Drug Information Center

• Drug Information Group
• Department of Pharmacy Practice
• About Us
• People
• Potential Partnerships
• The RxPress
• Residency Program
• Frequently Asked Questions
• Contact Us
• Feedback

Do any drugs for the treatment of diabetes reduce the risk of cardiovascular disease?

Background

Diabetes is a chronic illness that requires patient education and medical care to prevent acute problems and to reduce the risk of long-term complications.¹ An estimated 20.8 million Americans (7% of the population) have diabetes mellitus.² Guidelines from both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) state that patients with type 2 diabetes mellitus should receive all appropriate components of care (nutritional therapy, exercise, weight management, pharmacologic intervention, and diabetes education) as a means of achieving and maintaining recommended levels of glycemic control (i.e. A1C < 7%). The ADA guidelines recommend early intervention with metformin in combination with lifestyle changes for initial therapy. The oral medications currently available for the treatment and management of type 2 diabetes mellitus include metformin, sulfonylureas, thiazolidinediones, meglitinides, and alpha glucosidase inhibitors.

Type 2 diabetes is associated with an increased risk of all cause mortality and cardiovascular (CV) disease. However, clinical trials to date have not demonstrated that achieving a normal glucose level can reduce the risk of macrovascular events, including CV outcomes, despite the fact that microvascular complications (retinopathy, neuropathy) are reduced.^3,4 Some data suggest that intensive treatment regimens might increase the risk of CV outcomes in patients with type 2 diabetes.

The United Kingdom Prospective Diabetes Study (UKDPS) reported that intensive blood glucose control with sulfonylureas or insulin substantially reduced the risk of microvascular complications, but did not affect macrovascular disease outcomes.⁴ Metformin was included as a randomization option in overweight patients in the UKPDS as part of the original protocol. The results of this study showed that metformin therapy in diet-treated overweight patients reduced the risk of myocardial infarction (MI) and all-cause mortality. However, there was an increased risk for diabetes-related death and all-cause mortality when metformin was given in addition to a sulfonylurea, which was hypothesized by the authors to be due to chance. No definite conclusion was drawn from the study with respect to the use of metformin in reducing CV outcomes.

The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial evaluated patients with type 2 diabetes at high risk of CV events, and whether intensive glucose control with multiple combinations of oral agents would result in lower CV outcomes or death when compared to standard treatment.⁵ The final results of the trial showed that a greater percentage of patients in the intensive group died when compared to the standard treatment group (5% vs. 4%; hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.01 to 1.46, p=0.04). Due to these results, the data safety and monitoring board recommended that the study be discontinued for safety reasons.

In comparison, the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) compared standard glucose control to intensive glucose control, defined as the use of gliclazide plus other drugs as required to achieved an A1C of 6.5% or less.⁶ The results of the trial showed that compared with the standard control, intensive glucose control resulted in a significant reduction in the incidence of microvascualar events, but did not affect the incidence of major macrovascular events.

Literature review

A meta-analysis published in the New England Journal of Medicine, found that rosiglitazone recipients had an increased risk of MI when compared to the control group with an OR 1.43 (95% CI 1.03 to 1.98, p=0.03)).⁷ The odds ratio for CV death in the study was 1.64 (95% CI 0.98 to 2.74, p=0.06). However there were several limitations to this meta-analysis. Most of the studies were designed to assess endpoints other that CV disease, overall event rates were low partially due to short duration of trials, patient event data were unavailable for time to event analysis, and relevant events such as stroke or non-cardiovascular deaths were not reported.

The effects of rosiglitazone on CV events needed to be evaluated more closely in order to determine the clinical relevance. Accordingly, an interim analysis of the RECORD trial ( Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) was conducted to evaluate the CV effects of rosiglitazone.⁸ The trial included patients with type 2 diabetes with inadequate glycemic control while receiving metformin or sulfonylurea. Patients were randomized to receive add on rosiglitazone or a combination of metformin and sulfonylurea (control group). The primary outcome measure was hospitalization or death from CV causes. Two key secondary endpoints were death from CV causes and incidence of MI.

The interim results of this trial showed that after 3.75 years of follow up, there was no statistically significant difference between the rosiglitazone group and the control group in terms of the primary outcome (HR 1.08, 95% CI 0.89 to 1.31), MI (HR 1.16, 95% CI 0.75 to 1.81) and death from CV causes (HR 0.83, 95% CI 0.51 to 1.36).⁸ Rosiglitazone therapy was associated with a significantly higher incidence of heart failure (HR 2.15, 95% CI 1.30 to 3.57). The data thus far do not allow a conclusion as to whether treatment with rosiglitazone results in a higher rate of MI than does therapy with metformin or a sulfonylurea. Completion of the study will provide clearer results on the CV outcomes of rosiglitazone.

To date, no evidence has pointed to an increased risk of MI with pioglitazone. Data from PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events), a randomized, double-blind trial comparing pioglitazone to placebo in patients with diabetes and evidence of macrovascular disease, demonstrate the pioglitazone significantly reduced the incidence of the secondary composite endpoint of all-cause mortality, non-fatal myocardial infarction, and stroke (16% risk reduction, p=0.27).⁹ However, this trial has been criticized for the use of a composite endpoint and the fact that there was no significant difference between groups in the primary outcome, a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle.

Latest literature: meta-analyses

A meta-analysis of 9 trials evaluated the effects of combination therapy with metformin and sulfonylureas on the risk of all-cause mortality and CV disease among people with type 2 diabetes.³ The results of this analysis revealed that the combination increased the relative risk of the composite endpoint of CV hospitalization or mortality (RR 1.43, 95% CI 1.10 to 1.85) regardless of the reference groups (diet therapy, metformin monotherapy, sulfonylurea monotherapy). There were no significant effects of this combination on either CV mortality (RR 1.29, 95% CI 0.73 to 2.27) or all-cause mortality (RR 1.19, 95% CI 0.88 to 1.62). Diabetes is a progressive disease for which many patients are placed on combination oral antihyperglycemic agents in order to meet glycemic goals. A hypothetical explanation of the increased risk associated with this combination may be due to the fact that patients on combination therapy are likely to have advanced diabetes.

Selvin and colleagues conducted a meta-analysis to determine if newer antidiabetic agents (thiazolidinediones and meglitinides) were similar to older agents (metformin, and sulfonylureas) in terms of CV risk/safety.¹⁰ Overall, 40 trials that reported data on CV events and/or mortality were included. In the majority of these studies, CV outcomes were recorded as adverse events - not as a primary or secondary outcome with the exception of the PROactive study and the UKPDS trials. The analysis compared metformin to any comparator, any sulfonylurea vs. any comparator, rosiglitazone vs. any comparator, and pioglitazone vs. any comparator. The pooled results for comparisons of interest are highlighted in the table below.

Table 1. Meta-analysis results for between group comparisons.¹⁰

*Data reported as Odds Ratio (95% confidence interval); N/A=not available due to lack of comparative data

The authors found that metformin was associated with a statistically significant decrease in CV mortality (OR 0.74, 95% CI 0.62 to 0.89), and rosiglitazone was the only oral therapy that was associated with a possible increase in the risk of CV morbidity or mortality (OR 1.68 and 1.03, respectively), but these results were not statistically significant (95% CI 0.92 to 3.06 and 0.30 to 3.53, respectively). One of the limitations of this meta-analysis was the lack of sufficient number of trials for the various comparison groups; therefore, the total data were not pooled. In addition, only 2 studies in this meta-analysis had participant follow up for longer than 2 years.

Conclusion

The current evidence regarding the risk of CV morbidity and mortality from antidiabetes drugs is conflicting. At present, clinicians must rely on observational studies to arrive at conclusions and make appropriate recommendation for patients with diabetes. Any strategy that lowers glucose and is associated with a low risk of hypoglycemia should be considered appropriate in patients with type 2 diabetes. In addition, clinicians should continuously monitor for adverse events from these antidiabetic medications, and make appropriate changes when necessary. Metformin, the first-line recommendation from ADA, appears to have protective effects against CV complications, but this result must be confirmed from prospective trials. The final results of the RECORD trial will provide further insight into the CV effects of rosiglitazone.

References

1. American Diabetes Association. Standards of medical care in diabetes. Diabetes care. 2007;30(Supp 1):S4-S41.
2. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13(Suppl 1):1-68.
3. Rao AD, Kuhadiya N, Reynolds K, Fonseca VA. Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta analysis of observational studies. Diabetes Care . 2008; 31(8):1672–1678.
4. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-865.
5. Gerstein HC, Miller ME, Byington RP, et al. Effect of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358(24):2545–2559.
6. Patel A, MacMahon S, Chalmers J, et al . Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572.
7. Nissen S, Wolski S. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356(24):2457-2471.
8. Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes: an interim analysis. N Engl J Med. 2007;357(1):28-38.
9. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): a randomized, controlled trial. Lancet. 2005;366 (9493):1279-1289.
10. Selvin E, Bolen S, Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: a systematic review. Arch Intern Med. 2008;168(19):2070-2080.

By Kalpa Patel, PharmD