Beneficial cardio-metabolic effects of semaglutide in individuals living with overweight/obesity without type 2 diabetes. Additional analysis of the SELECT trial

Previous studies have shown benefits of the Glucagon-like peptide (GLP-1) receptor agonist Semaglutide (Wegovy, Ozempic) to reduce cardiovascular events in overweight/obese people without type 2 diabetes.¹ However, whether these benefits occurred due to further reductions in glucose levels is unclear. Furthermore, the effects of Semaglutide on the risk of progression to Type 2 diabetes is not fully clarified.

Two recent analysis by the Select investigators published in the journal Diabetes Care have provided additional information on these research questions.

The first analysis was led by Dr Ildiko, Professor of Internal Medicine at the University of Texas Southwestern Medical Center in Dallas.² The analysis investigated the effects of Semaglutide on Major Adverse Cardiovascular events (MACE) (cardiovascular mortality, nonfatal myocardial infarction, or stroke; coronary revascularization; or hospitalization for unstable angina), a heart failure composite (heart failure hospitalization or urgent medical visit or cardiovascular mortality), coronary revascularization, and all-cause mortality) by baseline A1c subgroup and categories of A1c change. The analysis showed that similar reduction in MACE was observed irrespective of baseline HbA1c categorized at <5.7%, 5.7%–6.0% and 6%–<6.5%. Importantly also, the beneficial effects of Semaglutide was observed irrespective of whether HbA1c decreased or increased by 0.3% or remained unchanged after intervention.

While these findings would support the use of Semaglutide across a broader spectrum of glycaemia, it would be intriguing to understand whether these benefits are driven by the recognized metabolic benefits (blood pressure, cholesterol, insulin resistance) of weight loss. In addition, since albuminuria is recognized to occur due to obesity per se and has been shown to reverse with weight loss, it would be interesting to understand the impact of semaglutide on urine albumin excretion rate, an important causal and marker of endothelial function and cardiovascular disease risks.

In another analysis, investigators looked at the effect of Semaglutide on the progression of HbA1c level in this same study group over a 156 weeks period.³ They observed, while there was a clear effect of Semaglutide to improve glycaemia, (i.e. a smaller number with pre-diabetes at baseline progressed to diabetes, and a greater proportion regressed to normal HbA1c levels than those taking placebo), semaglutide did not slow glycemic progression over time. At 3 years, 69.5% of study participants taking semaglutide had a normal HbA1c level, compared with 35.8% of those taking placebo (p < .0001). Among those with a normal HbA1c level at baseline, 9 of 1676 participants (0.5%) receiving semaglutide developed type 2 diabetes (compared with 18 of 1690 placebo recipients). For those in the intermediate glycemia group, 0.8% of those taking semaglutide developed type 2 diabetes compared with 3.5% of those taking placebo. In the highest-level glycemic group, 3.5% of those taking semaglutide developed type 2 diabetes compared with 17% of those receiving placebo. After 20 weeks, the HbA1c levels increased similarly in the placebo and semaglutide arms, but those taking semaglutide had smaller increases. The rate of glycemic deterioration was greatest in those who started with the highest HbA1c levels at baseline. Thus, while semaglutide has clear glycaemic benefits even in this group of individuals without overt type 2 diabetes, the risk of progressive decline in beta cell function persists especially in this group of individuals at high risk of developing type 2 diabetes. Holistic approach to weight loss strategy which incorporate balanced dietary intake with regular exercise should remain to be the mainstay of treatment strategy and used in conjunction with appropriate pharmacotherapy.