Article Text

ACE inhibitors and insulin sensitivity
  1. N N CHAN
  1. The EURODIAB Data Coordinating Centre, Department of Epidemiology and Public Health, University College London, 1–19 Torrington Place, London WC1E 6BT, UK
    1. G PIEDROLA
    1. Plaza de los Campos 5, 18009 Granada, Spain

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      Sir,I read with great interest the study by Piedrolaet al. 1 An improvement in insulin sensitivity was found after 6 months in patients with coronary artery disease (CAD) treated with captopril and to a lesser extent diltiazem, compared to isosorbide mononitrate and atenolol. They subsequently concluded that captopril might be regarded as first choice therapy in the management of CAD, especially associated with metabolic abnormalities. This conclusion is misleading and there are major weaknesses in their study design.

      Firstly, angiotensin-converting enzyme (ACE) inhibitors are only licensed for treatment of hypertension and heart failure. The use of this group of drugs in normotensive patients with stable CAD may lead to hypotension, resulting in worsening of myocardial ischaemia. This is more likely to occur with the co-administration of captopril (short half-life) and isosorbide mononitrate.

      Secondly, Piedrola and colleagues excluded subjects with a previous history of hypertension in their study but made no reference to their blood pressure measured before and 6 months after treatment in various treatment groups. It has been shown that, in patients with non-obese and normoglycaemic essential hypertension, steady-state plasma glucose is higher than in normotensive subjects during insulin sensitivity tests.2 Hence, it is possible that the improved insulin sensitivity in the ACE inhibitor group could be related to a blood pressure lowering effect rather than a drug class effect.

      Previous studies investigating the effect of ACE inhibitors on insulin sensitivity have produced conflicting results. The validity of these studies is often compromised by poor study design, lack of placebo data, and heterogenous patient populations in which the biochemical mechanisms of insulin resistance and drug responses may differ. Overall, ACE inhibitors probably have a modest class effect by increasing muscle blood flow, inhibiting local renin–angiotensin system and increasing kinin levels, thereby enhancing insulin-mediated glucose disposal.2 While the role of ACE inhibitors in improving insulin sensitivity (a surrogate marker of CAD) has not been fully established, they should only be used in the presence of a clear clinical indication.

      References

      This letter was shown to the authors who responded as follows:

      Sir,In our recently published study, we demonstrated that the use of captopril and, to a lesser extent, diltiazem in patients with coronary artery disease (CAD) was accompanied by an improvement in insulin sensitivity.1-1 Dr Chan suggests that the use of angiotensin-converting enzyme (ACE) inhibitors in these patients may lead to hypotension and that the improvement in insulin sensitivity may be due to a decrease in blood pressure instead of a class effect of captopril.

      We found no adverse effects with the combination of isosorbide mononitrate plus captopril in our CAD patients. There were no changes in blood pressure through the 6-month study in patients treated with captopril, as low doses were used (12.5 mg/12 h). In fact, other drugs which are conventional therapies for CAD, such as diltiazem and atenolol (also used in our work) may decrease blood pressure (they are also first line therapy for hypertension1-2) and, at least in theory, worsen myocardial ischaemia. They have been shown to improve morbidity and mortality in CAD, however, and are now part of our current approach in these patients.

      Arterial hypertension has been related to insulin resistance; non-obese non-diabetic hypertensive patients display a decrease in insulin sensitivity in comparison to adequately matched controls.1-3These metabolic abnormalities have been shown to improve with the use of ACE inhibitors but not with other antihypertensive drugs (such as thiazides), provided that the same reduction in blood pressure is achieved.1-4 This strongly suggests that it is not the blood pressure lowering effect of the drug which modifies insulin sensitivity but a drug effect. The use of an ACE inhibitor is thus a logical approach in patients with metabolic abnormalities and CAD, and an improvement in insulin sensitivity in such patients with these drugs was demonstrated in our study. This does not mean that all CAD patients should be treated with ACE inhibitors, as not all of them display metabolic abnormalities. Further, we realise that no definite conclusion on morbidity and mortality can be drawn from our study. But the results do suggest that ACE inhibitors may represent a coadjutant therapy in the management of patients with CAD and a deleterious metabolic profile.

      References

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