Cardiometabolic Response to Diabetes Agents Differ by Gender

Senior man and woman looking at a tablet device togetherWhile widely used diabetes medications have similar effects on glucose control regardless of gender, these agents may have different effects on the hearts of men and women, according to findings reported in the December issue of the American Journal of Physiology - Heart and Circulatory Physiology.

The most marked difference was found for metformin. "Instead of making heart metabolism more normal in men, metformin alone made it worse, looking even more like a diabetic heart," said senior author Robert J. Gropler, MD, Professor of Radiology, Washington University School of Medicine, St. Louis, Missouri. "But in women, metformin did not have this effect on the heart," Dr. Gropler said.

The study involved use of imaging studies to assess the cardiometabolic effects of anti-diabetes agents. "If you use standard measurements, you're going to miss the sex differences we observed," Dr. Gropler said. "This may mean we have to do more complex imaging of the heart to better understand which therapies are best for which patients."

"Further studies with a larger sample size and clear correlation with clinical outcomes are needed before the general scope of diabetes management can change," commented Hayder D. Hashim, MD, Fellow, Cardiovascular Diseases, Rutgers-New Jersey Medical School, Newark, NJ. "This is definitely a leading study in this field with an elegant design from which one can entertain the possibility of different treatment approaches based on gender/sex," said Dr. Hashim, who is also Vice President of the American Heart Assocation Fellows Society of Greater New York.

Imaging Studies Use to Measure Cardiac Metabolism
The investigators evaluated 78 patients, who were randomized to one of three groups: metformin alone; metformin plus rosiglitazone; and metformin plus omega-3-acid ethyl esters. The patients underwent positron emission tomography, echocardiography, and whole body tracer studies before and 3 months after randomization.

In the overall group, no differences in heart metabolism were seen. However, when the researchers assessed the data by gender, differences emerged despite similar effects on blood glucose control.

In men, metformin decreased whole-body fatty acid clearance and was linked to increased plasma fatty acid levels, myocardial fatty acid utilization and oxidation, and lower myocardial glucose utilization. Adding rosiglitazone or omega-3-acid ethyl esters to metformin appeared to mitigate some of these negative effects.

Women showed a nonsignificant trend toward increased whole-body fatty acid clearance with metformin and experienced further benefits by adding rosiglitazone with a further increase in fatty acid clearance, which was linked to decreased plasma fatty acid levels and myocardial fatty acid utilization.

The addition of omega-3-acid ethyl esters did not significantly affect triglyceride levels, but did improve diastolic function, particularly in men.

"Our study suggests that we need to better define which therapies are optimal for women with diabetes and which ones are optimal for men," Dr. Gropler said.

"It is imperative that we gain understanding of diabetes medications and their impact on the heart in order to design optimal treatment regimens for patients," said co-author Janet B. McGill, MD, Professor of Medicine at Washington University School of Medicine. "This study is a step in that direction," she said.

"It is quite difficult to draw conclusions based on this study that may alter the clinical practice due to the small sample size," Dr. Hashim commented. He added that this was not an outcomes study and, thus, "it is unclear whether the changes they found in myocardial metabolism and substrates uptake can be correlated with any clinical outcome."

Furthermore, he noted that the study does not describe whether patients had other comorbidities and whether patients were taking other medications for confounding conditions. Patients were excluded from the trial if they were taking thiazolidinedione treatment within the past 6 months, insulin therapy for more than 2 weeks in the past year, corticosteroids, hormone replacement medication, and niacin or fibrate treatment within 6 months, or had serum triglycerides >400 mg/dL, liver disease, creatinine >1.5 mg/dL for women or 1.6 mg/dl for men, or ≥2+proteinuria.

Intrinsic Gender Difference in Cardiac Metabolism
Previous work from Dr. Gropler and colleagues found gender differences in cardiac metabolism even among healthy men and women. Healthy male hearts tend to burn more glucose, while healthy female hearts tend to burn more fat. This difference may help explain why women with diabetes tend to develop more aggressive heart failure than men: women already burn more fat.

"We now know there are sex differences at baseline, both in the metabolism of healthy hearts and in the hearts of patients with diabetes," Dr. Gropler said. "We are adding to the message that these sex differences persist in how patients respond to drugs. For patients with diabetes, it appears we are going to have to be more attentive to sex differences when we design therapies," he said.

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