Blood pressure targets in patients with type 2 diabetes have been a controversial issue since the publication of the UK Prospective Diabetes Study (UKPDS) almost two decades ago 1. Diabetes and hypertension often coexist, and patients with type 2 diabetes are at an increased risk of developing cardiovascular disease, for which hypertension is the most important risk factor 2,3. The UKPDS showed a marked decrease in macrovascular and microvascular complications with intensive blood pressure lowering compared with standard blood pressure lowering. On the basis of this finding, together with epidemiological data suggesting a linear relation between blood pressure and cardiovascular disease 4, hypertension and diabetes guidelines have been recommending lower blood pressure targets for patients with diabetes compared with the general population 5,6. Since the publication of the Action to Control Cardiovascular Disease in Diabetes (ACCORD) trial, however, the evidence behind these recommendations has been questioned 7. On the basis of critical appraisal of the available trials, the current generation of guidelines generally reversed to more liberal targets compared with previous versions 8,9.
The aim of this review is to provide readers with an overview of available recommendations in major American and European guidelines, as well as recent systematic reviews and meta-analyses. We will critically assess the basis for the recommendations provided in relation to the evidence presented in reviews. When reviews differ in their results, we will discuss the reasons for such differences. We comment upon the results from recent studies in patients without diabetes and their potential implications for recommendations in patients with diabetes and, finally, conclude what targets are best in line with the totality of available evidence. Blood pressure targets for some specific subgroups of patients with diabetes are discussed in other articles in this issue.
We searched PubMed in July 2016 for clinical practice guidelines on hypertension management in diabetes. We considered only guidelines issued by well-known regional hypertension or endocrinology societies, and excluded country-specific recommendations. Target blood pressures according to each organization are presented in Table 110–15.
Generally, current guidelines are coherent in terms of systolic blood pressure targets, recommending patients with type 2 diabetes treatment to attain a systolic blood pressure less than 140 mmHg. Possible exceptions to this recommendation are provided in several guidelines, opting for lower targets in young individuals, patients with albuminuria and patients with multiple cardiovascular risk factors 11,13. The guidelines issued by the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) advocate more aggressive treatment, recommending less than 130 mmHg in general, and less than 120 mmHg in high-risk individuals 10.
The systolic blood pressure targets are sparsely supported in guideline publications. Of the hypertension guidelines referred here, only The Eight Joint National Committee (JNC 8) clearly explains the process leading up to the clinical recommendations, also providing evidence grades to each statement 15. They acknowledge that no trial has ever tested a target less than 140 mmHg, compared with more liberal targets, although three trials have tested less than 150 mmHg successfully 1,16,17 and one trial (ACCORD) tested less than 120 mmHg with no benefit on combined cardiovascular events 7. Thus, the recommendation to treat patients with diabetes to less than 140 mmHg is considered ‘expert opinion’, that is, the lowest grade of evidence. It is noteworthy that JNC 8 had very rigorous criteria for which evidence to consider in the guideline writing process, including only trials assessing blood pressure targets. This approach has been criticized for not considering all available evidence, omitting many placebo-controlled trials.
The endocrinology/diabetes guidelines reviewed here generally include a more thorough discussion on why targets were chosen. They also acknowledge that RCT evidence to treat to less than 130 mmHg is lacking, but instead refer to strong epidemiological evidence of an increased risk for cardiovascular disease at blood pressure levels more than 115 mmHg 4. Thus, in all guidelines, the choice of target appears to be somewhat arbitrary.
In terms of diastolic targets, guidelines differ more. Most guidelines recommend treating patients to less than 90 mmHg, whereas ESC/ESH have chosen less than 85 mmHg and AACE/ACE have chosen less than 80 mmHg. The choice of less than 85 mmHg in the ESC/ESH guidelines is attributed to the intensive treatment group in UKPDS and less than 85 mmHg treatment group in hypertension optimal treatment (HOT) 1,18. AACE/ACE once again refer to epidemiology.
Systematic reviews and meta-analyses
We searched PubMed during July 2016 for systematic reviews and meta-analyses on blood pressure treatment in patients with diabetes. We only included analyses of treatment versus no/less treatment, not analyses of specific drugs against each other. Only reviews published during the last decade were considered because many important trials have been published during this time span, and therefore, older reviews are out of date. The main results from the attained reviews are presented in Table 219–24.
The reviews by Arguedas et al.19 and McBrien et al.23 used the same inclusion criteria, restricting analyses to studies comparing different blood pressure targets. Both reviews included the same trials, but Arguedas analysed trials with systolic and diastolic blood pressure targets separately, whereas McBrien lumped these into combined meta-analyses. Both reviews conclude that lower blood pressure goals result in a lower risk of stroke. Arguedas note that intensive treatment increase the risk of serious adverse events, results based entirely on the ACCORD trial 7. Results for other outcomes were nonsignificant, but this lack of significance should be interpreted with caution. The analyses included very few trials, with low power to detect treatment effects.
In the reviews by Bangalore et al.20, Emdin et al.22 and ourselves 21, placebo-controlled trials were included, in addition to the target-driven trials included above. Bangalore used narrower blood pressure inclusion criteria, but included patients with impaired fasting glucose. The difference in numbers between Emdin’s review and ours is mostly because of the inclusion of previously unpublished data in our own analysis 21. The results coherently show that blood pressure-lowering treatment reduces the risk of death and cardiovascular disease if baseline systolic blood pressure is more than 140 mmHg. Generally, such treatment resulted in a systolic blood pressure between 130 and 140 mmHg (not shown in table), fitting well with the results from Bangalore, showing reduced mortality if systolic blood pressure is treated to less than 135 mmHg.
The reviews disagree, however, in terms of treatment effect at baseline blood pressure levels less than 140 mmHg. Here, we find an increased risk of cardiovascular mortality, with no benefit on any outcome 21. Emdin, in contrast, finds a decreased risk of stroke and albuminuria 22. The decrease in stroke is further supported by Bangalore’s finding that an attained blood pressure less than 130 mmHg is beneficial for this outcome 20. This is not easy to handle for the clinician. Unfortunately, the same risk factors predispose to cardiovascular death, stroke and renal disease, and one cannot know how cardiovascular disease will present in any given patient. It is important to note that several trials have been published after the compilation of Bangalore’s review. Also, the inclusion of patients with impaired fasting glucose might confound the analyses because these patients do not have the same vascular features as patients with established, and sometimes long-standing, diabetes. On the basis of this, we place the least emphasis on this review. On comparing Emdin’s work with our own, we can conclude that in terms of stroke analysis less than 140 mmHg, our inclusion of previously unpublished data did not result in very many new events. Instead, the difference in results can be explained by the use of different statistical methods. For a thorough discussion on this, we refer to the discussion section in our previous review 21. What it all comes down to is that we use raw data, with risk ratios reflecting the actual treatment effect in the included studies and study weights reflecting number of participants and events. Emdin, in contrast, ‘standardized’ data before they were included in meta-analyses, thereby exaggerating treatment effects and dissociating study weights from the number of participants and events.
Last but not least, Reboldi et al.24 add an additional study type to the analyses: drug versus drug trials. Although this may confer bias, possibly assessing blood pressure-independent effects of blood pressure-lowering agents, it provides more power to meta-regression analyses, used to assess whether the magnitude of blood pressure reduction in trials is associated with treatment effect. The authors find such an association for stroke, but not for myocardial infarction, these being the only outcomes analysed.
The only systematic review assessing the effect of blood pressure lowering at different diastolic blood pressure levels is our own 21. These results were presented in the appendix of the original publication. We found that treatment of patients with baseline diastolic blood pressure more than 80 mmHg resulted in reduced risk of death and various cardiovascular and renal outcomes (Table 2). At baseline levels less than 80 mmHg, however, there was neither a positive nor a negative treatment effect on any outcome.
Data from patients without diabetes
During the past year, two important studies of blood pressure lowering outside the field of diabetes have been published. These are important here because many have argued for lower blood pressure targets on the basis of these studies, and that their results should have implications for the diabetic population as well.
First, the Systolic Blood Pressure Intervention Trial (SPRINT) randomized high-risk individuals to systolic blood pressure targets less than 120 compared with less than 140 mmHg 25. The trial was stopped early because of the reduced risk of combined cardiovascular events and all-cause mortality. The results of SPRINT have been discussed as potentially guideline changing, paving the way for lower treatment goals 26. The results of SPRINT are difficult to interpret for several reasons. First, SPRINT used a blood pressure measurement method not used in previous hypertension trials. Blood pressure values were obtained through an average of three measurements performed by an automated measurement device (Omron 907, Kyoto, Japan) when patients were alone and seated for 5 min. Recent data indicate that such measurements yield 10–20 mmHg lower values compared with standard measurements, suggesting that SPRINT assessed treatment effect in patients with similar blood pressures as in other trials testing less than 140 against less than 160 mmHg 27. Second, SPRINT used diuretics as the first-line drug, known to decrease the risk of heart failure more than other antihypertensive drug classes 28. Heart failure was the most important event leading to treatment benefit in SPRINT, suggesting possible blood pressure-independent effects. Third, the trial was stopped preterm, which is known to be associated with more extreme treatment effects by chance fluctuations 29. The most important reason why the findings from SPRINT should not directly applied to patients with diabetes, however, is that patients with diabetes were excluded from the trial to start with.
The second major paper advocating lower blood pressure targets was a meta-analysis including more than 100 studies and 600 000 patients, irrespective of comorbidities 30. This systematic review used meta-analyses stratified according to baseline systolic blood pressure, in the same manner as the reviews by Emdin and ourselves, mentioned above. The authors conclude that blood pressure-lowering treatment reduced the risk of cardiovascular disease across blood pressure strata to baseline blood pressure levels less than 130 mmHg. Although this analysis included trials with patients with diabetes, most participants were non-diabetic. Hence, the applicability of the results in patients with diabetes may be limited. It is noteworthy that the presence of diabetes at baseline interacted significantly with the effect of treatment, suggesting less effect in patients with diabetes. Last but not least, this meta-analysis used the same method of standardization as that used by Emdin discussed above, and therefore has the same limitations.
In summary, recent studies in nondiabetic or mixed populations should not be given too much weight in the debate on blood pressure targets in patients with diabetes.
The available guidelines largely agree in terms of blood pressure targets in patients with diabetes. Interestingly, they arrive at their conclusions through different pathways, placing emphasis on different studies. The recommendation to treat systolic blood pressure to less than 140 mmHg is well supported by several systematic reviews, with both mortality and morbidity benefits 20–22. The less than 130 mmHg recommendation provided by AACE/ACE, and opted for by others, is less well supported, based mostly on observational data. Available systematic reviews diverge at this blood pressure level, suggesting an increased risk of cardiovascular death on the one hand 21 and reduced risk of albuminuria on the other 22. In our opinion, meta-analyses of randomized-controlled trials are more relevant than observational data, and cardiovascular death is more important than albuminuria. We therefore advocate a systolic blood pressure less than 140 mmHg as the general target in patients with type 2 diabetes. In terms of diastolic blood pressure targets, none of the available guidelines refer to any systematic review. The only systematic review assessing diastolic blood pressure levels was our own. We found that treating patients with baseline diastolic blood pressure in the interval 80–90 mmHg reduced the risk of mortality, myocardial infarction, heart failure and end-stage renal disease, whereas treating those less than 80 mmHg was neither harmful nor beneficial 21. On the basis of this, a treatment target less than 80 mmHg seems to be reasonable. Aiming for 140/80 mmHg thus appears to be the most evidence-based recommendation.
Conflicts of interest
There are no conflicts of interest.
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