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Are the thiazolidinediones associated with an increased risk of acute cardiovascular events in patients with type 2 diabetes?

Introduction
Diabetes affects 7.8% of the US population, which equates to about 23.6 million people, of which 6 million are undiagnosed.¹ Persons with impaired fasting glucose, signified by a fasting glucose level of 100 to 125 mg per deciliter, are considered pre-diabetic. It is estimated that 57 million adults in the US are pre-diabetic; without intervention these patients are at risk for developing diabetes. Type 2 diabetes mellitus (T2DM) accounts for approximately 90% to 95% of all diagnosed cases of diabetes. Obesity, physical inactivity, family history, and race/ethnicity are risk factors for developing T2DM.² Non-Hispanic blacks are known to be at higher risk for developing the disease.

Uncontrolled diabetes affects more than blood glucose. Microvascular (i.e. retinopathy, nephropathy, and neuropathy) and macrovascular complications (i.e. damage to major blood vessels, heart disease, myocardial infarction [MI], and stroke) may occur.² Of these, heart disease was noted on 68% of diabetes-related death certificates in persons 65 years of age and older.¹ The risk for stroke patients with diabetes is 2 to 4 times higher than the average person.² The best ways to reduce the risk of microvascular complications include maintaining a healthy diet, regular exercise, glucose control, and reducing hemoglobin A_1c (A1C) levels. The role of glycemic control in prevention of macrovascular complications is less clear based on recent literature.³

Clinical guidelines
The American Association of Clinical Endocrinologists (AACE) recommends initiating comprehensive care at the time of diagnosis of T2DM.⁴ This includes nonpharmacologic and pharmacologic interventions. Dietary modifications, increased physical activity, and weight management should be initiated first. For treatment-naïve patients with an A1C level between 6% to 7%, monotherapy with either metformin, thiazolidinediones (TZDs), secretagogues, dipeptidyl-peptidase 4 inhibitors, or α-glucosidase inhibitors is recommended. Combination therapy should be considered if glycemic control is not met after 3 months, or if the patient’s A1C is 7% to 8% at baseline. Unlike AACE, the American Diabetes Association (ADA) clinical consensus guidelines recommend metformin (unless contraindicated) in addition to lifestyle modifications as first-line (step 1) therapy in patients with T2DM.³ According to the ADA treatment algorithm, if the initiation of metformin does not produce goal A1C levels, then one may add either basal insulin (most effective) or a sulfonylurea. Step 3 therapy involves metformin in combination with intensive insulin therapy. All other oral agents are considered tier 2, less well-validated options. In regards to the TZDs, pioglitazone is the preferred agent; rosiglitazone is no longer recommended. In addition to controlling blood glucose, a crucial part of diabetic care is achieving and maintaining blood pressure and cholesterol goals. Early intervention in these aspects can decrease risk of macrovascular complications.

Background
An area of interest for researchers is the connection with medications used in glycemic control and their ability to reduce the occurrence of macrovascular events. The TZDs, which include rosiglitazone and pioglitazone, improve A1C and may also be beneficial in reducing cardiovascular events by improving lipid profiles (effects differ between agents), vascular, and hemodynamic parameters.^2,5 The adverse effect profile of TZDs includes water retention and weight gain; both pioglitazone and rosiglitazone include a boxed warning regarding an increased risk of developing or exacerbating heart failure.^5-7 The TZDs are contraindicated in class III and IV heart failure. A recent review article by Stafylas and colleagues summarized data on the controversial effects of TZDs on cardiovascular events.⁵ Seven studies were highlighted in the review and consisting of both meta-analyses and randomized, controlled clinical trials. Safety was the primary endpoint in these studies, which included risk of fatal or non-fatal MI, stroke, time to first hospitalization, cardiovascular mortality, or the composite of these outcomes. The authors concluded that although heart failure is a known adverse effect of both TZDs, pioglitazone is associated with less cardiovascular events. In order to justify a change in clinical practice, further studies are warranted to demonstrate the increased risk of cardiovascular events with TZDs and whether a difference does exist between the 2 available medications in this class.

Literature review
Juurlink and colleagues conducted a population based, retrospective, cohort study over 72 months to assess the risk of adverse cardiovascular events during treatment with TZDs.⁸ Subjects included those 66 years of age and older, all of whom were treatment naïve to TZDs (no TZD prescription within the previous year prior to current prescription/index date). A total of 39,736 patients were identified as started on either rosiglitazone (n=16,951) or pioglitazone (n=22,785); there were no differences in baseline characteristics between the 2 groups. The mean age in each group was 72 years, and the majority of patients had a history of diabetes for more than 5 years. Patients were excluded if they had taken insulin within the past year. The primary outcome measure was death from any cause or first admission into a hospital or emergency department for acute MI or heart failure. Secondary outcome measures were each of these occurrences individually.

Cox proportional hazards ratio (HR) was used to estimate the risk of cardiovascular events between the 2 TZDs.⁸ Both unadjusted HRs and adjusted hazard ratios (aHRs) were calculated. Baseline characteristics such as age, sex, duration of diabetes, and socioeconomic status were included in the aHR. Overall, 1563 (6.9%) patients taking rosiglitazone and 895 (5.3%) receiving pioglitazone reached the primary outcome. For the primary outcome, a statistically significant difference was found between the 2 groups in favor of pioglitazone (aHR 0.83, 95% CI 0.76 to 0.90). Analyses of the secondary outcomes also favored pioglitazone. There were statistically significant differences in heart failure (aHR 0.77, 95% CI 0.69 to 0.87) and all cause mortality (aHR 0.86, 95% CI 0.75 to 0.98); however no significant difference was found between the 2 groups in the risk of MI (aHR 0.95, 95% 0.81 to 1.11). Unadjusted HRs were similar to aHRs.

For the primary outcome, the authors estimated a number needed to harm (NNH) of 93, meaning that for every 93 patients treated with rosiglitazone instead of pioglitazone annually, one event would occur.⁸ The annual NNH for rosiglitazone compared with pioglitazone for congestive heart failure and death from any cause were 120 and 269, respectively.

Dose response was also analyzed, which compared low dose rosiglitazone (2 or 4 mg), low dose pioglitazone (15 mg), and high dose pioglitazone (30 or 45 mg) to high dose rosiglitazone (8 mg, served as the comparative control).⁸ Low dose rosiglitazone was not associated with a significant decrease in the primary outcome (aHR 0.94, 95% CI 0.83 to 1.07). A significant decrease in the primary outcome was demonstrated by both low dose (aHR 0.83, 95% CI 0.70 to 0.97) and high dose pioglitazone (aHR 0.76, 95% CI 0.66 to 0.88).

The authors concluded that compared to rosiglitazone, the risk of adverse cardiovascular effects are lower with pioglitazone.⁸ The study followed almost 40,000 patients and with an adequate power determined a difference in all cardiovascular events except for MI. There are limitations to this study that must be considered. This chart review was conducted only in patients over 65 years of age. Trends have shown T2DM affects young people, and the cardiovascular risks associated with this disease increase at a young age. This study also did not report racial backgrounds of the patients and may not be diverse enough to apply to every medical population. Finally, an assessment of baseline cardiovascular risk was not thoroughly completed; therefore, it is unclear if one group was at greater risk for developing cardiovascular complications. The Charlson score, which considers the co-morbidities of a patient in determining 10-year risk of death, was not calculated for 70% of the patients in each group at baseline. Additionally, the Framingham 10-year risk score could have been used to estimate the risk for MI or coronary death.

Conclusion
It is already known that rosiglitazone and pioglitazone have significant capability of improving glycemic control, although both TZDs carry a boxed warning of the risk for developing congestive heart failure. This adverse effect is primarily due to a mechanism that increases water retention; TZDs are contraindicated in class III and IV heart failure. Meta-analyses and clinical trials have concluded that there is a greater association of heart failure and MI when rosiglitazone was compared with other hypoglycemic agents or placebo. This cohort study was the first to investigate whether a class effect exists, or if rosiglitazone is more dangerous than pioglitazone in relation to cardiovascular events. The results from this cohort study compound the evidence against the use of rosiglitazone, especially due to the significantly higher risk of heart failure and death associated with its use. The lack of a class effect between the 2 TZDs, at least in patients over 65 years of age, suggests that pioglitazone is a better option for patients with T2DM. The AACE and ADA remain the standard for the treatment of diabetes. The impact of this cohort study in prescribing TZDs for T2DM remains to be seen. Although more research is warranted, this cohort study along with the ADA recommendations, should prompt healthcare professionals to be more vigilant in monitoring their patients who are prescribed TZDs, and rosiglitazone use should be avoided.

References

By Alina Meile, PharmD candidate