Redefining treatment success in type 2 diabetes mellitus: Comprehensive targeting of core defects

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A posthoc analysis of an open-label extension study involving patients who completed the original 30-week placebo-controlled studies showed that 46% of patients who remained on exenatide achieved the ADA goal of HbA1c less than 7.0% at 3 years. 41 Exenatide administered for up to 3.5 years was associated with sustained reductions in HbA1c of –1.0% ( P < .0001) and body weight of –5.3 kg ( P < .001). Pancreatic beta-cell function, assessed by homeostasis model assessment, improved, as did BP, triglyceride, high-density lipoprotein, low-density lipoprotein, and aspartate aminotransferase levels. 41

Comparison with insulin analogues. Comparative studies have highlighted the contrasting effects of exenatide and insulin analogues (eg, insulin glargine and fixed-ratio insulin). 42–45 In a 26-week trial comparing exenatide with insulin glargine in subjects with T2DM, both agents resulted in similar decreases in HbA1c. Exenatide was also associated with a –2.3-kg weight reduction, whereas insulin glargine was associated with a +1.8-kg weight gain. 42 Although rates of symptomatic hypoglycemia were similar, there were fewer cases of nocturnal hypoglycemia with exenatide (0.9 event/patient-year vs 2.4 events/patient-year with insulin).

In a 32-week study comparing exenatide BID with titrated insulin glargine QD, the HbA1c reductions for exenatide and insulin glargine were comparable. However, body weight decreased –4.2 kg over two 16-week treatment periods with exenatide, but increased +3.3 kg over the same periods with the basal insulin analogue. 43 The incidence of hypoglycemia was lower with exenatide than with insulin glargine (14.7% vs 25.2%), although the difference was not statistically significant.

In another study that compared exenatide with biphasic insulin aspart, patients who were treated with exenatide also lost weight while those who received the fast-acting insulin analogue gained weight (between-group difference, –5.4 kg). Patients treated with exenatide also demonstrated greater reductions in postprandial plasma glucose (PPG) excursions following their morning ( P < .001), midday ( P = .002), and evening meals ( P < .001). 44 Overall, hypoglycemia rates were similar at study end between exenatide and insulin aspart (4.7 events/patient-year vs 5.6 events/patient-year). In all of these studies, significant gastrointestinal adverse events (nausea and vomiting) occurred more frequently with exenatide, and more patients withdrew from exenatide than from insulin.

Formulations in development. Other advances in GLP-1 receptor agonist therapy include novel formulations under clinical development, such as exenatide once weekly 36,46 and liraglutide, a human analogue GLP-1 receptor agonist formulated for once-daily administration. 47,48 In a 52-week study in patients with T2DM, liraglutide significantly reduced HbA1c; the 1.2-mg SC QD dosage reduced HBA1c by –0.84% ( P = .0014) and the 1.8-mg SC QD dosage by –1.14% ( P < .0001). In comparison, glimepiride 8 mg orally QD achieved a –0.51% reduction. Liraglutide was also associated with greater reductions in weight, hypoglycemia, and systolic BP than glimepiride. 47

A 26-week study compared liraglutide (0.6, 1.2, and 1.8 mg SC QD), placebo, and glimepiride 4 mg QD in combination with metformin 1 g BID. HbA1c was reduced significantly in all liraglutide groups compared with placebo ( P < .0001). Mean HbA1c decreased –1.0% with liraglutide 1.2 mg and 1.8 mg and with glimepiride; it decreased –0.7% with liraglutide 0.6 mg; and it increased +0.1% with placebo. Body weight decreased –1.8 kg to –2.8 kg in all liraglutide groups but increased +1.0 kg in the glimepiride group ( P < .0001). The incidence of minor hypoglycemia with liraglutide (~3%) was comparable to that observed with placebo but less than that with glimepiride (17%; P < .001). 48

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