Incretin-based Therapies for Type 2 Diabetes
Incretin-based therapies now include two classes: glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. However, there are important differences between individual agents, even within these classes. This article will discuss mechanisms of action (MOA), efficacy and safety data, and effects on body weight, highlighting differences and similarities between GLP-1 receptor agonists and DPP-4 inhibitors, and the clinically relevant advantages both classes of incretins may provide compared with more established drugs.
Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors
All incretin-based therapies approved to date are for glycemic control in addition to diet and exercise for adults with type 2 diabetes, either as monotherapy or in combination with metformin, sulfonylureas, or thiazolidinediones.5–9
Sitagliptin and saxagliptin, and exenatide are also
The US Food and Drug Administration (FDA) approved the first GLP-1 receptor agonist, exenatide, twice daily, in April 2005, and the first commercial DPP-4 inhibitor, sitagliptin, in October 2006.10 Two additional DPP-4 inhibitors, saxagliptin and linagliptin, received FDA approval in July 2009 and May 2011, respectively.6,7
approved for use in combination with insulin and insulin glargine, respectively.5,8
The FDA
approved liraglutide, a once-daily GLP-1 receptor agonist with 97 % homology to native GLP-1, in January 2010.
Mechanisms of Action
The endogenous incretins, glucose-dependent insulin peptide (GIP) and GLP-1, are released from the gut in response to food intake. Both stimulate insulin secretion and promote beta-cell proliferation.11
Some, but not all, individuals with type 2 GLP-1,
but not GIP, also inhibits glucagon secretion, gastric emptying, food intake, and weight gain.11
diabetes have reduced GLP-1 secretion and a normal response to GLP-1, so increasing GLP-1 activity offers multiple potential benefits.11,12 In contrast, GIP secretion is normal in type 2 diabetes, but the response to GIP is blunted.11–13
GLP-1 receptor agonists act directly on GLP-1 receptors in pancreatic beta-cells, and deliver more sustained activity than endogenous GLP-1 because they resist breakdown by the enzyme DPP-4 and can be dosed to pharmacological levels. DPP-4 inhibitors slow DPP-4-catalyzed breakdown of both GLP-1 and GIP, and can double endogenous GLP-1 levels. This may explain the higher efficacy and weight loss seen with GLP-1 receptor agonists compared with DPP-4 inhibitors. The importance of increasing GIP levels in the mechanism of DPP-4 inhibitor activity is unclear, as target cells have an impaired response to GIP in type 2 diabetes.12,13
Some evidence suggests that these differences between the physiological effects of GLP-1 receptor agonists and DPP-4 inhibitors would predict superior outcomes for the former. Both drug classes act by increasing GLP-1 levels, but GLP-1 receptor agonists allow direct supplementation to pharmacologically active levels, while DPP-4 inhibitors offer less potential to achieve GLP-1 levels far above physiological levels via their mode of action (i.e., reducing degradation of endogenous GLP-1). Sitagliptin can double or triple plasma GLP-1 concentrations following an oral glucose tolerance test.14
GLP-1 levels were similar after a 25 mg or 200 mg dose of sitagliptin, suggesting that US ENDOCRINOLOGY
Efficacy in Non-comparative Trials Dipeptidyl Peptidase-4 Inhibitors
Randomized controlled trials (RCTs) have shown significant but modest
improvements in both HbA1c and fasting plasma glucose (FPG) with the three approved DPP-4 inhibitors—sitagliptin, saxagliptin, and linagliptin—from baseline versus placebo or existing drugs (see Table 1). These drugs appear to have little impact on body weight, and are generally well tolerated (see later sections).
Sitagliptin
An 18-week, placebo-controlled study of sitagliptin monotherapy reported significantly reduced post-prandial peaks from baseline versus placebo following a meal tolerance test (subset n=150; total randomized population n=521; mean diabetes duration 4.5 years).19 Placebo-subtracted changes in three-hour area under the curve (AUC) over 18 weeks were -6.7 and -7.6 mmol/hour l-1 for sitagliptin 100 mg and 200 mg once daily, respectively (both p≤0.001).14
Sitagliptin
demonstrated non-inferiority to metformin as monotherapy in 1,050 treatment-naive patients over 24 weeks.20
Long-term double-blind
follow-up studies revealed similar glycemic control for sitagliptin monotherapy and metformin monotherapy for up to two years.21–23
Sitagliptin demonstrated additive efficacy when combined with metformin in a study of 1,091 patients with type 2 diabetes (mean diabetes duration 4.5 years), of whom 50 % had received no oral hypoglycemic agent for at least eight weeks before randomization.21
This study compared sitagliptin
monotherapy, metformin monotherapy, combined sitagliptin/metformin, and placebo over 24 weeks. Combining sitagliptin with metformin seemed more effective than increasing the metformin dose to improve
efficacy—including improving HbA1c and both fasting and post-meal glucose levels.21
Double-blind extensions of 30 and 54 weeks confirmed the efficacy of this combination for up to two years.22,23
A 24-week trial in 701 metformin-treated patients with a mean diabetes duration of 6.2 years also reported significant improvements in post-meal glucose with 100 mg sitagliptin compared with placebo (two-hour AUC, p<0.001).24
any dose–response relationship had leveled out below 30 nM.14 Plasma
concentrations of liraglutide can increase in a dose-dependent manner to around 13,000 pmol/l, with no evidence of a plateau.15
DPP-4 inhibitors have an additional effect on GIP, which also stimulates insulin secretion and suppresses glucose.13,14
The
importance of increasing GIP levels in the mechanism of DPP-4 inhibitor activity is unclear; however, target cells have an impaired response to GIP in type 2 diabetes, and patients show smaller increases in insulin and less suppression of glucose than non-diabetic individuals.12,13
Studies have linked GIP with increased glucagon levels, in contrast with GLP-1, which suppresses glucagon.16,17
A recent
publication revealed that combining GIP with GLP-1 impairs the latter’s glucagon-lowering efficacy in patients with type 2 diabetes.18
Sitagliptin showed non-inferiority to glipizide as an adjunct to ongoing metformin treatment in a 52-week study that included 1,172 patients (average known type 2 diabetes disease duration 5.8 years).25
At two years’ extended follow-up, least squares mean changes in HbA1c were -0.54 % and -0.51 % with sitagliptin and glipizide, respectively, per
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