This commentary relates to the article by Yoonjee Park et al, on pages 38–45.
In this issue of the Journal, Park et al1 prospectively analyzed the incidence of on-set of diabetes mellitus in hypertensive patients receiving either selective or nonselective β-blockers over 60-month time span. This is an important question faced by all health care professionals that attempt to reduce morbidity and mortality in population of patients who suffer from high blood pressure. It is also a complex question. However, the outcomes from the analytics revealed a number of interesting outcomes that require careful thought.
Based on the evidence presented, it seems that nonselective β-blockers significantly increased the incidence of diabetes mellitus, whereas the selective β-blockers did not seem to do so. One of the early indications that treatment of hypertensive patients with β-blockers could lead to diabetes was a report by Bengtsson et al.2 The evidence from the latter investigation indicated that treatment with either β-blockers and/or thiazides resulted in the development of diabetes.2 Further evidence was provided by other reports.3–5 It is interesting that the evidence provided from the analysis by Park et al1 indicates that carvedilol but not metoprolol caused significant increase in the new on-set of diabetes mellitus in hypertensive patients. The data from the Carvedilol Or Metoprolol European Trial (COMET) in patients with chronic heart failure indicate that metoprolol rather than carvedilol was the β-blocker that increased the incidence of diabetes mellitus as assessed over 5 years.6 It is possible that the differential outcome is due to ethnicity of the population, as the patients in COMET were of predominantly of European decent, whereas those in the Park et al1 analysis are Asians. It is also possible that the differences in the outcome are related to the underlying nature of the pathophysiology of the cohort investigated.
One other important outcome from the analysis by Park et al1 was when the data for patients taking selective and nonselective β-blockers were combined, the dilution in analysis seems to suggest β-blockers as a class which do not significantly lead to the new on-set diabetes mellitus in matched hypertensive patients. This emphasizes the importance of stratification of mixed and nonhomogenous data sets. Hence, it would have also been helpful to determine sex differences in the new on-set of diabetes mellitus with this class of antihypertensive in this population. Furthermore, it seems that body mass index (BMI) was not a determining factor in the development of diabetes in patients treated with β-blockers. BMI has been identified as an independent risk factor in the development of diabetes mellitus in hypertensive patients taking antihypertensive drugs including β-blockers.5,7,8 It is not readily clear why BMI was not a factor in this particular analysis,1 but race may have an influence.
The evidence from the analysis by Park et al1 also seems to reveal that the only diuretic that led to the new on-set of diabetes was furosemide, and that the thiazide diuretics did not seem to readily cause the new on-set of diabetes mellitus in this cohort. This is not entirely surprising, as it has been previously suggested that thiazide-induced diabetes mellitus is likely linked to dose, and a lower dose of such a class of drugs would not significantly lead to the new on-set of diabetes.9 It is possible that the database1 contained patients who were predominately being treated with lower doses of the thiazides.
The differential effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers in causing new on-set of diabetes mellitus were also noted in the analysis.1 This is of interest because in some studies, angiotensin receptor blockers were noted to cause the new on-set of diabetes, whereas ACE inhibitors were believed to have protective effects.10,11 In general, there are many factors that could influence outcomes including baseline fasting plasma, BMI, systolic blood pressure, race, age, heart rate, and history of coronary heart disease.8,12
Of note, there is a dissociation of the development of diabetes mellitus and major adverse cardiovascular and cerebrovascular events (MACCE) in the analysis.1 Although the use of nonselective β-blockers and ACE inhibitors seems to lead to the new on-set of diabetes mellitus, neither class seems to significantly increase the risk of MACCE. By contrast, the use of nitrates seems to lead to significant risk of MACCE without causing new on-set of diabetes mellitus.1
A valid question directed at a better management of the health of hypertensive patients treated with drugs would be if the new on-set of diabetes mellitus was a major contributor of morbidity and mortality. This question has to be scrutinized very carefully. Accordingly, if the new on-set of diabetes mellitus due to antihypertensive therapy is not the enemy that is made out to be then lowering of blood pressure is of a greater importance. A meta-analysis to determine optimal control of high blood pressure in hypertensive patients in Spain has revealed that lowering of blood pressure did not seem to ideal during treatment for many of these individuals.13 If such a parallel is true worldwide, then the uncontrolled elevated blood pressure will clearly have a greater negative health impact than other matters such as the new on-set of diabetes mellitus in patients receiving antihypertensive drugs. An old dogma is whether uncontrolled high blood pressure eventually leads to the development of diabetes mellitus. Although this question remains controversial, a recent study of more than 4 million patients in United Kingdom has revealed some startling findings. It is reported that elevation of 20 mm Hg in systolic blood pressure and 10 mm Hg of higher diastolic blood pressure above the norm would be associated with 58% increase in the new on-set of diabetes mellitus.14 A meta-analysis of 30 prospective observational studies by the same group further revealed a 77% higher risk of new diabetes in adults with 20 mm Hg of higher systolic blood pressure.14 Taken together, such findings would strongly argue for a more optimal as well as better treatment and control of high blood pressure in hypertensive individuals. More importantly, such evidence may well support the notion that uncontrolled high blood pressure in cohorts treated with antihypertensive drugs would put them at the risk of developing diabetes mellitus irrespective of the class of drugs used. A daunting thought.
The bigger picture is the fact that based on the World Health Organization data for 2015, approximately 1.1 billion are believed to have high blood pressure as defined by values greater that 140/90 mm Hg (systolic/diastolic) worldwide. High blood pressure is a major risk factor for stroke and coronary heart disease and is killing about 7.5 million people every day. Essentially, high blood pressure has become a leading global burden as a disease, and unless this condition is taken seriously, hypertension is slowly turning into a pandemic of cardiovascular disease around the globe.
1. Park Y, Choi BG, Rha SW, et al., Selective β1-blockers are not associated with new-onset diabetes mellitus in hypertensive patients. J Cardiovasc Pharmacol. 2018;71:38–45.
2. Bengtsson C, Blohmé G, Lapidus L, et al. Do antihypertensive drugs precipitate diabetes? Br Med J. 1984;289:1495–1497.
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14. Emdin CA, Anderson SG, Woodward M, et al. Usual blood pressure and risk of new-onset diabetes: evidence from 4.1 million adults and a meta-analysis of prospective studies. J Am Coll Cardiol. 2015;66:1552–1562.