Upregulated bradykinin and nitric oxide, both of which promote increased skeletal muscle and pancreatic blood flow, are suggested to be the mediators of the improved glycemia noted during ACEI and ARB therapy [31]. Use of agents from these drug classes is also reported to improve angiotensin-II-mediated oxidative stress in the beta cell [32]. On account of their favorable glucose effect, ACEIs and ARBs are considered the “preferred” antihypertensive medications in people at high CVD risk (Chap.​ 36).

In the preceding section, we showed that lisinopril was associated with a slightly lower FG level as compared to the thiazide-like diuretic chlorthalidone with little or no clinical impact. The next question we address is whether RAS blockade prevents new-onset glucose disorders or ameliorates prevalent glucose disorders better than placebos.

In the Heart Outcomes Prevention Evaluation (HOPE) trial [33], the risk of self-reported incident diabetes was less in those assigned to the ACEI ramipril compared to placebo (3.6 % vs. 5.4 %; relative ratio [RR] 0.66 [95 % CI 0.51–0.85]; P < 0.001). In the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial [34], the risk of incident diabetes was less in those assigned to the ARB valsartan compared to placebo (33.1 % vs. 36.8 %; RR 0.86 [0.80–0.92]; P < 0.001). In contrast, treatment with ramipril did not reduce incident diabetes in people with impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) (17.1 % vs. 18.5 %; RR 0.91 [0.80–1.03]; P = 0.15) in the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial [35]. This study was specifically designed to investigate the effects of RAS blockade on diabetes prevention. The Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial [36] also found no evidence that the addition of telmisartan to usual care prevented incident diabetes or led to regression of IFG or IGT in persons at high risk for cardiovascular disease but free from diabetes. During a 56-month median period of treatment, 21.8 % of the participants treated with telmisartan compared to 22.4 % of their counterparts on placebo developed diabetes (RR 0.95 [95 % CI 0.83–1.10]; P = 0.51). Participants with IFG and/or IGT at baseline were equally likely to regress to normoglycemia (26.9 % vs. 24.5 %) or to progress to incident diabetes (20.1 % vs. 21.1 %; P = 0.59) during telmisartan or placebo therapy.

Variation in patient age and prior history of CVD may have played important roles in explaining study outcome differences. The NAVIGATOR trial (which used an ARB) enrolled individuals who were younger than those in TRANSCEND (which also used an ARB) and had a much lower prevalence of CVD (24 % vs. 80 %). Increasing age and prevalent CVD are associated with increased insulin resistance [37, 38].

Many of the ACEI studies were post hoc analyses in which incident diabetes was not a prespecified outcome. The results relied on physician-reported or self-reported incident diabetes rather than measures of FG or 2-h post-challenge levels of blood sugar. This makes it likely that many of the study participants with seemingly normal glucose metabolism would have been diagnosed with new-onset diabetes had they been thoroughly investigated.

In summary, there is no strong evidence that RAS blockade has an important antidiabetic effect when added to other cardiovascular agents for the treatment or prevention of atherosclerotic heart disease (ASHD) in people at high risk, most of whom have HTN.

First-generation β-blockers, such as propranolol and metoprolol, have been associated with worsening of glycemia and an increased risk of diabetes mellitus. The possible mechanisms include inhibition of pancreatic insulin secretion through nonselective blockade of β2-adrenergic receptors, inhibition of peripheral glucose uptake, and resultant unopposed α2-adrenergic receptor-mediated stimulation of hepatic glycogenolysis [39] (Fig. 44.1). Newer-generation beta-blockers, such as carvedilol and nebivolol, have fewer metabolic effects than first-generation beta-blockers and are considered metabolically favorable [40].

Despite their glycemic effects, first-generation beta-blockers such as propranolol, metoprolol, and atenolol are still widely used. They are effective for HTN management and for preventing ischemic cardiovascular disease and sudden death. In the UK Prospective Diabetes Study [41], atenolol-based therapy was as effective in cardiovascular protection as was ACE-based therapy. In the Beta-Blocker Heart Attack Trial [17], a first-generation beta-blocker (propranolol) was effective for preventing recurrence of ischemia compared to a placebo in people with diabetes mellitus. In other studies, diabetic people prescribed first-generation β-blockers had significantly lower 1-year mortality rates than those not receiving these agents, regardless of type and severity of diabetes mellitus [18, 19].

In the Atherosclerosis Risk in Communities (ARIC) study [42], an observational cohort, there was an increase in the risk of diabetes associated with the use of beta-blockers (RR, 1.28; 95 % CI, 1.04–1.57). Similar findings have been noted in other observational studies [43, 44], In contrast, a retrospective, observational cohort study [45] of previously untreated patients, aged ≥66 years, identified as new users of an antihypertensive drug class, found that neither ACE inhibitor use (HR 0.96 [95 % CI 0.84–1.1]) nor beta-blocker use (0.86 [0.74–1.0]) was associated with a statistically significant difference in type 2 diabetes mellitus incidence when compared with the CCB control group (n = 76,176). In the secondary analysis (n = 100,653), compared with CCB users, T2DM incidence was not significantly different between users of ACE inhibitors (0.97 [0.83–1.1]), beta-blockers (0.84 [0.7–1.0]), or thiazide diuretics (1.0 [0.89–1.2]).