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High blood pressure in US diabetic veterans with normal renal function

a plea for the design of a more powerful and conclusive outcome trial

Kjeldsen, Sverre E.; Os, Ingrid

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doi: 10.1097/HJH.0000000000000896
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Most patients with diabetes have high blood pressure (BP). Naturally thereof, a relationship between BP and impairment in glucose control would be expected – that is, with higher BP there is higher glucose level, and with higher glucose there is higher BP. This relationship between BP and blood glucose has been known for at least 40 years when Leren et al.[1] in 1975 reported rather strong positive correlations between blood glucose and SBP (r = 0.21) as well as with DBP (r = 0.11) in a healthy population of Caucasian men (n = 14 816) aged 40–49 years living in the city of Oslo. Intercorrelations between body weight, triglycerides, BP, and blood glucose had in the 1970s been observed in several large epidemiological surveys performed in parallel in Denmark, Finland, and Sweden. However, the association between BP and glucose received little or no attention until 1998. Then the results appeared from the treatment of hypertension in patients with diabetes in the Hypertension Optimal Treatment study [2] and the United Kingdom Prospective Diabetes Study (UKPDS) [3], and the interest and attentiveness for hypertension in patients with diabetes escalated. Large outcome trials have been carried out in patients with diabetes and hypertension [4,5], and other outcome trials in hypertensive patients [6,7] have been enriched with large subgroups of patients with diabetes. Today it is mostly a question of how low BP should be lowered in patients with diabetes to optimally protect against cardiovascular and renal disease [5]; though a well designed trial with proper statistical power is yet to be carried out.

In this issue of Journal of Hypertension, Gosmanov et al.[8] report from studies of 891 670 United States (US) diabetic African-American and Caucasian mostly elderly veteran men with normal renal function at the outset. The associations of glycosylated hemoglobin and SBP, both variables from low normal to high values, with the risk of all-cause mortality and incident chronic kidney disease, coronary heart disease, and stroke were examined in Cox models adjusted for baseline characteristics using patients with hemoglobin A1c 6.5–6.9% and SBP of 120–139 mmHg as the reference group. A total of 221 529 patients died, and 178 588, 43 373, and 36 935 developed chronic kidney disease, coronary heart disease, or stroke respectively during a median follow-up time of 7.4 years. SBP displayed a J-shaped association with each outcome except for the risk of chronic kidney disease that was linearly associated with SBP across all hemoglobin A1c categories. Hemoglobin A1c above 7.0% was associated with worse outcomes for all end points in all SBP categories. Patients with the combined highest hemoglobin A1c and SBP levels experienced the worst outcomes. Thus, SBP greater than 120–139 mmHg and hemoglobin A1c greater than 7.0% are associated with higher mortality and vascular complications in diabetic patients, and independent of each other. And the combination of the two risk factors undoubtedly is an important reason for the ‘epidemic’ of chronic renal disease, causing increased mortality, burden on health-care resources, and not least decreased health-related quality of life.

Gosmanov et al.[8] suggest that the combined efforts to improve both glycemic and BP control may lead to clinical benefits and thus improve outcome. However, the study is observational, and therefore the treatment effects cannot be ascertained, although intuitively it may be easy to agree. The issue of tight glucose control is not straight forward, particularly related to prevention of macrovascular complications. Except for one recent study [9], which needs confirmation, the issue of tight glucose control with glucose lowering medication in patients with diabetes to a large extent still depends on the early results in UKPDS [10] and perhaps the US Diabetes Prevention Program [11]. Further, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which randomized hypertensive patients with type 2 diabetes to SBP targets less than 120 vs. less than 140 mmHg came out without statistically significant benefit in the intensive treatment group [5]. ACCORD enrolled 4300 patients with normal renal function into a factorial design that included cholesterol and glucose lowering treatments as well as BP reduction. For all of these reasons, ACCORD was statistically underpowered to show a significant benefit of intensive BP reduction. However, ACCORD did show an 11% trend favoring the target BP less than 120 mmHg compared with less than 140 mmHg for the composite primary end point and a significant 48% stroke reduction. These results suggest that the ACCORD study should be repeated with sufficient statistical power. Though observational in nature the current data by Gosmanov et al.[8] nourish the urgent need for further research in both glucose-lowering and BP lowering treatment in patients with diabetes and hypertension.

In contrast to lack of J-curve for the end point chronic kidney disease, a J-curve did appear for coronary heart disease and stroke in the study by Gosmanov et al.[8] suggesting increased risk for patients with the lowest values of BP or glucose. Such findings may suggest ‘fragile’ patients at the lower end of the risk scale or merely lack of adjustment for yet not detected covariates in such a large data base. The data suggest a continuous and linear relationship between poor glucose control, higher BP, and a potentially synergistic effect of the two factors on the risk of renal disease. In the same way that the US National Institutes of Health (NIH) sponsored ACCORD [5] and the recently published Systolic Blood Pressure Intervention Trial (SPRINT) [12], the NIH should urgently sponsor an intervention trial in patients with diabetes and hypertension to demonstrate prevention and reduced progression of renal disease with a combined treatment strategy. But NIH should learn from previous mistakes [5,12] and design a trial with sufficient statistical power, mainly with enough participants at risk. A proper intervention trial must further avoid other obvious flaws in the design such as in SPRINT, where changes in diuretic treatment may mask or demask, and explain differences in heart failure outcome. Unobserved automated office BP measurements circumvented the issue of white-coat hypertension in SPRINT, and made the study incomparable with any other outcome trial in literature and for all practical purposes useless for clinical recommendations [13].

In conclusion, it is not surprising that the large observational study by Gosmanov et al.[8] showed that uncontrolled glucose and higher BP, and the synergism of the two, predicted renal and coronary disease and stroke. This knowledge has been at least partly available for 40 years or longer. But the huge size of the study of Gosmanov et al.[8] demonstrated the tight relationships between BP and hemoglobin A1c, also adjusted for multiple covariables, and the central role of chronic renal disease as end point. The astonishing aspect regarding the knowledge of hypertension in patients with diabetes is that interventional trials have been insufficient in design and not been able to convincingly show effective prevention. Thus, guidelines are yet not able to give conclusive clinical recommendations for lowering of BP and improved glucose control in patients with diabetes. The study of Gosmanov et al.[8] is actually a massive plea for the design of a more powerful and conclusive outcome trial in patients with diabetes and hypertension.

ACKNOWLEDGEMENTS

Conflicts of interest

S.E.K. has received lecture and consulting honoraria from Bayer, Merck & Co. and Takeda. I.O. reports no conflict of interest.

REFERENCES

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