Introduction & Objective: CagriSema (CS), a combination of the long-acting analogues of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide), is in clinical development for treatment of obesity and type 2 diabetes. Rodent studies have shown that CS treatment results in weight loss. It is unknown whether CS also leads to improvement of insulin sensitivity in diet-induced obese (DIO) rats which was the objective of this study.
Methods: DIO male rats were allocated into three groups (n=6) matched on body weight (BW), fat mass and fat-free mass: vehicle control (VC), CS, and a vehicle group that was weight matched (VWM) to CS by calorie restriction. BW and food intake (FI) were measured at baseline and during treatment. Food availability in VWM was adjusted daily. CS rats received 2 nmol/kg, sc, qd of each drug. After 21 days of treatment rats were instrumented (isoflurane) with carotid (sampling) and jugular (infusions) catheters. After 9-11 days recovery rats were subjected to a 180 min hyper-insulinemic (15 pmol/kg/min) euglycemic (~5.7 mM) clamp. 3H-glucose and 14C-2-deoxy-glucose (2DG) were employed to measure hepatic glucose production (HGP), glucose uptake (GU), and tissue 2DG uptake.
Results: FI initially decreased to 10% of baseline and BW reduced by 10% in CS and VWM rats. FI progressively returned to VC at the end of treatment without increase in BW. No change in fasting plasma glucose was observed, but insulin decreased by 40% (p<0.03) in CS compared to VC. Clamp glucose infusion rates increased by 4.2- and 2.6-fold over VC in CS (p<0.001) and VWM (ns), respectively. No significant differences in HGP but GU increased by 3.3- (p=0.002) and 1.6-fold (ns) over VC in CS and VWM, respectively. 2DG uptake increased in muscle but not in fat tissues in CS compared to VC.
Conclusion: CS increased insulin sensitivity in DIO rats by improving glucose uptake in muscle but not in fat tissues. An ongoing, higher-powered study will investigate the effects of CS and the two mono-components on insulin sensitivity in DIO rats.
A. Secher: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. C.L. Brand: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S. K. Raun: Employee; Novo Nordisk A/S. Stock/Shareholder; Novo Nordisk A/S.
