Hormone-substrate changes with exenatide plus dapagliflozin versus each drug alone: The randomized, active-controlled DURATION-8 study.

Abstract

AIM:

To determine the effects of individual and combined therapies on plasma insulin, glucagon, β-hydroxybutyrate (β-OH) and associated metabolites.

MATERIALS AND METHODS:

In DURATION-8, the combination of once-weekly exenatide (EQW) + 10 mg dapagliflozin (Dapa) in patients with type 2 diabetes poorly controlled with metformin-reduced HbA1c levels and body weight (at weeks 28 and 52) was compared with EQW + placebo (Plb) or Dapa + Plb. The study included 678 patients randomized 1:1:1 to EQW + Dapa, EQW + Plb, or Dapa + Plb. Plasma insulin and glucagon were measured at fasting and 2 hours after a mixed meal. Fasting plasma free fatty acids (FFA) and β-OH concentrations were measured.

RESULTS:

The fasting insulin-to-glucagon molar ratio (I/Glg) increased with EQW + Plb only; postprandial I/Glg increased in all groups but significantly more with EQW + Plb. β-OH, FFA, and glycerol concentrations showed a parallel response: larger increments with Dapa + Plb, larger decrements with EQW + Plb, and intermediate changes with EQW + Dapa. β-OH levels and I/Glg were inversely related to one another. Patients in the top quartile of β-OH changes from baseline [median (interquartile range): +207 (305) vs. -65 (-154) μmol/L; P < .0001] were more frequently treated with Dapa + Plb, had higher urine glucose-to-creatinine ratios, and lower fasting insulin [52 (51) vs. 68 (53) pmol/L; P = .0013) and I/Glg [1.76 (1.49) vs. 2.23 (1.70) mol/mol; P = .0020]. Haematocrit increased only in the Dapa group.

CONCLUSIONS:

The EQW + Dapa combination abolished the Dapa-induced rise in β-OH, reduced the EQW-induced increase in I/Glg, maintained glycosuria, and increased haematocrit in patients with poorly controlled type 2 diabetes. The drug combination may preserve any putative benefits while mitigating the risk of ketoacidosis.

• Authors: Ele Ferrannini, Simona Baldi, Juan P Frías, Cristian Guja, Elise Hardy, Enrico Repetto, Serge A Jabbour, Ralph A DeFronzo
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 22 Issue 1 Pg. 99-106 (01 2020) ISSN: 1463-1326 [Electronic] England
• PMID: 31469220 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons Ltd.

Chemical References

• Benzhydryl Compounds
• Blood Glucose
• Glucosides
• Hypoglycemic Agents
• dapagliflozin
• Exenatide

Topics

• Benzhydryl Compounds (administration & dosage, therapeutic use)
• Blood Glucose
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Therapy, Combination
• Exenatide (administration & dosage, therapeutic use)
• Glucosides (administration & dosage, therapeutic use)
• Humans
• Hypoglycemic Agents (therapeutic use)