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Telmisartan Improves Endothelial Function and Nitrate Tolerance in Patients With Coronary Artery Disease and the Metabolic Syndrome: Presented at ESC

By Chris Berrie

VIENNA, AUSTRIA -- September 11, 2007 -- The angiotensin II blocker telmisartan improves endothelial function and prevents nitrate tolerance and nitroglycerin-induced endothelial dysfunction in patients with coronary artery disease (CAD) and metabolic syndrome, according to a randomised study presented here at the European Society of Cardiology (ESC) Congress.

"Telmisartan is mainly an angiotensin II receptor blocker, but recently it has [shown] antioxidant effects and insulin resistance improvement effects," said principal investigator Hideki Watanabe, MD, Chief, Department of Internal Medicine (Outpatients), Kinn Medical Association Hospital, Mitsukaido, Japan.

These beneficial effects may arise from the drug's reported inhibition of peroxisome proliferators-activated receptor-gamma, which have been implicated in the progression of insulin resistance and oxidative stress.

In addition, metabolic syndrome has not only been associated with insulin resistance and impaired endothelial function, but it is an independent risk factor for CAD. As for continuous nitroglycerin treatment, it induces nitrate tolerance in these patients as well as endothelial dysfunction due to increased oxidative stress, Dr. Watanabe said in a presentation on September 5th.

Therefore, Dr. Watanabe and colleagues designed a study to investigate the effects of telmisartan on endothelial functions and nitrate tolerance in patients with CAD and metabolic syndrome.

The study excluded patients with renal failure, smokers, those taking of antioxidants, with heart failure, taking hormone replacement therapy or thioridazines. Thirty patients with CAD and metabolic syndrome were enrolled for 8 weeks of treatment.

A control group of 15 patients was randomised to standard CAD therapy (mean age, 66 years; male, 67%) and another 15 patients received standard therapy plus telmisartan 40 mg/day (mean age, 66 years; male, 80%). All patients received nitroglycerine from weeks 4 to 8 (patch; 20 mg/day)

Patient evaluations were performed at baseline and after weeks 4 and 8. Endothelial function was measured via flow-mediated dilatation (endothelium-dependent vasodilatation) and nitroglycerin-induced dilatation (endothelium-independent dilatation), as determined through measures of brachial artery diameter at rest and during reactive hyperaemia.

Oxidative stress and insulin resistance were determined biochemically following blood sampling. For oxidative stress, malondialdehyde levels were determined spectrophotometrically using thiobarbituric acid reacting substance, while insulin resistance was evaluated through the homeostasis model assessment for insulin resistance.

Exercise tolerance was determined using a treadmill exercise test following the Bruce procedure, as defined by total exercise time (ExT) until achievement of a 1-mm ST depression (at 60 ms post J point) on electrocardiogram.

After 4 weeks of treatment, the endothelium-dependant measure of flow-mediated dilatation was significantly increased in the telmisartan group (P <.01, vs control group), indicating improvements in endothelial dysfunction with telmisartan. For the endothelium-independent measure of nitroglycerin-induced dilatation, no effects were seen with telmisartan treatment.

There was also a significant decrease in thiobarbituric acid reacting substance with telmisartan (P <.01, vs control group), indicating improvements in oxidative stress conditions in this group. Furthermore, telmisartan produced a significant decrease in the elevated homeostasis model assessment for insulin resistance measures (P <.01, vs control group). No effects of telmisartan were seen on total exercise time at this stage.

Following application of nitroglycerin on weeks 4 to 8, a significant decrease in flow-mediated dilatation for control patients indicated nitroglycerin-induced endothelial dysfunction (P <.01). However, this add-on nitroglycerin treatment did not affect the previous telmisartan-induced improvements in endothelial function (P <.01), thus indicating that telmisartan also protects against nitroglycerin-induced endothelial dysfunction.

Similarly, for the nitroglycerin-induced dilatation measures at week 8, the nitroglycerin-induced nitrate tolerance in the control group (P <.01) was completely prevented by telmisartan (P <.01).

A similar effect was seen for thiobarbituric acid reacting substance measures of oxidative stress. Continuous nitroglycerin treatment caused a small but significant increase in oxidative stress in the control patients (P <.01). Here, the improved oxidative stress conditions of the telmisartan-treated patients at week 4 did not change further upon nitroglycerin application, indicating that telmisartan not only improves oxidative stress, but also prevents the increase in oxidative stress after continuous nitroglycerin therapy.

For insulin resistance, there were no changes with this nitroglycerin application.

Finally, while there was a small but significant decrease in total exercise time in control patients with nitroglycerin from weeks 4 to 8 (P <.01), which again was indicative of nitrate tolerance. Telmisartan treatment significantly increased total exercise time (P <.01), indicating improved exercise tolerance in telmisartan-treated patients under continuous nitroglycerin treatment.

Therefore, through use of these surrogate markers, telmisartan was seen to significantly improve endothelial function and prevent nitrate tolerance and nitroglycerin-induced endothelial dysfunction in patients with CAD and metabolic syndrome in this study. As such, Dr. Watanabe said, "There were no problems of any adverse effects or side effects, no problems, in this study... and I would recommend [telmisartan] very strongly for coronary artery disease patients."


[Presentation title: Effects of Telmisartan on Endothelial Function and Nitrate Tolerance in Patients With Coronary Artery Disease and the Metabolic Syndrome. Abstract 4698]

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