Clinician Article

SGLT2 inhibitors and GLP1 agonists administered without metformin compared to other glucose-lowering drugs in patients with type 2 diabetes mellitus to prevent cardiovascular events: A systematic review.

  • Escobar C
  • Barrios V
  • Cosin J
  • Gamez Martinez JM
  • Huelmos Rodrigo AI
  • Ortiz Cortes C, et al.
Diabet Med. 2021 Mar;38(3):e14502. doi: 10.1111/dme.14502. Epub 2021 Jan 4. (Review)
PMID: 33368612
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  • Family Medicine (FM)/General Practice (GP)
    Relevance - 6/7
    Newsworthiness - 7/7
  • General Internal Medicine-Primary Care(US)
    Relevance - 6/7
    Newsworthiness - 7/7
  • Endocrine
    Relevance - 6/7
    Newsworthiness - 5/7
  • Internal Medicine
    Relevance - 6/7
    Newsworthiness - 5/7


OBJECTIVES: To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors, administered without metformin on cardiovascular outcomes in type 2 diabetes patients.

METHODS: A systematic review was performed according to Cochrane's methodological standards. We included randomized clinical trials (RCTs) on adult type 2 diabetes patients, assessing the efficacy of SGLT2 inhibitors and GLP1-RAs compared to other glucose-lowering drugs and/or RCTs that presented data of a subgroup of type 2 diabetes patients without metformin use at baseline. The main outcome was the reduction of the risk of any major adverse cardiovascular events (MACE) reported individually or as a composite outcome.

RESULTS: Five RCTs including 50,725 type 2 diabetes patients, of whom 10,013 had not received metformin, were included in this meta-analysis. Three of these studies assessed the efficacy of GLP1-RAs and two of SGLT2 inhibitors. In patients without metformin at baseline, GLP1-RAs in comparison with placebo reduced the risk of MACE significantly by 20% (HR: 0.80; 95% CI: 0.71-0.89). SGLT2 inhibitors also significantly reduced the risk of MACE by 32% (HR: 0.68; 95% CI: 0.57-0.81).

CONCLUSIONS: SGLT2 inhibitors and GLP1-RAs provided without metformin at baseline may reduce the risk of MACE in comparison with placebo in type 2 diabetes patients at increased risk of cardiovascular events.

Clinical Comments


This is an interesting challenge to metformin's preeminence as the No.1 drug for type 2 diabetes. However, as the authors acknowledge, the data is too fragmentary at present.


This is important and provocative; the recommendations for the treatment of type II diabetes and the prevention of its cardiovascular consequences are challenged by SGLT2 inhibitors and GLP-1 receptor agonists. This meta-analysis based on data collected in >50,000 patients supports the promising expectations of the novel glucose-lowering therapies.

Internal Medicine

This study provides compelling evidence for the clinical benefit of SGLT-2 inhibitors and GLP-1 agonist in select population of patients with DM2T who are not receiving concomitant metformin therapy, a preferred initial pharmacological agent for DM2T in accordance with current ADA statement.

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