Abstract
Objectives
The authors of 2 large randomized trials have recently published their findings related
to the effects of a glucagon-like peptide 1 receptor agonist (GLP-1RA) (the HARMONY
trial) and a dipeptidyl peptidase 4 (DPP-4) inhibitor (the CARMELINA trial) on cardiovascular
(CV) outcomes in patients with type 2 diabetes mellitus. In light of these new data,
we conducted a systematic review and meta-analysis of GLP-1RAs and DPP-4 inhibitors
in CV outcome trials to assess their CV safety in patients with type 2 diabetes.
Methods
We conducted a comprehensive literature search in the Embase and MEDLINE databases
to identify trials involving GLP-1RAs and DPP-4 inhibitors with major CV-related outcomes
reported, including major adverse CV events, CV death, myocardial infarction, stroke,
death from any cause and hospitalization because of heart failure. A total of 9 CV
outcome trials were included. Odds ratios and 95% confidence intervals were calculated
based on the Mantel-Haenszel method.
Results
Relative to placebo, GLP-1RAs were associated with a statistically significant reduction
in the odds of major adverse CV events (13%), CV death (12%), death from any cause
(11%) and stroke (13%). DPP-4 inhibitors were comparable to placebo for all outcomes.
Moreover, DPP-4 inhibitors were associated with a nonsignificant 5% increase in the
odds of hospitalization from heart failure compared to placebo.
Conclusions
This meta-analysis demonstrated that GLP-1RAs were associated with a significant reduction
in major adverse CV events, CV death, stroke and death from any cause, while DPP-4
inhibitors were comparable to placebo for all CV outcomes, including hospitalizations
for heart failure.
Résumé
Objectifs
Les auteurs de deux grands essais randomisés ont récemment publié leurs conclusions
concernant les effets d'un agoniste du récepteur au glucagon-like peptide-1 (A-GLP-1R)
(essai HARMONY) et d'un inhibiteur de la dipeptidyl peptidase 4 (DPP-4) (essai CARMELINA)
sur les bénéfices cardiovasculaires (CV) chez les patients atteints de diabète sucré
de type 2. À la lumière de ces nouvelles données, nous avons effectué une revue systématique
et une méta-analyse des A-GLP-1R et des inhibiteurs de la DPP-4 dans des essais sur
les répercussions CV afin d'évaluer leur innocuité CV chez les patients atteints de
diabète de type 2.
Méthodes
Nous avons effectué une recherche documentaire exhaustive dans les bases de données
Embase et MEDLINE afin d'identifier les essais portant sur les A-GLP-1R et les inhibiteurs
de la DPP-4 dont les principaux effets liés au CV ont été rapportés, y compris les
événements CV indésirables majeurs, les décès CV, les infarctus du myocarde, les AVC,
les décès de toutes causes et les hospitalisations pour insuffisance cardiaque. Un
total de 9 essais avec des conséquences CV ont été inclus. Les risques relatifs rapprochés
et les intervalles de confiance à 95 % ont été calculés selon la méthode de Mantel-Haenszel.
Résultats
Par rapport au placebo, les A-GLP-1R ont été associés à une réduction statistiquement
significative des risques d'événements CV indésirables majeurs (13 %), de décès d'origine
CV (12 %), de décès toutes causes confondues (11 %) et d'AVC (13 %), tandis que les
inhibiteurs de la DPP-4 étaient comparables au placebo pour tous les résultats. Par
ailleurs, les inhibiteurs de la DPP-4 ont été associés à une augmentation non significative
de 5 % des risques d'hospitalisation pour insuffisance cardiaque comparativement au
placebo.
Conclusions
Cette méta-analyse a démontré que les A-GLP-1R étaient associés à une réduction significative
des événements CV indésirables majeurs, de la mortalité CV, des accidents vasculaires
cérébraux, des accidents vasculaires cérébraux et des décès de toute cause, tandis
que les inhibiteurs de la DPP-4 étaient comparables au placebo pour tous les effets
CV, notamment les hospitalisations pour insuffisance cardiaque.
Keywords
Mots Clés
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References
- Cardiovascular safety of therapies for type 2 diabetes.Expert Opin Drug Saf. 2017; 16: 13-25
- Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.https://academic.oup.com/endo/article-abstract/136/8/3585/3037253Date accessed: September 29, 2018
- Biological effects and metabolic rates of glucagonlike peptide-1 7–36 amide and glucagonlike peptide-1 7–37 in healthy subjects are indistinguishable.Am Diabetes Assoc. 1993;http://diabetes.diabetesjournals.org/content/42/5/658Date accessed: September 29, 2018
- Cardiovascular disease and risk management: Standards of medical care in diabetes, 2018.Diabetes Care. 2018; 41: S104
- Prevalence of cardiovascular disease in type 2 diabetes: A systematic literature review of scientific evidence from across the world in 2007–2017.Cardiovasc Diabetol. 2018; 17: 83
- Economic burden of cardiovascular disease in type 2 diabetes: A systematic review. Elsevier.https://www.sciencedirect.com/science/article/pii/S1098301517307775Date accessed: September 29, 2018
- Guidance for industry diabetes mellitus: Evaluating cardiovascular risk in new antidiabetes therapies to treat type 2 diabetes.2008
- Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.N Engl J Med. 2013; 369: 1317-1326
- Alogliptin after acute coronary syndrome in patients with type 2 diabetes.N Engl J Med. 2013; 369: 1327-1335
- Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2015; 373: 232-242
- FDA drug safety communication: FDA adds warnings about heart failure risk to labels of type 2 diabetes medicines containing saxagliptin and alogliptin.2016
- Cardiovascular mortality in patients with type 2 diabetes and recent acute coronary syndromes from the EXAMINE trial.Am Diabetes Assoc. 2016;http://care.diabetesjournals.org/content/early/2016/06/10/dc16-0303.abstractDate accessed: September 30, 2018
- Lixisenatide in patients with type 2 diabetes and acute coronary syndrome.N Engl J Med. 2015; 373: 2247-2257
- Liraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2016; 375: 311-322
- Semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med. 2016; 375: 1834-1844
- Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2017; 377: 1228-1239
- Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo. Elsevier.https://www.sciencedirect.com/science/article/pii/S014067361832261XDate accessed: October 6, 2018
- Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk.JAMA. 2019; 321: 69
- Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement.BMJ. 2009; 339: b2535http://www.ncbi.nlm.nih.gov/pubmed/19622551Date accessed: October 20, 2018
- The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.BMJ. 2011; 343: d5928
- Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): A randomised, open-label, multicentre, non-inferiority phase 3 study.Lancet Diabetes Endocrinol. 2014; 2: 289-297
- Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: A meta-analysis.Lancet Diabetes Endocrinol. 2018; 6: 105-113
- Cardiovascular and microvascular outcomes of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A meta-analysis of randomized controlled cardiovascular outcome trials with trial sequential analysis.BMC Pharmacol Toxicol. 2018; 19: 58
- Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: A systematic review and meta-analysis.CMAJ Open. 2017; 5: E152-E177
- Dipeptidyl peptidase-4 inhibitors and heart failure: A meta-analysis of randomized clinical trials.Nutr Metab Cardiovasc Dis. 2014; 24: 689-697
- Risk of heart failure with dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: A meta-analysis of randomized controlled trials.Int J Cardiol. 2016; 212: 203-205
- Cardiovascular safety of dipeptidyl-peptidase IV inhibitors: A meta-analysis of placebo-controlled randomized trials.Am J Cardiovasc Drugs. 2017; 17: 143-155
- Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: Systematic review and meta-analysis of randomised and observational studies.BMJ. 2016; 352: i610
- Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials.Diabetes Metab. 2017; 43: 48-58
- 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes, 2018.Diabetes Care. 2018; 41: S73-S85
- Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.Diabetologia. 2001; 44: S14-S21http://www.ncbi.nlm.nih.gov/pubmed/11587045Date accessed: October 14, 2018
Article info
Publication history
Published online: April 13, 2019
Accepted:
April 3,
2019
Received in revised form:
March 3,
2019
Received:
November 13,
2018
Identification
Copyright
© 2019 Canadian Diabetes Association.
