Clinician Article

Comparative Effectiveness of Glucose-Lowering Drugs for Type 2 Diabetes: A Systematic Review and Network Meta-analysis.

  • Tsapas A
  • Avgerinos I
  • Karagiannis T
  • Malandris K
  • Manolopoulos A
  • Andreadis P, et al.
Ann Intern Med. 2020 Jun 30. doi: 10.7326/M20-0864. (Review)
PMID: 32598218
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  • Internal Medicine
    Relevance - 7/7
    Newsworthiness - 6/7
  • Family Medicine (FM)/General Practice (GP)
    Relevance - 7/7
    Newsworthiness - 5/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 7/7
    Newsworthiness - 5/7
  • Cardiology
    Relevance - 6/7
    Newsworthiness - 6/7
  • Nephrology
    Relevance - 6/7
    Newsworthiness - 6/7
  • Endocrine
    Relevance - 5/7
    Newsworthiness - 3/7


BACKGROUND: Several pharmacologic options for type 2 diabetes are available.

PURPOSE: To compare benefits and harms of glucose-lowering drugs in adults with type 2 diabetes.

DATA SOURCES: Several databases from inception through 18 December 2019 and ClinicalTrials.gov on 10 April 2020.

STUDY SELECTION: English-language randomized trials that had at least 24 weeks of intervention and assessed the effects of glucose-lowering drugs on mortality, glycemic, and vascular outcomes.

DATA EXTRACTION: Pairs of reviewers extracted data and appraised risk of bias.

DATA SYNTHESIS: 453 trials assessing 21 antidiabetic interventions from 9 drug classes were included. Interventions included monotherapies (134 trials), add-on to metformin-based therapies (296 trials), and monotherapies versus add-on to metformin therapies (23 trials). There were no differences between treatments in drug-naive patients at low cardiovascular risk. Insulin regimens and specific glucagon-like peptide-1 receptor agonists (GLP-1 RAs) added to metformin-based background therapy produced the greatest reductions in hemoglobin A1c level. In patients at low cardiovascular risk receiving metformin-based background treatment (298 trials), there were no clinically meaningful differences between treatments for mortality and vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background treatment (21 trials), oral semaglutide, empagliflozin, liraglutide, extended-release exenatide, and dapagliflozin reduced all-cause mortality. Oral semaglutide, empagliflozin, and liraglutide also reduced cardiovascular death. Odds of stroke were lower with subcutaneous semaglutide and dulaglutide. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors reduced heart failure hospitalization and end-stage renal disease. Subcutaneous semaglutide and canagliflozin increased diabetic retinopathy and amputation, respectively.

LIMITATION: Inconsistent definitions of cardiovascular risk and low-level confidence in some estimates for patients at low cardiovascular risk.

CONCLUSION: In diabetic patients at low cardiovascular risk, no treatment differs from placebo for vascular outcomes. In patients at increased cardiovascular risk receiving metformin-based background therapy, specific GLP-1 RAs and SGLT-2 inhibitors have a favorable effect on certain cardiovascular outcomes.

PRIMARY FUNDING SOURCE: European Foundation for the Study of Diabetes, supported by an unrestricted educational grant from AstraZeneca. (PROSPERO: CRD42019122043).

Clinical Comments


Usually I am not too impressed by meta-analyses, but there is a useful lesson with this one.


Despite a few limitations, the study was well conducted and provides very useful information for treating patients with type 2 diabetes mellitus.


This is a very good overview & comprehensive review of a confusing array of studies of anti-diabetic agents in the treatment of type 2 diabetes.


While this is a well done and comprehensive meta-analysis, it generally supports results of individual large-scale RCTs.


This sophisticated analysis summarizes the many studies that show there is little difference in the effects of non-insulin drugs on A1C levels. Also, that GLP-1 agonists and SGLT-2 inhibitors have beneficial effects on CVD in patients at high risk, and SGLT-2 inhibitors have beneficial effects on heart failure and renal disease.

General Internal Medicine-Primary Care(US)

This extensive meta-analysis attempts to shed more light on the relative benefits of the array of antidiabetic agents currently available. Clearly, the GLP-1 agents and SGLT agents bring strong benefits to the options. As always, the aggressiveness of therapy should be matched with the patient’s level of risk factors and disease. There are no clear favorites yet among the classes of agents.

Internal Medicine

I am still worried that on a population-wide basis, important outcomes such as blindness, amputations, etc. have not really improved despite the plethora of new drugs.

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