Study Shows Impact of Coreg® (carvedilol) on Cardiovascular Risk Factors in Patients With Diabetes and Hypertension
Beta-blocker Coreg® (carvedilol) may provide advantages in patients with diabetes and hypertension, according to study results released by GlaxoSmithKline. GEMINI (Glycemic Effects in Diabetes Mellitus: Carvedilol Metoprolol Comparison in Hypertensives), presented at the 2004 American Heart Association Scientific Sessions, showed a positive impact of carvedilol on certain cardiovascular disease risk factors including blood pressure reductions, without negatively affecting HbA1c, a long term measure of blood sugar control, in diabetes patients with hypertension.

These findings are crucial since very few patients with diabetes have cardiovascular risk factors that are adequately controlled. In fact, it is estimated that only a little over seven percent of people with diabetes achieve treatment goals as recommended by medical experts, said Dr. George Bakris, Professor in the Departments of Preventive and Internal Medicine, and Director of the Hypertension Research Center at Rush University Medical Center in Chicago. It is our hope that the GEMINI trial will impact the future of diabetes management because it provides evidence of a positive impact of Coreg on cardiovascular risk factors for this hypertensive patient population without negatively affecting HbA1c.

Eighty percent of people with diabetes die of heart disease. Aggressive management of cardiovascular risk factors such as blood pressure, HbA1c, and microalbuminuria are very important since managing these risk factors may reduce the risk of heart attacks, strokes and death. Unfortunately, only 25 percent of people with diabetes reach blood pressure goals, about 37 percent reach HbA1c goals and up to 42 percent have microalbuminuria.

GEMINI is a six-month, randomized, double-blind active control trial that compared the effects of the newer beta-blocker carvedilol to the traditional beta-blocker metoprolol tartrate (marketed by Novartis as Lopressor). The 1,235 patients with type 2 diabetes and hypertension were on standard of care treatment consisting of antidiabetic therapies and ACE inhibitors or angiotensin II receptor blockers. Patients were randomized to receive 6.25 to 25 mg dose of carvedilol (n = 498) or 50 to 200 mg dose of metoprolol tartrate (n = 727) each twice daily, and were followed for approximately 6 months.

The primary outcome was the difference in change from baseline HbA1c between groups following 5 months of maintenance therapy. Secondary outcomes that were prespecified included key cardiovascular risk factors such as blood pressure control, glycemic control as measured by HbA1c and insulin resistance, microalbuminuria and weight gain, among others. The effects of the drugs on clinical outcomes have not been compared in long term clinical trials in hypertensive type 2 diabetic patients.

In the GEMINI trial, results included:
Blood Pressure: Patients on carvedilol reached protocol specified blood pressure goals at a mean daily dose of 35 mg; patients receiving metoprolol tartrate required a mean daily dose of 256 mg to reach protocol-specified blood pressure goals.
Diabetes control: In patients already receiving antidiabetic therapies, HbA1c was not negatively affected in patients receiving carvedilol while it worsened in patients receiving metoprolol tartrate. The difference between carvedilol carvedilol and metoprolol tartrate on HbA1c was 0.13 percent (p = 0.0039) and twice as many patients receiving metoprolol tartrate had changes of 1.0 percent or greater (p< 0.001).
- In carvedilol-treated patients, there was a statistically significant reduction in insulin resistance of 9.1 percent (p = 0.004); the reduction of insulin resistance of 2.0 percent for metoprolol tartrate treated patients was not statistically significant.
Microalbuminuria: The albumin: creatinine ratio (ACR), which is a measure of microalbuminuria, was measured in all of the patients in the trial and it was reduced in the patients treated with carvedilol by 16 percent (p=0.003) compared to metoprolol tartrate. At the start of the trial, 80 percent of the patients in GEMINI did not have microalbuminuria and in that group there was a 47 percent (p=0.03) risk reduction for the development of microalbuminuria in patients on carvedilol versus those on metoprolol tartrate.
Weight: Patients taking carvedilol did not gain weight. Patients taking metoprolol tartrate had a weight gain of 2.6 pounds (p<0.001).

Following Heart Care Guidelines Saves Lives
The closer hospitals adhere to national guidelines for treating potential heart attack patients, the greater the decline in their mortality rates, according to a analysis of treatment patterns at 315 U.S. hospitals by Duke Clinical Research Institute researchers.
The analysis is among the first of its kind to definitively link hospital™s improvement in use of guideline-recommended treatments with concomitant reductions in hospital death rates.

These findings should be a strong motivation to people, who until now found it difficult to commit to quality improvement initiatives without evidence that they work, said Eric Peterson, MD, who presented the results of the Duke analysis at the annual scientific sessions of American Heart Association (AHA). This study shows what a profound influence quality improvement can have on saving patients™ lives.

The study involved analyzing reports of hospitals™ adherence to treatment guidelines and mortality rates over a two-year period, from 2002 to 2003.

When we looked at the hospitals as a group at the beginning, they were almost indistinguishable from each other in their capabilities and services offered, said Peterson The only difference was that over time some changed their practices according to the guidelines and others did not.
However, when we then looked at how mortality rates changed from baseline to the latest quarter, what we found was remarkable, he continued. Those hospitals that were the worst at following the guidelines saw their mortality rates increase, while those hospitals that had the largest improvement in adherence had the greatest decrease in mortality rates. We believe this is the best argument for hospitals to devote the necessary time and effort into improving their systems for taking care of these patients.

Specifically, over time, the mortality risks rose by 3.1% at hospitals whose care had worsened. In contrast, mortality risks declined by 37% over the same time period among hospitals whose care patterns were most improved.

The guidelines, adopted after large-scale clinical trials demonstrated the effectiveness of specific therapies in saving lives, focus on giving suspected heart attack patients anti-platelet medications, heparin, glycoprotein IIb/IIIa inhibitors or beta-blockers within the first 24 hours of admission. The guidelines also call for prescribing aspirin, beta-blockers, ACE inhibitors or statins after discharge.

For the analysis, Peterson drew on the database of a national quality improvement initiative known as CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC and AHA Guidelines). CRUSADE maintains a national registry of data collected from more than 400 hospitals nationwide and then reports back to each hospital every three months on their adherence to the guidelines.
The current analysis focused on the quarterly changes in guideline adherence and mortality rate changes at 315 hospitals from all of 2002 through September of 2003. During that period, a total of 21,588 patients had been treated.

The hospitals were then divided into quartiles based on the degree to which they adhered to the guidelines. Each hospital was characterized as either: process worsening, no improvement, modest improvement or large improvement.

Altogether, adherence to the guidelines by the hospitals in the study improved from 67.9 percent to 77.3 percent during the study period. Over the course of analysis, the hospitals termed process-worsening had a negative 4.6 percent adherence to the guidelines and an average 3.1 percent increase in mortality. On the other end of the spectrum, the hospitals with the largest improvement had a 15.6 percent increase in adherence and a 37 percent decline in death rates.
The next step, according to Peterson, is to better understand the particular reasons behind each hospital™s inability to implement quality improvement initiatives.

Just because a hospital is participating in a program like CRUSADE is insufficient alone in making a change for the better, Peterson said. We will be conducting in-depth interviews at different hospitals to characterize why some are refractory to change, with a goal of helping them get better.

CRUSADE is coordinated by the DCRI. It is funded by Millennium Pharmaceuticals, Cambridge, Mass., and Schering Corp, Kenilworth, N.J. Bristol-Meyers Squibb/Sanofi Pharmaceuticals Partnership, NY, provided an unrestricted grant in support of CRUSADE.