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| Prevention of type 2 diabetes mellitus through inhibition of the
Renin-Angiotensin system.
Scheen AJ.
Division of Diabetes, Department of Medicine, Nutrition and Metabolic
Disorders, CHU Sart Tilman, Liege, Belgium.
Type 2 diabetes mellitus is becoming a major health problem associated with
excess morbidity and mortality. As the prevalence of type 2 diabetes is
rapidly increasing, prevention of the disease should be considered as a key
objective in the near future. Besides lifestyle changes, various
pharmacological treatments have proven their efficacy in placebo-controlled
clinical trials, including antidiabetic drugs such as metformin, acarbose
and troglitazone, or anti obesity agents such as orlistat. Arterial
hypertension, a clinical entity in which insulin resistance is common, is
strongly associated with type 2 diabetes and may precede the disease by
several years. While antihypertensive agents such as diuretics or
beta-adrenoceptor antagonists may worsen insulin resistance and impair
glucose tolerance, newer antihypertensive agents exert neutral or even
slightly positive metabolic effects. Numerous clinical trials have
investigated the effects of ACE inhibitors or angiotensin II receptor
antagonists (ARAs) on insulin sensitivity in hypertensive patients, with or
without diabetes, with no consistent results. Almost half of the studies
with ACE inhibitors in hypertensive nondiabetic individuals demonstrated a
slight but significant increase in insulin sensitivity as assessed by
insulin-stimulated glucose disposal during a euglycemic hyperinsulinemic
clamp, while the other half failed to reveal any significant change. The
effects of ARAs on insulin sensitivity are neutral in most
studies.Mechanisms of improvement of glucose tolerance and insulin
sensitivity through the inhibition of the renin-angiotensin system (RAS) are
complex. They may include improvement of blood flow and microcirculation in
skeletal muscles and, thereby, enhancement of insulin and glucose delivery
to the insulin-sensitive tissues, facilitating insulin signalling at the
cellular level and improvement of insulin secretion by the beta cells.Six
recent large-scale clinical studies reported a remarkably consistent
reduction in the incidence of type 2 diabetes in hypertensive patients
treated with either ACE inhibitors or ARAs for 3-6 years, compared with a
thiazide diuretic, beta-adrenoceptor antagonist, the calcium channel
antagonist amlodipine or even placebo. The relative risk reduction averaged
14% (p = 0.034) in the CAPPP (Captopril Prevention Project) with captopril
compared with a thiazide or beta(1)-adrenoceptor antagonist, 34% (p < 0.001)
in the HOPE (Heart Outcomes Prevention Evaluation) study with ramipril
compared with placebo, 30% (p < 0.001) in the ALLHAT (Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial) with lisinopril
compared with chlorthalidone, 25% (p < 0.001) in the LIFE (Losartan
Intervention For Endpoint reduction in hypertension study) with losartan
compared with atenolol, and 25% (p = 0.09) in the SCOPE (Study on Cognition
and Prognosis in the Elderly) with candesartan cilexetil compared with
placebo, and 23% (p < 0.0001) in the VALUE (Valsartan Antihypertensive
Long-term Use Evaluation) trial with valsartan compared with amlodipine. All
these studies considered the development of diabetes as a secondary
endpoint, except the HOPE trial where it was a post hoc analysis. These
encouraging observations led to the initiation of two large, prospective,
placebo-controlled randomised clinical trials whose primary outcome is the
prevention of type 2 diabetes: the DREAM (Diabetes REduction Approaches with
ramipril and rosiglitazone Medications) trial with the ACE inhibitor
ramipril and the NAVIGATOR (Nateglinide And Valsartan in Impaired Glucose
Tolerance Outcomes Research) trial with the ARA valsartan. Finally, ONTARGET
(ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint
Trial) will also investigate as a secondary endpoint whether it is possible
to prevent the development of type 2 diabetes by blocking the RAS with
either an ACE inhibitor or an ARA or a combination of both. Thus, the recent
consistent observations of a 14-34% reduction of the development of diabetes
in hypertensive patients receiving ACE inhibitors or ARAs are exciting. From
a theoretical point of view, they emphasised that there are many aspects of
the pathogenesis, prevention and treatment of type 2 diabetes that still
need to be uncovered. From a practical point of view, they may offer a new
strategy to reduce the ongoing epidemic and burden of type 2 diabetes.
PMID: 15516153 [PubMed - in process]
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