Reduction in the Incidence of Diabetes

The observations that fewer patients randomized to captopril developed diabetes than those randomized to the P-blocker in the CAPPP trial was initially met with skepticism about whether it was a real reduction with the ACE inhibitor or an increase in incidence of diabetes produced by the P-blocker comparator.6

However, this objection cannot apply to the results of the HOPE trial, which showed a 30% reduction in the new incidence of diabetes in the ramipril arm.98 There has been a rather consistent reduction in diabetes as assessed as a secondary end point in some of the major trials, including ALLHAT10 and PEACE.100

Similarly, major studies in hypertension comparing ARBs with other antihypertensive agents, such as in

LIFE13 and VALUE,15 and with placebo, such as in the

CHARM heart failure program,43 have indicated that both pharmacologic inhibitors of the RAS reduced the risk of developing new-onset diabetes. A meta-

analysis showed an approximately 20% reduction in the risk of developing diabetes in subjects receiving an ACE inhibitor or ARB.131

These observations have spurred basic research that has uncovered multiple potential mechanisms, such as reducing potential angiotensin II effect on the pancreatic fibrosis, improving insulin sensitivity in skeletal muscle, improving insulin signaling pathways, and other mechanisms whereby RAS

inhibition could influence glucose homeostasis.132 However, all the consistent and important observations from clinical trials must be considered as nondefinitive because they were derived from secondary end points from studies that were designed to address other questions. As part of a two-by-two factorial design, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone (DREAM) study much more directly and rigorously tested whether an ACE inhibitor could reduce the development of diabetes in an at-risk population.133 Although the primary end point of incidence of diabetes or death was 9% lower in the ACE inhibitor group, this difference was not statistically significant. A strong suggestion of an effect on glucose metabolism was, however, observed on prespecified secondary outcomes. An accompanying editorial indicated that hospitaliza-tion and ascertainment bias could have overestimated the RAS inhibitor influence on the incidence of diabetes in the prior trials and that the 95% confidence interval of DREAM (0.81 to 1.05) still encompassed an important possible benefit.134 The ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR), with more than 9000 subjects with impaired glucose tolerance randomized as part of a two-by-two factorial to the ARB valsartan or placebo, should settle this important issue.135

Renin Inhibitor Challenge

The cascade that leads to angiotensin II commences with the enzyme renin, which cleaves the peptide angiotensin I from angiotensinogen (see Fig. 12-1). Until recently, this first reaction has not been a clinically available pharmacologic target for inhibiting the RAS.136,137 Theoretically, inhibition at this site of initiation may provide a unique way to reduce both angiotensin I and II levels while preventing exposure to compensatory escape mechanisms. Renin inhibition would also be anticipated to reduce the influence of other angiotensin peptides138 more than ACE inhibitors or ARBs. Alternatively, combining a renin inhibitor with an inhibitor of angiotensin II generation (ACE inhibitor) or end receptor blocker (ARB) may provide the most effective means for long-term RAS inhibition. Commercialization of oral renin inhibitors has been severely hampered by a combination of poor bioavailability and a relatively expensive generation and production process. One agent, aliskiren, is emerging as an effective and apparently well-tolerated antihypertensive therapy.137 The relative merits and clinical usage will undoubtedly depend on clinical outcome studies that go beyond the surrogate of blood pressure reduction. For this agent to be a commercial success, the medical community must be convinced by robust outcomes studies, such as have been conducted with the ACE inhibitors and ARBs, that a renin inhibitor alone or in combination with other proven pharmacologic therapies is safe and effective in reducing cardiovascular risk to justify usage of a new agent.


The clinical utility of ACE inhibitors has evolved from limited use in severe, refractory hypertension to first-line therapy for essential hypertension. A similar pattern has emerged in the management of patients with ventricular dysfunction. ACE inhibitors were initially administered only to severely compromised patients with heart failure, until further studies (e.g., SOLVD, Pre-SAVE) demonstrated the survival benefits of ACE inhibitors in milder degrees of congestive heart failure and even when used in a preventive manner before the clinical manifestation of overt heart failure in patients with asymptomatic left ventricular dysfunction. With the proven benefits of ACE inhibitors first observed during acute and chronic MI, studies have now extended proof of benefits to high-risk vascular disease and stroke patients. This pattern of testing from severe to milder forms of disease was also used for patients with vascular disease. The development of ARBs offers a unique opportunity to determine whether more complete inhibition of the RAS could produce additional clinical benefits. This is an active area of clinical investigation that will likely determine the relative roles of ACE inhibitors and ARBs alone or in combination. The expanding indications for ACE inhibitor and ARB use have been based on an exciting convergence of basic and clinical investigations that have improved our understanding of pathophysiology, vascular biology, and patient care.

Some of the advancements in the use of these inhibitors of the RAS stemmed from hypotheses derived from basic laboratory research, such as renal nephron protection and the attenuation of adverse left ventricular remodeling after MI, which were translated into clinical benefits by randomized, controlled clinical trials. Other leads for innovative areas of research stemmed from observations of secondary, often not prespecified, end points from the clinical trial experience. These initially unexpected findings, such as reductions in atherosclerotic events and reductions of the incidence of diabetes and atrial fibrillation,139 provided the impetus for new randomized trials and important mechanistic studies. Inhibiting the angiotensin axis is perhaps one of the best examples of the importance of cross-fertilization between clinical outcomes and basic mechanistic studies.


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