Treatment With the Human Once-Weekly Glucagon-Like Peptide-1 Analog Taspoglutide in Combination With Metformin Improves Glycemic Control and Lowers Body Weight in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Alone: A double-blind placebo-controlled study

OBJECTIVE

To evaluate the efficacy and safety of taspoglutide (R1583/BIM51077), a human once-weekly glucagon-like peptide-1 analog, in patients with type 2 diabetes inadequately controlled with metformin.

RESEARCH DESIGN AND METHODS

Type 2 diabetic (n = 306) patients who failed to obtain glycemic control (A1C 7–9.5%) despite 1,500 mg metformin daily were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Glycemic control was assessed by change in A1C (percent) from baseline.

RESULTS

Significantly greater (P < 0.0001) reductions in A1C from a mean ± SD baseline of 7.9 ± 0.7% were observed in all taspoglutide groups compared with placebo after 8 weeks of treatment: –1.0 ± 0.1% (5 mg once weekly), –1.2 ± 0.1% (10 mg once weekly), –1.2 ± 0.1% (20 mg once weekly), –0.9 ± 0.1% (10 mg Q2W), and –1.0 ± 0.1% (20 mg Q2W) vs. –0.2 ± 0.1% with placebo. After 8 weeks, body weight loss was significantly greater in the 10 mg (–2.1 ± 0.3 kg, P = 0.0035 vs. placebo) and 20 mg (–2.8 ± 0.3 kg, P < 0.0001) once-weekly groups and the 20 mg once every 2 weeks (–1.9 ± 0.3 kg, P = 0.0083) group than with placebo (–0.8 ± 0.3 kg). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea; the incidence of hypoglycemia was very low.

CONCLUSIONS

Taspoglutide used in combination with metformin significantly improves fasting and postprandial glucose control and induces weight loss, with a favorable tolerability profile.Approximately 50% of patients with type 2 diabetes fail to achieve the American Diabetes Association–recommended target A1C level of 7% (1), indicating the need for additional treatment options. A new class of antidiabetic agents is the glucagon-like peptide-1 (GLP-1) receptor agonists, which act through multiple mechanisms (2), similar to the incretin hormone GLP-1 (3–6). Taspoglutide (R1583/BIM51077) is a human GLP-1 analog with a pharmacokinetic profile suitable for weekly subcutaneous administration, through two amino acid substitutions in positions 8 and 35 with aminoisobutyric acid and a sustained release formulation. Taspoglutide has 93% homology with endogenous GLP-1 and comparable in vitro potency. Taspoglutide is resistant to degradation by dipeptidyl peptidase-4 and other proteases, resulting in a 12-fold increase in stability over the native GLP-1 when incubated in rat serum (7). Taspoglutide has been shown to enhance the rate of glucose-induced insulin secretion from isolated, cultured rat islets and the perfused ZDF rat pancreas (7,8). Furthermore, in vivo studies with taspoglutide in Sprague-Dawley rats and diabetic db/db mice have shown a dose-related enhancement of glucose-dependent insulin release, which lowered blood glucose in the db/db mouse model of type 2 diabetes (9). Thus, the biological activity of taspoglutide is similar to that of native GLP-1, with the added benefit of a prolonged action profile.The sustained release formulation of taspoglutide showed a release profile up to 26 days in dogs, making it an attractive candidate for human investigation (10). Of note, in patients with type 2 diabetes not well controlled with metformin, a single 30-mg dose of the same 10% formulation of taspoglutide improved fasting and postprandial glucose for up to 14 days in nearly all subjects treated (11). The aim of the current study was to evaluate the efficacy, safety, and tolerability of a range of doses of taspoglutide, given either once weekly or once every 2 weeks, in patients with type 2 diabetes inadequately controlled with metformin alone.