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Current antihyperglycemic treatment strategies for patients with type 2 diabetes mellitus

December 1, 2009|Cleveland Clinic Journal of Medicine
Lawrence Blonde, MD
Author and Disclosure Information

Lawrence Blonde, MD
Director, Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Diabetes and Metabolism, and Associate Internal Medicine Residency Program Director, Ochsner Medical Center, New Orleans, LA

Correspondence: Lawrence Blonde, MD, FACP, FACE, Director, Ochsner Diabetes Clinical Research Unit, Department of Endocrinology, Diabetes and Metabolism, Ochsner Medical Center, 1514 Jefferson Hwy., New Orleans, LA 70121; lblonde@ochsner.org

Dr. Blonde reported that he has received research and grant support from Amylin Pharmaceuticals, Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, F. Hoffmann-LaRoche Ltd., MannKind Corporation, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., and Sanofi-Aventis; and honoraria for speaking/consulting from Abbott Laboratories, Amylin Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Bristol-Myers Squibb, Daiichi Sankyo Co., Ltd., Eli Lilly and Company, GlaxoSmithKline, Halozyme Therapeutics, LifeScan, Inc., MannKind Corporation, Merck & Co., Inc., Novartis, Novo Nordisk, Pfizer Inc., and Sanofi-Aventis. Dr. Blonde also reported that his spouse is a stock shareholder of Amylin Pharmaceuticals, Inc., and Pfizer Inc. in an account that is not part of their community property. Dr. Blonde reported that he did not receive an honorarium for writing this article.

Dr. Blonde reported that he wrote this article and received no assistance with content development from unnamed contributors. He reported that BlueSpark Healthcare Communications, a medical communications company, assisted with reference verification, proofing for grammar and style, table and figure rendering based on author instructions, copyright permission requests, and identification of topical overlap with other articles in this supplement.

ABSTRACT

The current epidemics of excessive weight and type 2 diabetes mellitus (T2DM) cause significant morbidity and mortality. T2DM frequently coexists with excess weight as well as hypertension and dyslipidemia, placing a significant percentage of the population at an elevated risk of cardiovascular disease. Maintaining effective glycemic control is linked with a diminished risk of developing microvascular complications, and recent studies have shown it may also reduce overall macro­vascular complications. Reduction of associated risk factors, including those related to excessive weight, high blood pressure, and dyslipidemia, are also necessary to meaningfully decrease cardiovascular risk. Agents that can improve glycemia with weight neutrality or weight loss could offer additional benefit to overweight patients with T2DM. Although the major pathophysiologic defects in T2DM are recognized to be beta-cell dysfunction and peripheral insulin resistance, derangements in the incretin system may contribute as well. Antidiabetes agents targeting this system include dipeptidyl peptidase–4 (DPP-4) inhibitors and glucagon-like peptide–1 (GLP-1) receptor agonists. Both classes have been shown to significantly reduce hyperglycemia. GLP-1 receptor agonists also promote significant weight loss and have potentially beneficial effects on cardiovascular risk markers.

KEY POINTS

  • Up to 65% of deaths among people with diabetes are caused by cardiovascular disease.
  • Glycemic control can delay or slow the progression of microvascular complications.
  • In addition to hyperglycemia, comprehensive diabetes therapy must target cardiovascular disease–related risk factors, including excess weight/obesity, elevated blood pressure, and abnormal lipid concentrations.
  • Diminished incretin hormonal activity contributes to the pathophysiology of diabetes.

THE ROLE OF INCRETIN HORMONES AND INCRETIN-BASED THERAPIES IN T2DM PATIENTS

Over the last few years, the role of incretin hormones and their contribution to diabetes pathophysiology has become more apparent. The incretin effect refers to the observation that orally administered glucose elicits a greater insulin response than does glucose administered intravenously to produce equivalent blood glucose concentrations.30,31 The incretin effect is diminished in patients with T2DM.

Hormone mediation of the incretin effect

The two hormones that mediate the incretin effect are GIP (also known as gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide) and glucagon-like peptide−1 (GLP-1).30,31 GLP-1 has several glucoregulatory actions, including enhancement of endogenous insulin release and suppression of inappropriate glucagon secretion, both in a glucose-dependent manner. Therefore, these effects of GLP-1 occur only when glucose concentrations are elevated, thereby minimizing the risk of hypoglycemia. GLP-1 also regulates gastric emptying; infusions of GLP-1 can slow the accelerated emptying that is often present in T2DM patients. GLP-1 also increases satiety and decreases food intake via a central mechanism.31

Because GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase–4 (DPP-4), therapeutic use of GLP-1 would require continuous infusion, which is impractical.30,31 Two strategies have been used to produce incretin-related therapies. One, inhibition of the DPP-4 enzyme, results in a two- to threefold enhancement of endogenous GLP-1. The other, involving agents that resist breakdown by DPP-4 but bind to and activate the GLP-1 receptor, produces glucoregulatory effects similar to those of GLP-1.30

Following subcutaneous (SC) injection, GLP-1 receptor agonists enhance insulin secretion and suppress inappropriately elevated glucagon, both in a glucose-dependent manner, as well as slow gastric emptying and enhance satiety.30 DPP-4 inhibitors provide glucose-dependent enhanced insulin secretion and glucagon suppression, but they do not have the same effects on gastric emptying or satiety.

Clinically, the GLP-1 receptor agonists improve glycemia and are associated with weight loss.32–35 Adverse gastrointestinal symptoms are relatively common during the first few weeks of treatment. DPP-4 inhibitors improve glycemia but are weight-neutral and are not generally associated with significant gastrointestinal symptoms.32,36–38

Incretin-based therapies

Incretin-based therapies are currently part of the antihyperglycemic armamentarium.25,32 The AACE guidelines11 and the ACE/AACE roadmaps23 include the GLP-1 receptor agonist exenatide and the DPP-4 inhibitor sitagliptin among antihyperglycemic therapies for patients with T2DM. The most recent update of the consensus algorithm statement of a joint ADA/EASD writing group included GLP-1 receptor agonists (but not DPP-4 inhibitors) in tier 2 of preferred agents, especially for patients who have concerns related to weight and hypoglycemia.24 They noted that DPP-4 inhibitors may be appropriate choices in selected patients.

DPP-4 inhibitors: sitagliptin, saxagliptin. Until recently, sitagliptin was the only DPP-4 inhibitor available in the United States. Sitagliptin is approved by the FDA for treatment of T2DM at a recommended oral dosage of 100 mg QD, either as monotherapy or in combination with other oral antihyperglycemic medications. The dosage of sitagliptin should be reduced to 50 mg/day in patients with creatinine clearance (CrCl) levels that are between 30 mL/min and 50 mL/min and to 25 mg/day in those with CrCl less than 30 mL/min.39

In a meta-analysis of incretin-based therapies, DPP-4 inhibitors produced a reduction in HbA1c compared with placebo (weighted mean difference of –0.74%; 95% confidence interval, –0.85% to –0.62%).32 DPP-4 inhibitor antihyperglycemic efficacy has been shown to be similar whether used as a monotherapy or add-on therapy.32,37,38 This same meta-analysis showed DPP-4 inhibitors as having a neutral effect on weight.32 More recently, a single-pill combination of metformin and sitagliptin was approved.40

A study comparing metformin, sitagliptin, and the combination of the two as initial monotherapy in T2DM patients with a baseline HbA1c of 8.8% showed 24-week HbA1c reductions from baseline of –0.66% with sitagliptin 100 mg QD, –0.82% with metformin 500 mg BID, and –1.90% with sitagliptin 50 mg + metformin 1,000 mg BID.41

On July 31, 2009, the FDA approved another DPP-4 inhibitor, saxagliptin, for the treatment of T2DM either as monotherapy or in combination with metformin, a sulfonylurea, or a TZD.42

GLP-1 receptor agonist: exenatide. Exenatide, the only FDA-approved GLP-1 receptor agonist, is the synthetic version of exendin-4, which binds to the human GLP-1 receptor and in vitro possesses many of the glucoregulatory effects of endogenous GLP-1.30,32 Exenatide is indicated as monotherapy or adjunctive therapy for patients with T2DM who have not achieved adequate glycemic control with metformin, a sulfonylurea, a TZD, or metformin in combination with a sulfonylurea or a TZD.43 Exenatide is administered by SC injection BID at a starting dosage of 5 mg BID for 4 weeks, followed by an increase to 10 mg BID.

Exenatide has been shown not only to enhance glucose-dependent insulin secretion but also to restore impaired first-phase insulin response in subjects with T2DM. Exenatide also helps control postprandial glycemic excursions by suppressing inappropriate glucagon secretion, slowing accelerated gastric emptying, and enhancing satiety. The increased satiety results in decreased food intake and weight loss.31,44 In a recent head-to-head crossover study, exenatide was shown to be more effective than sitagliptin in lowering postprandial glucose concentrations, increasing insulin secretion, and reducing postprandial glucagon secretion.45 Exenatide also slowed gastric emptying and reduced caloric intake.

Exenatide, in most studies, resulted in a placebo-subtracted HbA1c reduction of approximately –1.0% and in one study lowered HbA1c from baseline by –1.5%. Completer analyses have shown HbA1c reductions of –1.0% up to 3 years and –0.8% up to 3.5 years. Exenatide has also been associated with a mean weight loss of as much as –3.6 kg at 30 weeks and as much as –5.3 kg at 3.5 years.33–35,46,47 A 1-year study showed that exenatide improved beta-cell secretory function compared with insulin glargine in metformin-treated patients with T2DM.48 Long-term data, including findings from completed and intention-to-treat analyses of 82 weeks49 to at least 3 years47 have demonstrated that exenatide improved CV risk factors, including those related to BP, lipids, and hepatic injury biomarkers.

Therapies in development

Incretin-based therapies in development include a novel once-weekly formulation of exenatide; taspoglutide, another once-weekly GLP-1 receptor agonist; and liraglutide, a GLP-1 receptor agonist that is administered once daily.50 Liraglutide is currently being evaluated in clinical trials as a once-daily SC injection.51–53 Liraglutide has been reported to reduce HbA1c by –1.1% at 26 weeks and up to –1.14% at 52 weeks and result in weight loss (up to –2.8 kg at 26 weeks and up to –2.5 kg at 52 weeks) in patients with T2DM who are treatment-naïve or taking other antidiabetes agents, including metformin, sulfonylurea, and TZD.51–53 Evaluation of the once-weekly formulation of exenatide showed reductions in HbA1c of –1.9% at 30 weeks and –2.0% at 52 weeks with a weight loss of –3.7 kg at 30 weeks and –4.1 kg over 52 weeks of treatment.46,54

CONCLUSION

In the United States, the epidemics of excessive weight and T2DM have contributed to an increased medical risk for many individuals. Comprehensive diabetes treatments targeting not only hyperglycemia but also frequently associated overweight/obesity, hypertension, and dyslipidemia will be required to reduce such risk. Current treatment strategies have evolved based on updated clinical guidelines and trials, as well as practice experience, including those related to newer agents. Incretin-based therapies, such as the GLP-1 receptor agonist, exenatide, and the DPP-4 inhibitors, sitagliptin and saxagliptin, are important additions to the treatment armamentarium, offering a reduction in hyperglycemia and beneficial effects on weight (reduction with exenatide and neutral with sitagliptin), and have been shown to improve several CV risk factors.

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