Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4)

Abstract

OBJECTIVETo test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes.RESEARCH DESIGN AND METHODSPatients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily.RESULTSBaseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 (P = 0.620), −1.63 (P = 0.328), and −1.15 (P < 0.001), respectively. Weight changes (kg) were −2.0 vs. −2.0 (P = 0.892), +1.5 (P < 0.001), and −0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred.CONCLUSIONSEQW was noninferior to MET but not PIO and superior to SITA with regard to HbA1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.

Incretin-based therapies: can we achieve glycemic control and cardioprotection?

“…Nevertheless, small clinical studies in non-diabetic (Mistry et al 2008) and diabetic (Ogawa et al 2011) hypertensive patients treated with sitagliptin identified an association with reduction of BP in the absence of weight loss. Similar results were also observed in larger studies in T2DM patients (Bergenstal et al 2010, Russell-Jones et al 2012. Notably, these effects on BP occur in the absence of significant weight loss.…”

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

“…Exenatide once weekly reduces HbA 1c , FPG and postprandial glucose when used as monotherapy or add-on treatment 218,239,241,258 . Exenatide once weekly monotherapy has been noninferior to metformin, superior to sitagliptin and similar to pioglitazone with regard to HbA 1c reduction in RCTs at 26 weeks 239,258 .…”

Incretin-based therapies for obesity treatment

“…In addition to the glucose effects, GLP-1 receptor agonists lead to a significant loss of body weight in patients with type 2 diabetes mellitus and in obese people without diabetes [35][36][37][38][39][40][41][42][43]. Therefore, the use of GLP-1 receptor agonists, which are resistant to rapid enzymatic action, may be an interesting proposal for obesity treatment [44].…”

“…Mean change in bodyweight was −2.6 kg for patients treated with exenatide and 1.4 kg for those taking insulin glargine (p < 0.0001). DURATION-4 Russell-Jones et al[40] Body weight changes were −2 kg with exenatide, −2 kg with metformin (p = 0.892 vs. EQW), 1.5 kg with pioglitazone (p < 0.001 vs. exenatide) and −0.8 kg with sitagliptin (p < 0.001 vs. exenatide). to 10 μg exenatide BID Similar reductions in body weight were observed in both groups (−2.3 kg with exenatide LAR and −1.4 kg with exenatide BID).Both agents promoted weight loss, but patients taking liraglutide lost more weight (−3.57 kg with liraglutide vs. −2.68 kg with exenatide, p = 0.0005).…”