Effect of once‐weekly semaglutide on the counterregulatory response to hypoglycaemia in people with type 2 diabetes: A randomized, placebo‐controlled, double‐blind, crossover trial

Abstract

AimsTo investigate the effects of semaglutide vs placebo on glucagon and other counterregulatory hormones during hypoglycaemia in type 2 diabetes (T2D).MethodsIn this double‐blind, placebo‐controlled, single‐centre trial, we randomized 38 men and women (treated only with metformin) 1:1 to 2 12‐week crossover periods of once‐weekly subcutaneous semaglutide or placebo, each followed by a hypoglycaemic clamp procedure. The primary endpoint was change in glucagon concentration from target plasma glucose (PG) level 5.5 mmol/L to nadir (target 2.5 mmol/L).ResultsThe mean (range) participant age was 54.2 (41‐64) years, body mass index 29.4 (23.3‐36.1) kg/m2, glycated haemoglobin 60.8 (44.3‐83.6) mmol/mol (7.7 [6.2‐9.8]%), and diabetes duration 4.5 (0.3‐13.2) years. A total of 35 participants completed the trial and were included in the analyses. During the hypoglycaemic clamp from 5.5 mmol/L PG to nadir, the absolute change in mean glucagon concentration was similar for semaglutide vs placebo: 88.3 vs 83.1 pg/mL (estimated difference 5.2 pg/mL [95% confidence interval −7.7 to 18.1]). Concentrations of other counterregulatory hormones increased with both treatments, with a statistically significantly lower increase for noradrenaline and cortisol with semaglutide vs placebo. The glucose infusion rate to maintain constant clamp levels was similar for each treatment group, suggesting an overall similar counterregulatory response. The mean hypoglycaemic symptom score and proportion of participants recognizing hypoglycaemia during the study were lower for semaglutide vs placebo treatment at nadir, but cognitive function test results were similar. No new safety issues were observed for semaglutide.ConclusionsSemaglutide treatment did not compromise the counterregulatory glucagon response during experimental hypoglycaemia in people with T2D.

Safety of Semaglutide

“…However, since GLP-1RA mainly lower blood glucose by stimulating glucose-dependent insulin secretion, hypoglycemia is an infrequent problem. In addition, the inhibition of glucagon release does not occur under hypoglycemic conditions ( 35 ). In SUSTAIN-6, severe or plasma glucose-confirmed (<56 mg/dl [3.1 mol/L]) hypoglycemia occurred in similar rates between patients with semaglutide (23.1% in the 0.5 mg group and 21.7% in the 1 mg group) and placebo (21.2%) ( 28 ).…”

Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery

“…As for exogenous administration of GLP-1 RA, several studies have shown suppression of glucagon secretion vs placebo during normo-and hyperglycemia, particularly in the postprandial state (28,31,32). A glucose dependency of this effect is supported by studies in which no GLP-1 RA-mediated suppression of glucagon could be seen in during hypoglycemic, but in some cases also normoglycemic, clamps (33,34,35,36). However, suppression of glucagon secretion during mild hypoglycemia (glucose 3.2-5.0 mmol/L) that was not evident during more pronounced hypoglycemia (glucose <3.0 mmol/L) have also been reported in some studies (22,37,38).…”

The Effect of Glucagon-like Peptide-1 (GLP-1) on Obesity

“…Semaglutide demonstrated improved glycaemic control and decreased body weight with a safety profile similar to other GLP-1 Receptor Agonists (GLP-1RAs) [63]. Nevertheless, we noted an increased incidence of nausea, vomiting, and diarrhea.…”