Combination treatment may help type 2 diabetes patients

New research presented by Peter Weissman, M.D., from the University of Miami, at the 64th Annual Scientific Sessions of the American Diabetes Association shows that combination treatment with rosiglitazone maleate and metformin significantly improves certain markers of cardiovascular disease risk in patients with type 2 diabetes compared to metformin alone.

These data suggest that this combination of treatments provides certain cardiovascular benefits more effectively than metformin treatment alone. "Rosiglitazone has shown to be effective in improving glycemic control and reducing insulin resistance; now these new data show that the early addition of rosiglitazone to metformin monotherapy may offer other complementary and additive cardiovascular benefits in patients with type 2 diabetes," said Dr. Weissman, lead study author and associate clinical professor of Internal Medicine, University of Miami School of Medicine.

"These findings are important because cardiovascular disease is so prevalent and is the leading cause of diabetes-related deaths." Diabetes is a serious disease, which if not managed properly can cause debilitating and potentially life-threatening complications, such as cardiovascular disease. Cardiovascular disease is one of the most serious complications of diabetes and is attributed to 80 percent of diabetes-related deaths. Diabetes, in addition to smoking, high cholesterol levels and high blood pressure are all risk factors for cardiovascular disease.

Recent research shows that cardiovascular disease risk can also be assessed by "non-traditional" risk markers associated with the development of inflammation and atherosclerosis (the hardening of the arteries), including matrix metalloproteinase (MMP-9), plasminogen activator inhibitor-1 (PAI-1) and C-reactive protein (CRP) among others.

Combination Treatment Shows Potential Cardiovascular Benefits

These new data were from a sub-study of the EMPIRE clinical trial also presented at the American Diabetes Association Scientific Sessions. After 24 weeks of treatment, 90 patients in a sub-study were evaluated for changes in key cardiovascular biomarkers, including MMP-9, PAI-1 and CRP. This study compared two possible therapeutic strategies of uptitrating metformin monotherapy to a maximal level or adding rosiglitazone to a more moderate dose of metformin.

All study participants were initially treated with 500 mg twice daily of metformin for at least three weeks before being randomized in a blinded fashion to receive combination treatment with added rosiglitazone (2 mg bid, n=70) or an additional 500 mg of metformin (1500 mg daily dose, n=57, the uptitrated metformin group). After eight weeks, the doses were increased to a total daily dose of 8 mg of rosiglitazone plus 1 g of metformin or 2 g of metformin for an additional 16 weeks.

Treatment with rosiglitazone in combination with metformin resulted in positive improvements on known markers of cardiovascular disease risk beyond that of uptitrating metformin alone. Specifically, the rosiglitazone and metformin combination was found to have favorable treatment effects on MMP-9 [-29.92% (-46.21, -8.70) p=0.009] and PAI-1 [-32.38% (-51.36, -5.99) p=0.021], compared to uptitrating metformin monotherapy after 24 weeks.

The rosiglitazone plus metformin group demonstrated a significant reduction from baseline in CRP [-27.0% (-44.6, -3.8) p=0.026] compared to a non-significant reduction in CRP in the metformin uptitration group [-9.8% (- 38.1, 31.4) p=0.58]. The adverse events observed in the study were similar to those commonly seen with thiazolidinediones and metformin therapies, as described in the Avandia and metformin labels. "This study demonstrates the potential cardio-protective effects of combination therapy by adding a true insulin sensitizer, rosiglitazone, early to metformin therapy," said Dr. Weissman. "Since cardiovascular disease is such a common and dangerous complication of diabetes, using a treatment combination that can effectively manage blood sugar levels and offer potential cardiovascular benefits is extremely important."

Insulin Resistance, Diabetes and Cardiovascular Disease

Type 2 diabetes is characterized by high blood sugar levels that occur when the body cannot make enough insulin and/or is unable to respond normally to the insulin it already makes, a condition called insulin resistance.

Insulin resistance is one of the characteristics of the metabolic syndrome, which is a collection of health risks that increase a person's chance of developing heart disease, stroke, and diabetes. Research shows that insulin resistance is also an independent risk factor for cardiovascular disease. "The role that insulin resistance plays in the development of cardiovascular disease makes insulin sensitizers an attractive consideration when treating type 2 diabetes patients," said Dr. Weissman.

Important Safety Information About the Products Studied

The combination of rosiglitazone maleate and metformin HCl along with diet and exercise helps improve blood sugar control. A small number of people who have taken metformin have developed a rare yet serious condition called lactic acidosis (a buildup of lactic acid in the blood).

Lactic acidosis occurs most often in people with kidney problems and can be fatal in up to one half of the cases. Rosiglitazone and metformin combination therapy should not be used in people with kidney problems or in people 80 years of age and older whose kidneys are not functioning properly. Rosiglitazone and metformin combination therapy should not be used by people who drink alcohol excessively or by those taking medication for heart failure. It is not approved for use with insulin.

Some people may experience tiredness or weight gain with rosiglitazone and metformin combination therapy. Rosiglitazone and metformin combination therapy may also cause swelling, which, if left unchecked, could lead to or worsen heart failure. If you experience an unusually rapid increase in weight, swelling, shortness of breath, or have a history of these conditions, talk to your doctor immediately.

Rosiglitazone and metformin combination therapy is not recommended for people with liver disease. Also, blood tests to check for serious liver problems should be conducted before therapy, and periodically thereafter as determined by your doctor. If you experience unexplained tiredness, stomach problems, dark urine or yellowing of the skin, talk to your doctor immediately. Women who are nursing, pregnant, thinking about becoming pregnant or premenopausal should talk to their doctor before taking rosiglitazone and metformin combination therapy.