Patients with diabetes are at increased risk for hypertension as well as an increased incidence of cardiovascular events. Hypertension is a significant risk factor for cardiovascular disease and contributes to the progression of retinopathy and nephropathy, two common risk factors associated with diabetes. Many large, randomized trials have consistently shown that controlling blood pressure has a dramatic effect on and a vital role in the prevention of the macrovascular and microvascular complications of diabetes. The current target blood pressure in patients with diabetes is 130/80 mm Hg or lower. To achieve that blood pressure goal, a large majority of patients with diabetes and hypertension require more than one antihypertensive medication.

Arterial hypertension is frequently present in patients with diabetes. These patients also have increased incidence of cardiovascular (CV) events, such as stroke or myocardial infarction (MI), as well as increased incidence of CV disease (eg, coronary heart disease [CHD] or peripheral vascular disease) and nephropathy. Various factors have been linked to the development of hypertension in diabetes, including hyperinsulinemia, extracellular fluid expansion, and increased arterial stiffness. Several studies have shown that tight control of blood pressure (BP) prevents the macrovascular and microvascular complications associated with diabetes.^1,2 Randomized, controlled trials have also demonstrated that all patients whose BP is controlled, including those with diabetes, have a lower incidence of CV complications than those whose BP is not controlled.^1-4 The question of how much BP reduction is required to reduce CV morbidity and mortality has been extensively researched. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends the BP target goal of ≤130/80 mm Hg in patients with diabetes.⁵ Reducing BP and achieving this goal should be a priority in the management of patients with diabetes.

Definitions and Prevalence
In the general population, hypertension is currently defined as a BP ≥140/90 mm Hg (Table 1).⁵ Approximately 1 billion people worldwide have hypertension, and its prevalence is on the rise.⁶ Individuals who are normotensive at age 55 have a 90% lifetime risk for developing hypertension.⁷ Hypertension substantially increases the risk for MI, heart failure, stroke, and kidney disease.

Diabetes mellitus comprises a genetically and clinically heterogeneous group of chronic metabolic disorders that are characterized by hyperglycemia. It is associated with impaired insulin secretion and/or tissue resistance to the action of insulin. Type 1 diabetes—absolute insulin deficiency—accounts for 5% to 10% of all patients with diabetes. Type 2 diabetes—relative insulin deficiency and resistance—comprises 90% to 95% of the cases.⁸

According to the American Diabetes Association, the diagnosis of diabetes is based on a fasting blood glucose level of ≥126 mg/dL (7.0 mmol/L), a 2-hour oral glucose tolerance test result of ≥200 mg/dL (11.1 mmol/L), or a random plasma glucose level of ≥200 mg/dL (11.1 mmol/L) in the presence of symptoms.⁸

Diabetes is associated with an increased risk for CV events by 2-fold in men and by 4-fold in women.⁹ CV disease accounts for up to 80% of the deaths in patients with type 2 diabetes.¹⁰ This high incidence has been attributed to the association of diabetes with CV risk factors, such as hypertension and dyslipidemia.⁹

The Hypertension–Diabetes Link
Hypertension is a common comorbidity in diabetes, with a prevalence of 1.5 to 3.0 times greater than that in nondiabetic age-matched groups.¹¹ Hypertensive patients with diabetes have approximately twice the risk of developing CV disease compared with hypertensive patients without diabetes. In the Systolic Hypertension in the Elderly Program (SHEP) and the Systolic Hypertension in Europe (Syst-Eur) trials, the incidence of major CV events was 1.71 and 1.90 times greater, respectively, in patients with diabetes; the relative risk for coronary events was 2.12 and 1.86, respectively; the relative risk for stroke was 1.92 and 2.16, respectively; and for all-cause mortality, 1.63 and 2.09, respectively.^12,13

In the SHEP study, patients who were treated aggressively for hypertension had a 9.8-mm Hg reduction in systolic BP, a 2.2-mm Hg reduction in diastolic BP, and a 34% reduction in CV events (relative risk, 0.66; 95% confidence interval, 0.46-0.94).¹² In the Syst-Eur study, patients assigned to nitrendipine (an investigational calcium channel blocker) had an 8.6-mm Hg reduction in systolic BP, a 3.9-mm Hg reduction in diastolic BP, and a 70% reduction in CV events.¹³

The timing and presentation of hypertension differ in type 1 and type 2 diabetes. In persons with type 1 diabetes, hypertension usually develops after several years of the disease, whereas in those with type 2 diabetes, hypertension may be present at the time of diagnosis or even before they develop hyperglycemia. Approximately 20% to 60% of patients with type 2 diabetes will develop hypertension, depending on age, ethnicity, and obesity.⁹

Compared with hypertensive patients who do not have diabetes, those with diabetes have a 5- to 6-fold greater risk of developing end-stage renal disease.¹⁴

Diagnosis
All patients with diabetes should have their BP measured at the initial visit, as well as on each subsequent visit.

Accurate determination of BP level is important in establishing the diagnosis of hypertension. Patients should be seated quietly in a chair for at least 5 minutes before taking their BP, with their feet on the floor and one arm supported at heart level. An appropriate cuff size is vital to avoid over- or underestimation of true BP level.

Orthostatic measurement of BP should be performed to assess for the presence of autonomic neuropathy. Two or more readings should be averaged.⁵ Elevated BP should be confirmed on a separate day for patients with diabetes whose BP measurements are ≥130/80 mm Hg.⁹

Therapy
Lifestyle modifications can lower BP level
It has been well demonstrated that diet and exercise affect BP levels. Lifestyle changes, such as following the Dietary Approaches to Stop Hypertension (DASH) plan, using dietary sodium restriction, reducing weight, and increasing physical activity, can be critical to achieving and maintaining BP control. These measures have shown to lower BP, enhance antihypertensive drug efficacy, and decrease CV risk. The loss of 1 kg (2.2 lb) of body weight has been shown to reduce mean arterial BP by approximately 1 mm Hg.⁹ Regular aerobic physical activity for at least 30 minutes daily on most days of the week has been shown to reduce systolic BP by approximately 4 to 9 mm Hg.⁵ Appropriate lifestyle modifications may also help prevent hypertension and reduce other CV risk factors.

Antihypertensive drug therapy
The goal of antihypertensive therapy is to reduce excess morbidity and mortality related to CV and microvascular complications in diabetes. The use of antihypertensive agents to achieve BP goals has been shown to reduce the number of CV events as well as microvascular complications (ie, nephropathy, neuropathy, and retinopathy).¹

Because of the increased risk for CV disease associated with BP of >130/80 mm Hg in patients with diabetes, the goal of therapy is to achieve a BP of ≥ 130/80 mm Hg (Table 2).

Combination therapy with 2 or more antihypertensive drugs is typically required to achieve BP goals in most hypertensives with diabetes (Table 3).⁵ Many studies have shown that patients with diabetes who have lower BP levels have lower rates of CV events and better preservation of renal function than those with higher BP levels.

The Hypertension Optimal Treatment (HOT) study showed that intensive treatment to reduce diastolic BP to 80 mm Hg in persons with diabetes decreased the risk for major CV events by 51% compared with a target of 90 mm Hg.² Those who achieved the lowest BP had the fewest CV events. This study also demonstrated that combining an angiotensin-converting-enzyme (ACE) inhibitor and a calcium channel blocker decreased proteinuria.

In the UK Prospective Diabetes Study (UKPDS), patients who maintained tight BP control (<150/85 mm Hg) had a significantly reduced risk for diabetes-related death, diabetic complications, and progression of diabetic retinopathy compared with patients with less tight control (<180/105 mm Hg).¹ Those assigned to the tight BP control group had an average BP of 144/82 mm Hg, 32% reduction in diabetes-related mortality, 44% reduction in stroke, and 37% reduction in microvascular end points (ie, retinopathy requiring photocoagulation, vitreous hemorrhage, fatal/nonfatal renal failure) compared with the less-intensive BP control group (with an average BP of 154/87 mm Hg).

In the Heart Outcomes Prevention Evaluation (HOPE) randomized, double-blind, placebo-controlled trial, patients with diabetes who received the antihypertensive ramipril (Altace) had a 25% reduction in the primary outcomes of MI, stroke, or CV-related death compared with placebo-treated patients.³

The randomized, double-blind, multicenter Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included 33,357 participants (aged 55 years or older) with hypertension and at least 1 other CHD risk factor.⁴ Participants were randomly assigned to a calcium channel blocker, an ACE inhibitor, or an alpha-blocker; each agent was compared with a diuretic. Results demonstrated that the thiazide diuretic chlorthalidone (Thalitone) was better than the ACE inhibitor lisinopril (Prinivil, Zestril) at preventing CV adverse events and all-cause mortality and should be considered as a first-line therapy for patients with hypertension. ALLHAT also showed that diuretic therapy was superior to calcium channel blocker therapy in preventing heart failure among diabetic and nondiabetic patients.

The Losartan Intervention for Endpoint Reduction (LIFE) study, a double-masked, randomized, parallel-group trial, assigned patients with hypertension and signs of left ventricular hypertrophy to the angiotensin-receptor blocker (ARB) losartan potassium (Cozaar) or the beta-blocker atenolol (Tenormin).¹⁵ Among the 1195 patients with diabetes (mean age, 67 years; mean BP, 177/96 mm Hg), those assigned to losartan had a 39% reduction in total mortality and a 37% reduction in CV mortality.

The Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) demonstrated that patients receiving the ACE inhibitor fosinopril sodium (Monopril) had a significantly lower risk of the combined outcome of acute MI, stroke, and hospitalization for angina than those receiving the calcium channel blocker amlodipine (Norvasc), with 14 of the 189 patients in the fosinopril group having 1 such event compared with 27 of the 191 patients in the amlodipine group (hazard ratio, 0.49; 95% confidence interval, 0.26-0.95).¹⁶

The Steno type 2 randomized study, which included 160 patients with type 2 diabetes and microalbuminuria, showed that intensified multifactorial interventions that included diet, exercise, smoking cessation, adequate blood sugar and cholesterol control, and pharmacotherapy slowed the progression to nephropathy, as well as the progression of retinopathy and autonomic neuropathy, when compared with standard treatment.¹⁷

The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial was a randomized, double-blind, parallel-group study that compared the effects of 2 different beta-blockers in 1235 adults (aged 36-85 years) with hypertension and type 2 diabetes.¹⁸ All participants were taking a renin-angiotensin-aldosterone system (RAAS) blocker (ie, ACE inhibitor or ARB). Results showed that the use of carvedilol (Coreg) in the presence of RAAS blockade had no effect on glycemic control but did stabilize hemoglobin A1c, improved insulin resistance, slowed the development of microalbuminuria, reduced total cholesterol levels, and resulted in a smaller increase in triglyceride levels when compared with metoprolol (Lopressor).

A subanalysis of the prospective intervention trial Captopril Prevention Project (CAPPP) evaluated the effects of the ACE inhibitor captopril with that of conventional treatment (ie, beta-blocker, diuretic, or both together) among the 572 patients (aged 25-66 years) from the original cohort who had diabetes at baseline.¹⁹ Results showed a marked reduction in CV mortality in those diabetic patients assigned to captopril compared with conventional therapy (relative risk, 0.48; P = .084).

The Appropriate Blood Pressure Control in Diabetes (ABCD) trial was a prospective, randomized clinical trial that compared the effects of intensive and moderate BP control on the incidence and progression of diabetic complications in 470 patients (aged 40-70 years) with type 2 diabetes and hypertension (defined by a baseline diastolic BP ≥90 mm Hg).20 Participants were randomized to either intensive BP control (diastolic BP goal, 75 mm Hg) or moderate BP control (diastolic BP goal, 80-89 mm Hg). Patients in each group were further randomized to receive either the ACE inhibitor enalapril maleate (Vasotec) or the calcium channel blocker nisoldipine (Sular) as the primary antihypertensive medication. Over 5 years of follow-up, no between-group differences were seen in kidney function, progression to microalbuminuria or overt albuminuria, or progression of diabetic retinopathy or neuropathy. Nisoldipine and enalapril had similar effects on diabetic retinopathy and neuropathy. However, all-cause mortality was markedly reduced in the intensive treatment group (5.5% versus 10.7%, P = .037).

Evidence from clinical studies showing that BP >130/80 mm Hg increases the risk for CV events and mortality in persons with diabetes led to the JNC 7 recommendation for a target BP goal of ≥130/80 mm Hg in this patient population.⁵ Antihypertensive therapy should include an ACE inhibitor^3,4 or an ARB to provide maximum CV and renal benefits.^14,21 If one class is not tolerated, the other should be substituted.²¹

Benefits of ACE inhibitors in diabetes. Many trials have demonstrated the CV and renal protective benefits of ACE inhibitors in diabetic patients compared with other antihypertensives. The UKPDS showed that tight BP control with an ACE inhibitor or a beta-blocker compared with less tight control produced a significant reduction in the number of deaths related to diabetes, diabetic complications, and progression of diabetic retinopathy.¹ The ABCD trial demonstrated a higher incidence of fatal and nonfatal MI among those assigned to the calcium channel blocker than to the ACE inhibitor.²⁰ In the CAPPP trial, ACE inhibitor therapy in patients with diabetes reduced the combined outcome of fatal and nonfatal MI, stroke, and CV deaths when compared with a diuretic and/or beta-blocker therapy.¹⁹

The HOPE study and the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO) substudy of the HOPE study showed that ACE inhibition therapy reduced the incidence of death, MI, and stroke and reduced the progression of proteinuria compared with placebo.^3,22 And in the FACET study, patients randomized to ACE inhibition had a significantly lower risk of major CV events than those assigned to calcium channel blockade.¹⁶

Role of dual RAAS blockade with combination therapy. A recent meta-analysis of 14 randomized trials evaluated the benefits of combination therapy with an ACE inhibitor and an ARB compared with either agent alone.²³ Results showed that combination therapy significantly reduced the incidence of proteinuria, but the modest reduction in BP with the combination compared with monotherapy did not reach statistical significance. However, most of the studies included in the meta-analysis did not use the maximum allowed doses of the ACE inhibitors. They also failed to compare the ACE inhibitor/ARB combination therapy with other non– RAAS blocking drug combinations (eg, ACE inhibitor plus thiazide diuretic), leading the authors of the meta-analysis to conclude that better designed studies are needed before recommendations can be made.

Conclusion
Hypertension is a very common comorbidity in patients with diabetes. Patients with both conditions are at significantly increased risk of developing the macrovascular and microvascular complications of diabetes. With aggressive BP treatment, the risk for these complications can be dramatically reduced. Data from many trials indicate that it is difficult to achieve the desired BP goal of ≤130/80 mm Hg by monotherapy. Most hypertensive patients with diabetes will require combination therapy with a diuretic, a beta-blocker (which has an important role in BP control, especially with its ability to reduce CV events and mortality), and/or a calcium channel blocker, to achieve target BP goals. An ACE inhibitor/diuretic combination is ideal as initial antihypertensive therapy, since it will also reduce the incidence of CV events and lessen the progression to renal disease.

Self-assessment test
1. Which statement about CV disease in patients with diabetes is NOT true?
A. Risk for CV disease is higher in men than in women
B. CV disease accounts for more than three fourths of all deaths in patients with type 2 diabetes
C. Comorbid diabetes and hypertension doubles risk for CV disease versus diabetes alone
D. Hypertension is less common in type 1 diabetes than in type 2 diabetes

2. What is the goal BP for a hypertensive patient with diabetes?
A. <159/99 mm Hg
B. ≤140/90 mm Hg
C. ≤130/80 mm Hg
D. <120/80 mm Hg

3. Which BP screening recommendation is not appropriate in patients with diabetes?
A. Measure BP at time of diabetes diagnosis
B. Measure BP in supine position
C. Measure BP with patient standing
D. Confirm measurements of ≥130/80 mm Hg on a separate day

4. Which of the following patients with diabetes does NOT require antihypertensive drug therapy?
A. 45-year-old man with BP 145/95 mm Hg
B. 50-year-old woman with BP 150/90 mm Hg
C. 60-year-old man with BP 138/89 mm Hg
D. 65-year-old woman with BP 141/91 mm Hg

5. What is the least appropriate initial antihypertensive therapy in a patient with diabetes?
A. Diuretic plus ACE inhibitor
B. Diuretic plus ARB
C. Diuretic plus calcium channel blocker
D. Calcium channel blocker

(Answers at end of references list)

References
1. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 [published correction appears in BMJ. 1999;318: 29]. BMJ. 1998;317:703-713.

2. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351:1755-1762.

3. Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients [published corrections appear in N Engl J Med. 2000;342:1376 and N Engl J Med. 2000;342:748]. N Engl J Med. 2000;342:145-153.

4. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) [published corrections appear in JAMA. 2003;289:178 and JAMA. 2004;291:2196]. JAMA. 2002;288:2981-2997.

5. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report [published correction appears in JAMA. 2003;290:197]. JAMA. 2003;289:2560-2572.

6. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005;365:217-223.

7. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: the Framingham Heart Study. JAMA. 2002;287: 1003-1010.

8. American Diabetes Association. All about diabetes. Available at www.diabetes.org/about-diabetes.jsp Accessed January 3, 2007.

9. American Diabetes Association. Hypertension management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S65-S67.

10. Haffner SM, Lehto S, Ronnemaa T, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339: 229-234.

11. American Diabetes Association. Hypertension in diabetes. Diabetes Cardiovasc Dis Rev. 2002;2: 2-4.

12. Curb JD, Pressel SL, Cutler JA, et al, for the Systolic Hypertension in the Elderly Program Cooperative Research Group. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension [published correction appears in JAMA. 1997;277:1356]. JAMA. 1996;276:1886-1892.

13. Birkenhager WH, Staessen JA. Treatment of diabetic patients with hypertension. Curr Hypertens Rep. 1999;1:225-231.

14. Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000;36:646-661.

15. Lindholm LH, Ibsen H, Dahlof B, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:1004-1010.

16. Tatti P, Pahor M, Byington RP, et al. Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care. 1998;21:597-603.

17. Gaede P, Vedel P, Parving HH, et al. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet. 1999;353:617-622.

18. Bakris GL, Fonseca V, Katholi RE, et al, for the GEMINI Investigators. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: a randomized controlled trial. JAMA. 2004;292:2227-2236.

19. Niskanen L, Hedner T, Hansson L, et al, for the CAPPP Study Group. Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project. Diabetes Care. 2001;24: 2091-2096.

20. Estacio RO, Jeffers BW, Gifford N, et al. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(suppl 2):B54-B64.

21. American Diabetes Association. Standards of medical care in diabetes—2007. Diabetes Care. 2007;30(suppl 1):S4-S41.

22. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy [published correction appears in Lancet. 2000;356: 860]. Lancet. 2000;355:253-259.

23. Doulton TW, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension. 2005;45:880-886.

24. Buckalew VM Jr, Berg RL, Wang SR, et al, for the Modification of Diet in Renal Disease Study Group. Prevalence of hypertension in 1795 subjects with chronic renal disease: the modification of diet in renal disease study baseline cohort. Am J Kidney Dis. 1996;28:811-821.

Answers: 1. A; 2. C; 3. B; 4. C; 5. D.