Zhu J, Yu X, Zheng Y, et al. Association of glucose-lowering medications with cardiovascular outcomes: an umbrella review and evidence map. Lancet Diabetes Endocrinol. 2020 Mar;8(3):192-205. doi: 10.1016/S2213-8587(19)30422-X. Epub 2020 Jan 29. (Systematic review)

BACKGROUND: Considering the global burden of diabetes and associated cardiovascular disease, an urgent need exists for the best treatment, which should be based on the best available evidence. We examined the association between glucose-lowering medications and a broad range of cardiovascular outcomes, and assessed the strength of evidence for these associations.

METHODS: For this umbrella review we searched PubMed, Embase, and the Cochrane Library to identify systematic reviews and meta-analyses of randomised controlled trials examining the cardiovascular safety of glucose-lowering medications. Cardiovascular outcomes examined included major adverse cardiovascular events, cardiovascular death, myocardial infarction, stroke, heart failure, unstable angina, and atrial fibrillation. For each meta-analysis, we estimated the relative risk (RR) and 95% CI. We also created an evidence map showing the plausible benefits or harms of each intervention and the certainty of the evidence.

FINDINGS: We examined 232 meta-analyses evaluating ten classes of diabetes drugs. We identified six risk and 38 protective associations showing a high strength of evidence. Six associations increased the risk of cardiovascular disease, including glimepiride (stroke [RR 2·01; 95% CI 1·02-3·98]), rosiglitazone (myocardial infarction [1·28; 1·02-1·62] and heart failure [1·72, 1·31-2·27]), and pioglitazone (heart failure [1·40; 1·16-1·69]). 38 associations decreased the risk of cardiovascular disease, including glucagon-like peptide-1 receptor agonists as a class (major adverse cardiovascular events [RR 0·88; 95% CI 0·84-0·92], death from cardiovascular disease [0·87; 0·81-0·94], myocardial infarction [0·92; 0·86-0·99], stroke [0·84; 0·77-0·93], and heart failure [0·90; 0·83-0·99]), albiglutide (major adverse cardiovascular events [0·81; 0·68-0·96], myocardial infarction [0·77; 0·64-0·92], and heart failure [0·71; 0·55-0·93]), dulaglutide (stroke [0·78; 0·64-0·96]), exenatide (major adverse cardiovascular events [0·91; 0·83-1·00]), liraglutide (major adverse cardiovascular events [0·86; 0·77-0·96]), semaglutide (major adverse cardiovascular events [0·76; 0·62-0·92] and stroke [0·67; 0·45-1·00]), sodium-glucose co-transporter-2 inhibitors as a class (major adverse cardiovascular events [0·87; 0·82-0·93], death from cardiovascular disease [0·82; 0·75-0·90], myocardial infarction [0·86; 0·78-0·94], and heart failure [0·68; 0·63-0·73]), canagliflozin (major adverse cardiovascular events [0·84; 0·75-0·93], death from cardiovascular disease [0·82; 0·71-0·96], and heart failure [0·65; 0·54-0·78]), dapagliflozin (heart failure [0·70; 0·60-0·82]), empagliflozin (major adverse cardiovascular events [0·85; 0·77-0·94], death from cardiovascular disease [0·62; 0·50-0·78], and heart failure [0·64; 0·53-0·77]), and pioglitazone (major adverse cardiovascular events [0·84; 0·74-0·96], myocardial infarction [0·80; 0·67-0·95], and stroke [0·79; 0·65-0·95]).

INTERPRETATION: We found varied levels of evidence for the associations between diabetes drugs and cardiovascular outcomes; some drugs raised the risk of cardiovascular disease, whereas others showed benefit.


Discipline Area Score
Internal Medicine 7 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Cardiology 6 / 7
Endocrine 5 / 7
Comments from MORE raters

Endocrine rater

Although this is based on published data, this provides the first well-conducted and comprehensive summary of CV outcome trials for anti-hyperglycemic agents. This is very helpful for clinicians (and guideline writers like me!) to help direct management.

Endocrine rater

Endocrinologists will know the general conclusions of this umbrella review. The detailed comparisons will not have much of an effect on their clinical decisions, in my opinion.

General Internal Medicine-Primary Care(US) rater

This long complex meta-analysis looked at all ten diabetic treatment drugs and concluded that metformin DPP4, GLP1, and STGL2 all decreased cardiovascular risk modestly and to about the same degree, but the other drug classes like insulin and sulfonylureas were neutral in their effect on vascular disease.

Internal Medicine rater

CVD and diabetes medicines is a hot topic and there are so many publications on it, but it is difficult to read all of them. This manuscript is an excellent summary of all evidence in that area.
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