Clinical Application of Incretin-Based Therapy: Therapeutic Potential, Patient Selection and Clinical Use

https://doi.org/10.1016/j.amjmed.2009.03.015Get rights and content

Abstract

Incretin-based therapies address the progressive nature of type 2 diabetes mellitus, not only by addressing glucose control but also with weight-neutral (i.e., dipeptidyl peptidase–4 inhibitors sitagliptin and vildagliptin) and weight-reducing effects (i.e., glucagonlike peptide–1 [GLP-1] receptor agonists exenatide and liraglutide). Preclinical data suggest that incretin-based therapies may also preserve β-cell function, holding promise of a truly disease-modifying therapy. This article examines clinical trial data and accepted algorithms with a view toward elucidating the application of these agents in routine clinical practice. We propose a systematic approach to treatment, addressing (1) patient selection, (2) optimal treatment combinations, and (3) timing and guidance for both initiation and intensification of therapy. The GLP-1 receptor agonists, for example, could be particularly beneficial in patients whose weight significantly increases cardiovascular risk. Early use of these agents may be effective in preventing diabetes in those at risk, or in halting or retarding disease progression in patients with frank diabetes. Additional clinical investigation will be required to test such hypotheses. Given the ever-increasing incidence of diabetes worldwide, the link between obesity and the development of type 2 diabetes, and the need for more effective, weight-focused, convenient and sustainable treatments, the data from such studies will be invaluable to further clarify the role of the incretins in the management of patients with type 2 diabetes.

Section snippets

A Pathophysiologic Perspective

Progressive impairment of β-cell function and increased insulin demand as tissue becomes insulin resistant are core pathophysiologic defects in the development and progression of hyperglycemia in type 2 diabetes.1, 2 However, other important factors are also known to further exacerbate this pathology. Excess glucagon secretion, abnormal gastric emptying during hyperglycemia, obesity, and increased food intake all contribute to, or worsen, hyperglycemia in type 2 diabetes. Impaired release or

Incretin-Based Therapy: A Clinical Perspective

Traditional treatment strategies for type 2 diabetes use single therapies, often added in a sequential fashion. As additional therapies are added only when specific treatment targets are not achieved, this “failure-based” approach often results in a delay in advancing therapy.4, 5, 6 Current treatment recommendations for the management of type 2 diabetes advise lifestyle changes—moderate weight loss (5% to 10%) and physical activity for ≥30 minutes per day.7, 8 If appropriate, metformin is

Current Clinical Challenges in the Treatment of Diabetes Mellitus

The vast majority of patients with type 2 diabetes currently are treated with ≥1 oral hypoglycemic agent—with increasing numbers of patients now using insulin (most commonly basal insulin) earlier in the course of treatment. Despite the introduction of several new classes of antidiabetic agents in the United States and worldwide between 1995 and 2004, slightly >50% of patients with type 2 diabetes achieve HbA1c values ≤7% (the current community standard advised by the American Diabetes

A Pathophysiologic Perspective: The Natural History of Type 2 Diabetes Mellitus

Intelligent use of antidiabetic drugs is critically dependent on a sound understanding of the natural history of diabetes and of the underlying pathophysiologic defects that give rise to the disease. Type 2 diabetes is a complex metabolic disorder characterized by elevated blood glucose and a marked increase in the risk of cardiovascular disease. The increase in cardiovascular disease risk is a consequence of a cluster of metabolic and vascular abnormalities including hyperglycemia,

Clinical Application of Incretin-Based Treatments

Both GLP-1 receptor agonists and the DPP-4 inhibitors seek to leverage the pharmacologic effects of incretin hormones. Incretin-based agents provide clinicians with new interventional strategies for the improvement of fasting and postmeal glucose, islet function, and body weight.

Use of Incretin-Based Therapies: A Pathophysiologic Perspective

Currently, metformin is widely recommended as the initial therapy of choice for patients with type 2 diabetes. Metformin is commonly used in combination with lifestyle interventions as the first step in treatment or as add-on therapy if patients are unable to achieve or maintain adequate glycemic control (HbA1c ≤7%) with diet and exercise alone. Figure 338, 39, 40, 41, 42, 43, 44, 45, 46, 47 describes an approach to therapy selection based on the level of glycemic control at presentation, while

Clinical Comparison of DPP-4 Inhibitors and GLP-1 Receptor Agonists

Table 1 provides a summary of the clinical effects of both GLP-1 receptor agonists and DPP-4 inhibitors. Although the list of effects is not exhaustive, it should help clinicians quickly identify the potential role for each of these therapies. Both classes of drug work well in combination with other diabetes therapies, although efficacy may be greater with GLP-1 receptor agonists. Both classes differ in route of administration and may have differing side effect and tolerability profiles. Thus

Clinical Use of Incretin Based Therapy: A Practical Summary

Effective therapies for diabetes exist, but therapies that are even more effective, safer, and more durable in their ability to control glycemia are clearly needed. Incretin-based therapies are among the more recent attempts to meet those needs. The appropriate use of such therapies should assist the clinician in addressing the progressive nature of type 2 diabetes—not only preventing deterioration in glucose control but also the weight increase commonly observed in this disease and often

Author Disclosures

The authors who contributed to this article have disclosed the following industry relationships:

  • David M. Kendall, MD, has worked as a consultant to Amylin Pharmaceuticals, Inc., Daiichi-Sankyo Co. Ltd., Eli Lilly & Co., HealthPartners, Intarcia Therapeutics, Inc., Nektar Therapeutics, and Takeda Pharmaceuticals North America, Inc; has served on scientific/clinical advisory boards for Amylin Pharmaceuticals, Inc., Daiichi-Sankyo Co. Ltd., Eli Lilly & Co., HealthPartners, Intarcia Therapeutics,

Acknowledgment

We thank AdelphiEden for providing editorial services.

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    Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

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