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Massimo Volpe, Carlo Patrono, Blood pressure lowering drugs differ in their capacity to prevent type 2 diabetes, European Heart Journal, Volume 43, Issue 12, 21 March 2022, Pages 1189–1190, https://doi.org/10.1093/eurheartj/ehab878
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Comment on ‘Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis’ which was published in Lancet. https://doi.org/10.1016/S0140-6736(21)01920-6.
Individual participant data (IPD) meta-analyses were performed by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) from 22 studies conducted between 1973 and 2008, to investigate the effects of blood pressure (BP) lowering on the risk of new-onset type 2 diabetes (T2DM).1 An IPD network meta-analysis was used to investigate the effects of five major classes of antihypertensive drugs on the risk of new-onset T2DM. The meta-analysis included primary and secondary prevention trials that used a specific class or classes of antihypertensive drugs versus placebo or other classes of BP-lowering medications that had at least 1000 persons-years of follow-up in each randomly allocated arm.
The overall sample included 145 939 participants (61% men). After a median follow-up of 4.5 years, 9883 participants were diagnosed with new-onset T2DM with an incidence rate per 1000 person-years of 16.4 [95% confidence of interval (CI), 16.0–16.9] in the comparator group and of 15.9 (95% CI, 15.5–16.4) in the intervention group. A 5 mmHg reduction in systolic BP (SBP) was associated with 11% decreased risk of T2DM [hazard ratio (HR) 0.89; 95% CI, 0.84–0.95].
Analyses of the effects of five major classes of BP-lowering drugs showed that in comparison to placebo, angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduced the risk of new-onset T2DM [risk ratio (RR) 0.84; 95% CI, 0.76–0.93 and RR 0.84; 95% CI, 0.76–0.92, respectively]. A neutral effect was found for calcium channel blockers (RR 1.02; 95% CI, 0.92–1.13). In contrast, β-blockers (BBs) (RR 1.48; 95% CI, 1.27–1.72) and thiazide diuretics (RR 1.20; 95% CI, 1.07–1.35) increased the risk of T2DM compared with placebo.
In complementary analyses using Mendelian randomization, 5 mmHg genetically influenced lower SBP was associated with 12% lower risk of T2DM (RR 0.88; 95% CI, 0.84–0.92).
Comment
The rigorous and authoritative BPLTTC meta-analysis add important new information to the current knowledge on the potential role of BP lowering in preventing the development of T2DM and on the differential effects of major antihypertensive drug classes on the risk of new-onset T2DM.1 With consistent results from both randomized controlled trials and genetic analyses, the present study strongly suggests that elevated BP is a modifiable risk factor for new-onset T2DM, with a relative effect size similar to that seen for the prevention of major cardiovascular events.2
Previous observational and Mendelian randomization studies had yielded conflicting results with regard to the relationship between BP and T2DM, with only a few studies reporting suggestive evidence for such association.3,4
Similarly, although two previous tabular data meta-analyses5,6 had reported a significant preventive effect associated with ARBs compared with placebo with respect to new-onset T2DM, the effects of ACEi and BB remained statistically uncertain.
The mechanisms underlying the differential effects of these major antihypertensive drug classes are still unclear. However, the renin–angiotensin system blockers have been reported to reduce insulin resistance, vascular inflammation, endothelial dysfunction, and production of reactive oxygen species, these actions potentially contributing to their protective effect against the development of T2DM.1,7 On the other hand, BB and thiazide diuretics have been suggested to alter insulin secretion and carbohydrate metabolism and cause potassium depletion, respectively, although there is no certainty about the pathophysiological pathway(s) leading to an increased risk of T2DM.1,7 According to these and other findings, international guidelines on BP management discourage the use of BB and thiazide diuretics as first-line choice in patients with a potentially increased risk of diabetes on the basis of their history and clinical and metabolic profile, and recommend considering renin–angiotensin blockers in these subjects.8 Similarly, European guidelines on diabetes recommend the use of ACEi or ARBs in hypertensive patients with pre-diabetes since the risk of new-onset diabetes is lower with these pharmacological classes compared with BB or diuretics.9 However, previous uncertainties about the impact of BP lowering on new-onset T2DM have limited recommendations from international guidelines on the adoption of BP-lowering interventions for preventing the development of T2DM.9,10
Among the strengths of the current study, the use of a Mendelian randomization approach allows validating the main results and adding further weight to the robustness and importance of the IPD meta-analysis.
On the other hand, some limitations of the study should also be underlined. First, the effect of combinations of drugs with opposing or synergistic effects on T2DM risk has not been explored. Secondly, information on drug doses and post-randomization treatment was incomplete and the results are likely to reflect the effects of drug doses across the course of the studies. Thirdly, the studies included in the meta-analysis were conducted over a 45-year time frame, during which several new recommendations have been introduced with regard to BP targets and major changes in the pharmacological management of hypertension as well as in the diagnostic criteria for T2DM have occurred. Finally, diabetes development was not the primary endpoint of the trials included in the meta-analysis.
Although further studies may be required to elucidate the mechanisms underlying the relationship between BP and T2DM, the BPLTTC meta-analysis provides circumstantial evidence suggesting that BP lowering is likely to prevent new-onset T2DM. The achievement of lower BP targets and the preferential use of ARBs and ACEi may substantially contribute to preventing T2DM and thus should be recommended, especially in those patients at higher risk of developing diabetes.
Conflict of interest: M.V. reports personal fees for speaker bureau and/or consulting in Advisory Board from Amgen, Astra Zeneca, Daiichi-Sankyo, Menarini Int, MSD, Novartis Pharma, Novo Nordisk outside the submitted work. C.P. reports personal fees from Acticor Biotech, personal fees from Amgen, personal fees from Bayer, personal fees from GlaxoSmithKline, personal fees from Tremeau, personal fees from Zambon, grants from AIFA (Italian Drug Agency), grants from the European Commission, other from Scientific Advisory Board of the International Aspirin Foundation, outside the submitted work.
