Is the future bright for diabetes?

There is no doubt that there is an epidemic of diabetes raging in the United States. Type 2 diabetes is characterized by decreased sensitivity to insulin action in muscle, liver, and fat cells, as well as a progressive decline in pancreatic insulin production. The precise causes of insulin resistance and eventual [beta] cell failure remain unclear, however it appears that both genetic predisposition and environmental factors interact. (1-3) In particular, obesity and sedentary life-style are closely linked to the onset and progression of type 2 diabetes mellitus. Recent trials have confirmed conventional wisdom that weight loss, exercise, and some medications can delay or prevent the onset of diabetes. (4,5)

Cardiovascular disease is the leading cause of morbidity and mortality in patients with diabetes. Hyperinsulinemia (a marker of insulin resistance) is an independent risk factor for cardiovascular disease. (6) Diabetes treatments that decrease hyperinsulinemia and insulin resistance seem to be more protective against cardiovascular events than those that do not impact these factors. (7) Furthermore, aggressive treatment of dyslipidemia is critical in effective management of diabetes.

The current state of diabetes care is poor. Even in academic institutions in teaching settings, American Diabetes Association treatment goals are infrequently attained. (8)

In this issue of the Journal, Ali A. Rizvi (9) presents a concise review of the modern approach to treating type 2 diabetes, characterized by aggressive use of multi-oral-drug regimens early in the disease process and, when needed, the use of very long-acting insulin supplemented by very short-acting insulin to mimic the natural insulin secretion of the pancreas.

The future does appear to be bright. A continuous-sensing glucometer is now available, and it is only a matter of time until this is mated to an insulin pump to create an "artificial pancreas." Late-stage development efforts are under-way in the development of new medications that hold great promise for patients with diabetes. These include enhancing the effectiveness of existing pharmacologic agents as well as the development of revolutionary compounds and delivery devices.

Capitalizing on the success of PPAR-gamma receptor agonists or thiazolidinediones, new oral agents targeting both PPAR-gamma and PPAR-alpha receptors are in development. These dual acting agents increase insulin uptake at the cellular level (PPAR-gamma activity) and reduce atherogenic triglycerides while raising cardioprotective high-density lipoproteins (PPAR-alpha activity). Tesaglitizar, marketed as Galida (AstraZeneca, London, UK), is scheduled for release in 2006, and will likely be the first of these agents to be available. (10)

Amlynomimetic agents (pramlintide acetate [Symlin; Amylin Pharmaceuticals, San Diego, CA]) (11) and incretinmimetic agents (synthetic exendin-4 [Exenatide; Amylin Pharmaceuticals]) (12) are two new classes of hormone analogs which primarily target postprandial hyperglycemia. Both of these stimulate secretion of endogenous insulin during periods of glucose elevation but not during periods of hypoglycemia.

Glucagon-like peptide (GLP) analogs inhibit gastric emptying, decrease glucagon release, and increase insulin secretion. Early results are promising, demonstrating improved glycemic control without increased hypoglycemia. (13) GLPs are broken down by dipeptidyl peptidase IV (DPP-IV), and inhibitors of this enzyme have also shown promise in early clinical trials. (14)

Research into and development of alternative methods of insulin delivery have expanded in recent years, attempting to provide a safe, nonpainful method of insulin therapy in both type 1 and type 2 diabetic patients. Traditionally, oral insulin has not been the target of research primarily due to molecular size and gastrointestinal absorption limitations. However, research into oral delivery is ongoing. (15) In addition, inhaled insulin has continued to be the subject of much research and development. Exubera (Pfizer, New York, NY) is a micronized dry powder insulin inhalant which is currently in late-stage testing. Similarly, the AERx Diabetes Management System (Aradigm, Hayward, CA) is also in the late stages of testing, and is an aerosolized insulin delivery system. (16)

Many other compounds, drug delivery devices, and glucose monitoring devices are in early research and development. As with many previous pharmaceutical agents, it is likely that current and future therapies will work synergistically. However, none of these will replace the necessity of lifestyle modifications (ie, exercise, diet, and weight loss). Various therapies devoted to improved efficacy and improved patient quality of life are on the horizon. The future is bright for diabetes.

Obstacles are those frightful things you see when you take your eyes off
your goals
--Henry Ford

Accepted June 15, 2004.

Please see "Type 2 Diabetes: Epidemiologic Trends, Evolving Pathogenic Concepts, and Recent Changes in Therapeutic Approach" on page 1079 of this issue.

References

1. Eriksson J, Franssila-Kallunki A, Ekstrand A, et al. Early metabolic defects in persons at increased risk for non-insulin dependent diabetes mellitus. New Engl J Med 1989;321:337-341.

2. Matthaei S, Stumvoll M, Kellerer M, et al. Pathophysiology and pharmacological treatment of insulin resistance. Endocr Rev 2000;21:585-618.

3. Ferrannini, E. Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 1998; 19:477-490.

4. Hu G, Lindstrom M, Valle T, et al. Physical activity, body mass index, and risk of type 2 diabetes in patients with normal or impaired glucose regulation. Arch Intern Med 2004;164:892-896.

5. Diabetes Prevention Research Group. Reduction in the evidence of type 2 diabetes with life-style intervention or metformin. N Engl J Med 2002;346:393-403.

6. Despres JP, Lamarche B, Mauriege P, et al. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952-957.

7. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865.

8. Putzer G, Ramirez A, Sneed K, et al. Prevalence of patients with type 2 diabetes mellitus reaching the American Diabetes Association's target guidelines in a university primary care setting. South Med J 2004;97:145-148.

9. Rizvi AA. Type 2 diabetes: epidemiologic trends, evolving pathogenic concepts, and recent changes in therapeutic approach. South Med J 2004;11:1079-1087.

10. Anonymous. New chemical entities and line extensions [AstraZeneca International Web site]. Available at http://www.astrazeneca.com/article/501216.aspx.

11. Anonymous. Symlin (pramlintide acetate) [Amylin Pharmaceuticals Web site]. Available at http://www.amylin.com/Pipeline/Symlin.cfm.

12. Anonymous. Exenatide (synthetic exendin-4) [Amylin Pharmaceuticals Web site]. Available at http://www.amylin.com/Pipeline/AC2993.cfm.

13. Zander M, Madsbad S, Madsen JL and Holst JJ. Effect of 6-week course of glucagon-like peptide-1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 9 March 2002;359:9309.

14. Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schwiezer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucaton levels in type 2 diabetes. J Clin Endocrinol Metab May 2004;89(5):2078-84.

15. Anonymous. Product candidates: oral insulin [Emisphere Technologies, Inc. Web site]. Available at http://www.emisphere.com/pc_oi.asp.

16. Anonymous. Aradigm and Novo Nordisk release interim analysis of initial pulmonary insulin phase 3 trial. Available at http://ir.thomsonfn.com/InvestorRelations/PubNewsStory.aspx?partner=7677&storyId=113007.

Michael M. Bond, DO, Scott W. Yates, MD, MBA, FACP, FACPE 

From North Texas Medical Group and North Texas Medical Research, The Colony, TX.

Reprint requests to Scott W. Yates, MD, North Texas Medical Group, 6053 Main Street, Suites 210 and 235, The Colony, TX 75056-2062.