Newer Diabetes Drugs and Cardiovascular Disease Outcomes ...

This report is intended only for state employees in states participating in the Drug Effectiveness Review Project (DERP). Do not distribute outside your state Medicaid agency and public agency partners.

Newer Diabetes Drugs and Cardiovascular Disease Outcomes: Update

Systematic Review

February 2020

Table of Contents Executive Summary ......................................................................................................................................... 1 Table 1. List of Brand Names and Generics.............................................................................................. 11 Background ..................................................................................................................................................... 12 PICOS ............................................................................................................................................................... 12 Key Questions ................................................................................................................................................ 13 Methods........................................................................................................................................................... 13 Findings ............................................................................................................................................................ 13 Discussion........................................................................................................................................................ 51 References....................................................................................................................................................... 53 Appendix A. Methods ................................................................................................................................... 63 Appendix B. Full Evidence Tables............................................................................................................... 68 Appendix C. Bibliography of Included Studies.......................................................................................107 Appendix D. Bibliography of Excluded Studies......................................................................................113

Executive Summary Background

Traditional therapies for glycemic control in patients with type 2 diabetes (e.g., metformin) are effective in managing blood glucose levels in some patients.1,2 However, since the development of metformin, several classes of newer diabetes drugs have been approved by the U.S. Food and Drug Administration (FDA) as monotherapy and combination therapies, including3: Glucagon-like peptide-1 (GLP-1) agonists Dipeptidyl peptidase-4 (DPP-4) inhibitors Sodium-glucose cotransporter 2 (SGLT-2) inhibitors Historically, antidiabetic therapies had been approved by the FDA based on surrogate laboratory measures (e.g., reductions in body weight, blood glucose, cholesterol) without evidence of additional health outcomes or long-term effects. In 2005, analysis of phase 2 and 3 clinical trial data of the investigational diabetic drug muraglitazar found it was associated with an increased incidence of death, major adverse cardiovascular events (MACE), and chronic heart failure.4 In 2007, a meta-analysis of cardiovascular (CV) morbidity and mortality outcomes associated with the type 2 diabetes drug rosiglitazone, reported a significant association between treatment and increased risk of myocardial infarction (MI) and CV death.5 These results raised concern as an estimated 32.2% of individuals with type 2 diabetes around the world are affected by cardiovascular disease (CVD), the main cause of death for individuals with type 2 diabetes.6 This prompted the FDA to release a 2008 guidance requiring that new antidiabetic therapies for type 2 diabetes not be associated with an unacceptable increase (i.e., more than 30%) in CV event risk.7 State Medicaid administrators are interested in a targeted update of the 2017 Drug Effectiveness Review Project (DERP) systematic review on newer diabetes drugs8 focused specifically on the drugs' ability to prevent mortality and CVD outcomes associated with these interventions.

1

PICOS and Key Questions Population Adults with type 2 diabetes

Interventions

Table 1. Eligible Interventions for this Report

Class

Generic Names

Brand Names

Oral Drugs

SGLT-2 inhibitors

Ertugliflozin Empagliflozin Dapagliflozin Canagliflozin

DPP-4 inhibitors

Alogliptin Linagliptin Saxagliptin Sitagliptin

Fixed-Dose Combination Products of Oral Drugs

SGLT-2 inhibitor with DPP-4 Dapagliflozin-saxagliptin

inhibitor

Empagliflozin-linagliptin

SGLT-2 inhibitor with metformin

Ertugliflozin-metformin Empagliflozin-metformin ER Canagliflozin-metformin ER Empagliflozin-metformin Dapagliflozin-metformin ER Canagliflozin-metformin

DPP-4 inhibitor with TZD DPP-4 inhibitor with metformin

Alogliptin-pioglitazone

Linagliptin-metformin ER Alogliptin-metformin Sitagliptin-metformin ER Linagliptin-metformin Saxagliptin-metformin ER Sitagliptin-metformin

Subcutaneous Injection Drugs GLP-1 agonists

GLP-1 agonist with longacting insulin

Oral semaglutide Semaglutide Lixisenatide Dulaglutide Albiglutide Exenatide ER Liraglutide Exenatide Liraglutide-insulin degludec U100/3.6 mg Lixisenatide-insulin glargine U100/33 mg

Steglatro Jardiance Farxiga Invokana

Nesina Tradjenta Onglyza Januvia

Qtern Glyxambi Segluromet Synjardy XR Invokamet XR Synjardy Xigduo XR Invokamet

Oseni Jentadueto XR Kazano Janumet XR Jentadueto Kombiglyze XR Janumet

Rybelsus Ozempic Adlyxin Trulicity Tanzeum Bydureon Victoza Byetta Xultophy Soliqua

FDA Approval Date

12/19/17 8/1/14 1/8/14

3/29/13 1/25/13

5/2/11 7/31/09 10/16/06

2/27/17 1/30/15 12/19/17 12/9/16 9/20/16 8/26/15 10/29/14

8/8/14 1/25/13 5/27/16 1/25/13

2/2/12 1/30/12 11/5/10 3/30/07

9/20/19 12/5/17 7/27/16 9/18/14 4/15/14 1/27/12 1/25/10 4/28/05 11/21/16 11/21/16

Abbreviations. DPP-4: dipeptidyl peptidase 4; ER: extended release; FDA: U.S. Food and Drug Administration; GLP-1: glucagon-like peptide 1; SGLT-2: sodium-glucose cotransporter-2; TZD: thiazolidinediones; XR: extended release.

2

Comparators Another listed intervention (head-to-head comparisons) Combination therapies versus monotherapy of included intervention types Placebo

Outcomes Mortality (all-cause and cardiovascular-related) CVD outcomes (fatal or nonfatal myocardial infarction, fatal or nonfatal stroke,

hospitalization for heart failure [hHF]) Serious adverse events (e.g., serious adverse events [SAEs], withdrawals due to adverse

events [AEs], condition-specific AEs)

Study Design Randomized controlled trials (RCTs) Large prospective and retrospective cohort studies

o Sample size of 10,000 participants

Key Questions 1. What is the effectiveness of newer diabetes medications for cardiovascular events, including

mortality, in adults with type 2 diabetes? a. Does the effect differ when used as monotherapy versus combination therapy? b. Does the effect differ in patients with and without prior CVD? c. Is there evidence of a class effect? d. What are the harms associated with treatment?

2. What are the characteristics of ongoing studies for newer diabetes medications and CVD outcomes?

Methods We describe our complete methods in Appendix A. Briefly, we searched Ovid MEDLINE, Cochrane Library, , and several other websites to identify new eligible studies of newer diabetes drugs for CVD outcomes, from January 1, 2017 to October 2, 2019. Additional eligibility criteria included publication in English and a human study population. We rated the methodological quality of eligible RCTs and large cohort studies using standard instruments adapted from national and international quality standards.9-11 We rated the quality of the body of evidence for 5 outcomes (i.e., all-cause mortality, fatal or nonfatal stroke, fatal or nonfatal MI, hHF, and SAEs) when possible, using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.12,13 Imprecision was not assessed formally (i.e., by meta-analysis) in this report. We extracted data for outcomes of interest from eligible studies. If relevant statistical tests were not reported, we used OpenEpi (version 3.01) to calculate risk ratios, incidence rate ratios, and accompanying 95% confidence intervals (CI) based on data provided in the studies. We used OpenEpi (version 3.01) to test outcomes using a two-tailed Mantel-Haenzel chi-square test with mid-exact P-values based on data provided in the studies. We indicate calculated values with italics.

Key Findings We identified 16 eligible RCTs (in 50 publications) assessing CV outcomes in adults with type 2 diabetes. We identified 10 new RCTs in this updated review with 6 publications from the original systematic review:

3

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download