Compelling evidence for SGLT2 inhibitors and GLP-1 receptor agonists as first-line therapy in patients with diabetes at very high/high cardiovascular risk

This commentary refers to ‘Comments on the 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases’, by A. Jorsal et al., on page 328.

The authors thank Jorsal et al. for their comments concerning the 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases.^{1  ,  2} The guidelines recommend the use of SGLT2 inhibitors and GLP-1 RAs with proven cardiovascular benefit as first-line therapy for cardiovascular disease (CVD) reduction in patients with T2DM at very high/high risk based on multiple randomized controlled trials published over the last 4 years. As correctly stated by Jorsal et al., the majority of patients (around 70–80%) in these cardiovascular outcome trials (CVOTs) received metformin before and concurrently with the newer drug under test. The evidence for CV benefit from metformin stems from a small subgroup of overweight, newly diagnosed, drug-naïve T2DM without CVD in the United Kingdom Prospective Diabetes Study (UKPDS), in which metformin showed a 39% relative risk reduction for myocardial infarction compared to conventional therapy.³ Given that (i) the populations examined in the CVOTs cited above were different from the population in UKPDS, (ii) the fact metformin was similarly present in the active and placebo groups in these trial, and (iii) results from subgroup analyses from some of these trials (e.g. EMPA-REG OUCOME,⁴ Harmony Outcomes⁵), which did not show a significant difference for the beneficial effect of the respective drug between patients with or without metformin, it is unlikely that metformin treatment explains the beneficial effects of the newer drugs under test. However, we have recommended that metformin remains first-line therapy in patients at moderate CV risk and should be initiated in the higher risk group as second-line therapy if HbA1c values are not a target.

In addition, Jorsal et al. refer to a recent meta-analysis suggesting that SGLT2i and GLP-1 RAs reduce the 3P-MACE endpoint only in patients with known atherosclerotic CVD (ASCVD).⁶ This meta-analysis was performed on subgroups of the different CVOTs. However, meta-analyses based on subgroups from various trials are hypothesis-generating but not guideline relevant. None of the trials showed a significant difference for the subgroups of patients with or without ASCVD with respect to the reduction of CV events. Only in the LEADER trial, the P-value for interaction for the benefit of liraglutide vs. placebo was 0.04 between the group of patients ≥50 years of age and ASCVD and those ≥60 years and risk factors for CVD. However, this analysis is not corrected for multiple testing and is considered hypothesis-generating. The current guideline recommendations are based on the whole study population in the respective CVOTs and do not refer to certain subgroups. On the basis of what is becoming overwhelming evidence for beneficial effects of the novel agents on cardiovascular and renal outcomes in T2DM the task force committee felt compelled to recommend the use of these agents as first-line therapy in very high/high-risk patients. We would emphasize, that this judgement does not preclude the addition of metformin in such patients as early second-line therapy in the presence of poor glycaemic control, bearing in mind the critical importance of glycaemic control in the prevention of microvascular complications.

Conflict of interest: N.M. has received advisory board and speaker fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daichii Sankyo, Lilly, MSD, Novo Nordisk, OrionPharma, Sanofi-Aventis, Synexus. P.G. has received advisory board and speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Synexus, Takeda. F.C. has received advisory board and speaker fees from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, Mundipharma, Novo Nordisk, Pfizer.

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