Diabetes mellitus remains an epidemic, affecting approximately 220 million people worldwide
1 and 23.6 million in the United States.
2 It is a major risk factor for cardiovascular disease (CVD)
1,2 and, consequently, requires early intervention and consistently updated guidelines to ensure that the most effective interventions are applied. Unfortunately, clinical outcome trials of antidiabetic agents may take several years to complete and may demonstrate a clinical CVD benefit. Surrogate marker trials may be quicker, but they may not correlate with actual CVD outcome. However, CVD trials are mandated by the US Food and Drug Administration in certain situations to assure CVD safety, therefore influencing the choice of therapies in patients at risk for CVD.
New therapies for patients with type 2 diabetes mellitus (T2DM) should be developed with the use of noninferiority trials with patient safety as priority. Reduced insulin secretion and β-cell function remain significant components in the development of T2DM.
3 Likewise, understanding the dynamics of β-cell dysfunction and regeneration is key to the understanding of β-cell survival and will aid in the development of newer agents that demonstrate in vivo β-cell regeneration and function.
3
New observations on β-cell function and cellular defects, which result in impaired insulin secretion, continue to accumulate. The genetic basis for T2DM remains a highly active field of diabetes research. The crosstalk with β cells and other cells, including liver, fat, and bone cells, is also an area of interest among researchers.
4
Incretin-based therapies such as glucagon-like peptide-1 (GLP-1) agonists
5 and dipeptidyl peptidase-4 (DPP-4) inhibitors,
6 which have potential to improve β-cell function, have garnered much attention in recent years.
3 The increasing number of trials on this therapy class continues to demonstrate safety and efficacy for patients. Pleiotropic effects—including improved cardiac contractility in congestive heart failure and acute myocardial infarction and improved islet cell transplant survival—are areas of considerable interest for future incretin-based studies. Currently, incretin therapy is a favorable therapeutic choice for the treatment of patients with T2DM based on the improvement of glycemic control and weight loss in certain patients.
Recently, the American Association of Clinical Endocrinologists
7 published a therapeutic paradigm with a new algorithm to treat patients with T2DM. The guideline
7 helps busy practitioners choose from therapeutic options for initiating therapy and managing disease progression while prioritizing safety and efficacy for patients. Unlike previous algorithms, GLP-1 agonists and DPP-4 inhibitors are included as mainstay therapies.
7
The contents of this supplement to JAOA—The Journal of the American Osteopathic Association were developed from a symposium conducted during the American Osteopathic Association's 114th Annual Osteopathic Medical Conference and Exposition, held November 4, 2009, in New Orleans, Louisiana. This program brought together a panel of experts to discuss these topics—specifically, the role of islet cell dysfunction in T2DM, the role of incretin-based therapies in optimizing glucose control, and strategies to help patients achieve glycemic targets.
This supplement begins with a discussion by Craig Spellman, DO, PhD, on the pathophysiology of T2DM on the basis of genetic polymorphisms. Dr Spellman identifies blunted postprandial glucose responses and cellular defects responsible for the genesis of T2DM. He also highlights the role of glucagon in the pathogenesis of hyperglycemia.
Next, William Cephalu, MD, provides clinical applications of the physiologic role of incretin hormones in T2DM management by focusing on the physiologic role of incretins in normal patients as well as those with T2DM. He further expands the role of GLP-1 receptor agonists and DPP-4 inhibitors, highlighting several safety and efficacy trials, and discusses the use of these agents in an algorithmic approach.
In the final article of this supplement, I discuss the benefits of incretin therapies using specific case-based studies. Issues regarding long-term studies with exenatide and the use of DPP-4 inhibitors in specific scenarios are included. In addition, the use of these agents in special groups—particularly those with congestive heart failure and individuals older than 65 years—are illustrated.
In summary, the epidemic of diabetes continues to rise in the general population with a higher rate in African-Americans and Hispanics.
2,8,9 The condition also has a high economic toll, costing $174 billion in 2007.
2 With these statistics in mind, the development of antidiabetic agents that will ensure safety and improve therapeutic efficacy remains critical.
I hope you will find this symposium-based supplement useful in enhancing your education and understanding of the pathophysiology and therapeutics of diabetes. Drs Spellman, Cefalu, and I have provided comprehensive information regarding T2DM, which, I hope, will enable you to provide optimum care for your patients.