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

EVOLUTION OF ANTIDIABETES THERAPIES

Traditional antidiabetes agents used in the treatment of patients with T2DM have focused mainly on insulin secretion and insulin resistance, with treatment success defined as achieving HbA1c goals with a reduced incidence of hypoglycemia.²³ Secretagogues, such as sulfonylureas and glinides, stimulate the pancreas to release insulin. Insulin sensitizers, such as TZDs and metformin, enhance the action of insulin in muscle and fat^1,3,23 and lower hepatic glucose production. The alpha-glucosidase inhibitors alter carbohydrate absorption from the gastrointestinal tract.¹ The extent to which each agent achieves treatment success in terms of glucose lowering depends on several factors, including intrinsic attributes, duration of disease, and baseline glycemic control.³

GLP-1 receptor agonists

Exenatide effects. Although many agents are in development, to date exenatide is the only GLP-1 receptor agonist approved by the US Food and Drug Administration (FDA).^8,33 Exenatide is an exendin-4 GLP-1 receptor agonist with multiple glucoregulatory effects, including enhanced glucose-dependent insulin secretion, reduced glucagon secretion and food intake, and slowed gastric emptying.^22,34 Exenatide is detectable in the circulation for up to 10 hours following subcutaneous (SC) administration²² and has a greater potency in reducing plasma glucose than GLP-1 in preclinical studies.^35,36

By virtue of its beneficial effects on glycemic control, weight, BP, and lipids, exenatide addresses some of the components of the metabolic syndrome.^37–41 In pivotal 30-week studies, exenatide was associated with HbA1c reductions that ranged from –0.40% to –0.86% from baseline and decreases in body weight of approximately –1 kg to –3 kg from baseline, without severe hypoglycemia.^37–39 The percentage of patients who reached the ADA goal of HbA1c less than 7.0% at 30 weeks ranged from 24% to 34%. The addition of exenatide to TZD therapy in a 16-week study was associated with mean reductions in HbA1c of –0.98%, fasting plasma glucose (FPG) concentration of –1.69 mmol/L (–30.42 mg/dL), and body weight of –1.51 kg.⁴⁰

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

A once-weekly long-acting release (LAR) formulation of exenatide submitted to the FDA for approval may provide enhanced glycemic and weight control, potentially improving patient acceptance and adherence.^36,46 In a 15-week study, exenatide once weekly produced significant reductions in HbA1c, FPG, PPG, and body weight. There were no withdrawals due to adverse events, and the formation of anti-exenatide antibodies was not predictive of therapeutic end point response or adverse safety outcome. Instances of hypoglycemia were mild and not dose related.³⁶ In a 30-week study comparing exenatide LAR once weekly with exenatide BID, patients given exenatide LAR once weekly had significantly greater HbA1c reductions than did patients given exenatide BID (–1.9% vs –1.5%; P = .0023). Treatment adherence was 98% with both exenatide regimens, and no episodes of major hypoglycemia occurred with either formulation regardless of background sulfonylurea use. Favorable effects on BP and lipid profile were observed with both exenatide regimens.⁴⁶