed, EMBASE, CENTRAL and were searched for studies published up to May 24, 2016, without language or date restrictions. Randomized trials that reported at least 1 renal-related adverse outcome in patients with T2DM treated with SGLT2 inhibitors were included. Pairwise and network meta-analyses were carried out to calculate the odds ratios (ORs) with 95% confidence intervals (CIs), and a cumulative meta-analysis was performed to assess the robustness of evidence.\nRESULTS: In total, we extracted 1334 composite renal events among 39?741 patients from 58 trials, and 511 acute renal impairment/failure events among 36?716 patients from 53 trials. Dapagliflozin was significantly associated with a greater risk of composite renal events than placebo (OR 1.64, 95% CI 1.26-2.13). Empagliflozin seemed to confer a lower risk than placebo (OR 0.63, 95% CI 0.54-0.72), canagliflozin (OR 0.48, 95% CI 0.29-0.82) and dapagliflozin (OR 0.38, 95% CI 0.28-0.51). With regard to acute renal impairment/failure, only empagliflozin was significantly associated with a lower risk than placebo (OR 0.72, 95% CI 0.60-0.86). The cumulative meta-analysis indicated the robustness of our significant findings.\nCONCLUSIONS: The present meta-analysis indicated that dapagliflozin may increase the risk of adverse renal events, while empagliflozin may have a protective effect among patients with T2DM. Further data from large well-conducted randomized controlled trials and a real-world setting are warranted.","DOI":"10.1111/dom.12917","ISSN":"1463-1326","note":"PMID: 28240446","shortTitle":"Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes","journalAbbreviation":"Diabetes Obes Metab","language":"eng","author":[{"family":"Tang","given":"Huilin"},{"family":"Li","given":"Dandan"},{"family":"Zhang","given":"Jingjing"},{"family":"Li","given":"Yufeng"},{"family":"Wang","given":"Tiansheng"},{"family":"Zhai","given":"Suodi"},{"family":"Song","given":"Yiqing"}],"issued":{"date-parts":[["2017",8]]}}}],"schema":""} [36]. Dapagliflozin is not currently recommended for patients with an eGFR below 60 ml min-1 1.73m-2 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a106dp2v720","properties":{"formattedCitation":"[1]","plainCitation":"[1]","noteIndex":0},"citationItems":[{"id":"TeVZF1gX/dGSY580Q","uris":[""],"uri":[""],"itemData":{"id":522,"type":"webpage","title":"European Medicines Agency - Forxiga (dapagliflozin)","URL":"","accessed":{"date-parts":[["2017",9,8]]}}}],"schema":""} [1], ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2vIjBcZY","properties":{"formattedCitation":"[14]","plainCitation":"[14]","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":"TeVZF1gX/msur5mdd","uris":[""],"uri":[""],"itemData":{"id":"BvYBap6o/jxWihvcv","type":"article-journal","title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","container-title":"NEJM","page":"2117-2128","volume":"373","issue":"22","source":"Taylor and Francis+NEJM","abstract":"In this study, the addition of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, to standard care reduced cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk.","DOI":"10.1056/NEJMoa1504720","ISSN":"0028-4793","note":"PMID: 26378978","author":[{"family":"Zinman","given":"Bernard"},{"family":"Wanner","given":"Christoph"},{"family":"Lachin","given":"John M."},{"family":"Fitchett","given":"David"},{"family":"Bluhmki","given":"Erich"},{"family":"Hantel","given":"Stefan"},{"family":"Mattheus","given":"Michaela"},{"family":"Devins","given":"Theresa"},{"family":"Johansen","given":"Odd Erik"},{"family":"Woerle","given":"Hans J."},{"family":"Broedl","given":"Uli C."},{"family":"Inzucchi","given":"Silvio E."}],"issued":{"date-parts":[["2015",11,26]]}}}],"schema":""} 14, ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"lM43TB20","properties":{"formattedCitation":"[15]","plainCitation":"[15]","dontUpdate":true,"noteIndex":0},"citationItems":[{"id":"TeVZF1gX/PWd30Rat","uris":[""],"uri":[""],"itemData":{"id":"BvYBap6o/lG7uDVFK","type":"article-journal","title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","container-title":"NEJM","page":"644-657","volume":"377","issue":"7","source":"Taylor and Francis+NEJM","abstract":"In this report of two randomized trials, patients with type 2 diabetes at risk for cardiovascular disease received the sodium–glucose cotransporter 2 inhibitor canagliflozin or placebo and were followed for 188 weeks. Canagliflozin reduced the risk of cardiovascular events.","DOI":"10.1056/NEJMoa1611925","ISSN":"0028-4793","note":"PMID: 28605608","author":[{"family":"Neal","given":"Bruce"},{"family":"Perkovic","given":"Vlado"},{"family":"Mahaffey","given":"Kenneth W."},{"family":"Zeeuw","given":"Dick","non-dropping-particle":"de"},{"family":"Fulcher","given":"Greg"},{"family":"Erondu","given":"Ngozi"},{"family":"Shaw","given":"Wayne"},{"family":"Law","given":"Gordon"},{"family":"Desai","given":"Mehul"},{"family":"Matthews","given":"David R."}],"issued":{"date-parts":[["2017",8,17]]}}}],"schema":""} 15]. Our focus here was on effects on continuous outcomes for which there is adequate power rather than on CVD and other safety-events analyses, for which power is very low. Nonetheless we included such analyses for completeness. No significant safety signals were found. Whilst there was a significantly lower CVD event rate in those ever versus never exposed there was no significant cumulative effect of exposure on CVD. As we have described previously such ever versus never comparisons, whilst of some reassurance, cannot be interpreted as proof of a protective causal effect since it remains subject to allocation bias. As further follow up data accrues in this dataset we will be able to test for cumulative effects on events with more power. In addition, we intend to explore effects of other SGLT2i’s that were licensed later as further data accrue. We acknowledge the limitations of our analysis, the most important of which are that unbiased control comparisons cannot be achieved as they are in clinical trials. Also, as described within-person analyses can fail to take into account regression-to-the-mean and underlying calendar time trends. Nevertheless, we have made extensive efforts to estimate the likely magnitude of these latter two biases going well beyond many observational studies of this nature. ConclusionsThe effectiveness of dapagliflozin on HbA1c and other clinical outcomes observed in clinical trials was apparent in this real-world effectiveness study with treatment effect estimates being at least as large as in clinical trials even when likely observational analysis biases are considered. Dapagliflozin lowers HbA1c and SBP shortly after treatment-initiation but also appears to prevent worsening of these outcomes over the ensuring two years. Dapagliflozin also lowered BMI and weight. Informed ConsentThe study was carried out in accordance with the ethical principles in the Declaration of Helsinki as revised in 2008.AcknowledgementsWe thank the members of the Scottish Diabetes Research Network Epidemiology Group and the SCI Diabetes team (NHS Scotland). Data availabilityWe do not have governance permissions to share Individual level data on which these analyses were conducted. However, for any bona fide requests to audit the validity of the analyses, the verifiable research pipeline which we operate means that they can request to view the analyses being run and the same tabulations resulting. FundingThis study was funded by Astra Zeneca (grant ref 7462RH). Astra Zeneca had no right of veto over study design, choice of statistical methods, data analysis, data generation, data interpretation or writing of this manuscript, all of which were carried out by the authors. They were allowed to see and comment on the draft, their comments being that a quadrant plot would be useful, that effects in off-licence users should be detailed and that effects on weight should be presented. The corresponding author, HMC, had full access to the data in the study, drew up the analysis plan, supervised LBr and SM doing the analyses and had final responsibility for the decision to submit for publication.Duality of interestLBr, SM, PMM and HMC declare a grant from Astra Zeneca for the work under consideration for publication. Astra Zeneca had no right of veto over study design, choice of statistical methods, data analysis, data generation, data interpretation or writing of this manuscript, all of which were carried out by the authors (see Funding below for more details). The following authors have disclosed declarations of interest outside the submitted work: NS received grant and personal fees from Boehringer Ingelheim, personal fees from Janssen, Eli Lilly and Novo Nordisk and a grant from Astra Zeneca. JP received grant and personal fees from Sanofi Aventis, Quintiles and Janssen, personal fees from ACI clinical, Pfizer, Lilly and Novo Nordisk and non-financial support from Itamar Medical and Merck (Germany). RM received personal fees for advisory boards from Novo Nordisk, Sanofi Aventis and Lilly. HMC received grants (as part of EU Innovative Medicines programme collaborations) from AstraZeneca LP, Boehringer Ingelheim, Eli Lilly & Company, Pfizer, Roche Pharmaceuticals and Sanofi Aventis, and grants from Novo Nordisk. HMC is a shareholder in Bayer and Roche Pharmaceuticals. HMC is on trial steering committees or safety monitoring committees with Eli Lilly, Sanofi and Regeneron, Novartis Pharmaceuticals and Novo Nordisk and receives remuneration via her institution for this. She has received speaker fees and travel expenses for presenting trials she has helped design or other research she has led from Pfizer, Eli Lilly, Sanofi and Regeneron. JM received grants from Novo Nordisk, Lilly, Merck, Boheringer, GSK and non-financial support from Novo Nordisk. EP received personal honorarium fees from Lilly, MSD, Novo Nordisk and Astra Zeneca. TC received a grant from Diabetes UK and the British Heart Foundation. All other members of the writing committee declare no competing interests.Contribution statementSM performed data preparation, data analysis and table and figure generation and inputted to manuscript preparation. LBr contributed to the design and planning of the analysis, conducted the statistical analysis and contributed to writing the manuscript. GL contributed to data collection and manuscript review. SW made substantial contribution to the acquisition and interpretation of the work, revised work critically for important intellectual content and approved the final version. JP contributed to Scottish wide data collection, data interpretation and critical review and editing of the manuscript. RM contributed to study design, data collection, data analysis, data interpretation and writing of the manuscript. TC contributed to literature search, design and analyses of the safety studies and writing of the manuscript. NS contributed to Scottish wide data collection, data interpretation and critical review and editing of the manuscript. LBl ran data cleaning and transformation algorithms and integrity checks, loaded data into the database and provided support for analysis, drafted analytic tables and figures and contributed to manuscript review. HMC drew up the analysis plan, supervised LBl and SM during analyses, manuscript review and had final responsibility for the decision to submit for publication. JM was involved in leading the background work designing the collection of data from those with diabetes in Scotland that has enabled this research to be performed. JM also reviewed, edited and commented upon a draft of the manuscript. EP contributed to the review and editing of the manuscript. PMM designed and supervised statistical analysis and contributed to manuscript review. All authors approved the final version of the manuscript.GuarantorHelen Colhoun is responsible for the integrity of the work as a whole.References ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1. European Medicines Agency - Forxiga (dapagliflozin). . Accessed 8 Sep 20172. (2014) Summary Review for Regulatory Action - Farxiga (dapagliflozin)3. List JF, Woo V, Morales E, et al (2009) Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 32:650–6574. Wilding JP, Woo V, Soler NG, et al (2012) Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin - a randomized trial. Annals of internal medicine 156:405–4155. 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Fadini GP, Avogaro A (2017) SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System. The Lancet Diabetes & Endocrinology 5:680–681. (17)30257-719. Rosenstock J, Ferrannini E (2015) Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38:1638–1642. . Safety Alerts for Human Medical Products - SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood. In: Office of the Commissioner. . Accessed 28 Oct 201721. Rothwell PM (2005) External validity of randomised controlled trials: “To whom do the results of this trial apply?” Lancet 365:82–93. (04)17670-822. Sherman RE, Anderson SA, Dal Pan GJ, et al (2016) Real-World Evidence — What Is It and What Can It Tell Us? New England Journal of Medicine 375:2293–2297. . Anwar H, Fischbacher C, Leese G, et al (2011) Assessment of the under-reporting of diabetes in hospital admission data: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabet Med 28:1514–1519. . Read SH, Kerssens JJ, McAllister DA, et al (2016) Trends in type 2 diabetes incidence and mortality in Scotland between 2004 and 2013. Diabetologia 59:2106–2113. . Laird NM, Ware JH (1982) Random-effects models for longitudinal data. Biometrics 38:963–97426. Farran B, McGurnaghan S, Looker HC, et al Modelling cumulative exposure for inference about drug effects in observational studies. Pharmacoepidemiol Drug Saf. [epub ahead of print]27. Matthaei S, Bowering K, Rohwedder K, et al (2015) Dapagliflozin Improves Glycemic Control and Reduces Body Weight as Add-on Therapy to Metformin Plus Sulfonylurea: A 24-Week Randomized, Double-Blind Clinical Trial. Diabetes Care 38:365–372. . 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Tang H, Li D, Zhang J, et al (2017) Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab 19:1106–1115. 1: Baseline characteristics of dapagliflozin users and never-users ?All usersNever-usersn individuals8566230,310Age (years)57.72 (9.96)66.13 (12.05)Gender (% female)44.3 (43.2, 45.4)43.5 (43.3, 43.7)Duration of diabetes (years)11.36 (5.81)8.96 (6.80)HbA1c (mmol/mol)77.71 (16.50)58.63 (17.34)HbA1c (%)9.26 (1.51)7.51 (1.59)BMI (kg/m2)34.27 (6.83)31.97 (6.31)Weight (kg)97.76 (21.72)90.84 (19.81)SBP (mmHg)135.40 (15.54)132.98 (15.03)DBP (mmHg)76.44 (9.46)75.06 (9.53)eGFR (ml min-1 1.73m-2)80.39 (16.29)77.99 (21.67)Ever exposed to CVD drugs (%)99.1 (99.0, 99.2)98.2 (98.1, 98.3)Diabetes drug therapy pre-dapagliflozin initiation (%)No therapy5.4 (4.9, 5.9)27.0 (26.8, 27.2)Insulin therapy7.6 (7.1, 8.0)7.1 (7.0, 7.2)Monotherapy32.0 (31.0, 33.0)35.9 (35.7, 36.1)Dual therapy41.0 (39.9, 42.0)22.4 (22.2, 22.6)Triple therapy11.2 (10.6, 11.8)7.7 (7.6, 7.8) ≥ Four-class therapy0.5 (0.4, 0.6)0.5 (0.4, 0.5)Clinical albuminuric status (%)Normoalbuminuria75.2 (74.2, 76.2)78.1 (77.9, 78.3)Microalbuminuria22.3 (21.3, 23.2)18.8 (18.6, 19.0)Macroalbuminuria2.5 (2.2, 2.9)2.8 (2.7, 2.9)Smoking status (%)Current smoker15.5 (14.8, 16.2)18.3 (18.1, 18.5)Ex-smoker54.4 (53.4, 55.5)51.8 (51.6, 52.0)Never smoked29.9 (28.9, 30.9)29.3 (29.1, 29.5)Prior morbidities (%)Heart failure3.5 (3.1, 3.9)4.6 (4.5, 4.6)Hypertension29.4 (28.4, 30.5)30.6 (30.4, 30.8)Myocardial infarction6.7 (6.1, 7.3)7.2 (7.1, 7.3)Stroke2.3 (2.0, 2.7)3.6 (3.5, 3.6)Transient ischaemic attack1.2 (1.0, 1.5)1.5 (1.5, 1.6)No retinopathy75.0 (74.1, 76.0)79.5 (79.3, 79.7)Retinopathy status at last screening (%)Mild retinopathy19.3 (18.4, 20.2)16.6 (16.5, 16.8)Moderate retinopathy1.0 (0.8, 1.2)0.8 (0.7, 0.8)Referable retinopathy4.0 (3.6, 4.4)2.7 (2.7, 2.8)Note: Data shown are age, sex and diabetes duration adjusted mean (standard deviation) for continuous variables and adjusted proportions (95% CI) for categorical variables. Bold denotes characteristics significantly differing between users/never-users within adjusted linear regression/logistic regression/Chi-squared tests as appropriate, after applying Bonferroni correction for multiple testingTable 2: Within-person changes in clinical outcomes through time among all dapagliflozin usersBaseline3 months6 months9 months12 months15 months18 months21 months24 months27 months30 monthsn users85667554546840443082228216011124767491283HbA1cn users with data (% cohort)>8550(>96)3980(52.7)2610(47.7)1680(41.5)1393(45.2)859(37.6)640(40.0)419(37.3)289(37.7)165(33.6)87(30.7)Absolute change a(mmol/mol)--10.41 (14.57)-11.57 (16.28)-11.82 (15.60)-12.99 (15.47)-11.86 (15.43)-11.64 (16.21)-10.01 (15.57)-10.34 (16.39)-9.95 (14.59)-10.74 (17.42)Absolute change a %--0.95 (1.33)-1.06 (1.49)-1.08 (1.43)-1.19 (1.42)-1.09 (1.41)-1.06 (1.48)-0.92 (1.42)-0.95 (1.50)-0.91 (1.34)-0.98 (1.59)BMI (kg/m2)n users with data (% cohort)7787(90.9)1905(25.2)1415(25.9)863(21.3)737(23.9)436(19.1)296(18.5)189(16.8)149(19.4)83(16.9)47(16.6)Absolute change a--0.74 (1.14)-0.87 (1.35)-0.90 (1.29)-0.83 (1.44)-0.93 (1.48)-0.86 (1.35)-0.98 (1.52)-0.86 (1.29)-1.04 (1.44)-0.88 (1.74)Weight (kg)n users with data (% cohort)7189(83.9%)1589(21.0%)1165(21.3%)726(18.0%)600(19.5%)352(15.4%)255(15.9%)163(14.5%)125(16.3%)64(13.0%)35(12.4%)Absolute change a--2.10 (3.11)-2.37 (3.70)-2.53 (3.73)-2.38 (3.55)-2.14 (4.18)-2.62 (3.78)-2.98 (4.44)-2.75 (3.90)-3.33 (4.27)-2.53 (4.74)SBP (mmHg)n users with data (% cohort)8535(99.6)2811(37.2)2297(42.0)1538(38.0)1301(42.2)836(36.6)620(38.7)391(34.8)286(37.3)151(30.8)81(28.6)Absolute change a--4.32 (16.11)-4.18 (15.73)-3.44 (16.54)-2.67 (16.62)-3.29 (16.55)-4.51 (17.64)-5.03 (16.62)-5.69 (17.20)-4.51 (19.97)-6.69 (17.69)DBP (mmHg)n users with data (% cohort)8535(99.6%)2808(37.2)2297(42.0)1537(38.0)1301(42.2)836(36.6)620(38.7)391(34.8)286(37.3)151(30.8)81(28.6)Absolute change a--1.89 (10.12)-1.87 (9.98)-1.50 (10.04)-1.36 (9.97)-1.85 (10.23)-2.67 (11.49)-2.31 (10.40)-3.56 (10.96)-4.14 (12.30)-5.54 (16.48)eGFR (ml min-1 1.73m-2)n users with data (% cohort)8494(99.2%)3305(43.8)2266(41.4)1572(38.9)1319(42.8)825(36.2)596(37.2)406(36.1)288(37.5)164(33.4)87(30.7)Absolute change a--1.32 (9.22)-1.38 (9.53)-1.40 (9.87)-1.48 (9.67)-1.97 (10.24)-1.74 (9.17)-3.49 (10.03)-2.30 (10.68)-2.98 (10.17)-3.14 (10.92)Note: Greater than symbols are used where differences are less than 10 and statistical disclosure control has been applied.a Data shown are mean (SD) of the absolute within-person average from the baseline value.Table 3: Estimated effects of time and dapagliflozin exposure from final covariate-adjusted linear mixed regression models predicting clinical outcomes of interestHbA1c (mmol/mol)HbA1c (%)BMI (kg/m2)Weight (kg)SBP (mmHg)eGFR(ml min-1 1.73m-2)Effect of time on outcome (years)4.41 (4.15, 4.66)0.40 (0.38, 0.43)-0.03 (-0.05, 0)-0.12 (-0.18, -0.06)0.59 (0.36, 0.81)-1.21 (-1.37, -1.06)Change in outcome post-dapagliflozin initiation by time of follow-up0 - 3 months-7.40 (-7.81, -7.00)-0.68 (-0.71, -0.64)-0.45 (-0.49, -0.41)-1.35 (-1.46, -1.24)-4.32 (-4.84, -3.79)-1.81 (-2.10, -1.52)3 - 6 months-11.64 (-12.12, -11.15)-1.06 (-1.11, -1.02)-0.82 (-0.87, -0.77)-2.20 (-2.34, -2.06)-4.27 (-4.87, -3.67)-0.59 (-0.92, -0.26)6 - 9 months-13.35 (-13.95, -12.75)-1.22 (-1.28, -1.17)-0.83 (-0.89, -0.78)-2.25 (-2.42, -2.08)-4.84 (-5.54, -4.13)-0.56 (-0.96, -0.16)9 - 12 months-15.14 (-15.87, -14.41)-1.39 (-1.45, -1.32)-0.85 (-0.92, -0.78)-2.46 (-2.67, -2.25)-3.72 (-4.59, -2.85)-0.06 (-0.52, 0.40)12 - 15 months-16.05 (-16.91, -15.19)-1.47 (-1.55, -1.39)-0.89 (-0.98, -0.81)-2.31 (-2.56, -2.06)-4.78 (-5.78, -3.78)-0.24 (-0.77, 0.30)15 - 18 months-16.61 (-17.64, -15.57)-1.52 (-1.61, -1.43)-0.93 (-1.04, -0.82)-2.25 (-2.57, -1.93)-4.12 (-5.41, -2.83)0.37 (-0.28, 1.02)18 - 21 months-16.87 (-18.15, -15.60)-1.54 (-1.66, -1.43)-0.89 (-1.02, -0.75)-2.54 (-2.93, -2.16)-6.48 (-8.06, -4.90)-0.41 (-1.21, 0.39)21 - 24 months-16.12 (-17.64, -14.60)-1.47 (-1.61, -1.34)-1.01 (-1.17, -0.84)-2.71 (-3.18, -2.23)-5.72 (-7.75, -3.69)-1.19 (-2.12, -0.25)> 24 months -17.20 (-18.85, -15.55)-1.57 (-1.72, -1.42)-0.94 (-1.10, -0.78)-2.32 (-2.80, -1.84)-5.60 (-7.70, -3.50)-0.65 (-1.63, 0.32)Variation in random intercepts (SD)5.010.460.501.325.884.61Variation in random slopes (SD)5.910.540.641.583.643.17Data shown are adjusted proportions (95% CI) for categorical variablesFigure legendsFigure 1: Estimates of treatment effect through time from final covariate-adjusted mixed linear regression models, for clinical outcomes of interest: A) HbA1c, B) BMI, C) weight, D) SBP, E) eGFR. Footnote for Figure 1: Time post-dapagliflozin initiation is specified as categories at 3-month intervals. As models are adjusted for baseline value and pre-initiation trajectory, points represent estimated mean difference from expected trajectory in the absence of dapagliflozin exposure. Dashed line denotes value under null hypothesis (i.e. zero; no treatment effect). Vertical bars represent 95% confidence interval. Size of points and bars denotes number of observations within the respective time category. ................
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