Cardiovascular disease continues to be the largest contributor to both morbidity and mortality in adults in the USA, with over 600 000 deaths per year according to the Centers for Disease Control and Prevention 1. This observation is similar in other high-income westernized countries, including Europe. Unfortunately, a similar trend is also emerging in low-income to middle-income countries. Hypertension (an elevated blood pressure) is a major risk factor for cardiovascular disease, especially in individuals with diabetes mellitus. As a result, the early diagnosis and the appropriate management of hypertension in those with diabetes mellitus is of great clinical importance to prevent and/or reduce the effect of cardiovascular disease on morbidity and mortality in this patient population.
Despite the universal recognition of the importance of hypertension management in those with diabetes mellitus, there continues to be considerable controversy and debate on the appropriate blood pressure threshold to initiate pharmacologic therapy as well as the blood pressure target to achieve once therapy is initiated. Over the last several decades, numerous clinical trials have attempted to clarify these issues. These studies, reviewed below, have contributed toward the body of evidence-based medicine that has formed the basis of nearly all the guidelines published recently with respect to the management of hypertension in various patient populations, including and some specifically pertaining to adults with diabetes mellitus. This paper will review the recommendations published in recent major guidelines on the treatment of hypertension in diabetes mellitus. It will examine the literature (evidence-based medicine) used to form the basis of these guidelines. Finally, it will discuss major updates in the literature, since the publication of the present guidelines, which may significantly impact these current guidelines and alter the clinical management and treatment of hypertension in individuals with diabetes mellitus.
The seventh edition of the Joint National Committee Report (JNC-7) was released in 2004 and recommended a threshold blood pressure for the pharmacologic treatment of 130/80 mmHg or more and, once initiated, a target blood pressure of 130/80 mmHg or lower in patients with diabetes mellitus and hypertension (Table 1) 2. These recommendations were in line with other contemporary guidelines released by the Canadian Hypertension Education Project and the WHO/International Society of Hypertension 3,4.
Since the release of JNC-7, various other societies or groups have released guidelines on the management of hypertension in their respective patient populations. Although there is general consensus between guidelines, some significant differences remain. It is possible that any differences observed are the result, in part, of differences in the interpretation of the data (evidence-based medicine) used in the development of individual guideline in a given specific population (i.e. the ‘beauty lies with the beholder’ theme). The European Society of Hypertension/European Society of Cardiology (ESH/ESC) and the American Diabetes Association (ADA) released guidelines in 2013 and 2016, respectively. The ADA recommended 140/80 mmHg both as the initiation threshold and as the target blood pressure, whereas ESH/ESC has a higher initiation threshold and target diastolic blood pressure of 85 mmHg 5,6. The ADA has also released annual guidelines and, in 2016, added the recommendation that 130/80 mmHg may be a more appropriate target for certain individuals with diabetes 5. These certain individuals could include younger individuals, individuals with albuminuria, and individuals with hypertension plus one or more additional atherosclerotic cardiovascular disease risk factor 5. Finally and probably the most discussed, both the report published as the eighth edition of the Joint National Committee panel members (JNC-8) and the American Society of Hypertension released guidelines in 2014, which recommended treatment threshold and target blood pressures of 140/90 mmHg in the hypertensive patients with diabetes 7,8.
The important aspect that these guidelines have in common may not be what the recommendations are, but what data they used to generate and support the recommendations. A major contributor to current guidelines is the Action to Control Cardiovascular Risk in Diabetics (ACCORD) trial 9. Released in 2010, this trial found no significant difference in primary outcomes (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular mortality) between patients with type 2 diabetes aggressively treated to a systolic blood pressure of 120 mmHg compared with those treated to 140 mmHg. The result of the ACCORD study was paramount in establishing recent goal systolic blood pressures in patients with diabetes, as all except one guideline after its release (Canadian Hypertension Education Project) cited 140 mmHg systolic as threshold and target blood pressures 3.
Although older than ACCORD, other prominent trials examined blood pressure goals in the hypertensive diabetic patient. The United Kingdom Prospective Diabetes Study Group Study 38 provided evidence for diastolic blood pressure targets 10. Similar to ACCORD, patients were divided into tight blood pressure control and less tight blood pressure control. Goal blood pressure in the tight control arm was lower than 150/85 mmHg, with a mean achieved blood pressure of 144/82 mmHg, whereas blood pressure in the less tight control arm was lower than 180/105 mmHg, with a mean achieved blood pressure of 154/87 mmHg. Patients in the tight control arm showed a statistically significant reduction in death related to diabetes mellitus as well as the endpoints of stroke, heart failure, and microvascular endpoints.
Another study, the Action in Diabetes and Vascular Disease (ADVANCE) trial, largely looked at intensive glycemic control versus standard glucose control, but included a subgroup analysis evaluating patients treated with antihypertensive medications 11. The initial systolic blood pressure of the cohort was 145 mmHg and antihypertensive therapy lowered the systolic blood pressure by 5.6 mmHg compared with placebo. The results indicated that the antihypertensive therapy group showed a significant reduction in multiple cardiovascular events compared with the placebo-treated group.
Important in helping establish diastolic blood pressure targets in hypertensive patients with diabetes, the Hypertension Optimal Treatment trial was a study that assigned patients to three goal diastolic blood pressure targets: ≤90, ≤85, and ≤80 mmHg 12. The mean achieved diastolic blood pressures were 85.2, 83.2, and 81.1 mmHg, respectively. In the diabetes mellitus population, reductions in cardiovascular mortality and major cardiovascular events were observed in a continuous manner down to the lowest blood pressure target group compared with the highest. The blood pressures achieved in all three of these studies supported the recommendations put forth by the JNC 8 panel members.
Recent evidence in the hypertensive patient with diabetes
Since the publication by the JNC 8 panel members in early 2014, there have been several major studies, specifically addressing the management and blood pressure targets in hypertensive patient with diabetes. These publications consist either of specific hypothesis and protocol-driven clinical trials or broad-based meta-analysis reviews, clearly the two spectra of scientific study. Thus, given the availability of such new information, it is important to review these studies and to determine their potential impact on the current guidelines. Although there may be other studies to review, the main new clinical studies of interest include the Systolic Blood Pressure Intervention Trial (SPRINT), which did not include individuals with diabetes mellitus, the extension to the ACCORD trial, the ACCORDION data, and the Heart Outcomes Prevention Evaluation (HOPE-3) trial.
The Systolic Blood Pressure Intervention Trial, also known as SPRINT, specifically excluded patients with diabetes mellitus because the ACCORD trial was already underway 13. However, as it did include a high cardiovascular risk population and the patients with diabetes are an inherent high cardiovascular risk population, comparisons between SPRINT and studies specifically within the population with diabetes are inevitable. SPRINT was a randomized, controlled, open-labeled trial that tested the hypothesis that a lower systolic blood pressure goal of lower than 120 mmHg would reduce clinical events more than the current standard goal of lower than 140 mmHg. It is important to note that SPRINT participants were required to fulfill the following inclusion criteria: age 50 years old, a systolic blood pressure of 130–180 mmHg (with a number of medication guidelines), and an increased risk of cardiovascular events defined as at least one of the following: clinical or subclinical cardiovascular disease (other than stroke), chronic kidney disease defined as an estimated glomerular filtration rate of 20–60 (not including polycystic kidney disease), a Framingham Risk Score for a 10-year cardiovascular risk of more than 15%, or age 75 years or older. As with ACCORD, the goal of the protocol was achieved in that the blood pressures of the two study groups were achieved and maintained throughout the study period. Importantly, the study was stopped early by the safety monitoring committee because the intensively treated group showed a significant reduction in the primary composite endpoint. Specifically, total deaths were significantly reduced in the intensive-treatment group (hazard ratio, 0.73) and the relative risk of death from cardiovascular causes was 43% lower (hazard ratio, 0.57) in the intensive-treatment group. Most of this difference arose from a significant reduction in heart failure (hazard ratio, 0.62) in the intensive-treatment group. Other individual cardiovascular endpoints were not significantly reduced in the intensive-treatment group including stroke (hazard ratio, 0.89). However, hypotension (hazard ratio, 1.67), syncope (hazard ratio, 1.33), electrolyte abnormalities (hazard ratio, 1.35), and acute kidney injury or acute renal failure (hazard ratio, 1.66) were significantly increased in the intensive-treatment group. Two important clinically relevant points need to be noted when the positive results of SPRINT are discussed and interpreted. First, and probably most important, is the way in which blood pressure was determined. Blood pressure was obtained on the basis of the mean of three measurements at an office visit while the patient was seated and after 5 min of quiet rest, and the measurements were obtained by an automated measurement system (Model 907; Omron Healthcare, Milton Keynes, UK). One issue that has arisen is that this methodology may result in significantly lower blood pressures (5–10 mmHg lower) than those obtained by other more commonly used office methods. The second point is that SPRINT was very labor intensive.
The second new clinical trial-related data to review are the extension of the ACCORD trial, known as ACCORDION. As mentioned previously, the ACCORD trial, with a design similar to SPRINT, did not show a difference in the primary combined endpoint of composite cardiovascular events between the intensive-treatment (<120 mmHg systolic) and the standard treatment (<140 mmHg systolic) diabetes groups (a nonsignificant reduction of 12% favoring the intensive-treatment group was observed) 14. Interestingly, a significant reduction in strokes was observed in the intensive-treatment group, but the number was small and stroke was only one of many individual endpoints. However, ACCORD was a 2×2 factorial designed trial with glucose and blood pressure interventions 9. The clinically important finding of ACCORD was that intensive glucose control increased event rates, which could confound the interpretation of the blood pressure control arms. In the original analysis of ACCORD, there was a suggestion (but nonsignificant) of an interaction between glucose and blood pressure control such that the increased event rates of intensive glucose control could off-set any potential benefit of blood pressure control. Of interest now is that a significant number of the original ACCORD study individuals (3957) were followed for up to an additional 5 years. As the original study was negative, the blood pressure difference between the two groups narrowed from approximately 14 to 4 mmHg systolic 14. The evaluation of the follow-up period (approximately a total median of 9 years) data, ACCORDION, now indicates an interaction between glucose and blood pressure control (P=0.037) 14,15. Thus, when only the standard glucose treatment individuals are analyzed separately, the intensive-blood pressure treatment group gained a significant benefit in endpoints compared with the standard blood pressure treatment group (hazard ratio, 0.79) 14. This 21% reduction in the intensive-treatment group of patients with diabetes compares favorably with the SPRINT data noted above. In addition, the initial favorable reduction in stroke rate in the intensive-treatment group in ACCORD was absent in ACCORDION (note that the original blood pressure difference between the two groups no longer remained), suggesting that the original stroke reduction observed was probably a real finding.
Finally, HOPE-3 study was a primary cardiovascular prevention trial in a large number (12 705) of intermediate-risk individuals 16. Although not specifically a trial of diabetes, it is pertinent, given its inclusion criteria defining intermediate risk. The inclusion criteria comprised of at least one of the following: increased waist-to-hip ratio, high-density lipoprotein cholesterol of less than 39 mg/dl (<1.0 mmol/l) for men and less than 50 mg/dl (<1.3 mmol/l) for women, current or recent smoking, prediabetes mellitus or diet-controlled diabetes mellitus, premature coronary disease in first-degree relatives, or early renal dysfunction. Like ACCORD, HOPE-3 was a 2×2 factorial design, with each participant receiving the statin, rosuvastatin, or placebo, plus the antihypertensive agent candesartan/hydrochlorothiazide or placebo. For the purposes of the blood pressure component of the trial, the baseline blood pressure was 138/82 mmHg. The major positive finding of HOPE-3 was that rosuvastatin, which lowered low-density lipoprotein cholesterol by ∼35 mg/dl (0.9 mmol/l), significantly decreased the primary outcome (cardiovascular related death, nonfatal stroke, or nonfatal myocardial infarction) compared with placebo. However, candesartan/hydrochlorothiazide, which lowered the blood pressure by 6 mmHg systolic and 3 mmHg diastolic compared with placebo, did not significantly lower the primary outcome measure. In keeping with the known increased risk with increasing systolic blood pressure, the antihypertensive regimen did lower the primary outcome measure in the subgroup with the highest entry systolic blood pressure (>143 mmHg) compared with placebo (4.8 vs. 6.5%). In addition, the combination of a statin and the antihypertensive regimen had no additional effect.
On the other end of the clinical research spectrum, two recent meta-analyses on blood pressure lowering in diabetes have been published. Emdin et al. 17 reported a meta-analysis on the effect of blood pressure lowering in type 2 diabetes mellitus that included 40 trials and over 100 000 participants. Their analysis indicated that blood pressure-lowering treatment was associated with a significantly lower risk of all-cause mortality, cardiovascular disease, and coronary heart disease events, and stroke events in patients with diabetes mellitus. These outcomes were particularly prominent at a baseline systolic blood pressure of 140 mmHg or more. However, when trials were stratified by baseline systolic blood pressure of greater than or lower than 140 mmHg, the relative risk for outcomes other than stroke, retinopathy, and renal failure was lower in studies with greater baseline systolic blood pressure. When the achieved systolic blood pressure was examined, only stroke and albuminuria were significantly reduced further at blood pressure lower than 130 mmHg. When individual classes of antihypertensive agents were examined, diuretics (largely driven by ALLHAT) and angiotensin receptor blockers were associated with a lower relative risk for heart failure than the other classes. Calcium channel blockers were associated with an increase in the relative risk of heart failure, but a lower relative risk of stroke compared with the other classes. β-Blockers, however, were associated with a higher relative risk of stroke.
Brunström and Carlberg 18 reported a more recent meta-analysis examining the effect of antihypertensive treatment at different blood pressure levels in patients with primarily type 2 diabetes mellitus. Their analysis included 49 trials consisting of almost 74 000 participants and found that if the baseline systolic blood pressure was greater than 150 mmHg, antihypertensive treatment reduced the risk of all-cause mortality (relative risk, 0.89), cardiovascular mortality (relative risk, 0.75), myocardial infarction (relative risk, 0.74), stroke (0.77), and end-stage renal disease (0.82). This risk improvement also extended to baseline systolic blood pressures between 140 and 150 mmHg for some but not all risk factors. However, their results indicated that for baseline blood pressure of lower than 140 mmHg, further antihypertensive treatment actually increased cardiovascular mortality. These results suggest a ‘U’ or a ‘J’ effect of blood pressure lowering in patients with diabetes mellitus.
By 2010, it was well established that hypertension was the leading global risk for mortality and the WHO noted hypertension to be responsible for 12.8% of the total deaths worldwide 19. At that time, the residing ESH council members asked whether aggressive blood pressure management in diabetes mellitus would produce more benefit than harm. The ADVANCE trial, published in 2007, suggested that microvascular and macrovascular outcomes were reduced with antihypertensive goals of a systolic blood pressure of lower than 135 mmHg compared with a placebo-treated population who had systolic blood pressures of ∼140 mmHg 11. Ultimately, the ESH/ESC guidelines reflected the threshold and goal of treatment at 140/85 mmHg 6. However, the committee made it a point to acknowledge that many important decisions on creating these guidelines had to be made without the assistance of largely supported randomized trials – that is, on the basis of expert opinion.
After the release by the JNC 8 panel members, there was renewed controversy on the specific management of hypertension in the elderly and in patients with diabetes mellitus and chronic kidney disease. Shortly after the guidelines were released by the JNC 8 panel members, the American Heart Association stated, ‘We are concerned that relaxing the recommendations may expose more persons to the problem of inadequately controlled blood pressure.’ 20. This leaves room for the following question: how and where do we proceed from here? With the recent release of SPRINT favoring treatment to lower systolic blood pressure goals in high cardiovascular risk patients, there is the temptation to extrapolate these data to diabetes mellitus patients who are at equal if not higher cardiovascular risk. This extrapolation would be in contrast to the previous findings from ACCORD; however, complicating matters further, many may have noted that ACCORD was underpowered to show a statistical difference between the intensive and standard blood pressure treatment groups, given the low event rates observed.
Ultimately, clinical guidelines are ‘living documents’ – that is, generated from revisiting previous, ‘older’ literature while exploring and integrating new literature when appropriate. With respect to systolic blood pressure management, the SPRINT trial suggests that populations without diabetes treated for a goal of lower than 120 mmHg compared with lower than 140 mmHg had statistically significant lower rates of fatal and nonfatal sequelae, particularly from congestive heart failure 13. Extrapolating these data to patients with diabetes mellitus may be possible as mentioned above, but caution should be maintained as there may be unforeseen and important differences between these populations. Given the newer data reviewed above, it may be time to reconsider the threshold and target blood pressure goals for hypertensive patients with diabetes. The above-mentioned meta-analyses seem to indicate that a threshold of 140/90 mmHg with a goal target to 130/80 mmHg may be appropriate. Given the extended follow-up period and interpretation of ACCORD to ACCORDION, it can also be argued that more aggressive blood pressure goals are indicated, including a threshold of 130/80 mmHg and a target below 130/80 mmHg in hypertensive patients with diabetes. Referring back to the title and theme of this paper, it seems clear that indeed there continues to be ‘Too many guidelines and NOT enough data’. Therefore, what is needed? Either or both can be proposed: planning and implementing a large-scale clinical trial similar to the SPRINT with blood pressure intensive and standard treatment groups in all hypertensive patients including low-risk individuals and those with diabetes and/or another similar trial to ACCORD, but with greater statistical power to detect significant differences, if indeed they were to occur.
Hypertension increases morbidity, mortality, and overall cardiovascular risk in patients with diabetes mellitus. Current guidelines vary across numerous organizations about when and how to treat individuals with diabetes mellitus and hypertension, and the debate continues today. Originally, the less stringent blood pressure guidelines, hypertension in the patient with diabetes recommended by the JNC 8 panel members, were a result of the charge to the committee to use evidence-based medicine, wherever possible. However, recent results from the SPRINT trial and ACCORD extension (ACCORDION) provide reason to believe that guidelines to come may recommend more aggressive blood pressure treatment goals.
The American College of Cardiology and American Heart Association have recently formed another committee to develop another set of guidelines on the treatment of hypertension and it will be interesting to see whether there is specific commentary on hypertensive management and treatment in patients with diabetes mellitus. Until new and hopefully definitive data become available, a reasoned approach to treating hypertension in the patient with diabetes includes therapeutic goals tailored for the individual following present guidelines and ‘expert opinion’ that includes more recent studies and data. Hopefully, future guidelines will be developed according to formulated evidence-based medicine to come and will be uniform between one another. The practice of medicine has always been and will continue to be a blend of art and science. In the spirit of blending art and science, there presently are ‘Too many guidelines and Not enough’ in individuals with hypertension and diabetes.
Donald J. DiPette, MD, supported in part by the Health Sciences Distinguished Professorship, University of South Carolina, Columbia, South Carolina, USA.
Conflicts of interest
There are no conflicts of interest.
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