Advances in therapy for type 2 diabetes: GLP–1 receptor agonists and DPP–4 inhibitors

CLINICAL TRIALS: GLP-1 RECEPTOR AGONISTS AND DPP-4 INHIBITORS

This section summarizes clinical trials of GLP-1 receptor agonists and DPP-4 inhibitors. The summary is based on literature published from 2005 to 2009 relevant to phase 3 or 4 T2DM clinical trials with currently available agents, or agents with pending new drug applications.

Table 1 summarizes the data on the effects of the GLP-1 receptor agonists on glucose lowering based on glycosylated hemoglobin (HbA1c) mean changes from baseline, body weight, and hypoglycemia. Eleven studies were identified for exenatide, including three pivotal trials,^31–33 three insulin-comparator studies,^34–36 one long-term study,³⁷ one monotherapy study (a use for which it is not currently indicated),³⁸ one head-to-head study with a DPP-4 inhibitor,³⁹ and two studies with exenatide once weekly (which is currently investigational).^21,22 Five primary efficacy studies with liraglutide were also identified.^{23,25,26,40,41}

Table 2 summarizes the corresponding data for the DPP-4 inhibitors. Ten studies with sitagliptin were identified, including four monotherapy studies,^42–45 one head-to-head study with a GLP-1 receptor agonist,³⁹ and five studies in which sitagliptin was used in combination or as add-on therapy.^46–50 Five saxagliptin studies are reviewed, including two in which saxagliptin was used in combination with metformin and one in combination with glyburide.^51–55 Six studies with vildagliptin were reviewed,^56–61 but no trials specific to the single-tablet formulation of sitagliptin plus metformin were identified.

Effects on HbA1c and weight

GLP-1 receptor agonists reduced HbA1c. Based on the studies reviewed in Table 1, exenatide BID reduced baseline HbA1c by a maximum of –1.5% at 30 weeks.^21,31,32 Exenatide has demonstrated sustained reductions in HbA1c of –0.8% for up to 3.5 years in an open-label extension trial.³⁷ Even greater reductions in HbA1c (–1.4% at 15 weeks and –1.9% at 30 weeks) have been reported with the once-weekly formulation under clinical development.^21,22 Liraglutide, another GLP-1 receptor agonist under development, has reported HbA1c reductions from baseline up to –1.67% at 14 weeks,^40,41 up to –1.1% at 26 weeks,^23,26 and up to –1.14% at 52 weeks.²⁵ The reductions quoted generally refer to means, and individual patients may have greater or lesser responses. Also, baseline HbA1c is a significant determinant of the potential HbA1c reduction. Higher baseline values drop more significantly than do baseline values that are closer to normal.

Weight reduction with GLP-1 receptor agonists. In addition to effective glucose lowering, the GLP-1 receptor agonists, particularly exendin-4 agonists, produced beneficial effects on weight (Table 1). Exenatide BID elicited mean weight reductions up to –3.6 kg at 30 weeks^21,31,32 and –5.3 kg at 3.5 years.³⁷ Exenatide once weekly resulted in mean weight reductions of up to –3.8 kg at 15 weeks²² and –3.7 kg at 30 weeks.²¹ Effects on weight with liraglutide varied from a mean reduction of up to –2.99 kg to a slight gain of up to +0.13 kg at 14 weeks^40,41 and with weight loss of up to –2.8 kg at 26 weeks^23,26 and up to –2.5 kg at 52 weeks.²⁵ In this review, only exenatide has been assessed in insulin-comparator studies, where it was shown to reduce weight compared with the insulin analogues, which led to weight gain.^34–36

Hypoglycemia. Patients receiving exenatide experienced lower rates of hypoglycemia (up to 17%) than patients treated with either insulin glargine or insulin aspart (~25%).^34,36 The rate of hypoglycemia with exenatide is comparable to that seen with metformin (up to 21%) in a systematic review of oral antidiabetes agents conducted by the Agency for Healthcare Research and Quality.⁶² No major hypoglycemic events were reported in the liraglutide studies reviewed. The incidence of hypoglycemia reported with DPP-4 inhibitors (Table 2) is also low (2% or less in most studies). The glucose-dependent mechanisms of the incretin-based therapies minimizes the risk of hypoglycemia.

DPP-4 inhibitors and sustained HbA1c reduction. The effects of the DPP-4 inhibitors on HbA1c and weight, either as monotherapy or in combination with other agents, were evaluated in studies ranging in duration from 12 to 52 weeks (Table 2). No studies were identified that compared the glycemic control effects of DPP-4 inhibitors and insulin analogues. Sitagliptin led to a mean reduction in HbA1c from baseline of up to –0.65% at 12 weeks,^43,45 up to –0.48% at 18 weeks,⁴⁴ up to –0.85% at 24 weeks,^42,46,47,50 up to –1.0% at 30 weeks,⁴⁹ and up to –0.67% at 52 weeks.⁴⁸ Saxagliptin mean reductions in HbA1c ranged from –0.43% to –1.17%.^51–54 Data from four 24-week T2DM studies^56–60 showed vildagliptin reducing HbA1c up to –1.4% at 24 weeks, with the greatest reduction in a study that involved drug-naïve patients with a relatively short duration of disease (mean, 1.2 years).⁵⁹ Reductions in HbA1c of –1.0% were sustained in a 52-week study⁶¹ and its 52-week extension.⁵⁸

DPP-4 inhibitors: weight neutral. The DPP-4 inhibitors appear to have a weight-neutral effect (Table 2). The effects of sitagliptin on weight ranged from a loss of –1.5 kg⁴⁸ at 52 weeks to a gain of +1.8 kg at 24 weeks.⁵⁰ Weight changes with saxagliptin ranged from a mean reduction of –1.8 kg⁵³ to a gain of +0.7 kg.⁵¹ Two vildagliptin studies showed varying effects on weight ranging from a loss of up to –1.8 kg from baseline⁵⁶ to a gain of up to +1.3 kg⁵⁷ relative to placebo, both at 24 weeks.

Potential for CV risk reduction

Potentially beneficial effects on CV risk factors, including blood pressure (ie, reduction) and lipid concentrations (ie, differential effects on low-density lipoprotein and high-density lipoprotein cholesterol), were identified in seven GLP-1 receptor studies—three with exenatide (two with exenatide BID,^37,38 and one with the investigational exenatide once weekly²¹) and four with liraglutide.^23,25,26,41 For the DPP-4 inhibitors, three studies were identified—two with sitagliptin^45,50 and one with vildagliptin⁶¹—in which potentially beneficial effects on CV risk factors were demonstrated.The data have been encouraging, although the clinical implications have yet to be fully understood.

Head-to-head comparison

A recent study compared the effects of the GLP-1 receptor agonist exenatide and the DPP-4 inhibitor sitagliptin on postprandial glucose (PPG) concentrations, insulin and glucagon secretion, gastric intake, and caloric intake.³⁹ Although limited by a short treatment duration (2 weeks), the study showed that the GLP-1 receptor agonist had a greater effect than the DPP-4 inhibitor in reducing PPG concentrations, a more potent effect in increasing insulin secretion and decreasing postprandial glucagon secretion, and a relatively greater effect in reducing caloric intake; and that it decreased the rate of gastric emptying (sitagliptin had no effect). These differences suggest that exenatide may provide a greater degree of GLP-1 receptor activation than the more physiologic concentrations of GLP-1 reached with DPP-4 inhibition.³⁹ Results of a scintigraphic study showed that exenatide substantially slows the gastric emptying that is accelerated in patients with T2DM. This could be another beneficial mechanism in treating postprandial glycemia.⁶³

Adverse effects

Exenatide has shown effects on hepatic injury markers (ie, improvement in alanine and aspartate aminotransferases) for up to 3.5 years of treatment.³⁷ For the GLP-1 receptor agonist and DPP-4 inhibitor studies reviewed, the adverse events were generally mild and included nausea and vomiting, nasopharyngitis, and mild hypoglycemia.