Abstract
Hypertension is a very common cardiovascular disease (CVD) risk factor in diabetes, affecting more than half of diabetic patients. Major guidelines on the management of hypertension recommend to start antihypertensive drugs in all diabetic patients with a systolic blood pressure (SBP) 140 mmHg or more and/or a diastolic blood pressure (DBP) 90 mmHg or more, and to adjust the treatment strategy in order to lower their BP below these values. The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a SBP treatment goal of 130 to 135 mmHg is acceptable. Aiming at SBP levels of 130 mmHg decreases stroke risk, but the risk of serious adverse events may increase with very low BP levels. The results regarding the attained DBP level is somewhat complex, since middle-aged people with diastolic hypertension and pre-existing CVD may have increased CVD mortality if their DBP is lowered drastically to a very low level. With the currently available very limited trial data on low attained BP level, it is not possible to set a specific treatment target regarding BP levels for diabetic hypertensive patients, but it is important to use a personalized approach in their antihypertensive treatment.
| Abbreviations | ||
| ABCD | = | Appropriate Blood Pressure Control in Diabetes |
| ACCOMPLISH | = | Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension |
| ACCORD-BP | = | Action to Control Cardiovascular Risk in Diabetes-Blood Pressure |
| AHT | = | antihypertension treatment |
| ADVANCE | = | Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation |
| CVD | = | cardiovascular disease |
| DBP | = | diastolic blood pressure |
| FINRISKI | = | Finnish National Chronic Disease Surveys |
| HR | = | hazard ratio |
| HOT | = | hypertension optimal treatment |
| IDF | = | International Diabetes Federation |
| MI | = | myocardial infarction |
| NHANES | = | National Health and Nutrition Examination Surveys |
| RCT | = | randomized controlled clinical trials |
| SBP | = | systolic blood pressure |
| SHEP | = | Systolic Hypertension in the Elderly |
| Syst-Eur | = | Systolic Hypertension in Europe |
| UKPDS | = | United Kingdom Prospective Diabetes Study |
| VADT | = | Veterans Affairs Diabetes Trial |
Key messages
Various guideline committees had recommended that, in patients with diabetes mellitus and hypertension, the target BP should be < 130/80 mmHg despite a lack of supporting evidence from randomized clinical controlled trials.
The present body of evidence suggests that in patients with type 2 diabetes mellitus/impaired fasting glucose/impaired glucose tolerance, a systolic BP treatment goal of 130 to 135 mmHg is acceptable.
In patients with isolated systolic hypertension DBP may be safely lowered below 80 mmHg.
With the currently available very limited trial data on low attained BP level, it is not possible to set a specific treatment target regarding BP levels for diabetic hypertensive patients.
Introduction
Type 2 diabetes is one of the fastest growing public health problems in both developed and developing countries. The International Diabetes Federation (IDF) estimates that the number of adults with diabetes will increase to more than 400 million in the year 2030 (Citation1). The growing prevalence of type 2 diabetes, with the high morbidity and excess mortality associated with it, will impose a heavy burden on patients and also health care systems (Citation1). Indeed, the prevention and treatment of diabetes has become a major challenge for clinicians and public health policy-makers worldwide (Citation1,Citation2).
Approximately 75%–80% of people with diabetes die from cardiovascular diseases (CVD). People with type 2 diabetes have a 2–4-times higher risk of coronary heart disease than the rest of the population, and their prognosis is poorer (Citation3). The risk of cerebrovascular and peripheral vascular disease is also significantly higher (Citation4). Premature mortality caused by diabetes results in an estimated 12–14 years of life lost among diabetic patients (Citation5).
Hypertension, defined as a blood pressure (BP) >140/90 mmHg, is a very common CVD risk factor, affecting more than half of diabetic patients. Hypertension is particularly harmful for people with diabetes because it further increases the risk of CVD morbidity and mortality 2–4 times compared with diabetic people without hypertension (Citation6,Citation7). Thus, effective treatment and control of hypertension is a key element in the management of diabetic patients. It has even been suggested that the BP targets in diabetic patients should be lower than in non-diabetic hypertensive patients. However, only limited data exist to justify the currently recommended treatment targets; thus, it is not clear how low ideal systolic and diastolic BP targets may be set in diabetic patients. Thus, the aim of this review is to present the current evidence in antihypertensive drug treatment targets in type 2 diabetic patients.
Trends in mean BP in people with diabetes
Only few published reports exist from national diabetes or population-based data regarding trends of BP in people with diabetes. The proportion of people with diabetes with poorly controlled BP declined considerably from the 1970s to the 1990s in the Unites States (US) (Citation8). Data from the National Health and Nutrition Examination Surveys (NHANES), however, did not reveal any changes in BP control in diabetic patients from 1988–1994 to the early 2000s or from 1999 to 2006, respectively (Citation9,Citation10). Nevertheless, a recent analysis of the NHANES data regarding long-term changes in BP levels among US adults with diagnosed diabetes showed decreasing BP from 1988–1994 to 2001–2008 (Citation11); mean BP levels declined from 135/72 mmHg to 131/69 mmHg, and the prevalence of diabetic patients with BP > 140/90 mmHg increased from 64% to 69%. However, there was no sign of improvement in adults aged 20–44 years.
The latest data from the Swedish National Diabetes register using three cross-sectional samples in 2005, 2007, and 2009—not all the same patients—showed a decrease of mean BP from 141/77 to 136/76 mmHg and a decrease in the proportion of patients with BP ≥ 140/90 mmHg from 58% to 46% (Citation12).
Our FINRISKI data showed a mean decline in BP from 154/87 mmHg to 150/84 mmHg in diabetic men with antihypertensive drug treatment and from 149/82 mmHg to 148/78 mmHg in women, respectively, during 1997 and 2002 (). However, only the changes in diastolic blood pressure (DBP) were statistically significant. It has to be mentioned that similar changes in systolic blood pressure (SBP) and DBP in men and women with diabetes but not treated for hypertension were observed.
Table I. Systolic and diastolic blood pressure levels in men and women with and without antihypertensive (AHT) drug treatment and in the diabetic and non-diabetic population in Finland 1997 and 2002, adjusted for age.
Current guidelines regarding treatment of hypertension in diabetes patients
Major guidelines on the management of hypertension recommend to start antihypertensive drugs in all diabetic patients with SBP ≥ 140 mmHg or DBP ≥ 90 mmHg and to adjust the treatment strategy in order lower their BP below these values (Citation13–23). A majority of these guidelines further recommend antihypertensive drug treatment to be initiated in diabetic patients with SBP between 130 and 139 mmHg or DBP between 85 and 89 mmHg aiming at achieving both SBP <130 mmHg and DBP <80 mmHg (Citation13–21,Citation23). The vast majority of these guidelines seem to be based on two landmark studies that demonstrated that the effective BP control is crucial to reduce vascular complications and improve survival among people with diabetes (Citation24,Citation25). There are, however, very limited data about patients with diabetes to support such a recommendation for a lower DBP treatment target, particularly in the growing population of diabetic patients with coronary artery disease (Citation21).
The reappraisal of European guidelines in 2009 stated that initiation of antihypertensive drug therapy in diabetic patients with ‘high normal’ BP is presently unsupported by prospective trial evidence (Citation22). They recommend treatment initiation in high normal BP diabetic patients only if subclinical organ damage (particularly microalbuminuria or proteinuria) is present, suggesting less ambitious but safer targets (130–139 mmHg for SBP and 80–85 mmHg for DBP, respectively).
Current evidence for BP control in diabetic patients with regard to CVD, stroke, and all-cause mortality ()
Table II. Randomized control trials testing a blood pressure strategy in diabetes patients.
It is a concern to see that various guideline committees had recommended that in patients with diabetes mellitus and hypertension, the target BP should be < 130/80 mmHg (and even lower to 125/75 mmHg in those with renal impairment) without proper supporting evidence from randomized clinical controlled trials (Citation26). Early data from four landmark trials such as the United Kingdom Prospective Diabetes Study (UKPDS) (Citation25), Hypertension Optimal Treatment (HOT) (Citation24), Systolic Hypertension in the Elderly (SHEP) (Citation27), and Systolic Hypertension in Europe (Syst-Eur) (Citation28) showed that aggressive BP control was beneficial in hypertensive patients with diabetes. It is worth noting that by definition DBP in SHEP and Syst-Eur was <90 mmHg, and during treatment the mean value fell below 80 mmHg (Citation29). However, it has to be kept in mind that in these studies the achieved SBP in the tight control arm was 140–150 mmHg. In the Hypertension Optimal Treatment (HOT) randomized trial 18,790 patients, from 26 countries, aged 50–80 years, with hypertension and DBP between 100 mmHg and 115 mmHg (mean 105 mmHg) were randomly assigned a target DBP (Citation24). All in all, 6264 patients were allocated to the target DBP ≤ 90 mmHg, 6264 to ≤ 85 mmHg, and 6262 to ≤ 80 mmHg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. DBP was reduced by 20.3 mmHg, 22.3 mmHg, and 24.3 mmHg, in the ≤ 90 mmHg, ≤ 85 mmHg, and ≤ 80 mmHg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved DBP of 82.6 mmHg; the lowest risk of cardiovascular mortality occurred at 86.5 mmHg. Further reduction below these BP levels was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in the ≤ 80 mmHg target group compared with the ≤ 90 mmHg target group.
The results from the Syst-Eur trial showed that in patients with diabetes active antihypertensive treatment reduced total mortality by 55%, CVD mortality by 76%, all CVD events combined by 69%, and fatal and non-fatal strokes by 73%, more than in non-diabetic patients (Citation28). The UKPDS found that tight BP control (< 150/85 mmHg) reduced diabetes-related deaths by 32% without a significant reduction in all-cause mortality after a median follow-up of 8.4 years (Citation25), while the Appropriate Blood Pressure Control in Diabetes (ABCD) trial demonstrated a decrease in all-cause mortality (P = 0.037) for intensive (DBP < 75 mmHg) versus moderate antihypertensive therapy in patients with type 2 diabetes (Citation30). In the ACCOMPLISH trial the baseline BP was 145/79 mmHg and attained BP during treatment 132/73 mmHg, with 45% of patients having SBP < 130 mmHg and DBP < 80 mmHg (Citation31). The combination of an ACE inhibitor with amlodipine, compared with its combination with hydrochlorothiazide, was more effective in reducing BP and preventing fatal and non-fatal cardiovascular outcomes in hypertensive diabetic patients, particularly in high-risk diabetic patients with histories of cardiovascular, stroke, and renal events. No evidence was reported on adverse outcome in patients with low attained BP in the ACCOMPLISH trial. Finally, the Action in Diabetes and Vascular Disease Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial emphasized the clinical benefits of achieving a SBP of < 140 mmHg in high-risk patients with type 2 diabetes. It compared clinical outcomes associated with an ACE inhibitor–diuretic combination (perindopril/indapamide) versus placebo in 11,740 middle-aged, high-risk patients with diabetes (Citation32). Active therapy was associated with an average BP lowering of 5.6 (SBP), respectively 2.2 (DBP) mmHg after 4.3 years, a 14% reduction in all-cause mortality and an 18% reduction in cardiovascular death.
The recent findings of the Action to Control Cardiovascular Risk in Diabetes (ACCORD-BP) study, however, are challenging the existing assumption that the lower BP, the more beneficial antihypertensive therapy is for diabetes patients (Citation33). The ACCORD-BP trial randomized 4733 patients with type 2 diabetes to either an intensive treatment strategy to achieve a target SBP of < 120 mmHg or a standard treatment strategy targeting a SBP of < 140 mmHg (Citation31); achieved BPs were 119 mmHg and 133 mmHg, respectively, during 4.7 years. The primary composite end-point was non-fatal myocardial infarction, non-fatal stroke, and CVD death. The intensive strategy found a statistically non-significant reduction in the primary outcome rate (1.87% versus 2.09%; hazard ratio (HR) 0.88, 95% CI 0.73–1.06) or all-cause mortality. Furthermore, the study reported a statistically significant reduction of stroke, one of the secondary end-points (0.32 versus 0.53%, HR 0.59, 95% CI 0.39–0.89). Intensive therapy did, however, increase the risk of major adverse events including symptomatic hypotension, bradycardia, arrhythmia, and hyperkalemia. Interestingly, although the overall effect was non-significant the ACCORD-BP trial investigators observed from the stratified post-hoc analysis according to moderate or intensive glucose-lowering that intensive BP-lowering did statistically significantly reduce the primary end-point in the moderate glucose-lowering stratum. This may suggest that benefits of BP-lowering with regard to cardiovascular risk may differ according to glucose treatment targets.
Nevertheless, some major issues complicate the interpretation of the ACCORD-BP trial. The study may have been underpowered, as event rates were nearly 50% lower than expected. The reduced power was reflected in the relatively wide confidence interval that does not exclude a 27% benefit for the primary end-point. In addition, the ACCORD trial did not explicitly examine the SBP threshold of 130 mmHg, and therefore the trial does not directly inform whether current thresholds proposed are most appropriate (Citation34). Nevertheless, the ACCORD trial has raised the possibility that the benefits of lowering BP gradually flatten at lower SBP and/or DBP values. Likewise, Cooper-DeHoff et al. (Citation35) found in their cohort study that tight control of systolic BP in patients with diabetes and coronary artery disease did not decrease mortality. The hazard ratio for all-cause mortality was 1.20 (95% CI 0.99–1.45) suggesting a non-significant excess of deaths in patients with tight BP control compared with those receiving usual care. They also showed that SBP of less than 110 mmHg was associated with an increase in all-cause mortality compared with SBP of 125–130 mmHg.
In line with these results, the Veterans Affairs Diabetes Trial (VADT) observed an increased risk of CVD events with DBP < 70 mmHg, even when combined with SBP in guideline-recommended target ranges (Citation36). The VADT included 1791 participants with hypertension receiving stepped treatment to maintain BP below the target of 130/80 mmHg in standard and intensive glycaemic treatment groups (Citation36). The primary outcome was the first occurrence of myocardial infarction, stroke, congestive heart failure, surgery for vascular disease, inoperable coronary disease, amputation for ischemic gangrene, or CVD death.
Thus, these studies question the notion that there is no threshold for BP-lowering as recently exposed by the American Diabetes Association, American Heart Association, and others. Also, Bakris et al. reported a significant increase in cardiovascular risk in patients with diabetes, hypertension, and coronary artery disease among those who achieved SBP of 110 mmHg or lower (Citation37). However, the power of the HR for the < 110/60 mmHg group was severely limited because of a small sample size.
The recent meta-analysis by Bangalore et al. has summarized the data from the available randomized controlled clinical trials (RCT) examining the role of intensive BP-lowering in patients with diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance (Citation38). This analysis does not support the recommendations of the major clinical guidelines of lowering SBP to < 130 mmHg, because their results did not find significant benefits of an intensive blood-pressure-lowering strategy in comparison to the standard BP control strategy on macrovascular and microvascular (cardiac, renal, and retinal) events (Citation25,Citation33,Citation38). However, they did not analyse results regarding DBP control where several RCTs, even placebo-controlled ones, have unequivocally shown benefits from intensive BP-lowering below 80 mmHg. Furthermore, it has to be kept in mind that their study was not designed to test the efficacy of more-tight versus less-tight BP strategies but to test outcomes based on average achieved BP rather than randomized comparisons of BP control strategies. The meta-analysis conducted by Reboldi et al., however, was specifically designed to investigate the conclusiveness of available evidence on different BP control strategies using cumulative sequential analysis of available evidence including a total of 73,913 patients with diabetes in 31 randomized controlled trials (Citation39). The outcome measures were myocardial infarction (MI) and stroke. Overall, experimental treatment reduced the risk of stroke by 9% and that of MI by 11%. Allocation to more-tight, compared with less-tight, BP control reduced the risk of stroke by 31%, whereas the reduction in the risk of MI approached, but did not achieve, significance. In a meta-regression analysis, the risk of stroke decreased statistically significantly by 13% for each 5 mmHg reduction in SBP, and by 11.5% for each 2 mmHg reduction in DBP. However, the risk of MI did not show any association with the extent of BP reduction.
Nevertheless, we would also like to remind of the issue of the J-shaped curve of CVD mortality in relation to DBP in patients treated with antihypertensive drugs that has repeatedly been reported in therapeutic trials (Citation40). The increased risk in the low end of the attained DBP distribution has been attributed to the presence of cardiac diseases. Although these findings have not specifically been obtained in diabetic patients, there is no reason to believe that there would be a difference between diabetic and non-diabetic people in this respect. Thus, the present body of evidence suggests that in patients with type 2 diabetes/impaired fasting glucose/impaired glucose tolerance, a SBP treatment goal of 130–135 mmHg is acceptable. The results regarding the attained DBP level is somewhat complex, since middle-aged people with diastolic hypertension and pre-existing CVD may have in-creased CVD mortality if their DBP is lowered drastically to a very low level. On the other hand, many older hypertensive patients have isolated systolic hypertension, and in them lowering DBP to 80 mmHg or lower seems to be safe. With the currently available very limited trial data on the low attained BP level, it is not possible to set a specific treatment target regarding BP level for diabetic hypertensive patients, but it is important to use a personalized approach in their antihypertensive treatment. In any scenario, high BP in diabetic patients is dangerous and must be avoided. Finally, we would like to point out that still almost half of all patients with diabetes and antihypertensive treatment are not reaching BP treatment targets at all. Thus, the main problem may be how to increase the prevalence of patients with SBP below 140 mmHg, rather than patients who are too well controlled.
Declaration of interest: The authors report no conflicts of interest.
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