XII. Treatment of Hypertension in Association With Diabetes Mellitus

Prevention and Treatment

Subgroup Members: Richard E. Gilbert, MD, PhD; Lawrence A. Leiter, MD; Charlotte Jones, MD, PhD; Sheldon W. Tobe, MD, MSc(HPTE); Vincent Woo, MD
Central Review Committee: Stella S. Daskalopoulou, MD, PhD; Kaberi Dasgupta, MD, MSc; Kelly B. Zarnke, MD, MSc; Kara Nerenberg, MD, MSc; Alexander A. Leung, MD, MPH; Kevin C. Harris, MD, MHSc; Kerry McBrien, MD, MPH; Sonia Butalia, BSc, MD; Meranda Nakhla, MD, MSc
Chair: Doreen M. Rabi, MD, MSc
This information is based on the Hypertension Canada guidelines published in Leung, Alexander A. et al. Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults. Can J Cardiol 2017; 33(5): 557-576.

Guidelines

  1. Persons with diabetes mellitus should be treated to attain SBP of <130 mmHg (Grade C) and DBP of <80 mmHg (Grade A) (these target BP levels are the same as BP treatment thresholds). Combination therapy using 2 first-line agents may also be considered as initial treatment of hypertension (Grade B) if SBP is 20 mmHg greater than target or if DBP is 10 mmHg greater than target. However, caution should be exercised in patients in whom a substantial decrease in BP is more likely or poorly tolerated (e.g., elderly patients and patients with autonomic neuropathy).
  2. For persons with cardiovascular or kidney disease, including microalbuminuria, or with cardiovascular risk factors in addition to diabetes and hypertension, an ACE inhibitor or an ARB is recommended as initial therapy (Grade A).
  3. For persons with diabetes and hypertension not included in other guidelines in this section, appropriate choices include (in alphabetical order): ACE inhibitors (Grade A), ARBs (Grade B), dihydropyridine CCBs (Grade A), and thiazide/thiazide-like diuretics (Grade A).
  4. If target BP levels are not achieved with standard-dose monotherapy, additional antihypertensive therapy should be used. For persons in whom combination therapy with an ACE inhibitor is being considered, a dihydropyridine CCB is preferable to a thiazide/thiazide-like diuretic (Grade A).

Background

1. Persons with diabetes mellitus should be treated to attain SBP of <130 mmHg (Grade C) and DBP of <80 mmHg (Grade A) (these target BP levels are the same as BP treatment thresholds). Combination therapy using 2 first-line agents may also be considered as initial treatment of hypertension (Grade B) if SBP is 20 mmHg greater than target or if DBP is 10 mmHg greater than target. However, caution should be exercised in patients in whom a substantial decrease in BP is more likely or poorly tolerated (e.g., elderly patients and patients with autonomic neuropathy).

Observational studies and randomized, clinical trials show a strong association between raised SBPs and DBPs, and clinically important microvascular complications (e.g., retinopathy and nephropathy), as well as macrovascular complications in patients with hypertension, who have diabetes mellitus. The association between BP level (systolic and diastolic) and cardiovascular risk is continuous and graded in patients with diabetes mellitus. Treatment of hypertension appears to confer greater benefits in people with diabetes than in age-matched people with hypertension, who do not have diabetes (1–3), and the benefits of aggressive blood pressure lowering may even exceed those of aggressive glycemic control in people with diabetes mellitus for the prevention of cardiovascular complications (4,5). Because cardiovascular disease is the most common cause of death in patients with diabetes mellitus (6), BP control is paramount in these patients.

In subjects with diabetes, there is randomized, clinical trial evidence supporting lower BP levels (two major trials are the United Kingdom Prospective Diabetes Study Group [UKPDS]-38 trial and the Hypertension Optimal Treatment [HOT] Trial) (8,4). In the UKPDS-38 trials, more intensive BP lowering led to reductions in risk of microvascular diabetic endpoints of 37% (95% CI, 11% to 56%) and in stroke of 44% (95%CI, 11% to 65%) (4). In the treat-to-target HOT trial, within the a priori-specified subgroup of diabetic patients, the rate of major cardiovascular events was 51% lower in patients randomly assigned to achieve target BPs < 80 mm Hg than in those patients with target pressures of 85 to 90 mm Hg (8). Therefore, the HOT trial results support a DBP treatment goal of ≤ 80 mm Hg (thus, a Grade A recommendation).

Use of combination therapy is supported by the results of the BP-lowering arm of the ADVANCE trial (9).  In this trial, 11,140 patients with type 2 diabetes older than 55 years of age with a history of major vascular disease or vascular risk factors, were randomly assigned to receive perindopril/indapamide versus placebo in addition to current antihypertensive therapy (9). After a mean follow-up period of 4.3 years, combination therapy was associated with a 5.6/2.2 mm Hg greater reduction in blood pressure compared with placebo. There were no significant differences in the macrovascular or microvascular primary endpoints between combination therapy and placebo. In the secondary endpoint analysis, however, combination therapy was associated with a significant reduction in cardiovascular death (hazard ratio [HR], 0.82; 95%CI, 0.68 to 0.98; P=0.03) and total mortality (HR, 0.86; 95%CI, 0.75 to 0.98; P=0.03) compared with placebo. Rates of serious adverse events and permanent discontinuation for hypotension or dizziness were similarly low in combination and placebo groups.  Several trials in non-diabetic patients also found combination therapy to be associated with greater BP lowering, reduced rates of cardiovascular endpoints and low rates of adverse events (10,11). Given the significantly greater BP reductions associated with combination therapy, a combination of two first-line agents should be used in patients with significant elevations in blood pressure. Caution, however, should be exercised in patients in whom a substantial fall in BP is more likely to occur or is more poorly tolerated (e.g., the elderly and patients with autonomic neuropathy).

Regarding systolic BP targets, two major meta-analyses have examined the relative benefits and risks of achieving lower SBP in patients with diabetes mellitus and hypertension. The Bangalore et al. meta-analysis included trials comparing achieved SBP levels of < 135 mm Hg, < 130 mm Hg, and < 140 mm Hg (17) in patients with diabetes or impaired fasting glucose (IFG). The primary outcome was major adverse cardiovascular events including mortality, cardiovascular mortality, MI, stroke, and heart failure. The analysis showed that achieving SBP levels of < 135 mm Hg reduced mortality (odds ratio [OR], 0.87; 95%CI, 0.79–0.95), while levels <130 mm Hg  reduced risk of stroke (OR, 0.53; 95%CI, 0.38–0.75). The other meta-analysis, by Reboldi et al., included all antihypertensive trials that enrolled patients with hypertension and diabetes but not IFG. A series of stratified meta-analyses and meta-regression analyses were conducted to determine the benefit associated with different levels of SBP on MI and stroke (18). Decreasing levels of SBP were associated with increasing benefit in terms of stroke, but not in terms of MI. A meta-regression examining the association between the degree of SBP lowering and stroke found for every 5% reduction in SBP, risk of stroke was reduced by 13%. Such a linear association between SBP reduction and MI risk reduction was not noted.  Both of these reviews were limited by the fact they were not limited exclusively to treat-to-target trials, but rather examined achieved SBP. This, in part, explains the Grade C assigned to the systolic BP target.  Additionally, these reviews could not control for differences in duration of diabetes or glycemic control.

Included in these meta-analyses, are data from the major treat-to-target study,  the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial.  This trial enrolled 4733 subjects with diabetes were randomly assigned to systolic treatment targets of 120 mm Hg versus 140 mm Hg) (15,19). Achieved systolic BP levels were 119.3 mmHg in the intensive arm and 133.5 mmHg in the standard arm.  No significant reduction in the risk of the primary endpoint (non-fatal MI, non-fatal stroke, or cardiovascular death) was seen (HR 0.88; 95% CI 0.73 to 1.06).  Stroke rates were significantly reduced with intensive therapy, but the absolute risk reduction was small (0.32% vs. 0.53%; hazard ratio, 0.59; 95% CI, 0.39 to 0.89).  Intensive therapy led to increased bradycardia, hypotension and hyperkalemia.

ACCORD indicates SBP reductions to < 120 mm Hg in subjects with diabetes slightly reduces the risk of stroke on one hand, but increases risk of adverse events on the other, with the majority of adverse effects associated with SBP < 120 mm Hg. Limitations of the ACCORD trial deserve mention.  The study utilized a factorial design, examining also the effect of intensive glycemic control and lipid control in subjects with diabetes), and this complex design likely resulted in the trial being underpowered to detect important reductions in endpoints with intensive BP control. In addition, evidence for interaction was seen, whereby intensive BP control significantly reduced events in subjects randomized to standard glucose control but not in those randomized to intensive glucose control (20). Because of these limitations, ACCORD does not definitively answer the question of whether or not intensive blood pressure control in diabetes is beneficial.

Neither the UKPDS-36 nor the HOT trials identified a threshold below which clinical benefit was no longer evident. The recommendation to lower SBPs to 130 mm Hg or less is partly based on prospective cohort data; specifically, the Pittsburgh Epidemiology of Diabetes Complications Study (in patients with type 1 diabetes mellitus) and the UKPDS-36 (in patients with type 2 diabetes mellitus) demonstrated a linear relationship between SBP levels and mortality, coronary artery disease, overt diabetic nephropathy and proliferative retinopathy (13,14). These associations were maintained even after adjustment for other confounding factors (such as lipid levels, age, sex and glycemic control). In these studies, direct relationships were seen between the magnitude of incremental BP reduction and reductions in risk of hypertension-related complications over time.  These data also support a Grade C rating.

2. For persons with cardiovascular or kidney disease, including microalbuminuria, or with cardiovascular risk factors in addition to diabetes and hypertension, an ACE inhibitor or an ARB is recommended as initial therapy (Grade A).

These guidelines identify specifically those patients with diabetes, and those patients with evidence of increased urinary albumin excretion, as persons at high risk for cardiovascular events. In addition, the recommendations also recognize those patients with known cardiovascular disease, renal disease, or elevated urinary albumin excretion, as well as those patients with additional cardiovascular risk factors to be high-risk patients who should receive an ACE inhibitor or an ARB as first-line therapy (38–40). This risk assessment strategy is consistent with strategies currently recommended by the CDA (42). (Additional references 41–55)

3. For persons with diabetes and hypertension not included in other guidelines in this section, appropriate choices include (in alphabetical order): ACE inhibitors (Grade A), ARBs (Grade B), dihydropyridine CCBs (Grade A), and thiazide/thiazide-like diuretics (Grade A).

Using ACE inhibitors or ARBs as first-line therapeutic agents is appropriate for persons at high risk for cardiovascular events (Section XII, recommendation 2).

Based on publication of the diabetes subgroup results from the ALLHAT trial (56), dihydropyridine CCBs were added to the list of potential first-line agents for persons with diabetes and with normal urinary albumin excretion (< 30 mg/day). In the ALLHAT study subgroup, 13,101 patients with type 2 diabetes mellitus were randomly assigned to chlorthalidone, amlodipine or lisinopril. Although SBP was significantly lower among those patients randomly assigned to chlorthalidone compared with lisinopril or amlodipine, no difference was shown in primary endpoint of coronary heart disease (HR, 0.97; 95%CI, 0.86 to 1.10) between amlodipine and chlorthalidone. While this lack of difference was consistent generally for other cardiovascular secondary endpoints, the study was too underpowered to detect differences in development of end-stage renal disease (ESRD). Thus, the proviso was added that ACE inhibitors and ARBs also appear to have renal benefits beyond that expected from their BP-lowering effects; therefore, physicians may wish to consider these additional benefits when selecting first-line agents. Remaining recommendations are unchanged (55,56). (Additional references 59–69)

4. If target BP levels are not achieved with standard-dose monotherapy, additional antihypertensive therapy should be used. For persons in whom combination therapy with an ACE inhibitor is being considered, a dihydropyridine CCB is preferable to a thiazide/thiazide-like diuretic (Grade A).

This recommendation supports ACE/CCB combination therapy in patients with type 2 diabetes, and is based on the ACCOMPLISH trial, which compared benzapril/amlodipine combination treatment vs. benzapril/thiazide therapy (70). The primary endpoint was a composite of MI, stroke, cardiovascular death, hospitalization for angina, resuscitated cardiac arrest, and coronary revascularization. The trial enrolled 6946 high-risk subjects with type 2 diabetes; 2842 participants were deemed to be particularly “high risk” by virtue of a previous cardiac, cerebrovascular, or renal event. Benzapril/amlodipine reduced occurrence of the primary event compared to benzapril/thiazide in all subjects with diabetes (8.8% vs. 11%; HR, 0.79; 95%CI, 0.68–0.92) and subgroups of subjects who were considered high risk (13.6% vs. 17.3%; HR, 0.77; 95%CI, 0.64–0.93).

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