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

• Published in: Diabetes, obesity & metabolism Vol. 22; no. 1; pp. 99 - 106
• Main Authors: Ferrannini, Ele, Baldi, Simona, Frías, Juan P., Guja, Cristian, Hardy, Elise, Repetto, Enrico, Jabbour, Serge A., DeFronzo, Ralph A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-01-2020; Wiley Subscription Services, Inc
• Subjects: Antidiabetics; Benzhydryl Compounds - administration & dosage; Benzhydryl Compounds - therapeutic use; Blood Glucose; Body weight; combination therapy; Creatinine; dapagliflozin; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetic ketoacidosis; Drug Therapy, Combination; exenatide; Exenatide - administration & dosage; Exenatide - therapeutic use; Fasting; Fatty acids; Glucagon; glucagon‐like peptide‐1 agonist; Glucosides - administration & dosage; Glucosides - therapeutic use; glycaemic control; Glycerol; Hematocrit; Humans; Hypoglycemic Agents - therapeutic use; Insulin; Ketoacidosis; Metabolites; Metformin; sodium‐glucose co‐transporter‐2 inhibitor; Urine; glucagon-like peptide-1 agonist; combination therapy; glycaemic control; dapagliflozin; sodium-glucose co-transporter-2 inhibitor; exenatide
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.13870

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.