Diabetes mellitus type 2 (T2DM) is a serious and life-threatening disease currently affecting an estimated 19 million Americans, of which as many as six million remain undiagnosed.¹ An estimated 1.5 million new cases are diagnosed each year.² Diabetes is a serious condition with complicated sequelae, costing about 11 percent of the U.S. health care expenditure.³ Microvascular complications such as neuropathy, retinopathy, and nephropathy can lead to limb amputations, blindness, and kidney failure. Macrovascular complications, which include, but are not limited to cardiovascular disease, can lead to significant diabetic mortality and morbidity.⁴ It is therefore imperative for the patient’s well-being and societal healthcare cost that the disease is diagnosed early and effectively treated to prevent future complications.

Treatment recommendations of the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) include a multi-faceted plan for managing diabetes. The primary goal of diabetes treatment is to achieve and maintain near-normal glycemic levels early in the progression of the disease to preserve the insulin producing beta-cell function. Improvement of beta-cell function and delaying its progressive loss will result in the reduction of diabetic complications. ⁵ Studies have documented that for every 1 percent reduction in HbA1C, there is a 35 percent reduction in the risk of microvascular complications.⁶ Macrovascular diseases associated with diabetes can be minimized by the reduction of cardiovascular risks such as regulation and control of hypertension and hyperlipidemia.^7,8 Current treatment guidelines do not outline systematic pharmacologic treatment regimens for diabetes; they only provide treatment goals as listed in the following chart.⁹

Chart 1

AACE and ADA Recommended Treatment Goals
Glycemia	Lipids	Blood Pressure
HbA1C ≤ 6.5% Fasting Blood Glucose <110mg/dL 2-hour Postprandial Glucose <140mg/dL	LDL-C < 100 mg/dL LDL-C < 70 mg/dL (Pt with DM & CAD)	<130/80mm Hg
	HDL-C >40mg/dL in Men HDL-C >50mg/dL in Women
	Triglycerides <150mg/dL

Current standard treatment guidelines also emphasize the importance of lifestyle modifications such as patient education, diet and exercise, and regular follow-up appointments to prevent or delay complications. It is estimated that weight reduction of 10 kg (or 22 lbs) can result in a 5 to 20 mm Hg reduction in blood pressure; for each 10 mm Hg reduction in systolic blood pressure, there is an approximate 12 percent decrease in diabetes complications, 15 percent decrease in diabetes-related deaths and an 11 percent reduction in myocardial infarction.¹⁰ When lifestyle modifications are not effective in achieving normal glycemic levels, oral therapeutic classes of medications, used as monotherapy or in various combinations, are available for the treatment of diabetes. These include sulfonylureas, biguanides, alpha-glucosidase inhibitors, glinides, dipeptidyl-peptidase-4-inhibitors and thiazolidinediones.

Recently, the Food and Drug Administration (FDA) has re-reviewed the safety profile of the thiazolidinediones drug class and has issued a black box warning against its usage in certain patient populations. Thiazolidinedione’s (TZD) mechanism of action is not fully understood; however, studies have shown it to improve beta-cell activity, slow the progressive loss of beta-cells, and act to improve muscle, liver, and adipose tissue sensitivity to insulin.^{11, 12} TZD generally lowers HbA1c levels to the same degree as metformin and sulfonylureas.¹³ The side effect profile of this class of drugs includes weight gain, frequent edema and increased LDL levels and has been associated with an increased risk of heart failure and heart attack.

According to the FDA and Nesto et al., significant, excessive, rapid weight gain, shortness of breath and edema, which are indications of heart failure, occurred after starting TZD therapy.^{14, 15} In August, following multiple reviews and warnings against its usage in certain patient populations, the TZD class of drugs received a black box warning in regard to the increased risk of heart failure.¹⁶ On November 14th, the FDA added new information to the existing black box warning to the drug rosiglitazone (Avandia®) regarding the potential increased risk for heart attacks.¹⁷ This revised warning was based on the Nissen and Wolski’s meta-analysis of 42 clinical studies, comparing rosiglitazone to placebo, with results showing rosiglitazone to be associated with a significantly increased risk of myocardial ischemic events such as angina or myocardial infarction.¹⁸ In addition, the study found “an increase in the risk of death from a cardiovascular event that was of borderline significance.”¹⁹

Meta-analysis estimates of cardiovascular morbidity have limitations and are less convincing than a large prospective trial designed to assess specific outcomes and endpoints. Three important clinical trials, the ADOPT (A Diabetes Outcome Progression Trial), the DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication), and the interim analysis of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes), did not show conclusive evidence confirming or excluding the increase overall risk of hospitalization or death from cardiovascular causes in patients on rosiglitazone versus placebo or other oral antidiabetic agents.^{20, 21, 22} However, an analysis of a retrospective cohort study by Lipscombe et al. using health care databases in Ontario for patients 66 years and older, has shown that treatments with rosiglitazone are associated with significantly increased risks of congestive heart failure, acute myocardial infarction and mortality among older persons with diabetes compared with other oral diabetes medications.²³ Despite non-conclusive results, continuation of rosiglitazone should be considered on an individual basis for potential benefits and risks.

A retrospective analysis of Medi-Cal Fee for Service (FFS) recipients was conducted to determine whether patients who filled a prescription for rosiglitazone (N=6880) had also been diagnosed with one or multiple co-morbid conditions that may potentially increase their risk for heart attack and/or heart failure (N=4651). Patients diagnosed with co-morbid conditions listed in Chart 3 between September 1, 2005 and August 31, 2007 were compared to patients taking prescription drugs for diabetes between August 1, 2007 and November 30, 2007 in Chart 2.

Chart 2

Results of the 77,799 patient filled prescriptions for diabetic drugs between 8/1/07 to 11/30/07
6,880	patients filled a prescription for rosiglitazone
1,484	patients filled ONLY rosiglitazone
979	patients had a diagnosis for a co-morbid condition
5,396	patients filled rosiglitazone and other diabetic drugs
3,672	patients had a diagnosis for a co-morbid condition

Chart 3

Co-morbid Conditions at Risk with Rosiglitazone
Diagnosis	ICD-9
Acute Myocardial Infarction	410, 414.8, 412, 411.1
Congestive Heart Failure	428
Stroke	434.91, 434.11, 434.01
Unstable Angina	411.1
Stable Angina	413.9
Transient Ischemic Attack	435.1,435.9,437.0,437.1,414.9
Elevated LDL	272.0, 272.4

The result of the analysis indicates that approximately 67 percent of patients who filled a prescription for rosiglitazone may have one or multiple co-morbid conditions that may increase their potential risk of heart attack and/or heart failure. It is per FDA recommendations that patients with T2DM who have underlying heart disease or who are at high risk of heart attack and who are currently taking rosiglitazone should be re-evaluated for appropriate treatment options or closely monitored for cardiovascular risks.²⁴

Although the FDA has concluded that there is currently not enough evidence to indicate that the risk of heart attack or death is different between rosiglitazone and other oral diabetes treatments, the FDA advises health care providers to closely monitor patients taking rosiglitazone for cardiovascular risks.²⁵ Effective management of T2DM requires persistent monitoring and adjustment of therapy.²⁶ Early and aggressive management of glycemia by addressing mean glucose levels is vital to preventing or delaying the development of diabetic complications.²⁷ Medi-Cal recommends following AACE and ADA guidelines for treatment goals and for physicians and patients to weigh the benefits and risks of treatment with rosiglitazone.

References

1. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus. Endocrine Practice 2007; 13 (Suppl 1); 3-68
   www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf
2. Nathan, DM. Thiazolidinediones for Initial Treatment of Type 2 Diabetes? NEJM 2006; 355; 2477-2480
3. Brown, DA and Unrein, C. A Review of Cardiovascular Comorbidities of Diabetes. The American Journal of Managed Care;8: Supplemental 2: 3-10
4. Chitre, MM and Burke S. Treatment Algorithms and the Pharmacological Management of Type 2 Diabetes. Diabetes Spectrum 2006; 19: 249-255
5. Chitre, MM and Burke S
6. Chitre, MM and Burke S
7. Chitre, MM and Burke S
8. Brown, DA and Unrein, C
9. www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf
10. Brown, DA and Unrein, C
11. Kahn, SE et al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. NEJM 2006; 355: 2427-43
12. Chitre, MM and Burke S
13. www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf
14. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01683.html
15. Nesto, et al. Thiazolidione Use, Fluid Retention, and Congestive Heart Failure. Circulation 2003; 108: 2941-2948
16. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01683.html
17. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html
18. Nissen SE and Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. NEJM 2007; 356: 2457-71
19. Nissen SE and Wolski K
20. Krall, RL. Cardiovascular Safety of Rosiglitazone. The Lancet 2007; 369: 1995-1996
21. Kahn, SE et al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. NEJM 2006; 355: 2427-43
22. Home PD et al. Rosiglitazone Evaluated for Cardiovascular Outcomes – An Interim Analysis. NEJM 2007; 357: 28-38
23. Lipscombe, LL et al. Thiazolidinediones and Cardiovascular Outcomes in Older Patients with Diabetes. JAMA 2007; 298: 2634-2643
24. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html
25. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html
26. www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf
27. www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf