As I think about the many new advances in our understanding and treatment of Type 2 diabetes mellitus (T2DM), three points come to mind that have implications for future treatment of diabetes in primary care:
- If we accept that the earliest form of T2DM occurs when the beta cell is no longer able to overcome insulin resistance and beta cells are in jeopardy, then first-line therapy for T2DM should target both insulin resistance AND preserving or increasing beta cell function and mass.
- Early intensive insulin therapy may improve beta cell function and lead to protracted glycemic control better than oral hypoglycemic agents for at least a year after diagnosis.
- Decline in beta cell mass may be slowed or reversed in part by euglycemia.
The therapeutic implications of these points can be significant in our ability to modify this disease and its progression. A key limitation of conventional therapies for T2DM is their failure to address an important cause of disease progression, namely the eventual decline in beta cell mass and function. This leads to the high failure rate of most oral agents over time. New drugs that target the incretin system may provide more viable alternatives or beneficial addition to conventional T2DM treatments. Early intensive insulin therapy appears to improve beta cell function and lead to protracted glycemic control better than oral hypoglycemic agents for at least a year after the diagnosis. In vitro and in animal studies have also shown that GLP-1 promotes beta cell neogenesis and preservation and could be potentially helpful in preserving beta cell function.
The promise for improved care of diabetes may lie in better understanding of the effect on the beta cells of these new therapies.
This promise seems particularly bright when considering the treatment of T2DM in African Americans, who have among the highest incidence and prevalence of any other ethnic group in the United States of diabetes and its associated morbidities. Approximately 3.7 million—a staggering 14.7%—of non-Hispanic black adults 20 years or older in this country have diabetes, primarily T2DM.
This unusually high incidence, coupled with the often related conditions of obesity, hypertension, and dyslipidemia, make the need particularly pressing for new therapies that address the elevated blood glucose levels, as well as other clinical features of the metabolic syndrome.
Ethnic Differences in Incretin Response
While little is known about differences between specific ethnic groups with respect to diabetes-related changes in native GLP-1, two recently published studies—one in non-diabetic children, and the other in obese adolescents—suggest that, despite a greater insulin response, African American children may have a lower GLP-1 response to oral carbohydrate than European Americans. While potential clinical implications of these findings remain to be explored, these findings are interesting because they may help explain the greater predisposition to T2DM in African Americans. In addition, they raise the possibility that African Americans could potentially respond better to incretin-based therapies than Caucasians.
Whether or not incretin therapy is unusually effective in certain subpopulations, particularly those with lower baseline GLP-1 reponses, remains to be seen. For now, the only available data come from the year-long LEAD 3 study, in which researchers compared liraglutide monotherapy to glimepiride monotherapy. A subset of 94 African Americans in this study had their A1C reduced by 1.2% with 1.8 mg of the once-daily human GLP-1 analog liraglutide, significantly greater than the 0.2% lowering with 8 mg of glimepiride. In addition, 64.3% of the liraglutide-treated subjects achieved an A1C of under 7.0%, in contrast to just 10.7% of the glimiepiride-treated subjects. A recent poster and oral presentation of these findings also showed that the African Americans in the liraglitude group had a mean weight loss of 3.0 kg, compared to a 0.5 kg weight loss in those taking glimepiride. In addition, African Americans in the liraglutide group had slightly greater absolute and relative improvements in
A1C than did the overall cohort.
T2DM poses a major health challenge to African Americans. The new generation of incretin-based therapies, particularly the GLP-1 analogs, is particularly promising for this subset of patients because these therapies lower blood glucosewithout compromising weight, blood pressure, or lipid levels. In addition, the ancillary properties of this drug class may even help preserve or improve beta cell mass and function. Additional beneficial effects of this class may be their ability to counteract cardiovascular risk. Both of these hypotheses need to be clinically validated.
 Shomali M, Hale P, Zdravkovic M, et al. Liraglutide, a once-daily human GLP-1 analog, improves glycemic control more than glimepiride in African American or black individuals with type 2 diabetes. Poster and oral presentation at the 2009 National Medical Association Annual Convention & Scientific Assembly; July 25-29, 2009; Las Vegas, NV.