Is intensive blood pressure reduction a possible solution to counteract the development of diabetes mellitus?

This editorial refers to ‘Intensive blood pressure lowering and the risk of new-onset diabetes in patients with hypertension: a post-hoc analysis of the STEP randomized trial’, by R. Yang et al., https://doi.org/10.1093/eurjpc/zwad105. Since the publication of the SPRINT trial1 in 2015, it became clear that in order to reduce cardiovascular (CV) burden in hypertensive patients, ‘the lower is the better’. Similarly, the STEP trial,2 focusing its investigation among elderly individuals (60–80 years), again confirmed that more intensive treatment [target of systolic blood pressure (SBP) less than 130 mmHg], in comparison to standard treatment (target of SBP less than 150 mmHg), resulted in a lower incidence of CV events [a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from CV causes] during 3.34 years of follow-up. The BP reduction to a lower target was demonstrated to be correlated with several beneficial effects such as lower rate of developing new left ventricle hypertrophy and regression of existing left ventricle hypertrophy,3 or attenuation of age-related artery stiffening,4 without affecting cognitive function.5 However, the potential effect on glucose level and new development of diabetes according to BP reduction still remains an open question. A secondary analysis from the SPRINT trial6 showed that among patients with impaired fasting glucose, the intensive treatment led to a small increased risk of new onset type 2 diabetes mellitus, even if not statistically significant [HR 1.18 (95% CI, 1.00–1.40), P = 0.052]. This finding is similar to that by Roumie et al.7 who observed a small nonsignificant increase in risk of incident diabetes mellitus among SPRINT study participants [HR 1.19 (95% CI, 0.95–1.49)]. However, in the same study, the authors found a statistically significant increased risk of impaired fasting glucose [HR1.17 (1.06–1.30) P = 0.002] among participants normoglycemic at the baseline. A possible explanation for this unfavourable impact on the metabolism of glucose was supposed to be the effect of different classes of drugs and their associations with the risk of type 2 diabetes mellitus. However, the use of multiple antihypertensive drugs among both the intensive and standard BP control groups makes it difficult for the authors to test a relationship between drug–drug interaction and the risk of elevated blood glucose levels.6,7 Moreover, due to the observational nature of the studies, a causal relationship cannot be established by the authors.6,7 On the opposite side, according to literature, it was clear that the CV benefit with an intensive BP treatment was achieved even among those affected by diabetes mellitus.8–10 The meta-analysis by Thomopoulos et al.8 investigated 61 772 patients with diabetes mellitus at baseline and 191 535 normoglycemic subjects and demonstrated that BP lowering strategy significantly and importantly reduced the CV risk in both groups, with a greater benefit among the former than the latter group [relative risk for coronary heart disease reduction was 0.71 (0.61–0.81) for diabetic patients and 0.81 (0.74–0.88) for non-diabetic subjects P = 0.039]. However, this difference disappeared below 130 mmHg. Similar results were recently obtained by Yang et al.9 in a pooled analysis of STEP and ACCORD-BP randomized trials. Again, diabetic patients that underwent more intensive treatment (in this study, the lower SBP target was 110 to <130 mmHg) had a reduction of the CV outcomes in comparison with the standard target of SBP (<130 to 150 mmHg). Moreover, the meta-analysis by Nazarzadeh et al.,10 investigating 145 939 subjects, from 19 randomized controlled trials, clearly demonstrated that 5 mmHg reduction of SBP can lead to a 11% risk reduction of type 2 diabetes [HR 0.89 (95% CI 0.84–0.95)]. Several potential mechanisms have been proposed to be responsible for this association like insulin resistance, vascular inflammation, and endothelial dysfunction, which tend to precede the clinical manifestation of diabetes11–13 and may be consequences of hypertension development.14,15 Other mechanisms involved are increased sympathetic nervous system activity and chronic inflammation that promote endothelial dysfunction and may be a possible link between hypertension and diabetes.16 These uncertainties have led to the absence of clear recommendations from international guideline committees as to the adoption of BP lowering via pharmacological or non-pharmacological interventions for the prevention of type 2 diabetes. The paper by Yang et al.17 explored the important issue of the development of diabetes mellitus or impaired fasting glucose according to anti-hypertensive treatment strategy, intensive vs. standard, in a population of elderly patients. This issue is of particular importance in this age category because aging of populations is associated with increased prevalence of diabetes.18 Thus, clarifying whether intensive SBP lowering increases or reduces the risk of new-onset diabetes in older patients is of mandatory importance in this peculiar setting. In contrast to what was previously found in SPRINT trial,6,7 Yang et al.17 observed that intensive treatment (SBP < 130 mmHg) did not increase the risk of new onset diabetes [HR was 1.01 (95% CI, 254 0.86–1.20; P = 0.87)] or of new onset of impaired fasting glucose [HR was 1.04 (95% CI, 0.91–1.18; P = 0.56)]. Oxidative stress, chronic inflammation that causes endothelial dysfunction, together with altered sodium balance, renin-aldosterone system dysfunction, and activation of sympathetic nervous system were supposed to be the link between hypertension and diabetes. Unfortunately, neither previous studies8–10 nor the paper by Yang et al.17 explored an unresolved question: the relationship between new onset diabetes and/or impaired fasting glucose with the administration of diuretics and/or beta-blockers. While angiotensin II receptor blockers (ARBs) and angiotensin-converting ezyme inhibitors (ACEIs) were demonstrated to be protective for the development of new onset diabetes,19,20 conflicting results do exist for beta-blockers and diuretics. The study by Cooer-DeHoff et al.21 showed a clear association between thiazide diuretics and new incidence of diabetes, while the ALLHAT study highlighted the detrimental role of chlortalidone.22 For beta-blockers, the meta-analysis by Bangalore et al.23 documented increased risk for new-onset diabetes with the use of these drugs (RR 1.22, 95% CI 1.12–1.33) compared with nondiuretic antihypertensive agents, in agreement with the results from the LIFE study for comparison of atenolol with losartan.20 It should be noted, however, that opposite results were observed for the new-generation vasodilating beta-blocker carvedilol that may improve or have no effect on glucose metabolism compared with atenolol or metoprolol.24,25 Both SPRINT and STEP trials,6,7,9 together with the current Yang study,17 cannot distinguish between the effects of different antihypertensive drug classes, as several treatments were used both in intensive and standard treatment arms and the majority of participants were taking combinations of antihypertensive drugs, and were able to change drug classes and doses during the trial, making it difficult to determine the effects of single antihypertensive drugs on glucose metabolism.