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Diabetes Distilled: Does metformin co-treatment impact SGLT2 inhibitor benefits?

Pam Brown
This meta-analysis of studies of people with long-standing type 2 diabetes demonstrates that concomitant metformin treatment does not appear to influence the benefits of sodium–glucose cotransporter 2 (SGLT2) inhibitors in terms of major adverse cardiovascular events, hospitalisation for heart failure, cardiovascular death or renal outcomes. Treatment with SGLT2 inhibitors demonstrated clear improvements in cardiovascular, kidney and mortality outcomes in both those treated with metformin and those without. The authors warn that, as with all studies, it is important not to extrapolate the findings to other populations without evidence.

Much has changed in terms of cardioprotective and renoprotective treatments since the UKPDS (UK Prospective Diabetes Study) first demonstrated reductions in diabetes complications, myocardial infarction and all-cause mortality, both after a decade of intensive glycaemic management and at longer-term follow-up, in people with type 2 diabetes. It is important to ensure that metformin co-treatment does not blunt or dilute the benefits that have been observed more recently with the sodium–glucose cotransporter 2 (SGLT2) inhibitor class.

This meta-analysis of six randomised, placebo-controlled trials (using participant-level data from the CANVAS programme and the CREDENCE trial, and using study-level data from EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS-CV and DAPA-HF) sought to answer this important question. In the studies, there were significant differences in metformin use at baseline, with rates ranging from 21% in the DAPA-HF study (in which around half of participants did not have type 2 diabetes) to 82% in DECLARE-TIMI 58.

In a total of 51 743 participants, with median follow-up times ranging from 2.4 to 4.2 years, the analysis demonstrated that SGLT2 inhibitors reduced the risk of major adverse cardiovascular events with or without concomitant metformin, with no difference observed between the groups. The benefits on reductions in hospitalisation for heart failure (HHF) and cardiovascular death, as well as major kidney outcomes and all-cause mortality, were likewise the same irrespective of metformin use.

It is, however, important to note that the participants generally had a long duration of type 2 diabetes (around 10 years) and were at high risk of cardiovascular and renal events, which is not typical of newly diagnosed people with type 2 diabetes, for whom there have been calls to consider early use of combination therapy. Further research, such as the randomised registry study SMARTEST (NCT03982381), will explore the benefits of metformin and SGLT2 inhibitors in people newly diagnosed with the condition.

As a result of the VERIFY study (Matthews et al, 2019), recommendations are strengthening that early combination therapy with metformin and another glucose-lowering drug provides better glycaemic durability (Buse et al, 2019; Matthews et al, 2020), as well as allowing people to receive the non-glycaemic benefits of SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists earlier in the course of their condition (Seidu et al, 2020). Other guidelines, notably those of the European Society of Cardiology (Cosentino et al, 2019), recommend that people with type 2 diabetes and either cardiovascular disease or high or very high cardiovascular risk should be treated first-line with canagliflozin, dapagliflozin or empagliflozin, or liraglutide, dulaglutide or semaglutide, with metformin use restricted to overweight people with type 2 diabetes who are only at moderate cardiovascular risk. The variation amongst guidelines may contribute to confusion and early clinical inertia.

A recent editorial on the heart failure benefits of SGLT2 inhibitors by Professor Milton Packer flagged that there may be a partial overlap in the mechanisms of action of metformin and SGLT2 inhibitors at a cellular level which might reduce some SGLT2 inhibitor benefits (Packer, 2020a). Professor Packer had previously raised similar concerns in relation to metformin potentially reducing renal benefits of SGLT2 inhibitors (Packer, 2020b). Further studies or analyses of existing data are urgently needed to clarify this.

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Buse JB, Wexler DJ, Tsapas A et al (2019) 2019 Update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 43: 487–93

Cosentino F, Grant PJ, Aboyans V et al; ESC Scientific Document Group (2019) 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 41: 255–323

Matthews DR, Paldánius PM, Proot P et al; VERIFY study group (2019) Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. Lancet 394: 1519–29

Matthews D, Del Prato S, Mohan V et al (2020) Insights from VERIFY: early combination therapy provides better glycaemic durability than a stepwise approach in newly diagnosed type 2 diabetes. Diabetes Ther 11: 2465–76

Packer M (2020a) Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care. Eur Heart J 41: 2393–6

Packer M (2020b) Concerns about the use of metformin as a first-line agent to slow the progression of chronic kidney disease in diabetes. Diabetes Res Clin Pract 160: 108024

Seidu S, Cos X, Brunton S et al (2020) A disease state approach to the pharmacological management of type 2 diabetes in primary care: a position statement by Primary Care Diabetes Europe. Prim Care Diabetes 9 Jun [Epub ahead of print].

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