Blood pressure (BP) control is a critical part of managing patients with type 2 diabetes. Perhaps it is the single most important aspect of diabetes care, which unlike hyperglycemia and dyslipidemia can reduce both micro- and macrovascular complications. Hypertension is more prevalent in individuals with diabetes than general population, and in most cases its treatment requires two or more pharmacological agents (about 30% of individuals with diabetes need 3 or more medications to control BP).

In this article we describe the key evidence that has contributed to our understanding that reduced BP translates into positive micro- and macrovascular outcomes. We review the data supporting current recommendation for BP target < 130/80 mmHg. Two studies suggest that a lower BP goal could be even more beneficial. We also present the comparative benefits of various antihypertensive drugs in reducing diabetes-related micro- and macrovascular complications.

Finally we propose an evidence-based algorithm of how to initiate and titrate antihypertensive pharmacotherapy in affected individuals. Overall, achieving BP < 130/80 mmHg is more important than searching for the “best” antihypertensive agent in patients with diabetes.

GT

Integr Blood Press Control

Review Article

May 2010

Diabetes is very prevalent and places high financial burden to our society. In the United States during 2009 to 2034 the number of persons with diabetes is anticipated to increase from 23.7 million to 44.1 million. The relative annual cost is also expected to rise from $113 billion to $336 billion during the same period.1  Worldwide, 366 million individuals are projected to have diabetes by year 2030.2  Type 2 diabetes, the predominant form, comprises 90% to 95% of all cases.

Macrovascular disorders are common in affected individuals. Specifically, cardiovascular disease (CVD) is 2 to 5 times more prevalent in persons with diabetes than general population.3–5  Importantly it is the most serious complication by contributing 70% to all-cause mortality in affected patients.6  In the United States, diabetes is also the leading cause of microvascular disorders of end stage renal disease (ESRD)7,8 and retinopathy.9

Hypertension is 1.5 to 2.0 times more common in patients with diabetes than without diabetes,10 and more so in females than males.11  For example, about 40% of individuals between ages 25 to 65 already have high blood pressure (BP) at the time of diagnosis of diabetes.11  This figure increases further with age.4,11  Coexistence of hypertension with diabetes is likely due to the confounding effect of metabolic syndrome that often predates both conditions.

Hypertension is not only common but also a major cause of cardiovascular (CV) pathology11–14 and thus mortality in individuals with diabetes. It is also a direct contributor to microvascular complications of nephropathy7,15,16 and retinopathy.16–18  As described in the main text, many randomized clinical trials have documented that good BP control reduces both micro- and macrovascular complications. This could make hypertension the single most important determinant of diabetes-related morbidity and mortality compared to hyperglycemia that mainly causes microvascular disease and dyslipidemia that mostly contributes to macrovascular complications.

For this review article, we searched the literature for clinical studies related to treatment of hypertension in type 2 diabetes. We utilized PubMed to find trials published in 2005 to 2010. We then used citations from identified articles to select landmark studies printed before 2005. For this paper we chose mainly randomized clinical trials with large sample size and long duration of follow up. We narrowed further our selection to original works that emphasized renal and CV outcomes of various antihypertensive therapies in subjects with type 2 diabetes.

The purpose of this article is 5-fold. First, to provide evidence that reducing BP is beneficial in patients with diabetes; second, to demonstrate that optimal BP target is <130/80 mmHg; third, to show that hypertension is poorly controlled in clinical practice worldwide; fourth, to explain the rationale of choosing the right antihypertensive medications; and fifth, to provide a descriptive algorithm of how to initiate and titrate pharmacotherapy.

Recommendations:

Hypertension is not only the main contributor of increased CV morbidity and mortality in patients with type 2 diabetes, but also the least controlled variable compared to hyperglycemia and dyslipidemia risk factors.35–37  This calls for an aggressive approach in reducing BP under 130/80 mmHg in all individuals with diabetes. Perhaps a lower target might be considered in the future.29,30  Similar to guidelines by several major organizations,24–28 we recommend that if BP is persistently ≥130/80 mmHg, then life-style intervention should be initiated. However, if BP ≥ 140/90 mmHg, pharmacotherapy must be started as well.

Life-style changes that reduce BP93 are low sodium diet < 1.5 g/day,94 increased potassium intake >4.7 g/day, BMI <25 kg/m2, weight loss by >4.5 to 5.0 kg,95,96 increased intake of fruits and vegetables (8 to 10 servings/day), decreased consumption of dairy products that are rich in fat (2 to 3 servings/day), avoidance of excessive alcohol use (≤2 drinks/day/men and ≤1 drink/day/women) and increased physical activity.96,97  Studies in patients without diabetes have shown that these measures are equivalent to drug monotherapy for mild hypertension.94  But unlike medication monotherapy, life-style interventions in the form of exercise and weight loss could help control other aspects of diabetes such as hyperglycemia and dyslipidemia.

If life-style changes are unsuccessful or BP ≥ 140/90 mmHg then pharmacotherapy should be added immediately. Beta-blocker must be given to all patients with established CAD or MI.98  In Figure 1 we present 2 different protocols based on initial BP value. In the first, when BP is 130/80 to 140/90 mmHg, we advise first-line monotherapy with either an ACEi or ARB, depending on availability, cost and tolerability. Equivalence of ARB with ACEi was documented in the trials DETAIL,73 ONTARGET75 and VALIANT.76

In the second protocol, when BP is ≥ 140/90 mmHg, we recommend starting a low-dose fixed combination regimen containing either ACEi or ARB. Here we also consider patient adherence, clinical inertia and the fact that most individuals will require 2 or more drugs to control their hypertension. Early initiation of combined therapy is increasingly recommended for glucose management as well.99  Based on indirect evidence from SCOPE,70 VALUE,71 and TRANSCEND,72 one could favor treatment with ACEi over ARB. Given the results of ONTARGET75 and VALIANT,76 we advise against concomitant use of ACEi with ARB, since together they cause significantly higher rates of adverse events without additional benefits.

In both protocols, for second-line therapy we suggest using dihydropyridine CCB over diuretics, based on outcomes from ACCOMPLISH82 and GUARD.83  The choice would also depend on relative contraindications of each drug class. For example, a CCB is favored over a thiazide in an individual with electrolyte anomalies but less so in someone who suffers from HF or edematous conditions. A loop diuretic is recommended over a thiazide if GFR ≤ 30 mL/min due to patients’ state of fluid overload. The dose of medications must be increased or maximized based on BP response. If BP is still uncontrolled then we recommend adding either a CCB or diuretic, whichever is not part of the current combination therapy.

If BP goal is not achieved, we suggest adding a β-blocker. We chose β-blockers to be third-line agents primarily due to poor side effect profile of bradycardia and worsening of insulin resistance,100,101 although UKPDS,18 NORDIL80 and INVEST81 clearly show their equivalence to ACEi and CCB. At this point we also consider screening for secondary causes of hypertension like renal artery stenosis, hyperaldosteronism,88 Cushing’s syndrome or pheochromocytoma.

As a fourth-line therapy, we choose aldosterone antagonists due to their BP-lowering potency, revealed in the ASCOT-BPLA86 trial. Finally, the renin inhibitors and α-blockers can also be utilized, if necessary, to control BP in persons with diabetes. We advise peripheral α-blockers to be a last-line therapeutic option based on results of ALL-HAT78 and their propensity to cause orthostatic hypotension – although they could be used earlier in someone with benign prostate hyperplasia.

Conclusion:

Hypertension continues to be a key determinant of morbidity and mortality in type 2 diabetes. Despite clear evidence for a BP goal < 130/80 mmHg, most patients do not achieve optimal results. Early initiation of fixed-dose combination therapy and aggressive titration of medications can improve patient adherence, reduce clinical inertia and bring BP to target, thereby reducing both micro- and macrovascular complications in individuals with diabetes.