CORRESPONDENCE: LETTER TO THE EDITOR
Preventing Type 2 Diabetes Mellitus With Angiotensin Blockade: Is it Clinically Relevant?
Anis Rassi, Jr., MD, PhD, FACC*
* Department of Cardiology, Anis Rassi Hospital, Avenida Jose Alves, 453, Setor Oeste, Goiânia, GO 74110-020, Brazil (Email: arassijr{at}terra.com.br).
Diabetes mellitus is a serious, costly, and increasingly common disease. In light of the dramatic epidemic of type 2 diabetes and its adverse prognostic implications, strategies to prevent or delay this major health problem are of paramount importance.
Abuissa et al. (1), in a meta-analysis of 12 recent randomized controlled clinical trials that enrolled patients with hypertension, chronic heart failure, or coronary heart disease, showed that angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) produced a highly significant 25% reduction (95% confidence interval [CI], 18% to 31%) in the incidence of new-onset diabetes when compared to placebo, diuretics, beta-blockers, or calcium channel antagonists. Apart from some limitations (e.g., new-onset diabetes as secondary end point or as post hoc analysis; open-blinded end point design in some trials; higher proportion of patients receiving drugs that increase insulin resistance such as diuretics and beta-blockers in the comparator groups; and absence of standardization for serial testing of blood glucose levels), the investigators concluded that the use of an ACE inhibitor or ARB should be considered in patients with prediabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.
However, focusing solely on the relative risk (RR) reduction and utilizing a surrogate marker (prevention of a fasting plasma glucose  126 mg/dl at two different visits in patients with no diabetes at the time of presentation) make it difficult to estimate the real benefit of the proposed intervention.
On the basis of the Abuissa et al. (1) meta-analysis, despite a significant RR reduction of 25%, the absolute risk difference between an ACE inhibitor or an ARB and the other agents was only 3.1 cases per 1,000 patient-years (decreasing from 17.4 to 14.3 per 1,000 patient-years), which means that 323 patients (1/0.0031) must be treated for one year to prevent the new onset of one case of diabetes mellitus. Moreover, it is important to mention that the final goal of the inhibition of the renin-angiotensin-aldosterone system in this particular situation is to prevent the diabetes-related morbidity and mortality rather than merely the diagnosis of diabetes. If one assumes that the risk of any diabetes-related macrovascular or microvascular complication is about 46 per 1,000 patient-years for newly diagnosed patients with type 2 diabetes (2), the number needed to treat (NNT) per year in order to prevent not only the development of type 2 diabetes mellitus but also any one of its subsequent complications increases to 7,013 [(1/0.0031) x (1/0.046)]. Even with a longer-term follow-up, let us say 10 years, given the time frame from onset of diabetes to diabetes-related complications, the NNT to prevent a clinical event would be extraordinarily high.
Needless to say, this type of analysis does not contemplate the already proved beneficial effects of ACE inhibitors and ARBs (by other mechanisms) on the reduction of major vascular events in certain conditions such as heart failure or after myocardial infarction. Of note, in another recent meta-analysis (3), ACE inhibitors or ARBs decreased patients’ odds of developing new-onset type 2 diabetes but did not reduce the odds of mortality, cardiovascular, or cerebrovascular outcomes among patients with hypertension. Therefore, instead of searching for pharmacological therapies that are statistically attractive but will never be clinically relevant or cost-effective, prevention of diabetes mellitus should be fundamentally approached by reducing the patient’s weight and increasing his or her physical activity (4,5).
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1. Abuissa H, Jones PG, Marso SP, O’Keefe Jr JH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes. A meta-analysis of randomized clinical trials J Am Coll Cardiol 2005;46:821-826.[Abstract/Free Full Text]2. UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998;352:837-853.[CrossRef][Web of Science][Medline] 3. Gillespie EL, White CM, Kardas M, Lindberg M, Coleman CI. The impact of ACE inhibitors or angiotensin II type 1 receptor blockers on the development of new-onset type 2 diabetes Diabetes Care 2005;28:2261-2266.[Abstract/Free Full Text] 4. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance N Engl J Med 2001;344:1343-1350.[Abstract/Free Full Text] 5. Lindstrom J, Louheranta A, Mannelin M, et al. The Finnish Diabetes Prevention Study (DPS)lifestyle intervention and 3-year results on diet and physical activity. Diabetes Care 2003;26:3230-3236.[Abstract/Free Full Text]
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