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Blood glucose and hypertension development

the hen and egg controversy

Nilsson, Peter M.

doi: 10.1097/HJH.0000000000001946
EDITORIAL COMMENTARIES

Department of Clinical Sciences, Lund University, Skane University Hospital, Malmö, Sweden

Correspondence to Peter M. Nilsson, MD, PhD, Professor, Department of Clinical Sciences, Lund University, Skane University Hospital, Jan Waldenströms gata 15, 5th floor, S-20502 Malmö, Sweden. Tel: +46 40 33 24 15; e-mail: Peter.Nilsson@med.lu.se

The link between impaired glucose metabolism and elevated blood pressure is well established and part of what has often been referred to as the metabolic syndrome, a concept that is perhaps not more than its components according to cardiovascular risk [1]. There are several possible links between impaired glucose regulation and haemodynamic changes, for example based on the influence of insulin resistance [2] or even early life programming [3]. In established diabetes, the diagnosis and treatment of hypertension is of great importance as told in guidelines.

One may wonder if hyperglycaemia is also predictive of elevated blood pressure and hypertension, and not only the other way around, as often shown. In this issue of the journal, a report is published based on observational associations on this topic in 10 157 Japanese subjects without diabetes or hypertension (age range 30–85 years) enrolled in a 5-year cohort study in Tokyo [4]. The main finding was that higher fasting blood glucose levels at baseline is an independent risk marker for new onset hypertension (incidence rate 10.2% over 5 years) after full adjustments for age, sex, BMI, smoking and drinking habits, dyslipidaemia, chronic kidney disease, and serum uric acid by logistic regression analyses. After multiple adjustments, higher baseline blood glucose levels (per 10 mg/dl increase) was an independent risk for hypertension [odds ratio (OR) 1.18; 95% confidence interval (CI) 1.09–1.28], as well as aging, women, higher BMI, drinking habits, and higher serum uric acid. After stratifying by sex, higher baseline blood glucose levels were still an independent risk marker for hypertension, both in women (OR 1.30) and men (OR 1.11). However, when HbA1c was used instead of blood glucose, HbA1c was not an independent risk marker for incident hypertension. Finally, there was also noted an interaction between hyperglycaemia and hyperuricemia at baseline for risk of new-onset hypertension [4]. The findings are observational by nature, and therefore, cannot prove causality. Among limitations stated, the lack of oral glucose tolerance testing (OGTT) for a proper diagnosis of impaired glucose metabolism/diabetes, and 24-h ambulatory recordings for a proper diagnosis of elevated blood pressure/hypertension, should be noted. The authors state that the control of hyperglycaemia could be believed to contribute to reduced risk of hypertension.

The traditional way to prove causality in epidemiology was to apply the so called Bradford-Hill criteria from 1965 with its different components to address time aspects of exposure, as well as dose-effects and plausible biological mechanisms [5]. One of these criteria also stated experiment, in modern terms, a clinical intervention to control the supposed causative factor and look for effects on the outcome variable. In response to this, modern antidiabetic drugs to control hyperglycaemia have shown some favourable influences on haemodynamics including a reduction of blood pressure [6]. This concerns DPP-4 inhibitors such as sitagliptin, as well as GLP-1 analogues such as liraglutide and semaglutide, to mention a few [7]. In addition, the SGLT-2 inhibitor empagliflozin has shown a documented blood pressure-lowering effect, both according to office and ambulatory blood pressure when added to antihypertensive drugs [8]. A remaining question is how much of this effect is direct or indirectly attributable to weight loss or antiinflammation in addition to the effect on hyperglycaemia.

With the introduction of modern genetics, however, the new methodology of Mendelian randomization in bioinformatics can be applied to test putative associations for causality. If a set of genetic markers (score) can be reliably associated with a biological trait (i.e. hyperglycaemia or hyperuricemia), this could be linked to the outcome in question (i.e. hypertension or clinical events). There is some evidence to suggest that genetic markers of hyperglycaemia as a trait in nondiabetic populations is independently associated with coronary artery disease [9] and arterial stiffness [10], but still no proof of an association with hypertension exists. The many genetic markers of type 2 diabetes are not associated with hypertension, a paradox in itself. In a similar way, genetic markers of hyperuricaemia are, however, associated with incident hypertension [11], even if the link with cardiovascular disease manifestations is still disputed.

In summary, the epidemiological link between impaired glucose metabolism/diabetes and elevated blood pressure/hypertension is well established. Hypertension and type 2 diabetes co-predict each other in both Hispanic and non-Hispanic whites [12]. Many studies have previously shown that elevated blood pressure may predict incident type 2 diabetes, but now a Japanese study has shown that impaired glucose metabolism (hyperglycaemia) can predict incident hypertension, an effect even more pronounced by the influence of hyperuricaemia. These three conditions (traits) cluster together, as already the Swedish physician, Kylin [13] pointed out in 1923, and later on combined in the so-called metabolic syndrome driven by insulin resistance by Reaven [14]. However, the causal links between the three entities are not fully known. There is a need of both targeted clinical intervention trials, inspired by not at least the Bradford-Hill criteria [5], and genetic studies, based on whole-genome scans and Mendelian randomization, to further dissect these associations. A promising fact is that some modern antidiabetic drugs are also capable to lower both office and ambulatory blood pressure. This can contribute to the favourable effect on some clinical endpoints, most importantly the reduction of congestive heart failure and cardiovascular mortality [15,16].

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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