Management of Blood Pressure in Patients With Diabetes

nature publishing group STATE OF THE ART Management of Blood Pressure in Patients With Diabetes Ehud Grossman 1 and Franz H. Messerli 2 Hypertension is a major modifiable risk factor for cardiovascular morbidity and mortality in patients with diabetes. Lowering blood pressure (BP) to 135/85 mm Hg is the main goal of treatment. A nonpharmcologic approach is recommended in all patients. If BP levels remain above the target despite nonpharmacologic treatment, drug therapy should be initiated. Blockers of the renin angiotensin aldosterone system (RAAS) represent the cornerstone of the antihypertensive drug arsenal; however, in most patients, combination therapy is required. For many patients, a combination of RAAS blocker and calcium antagonist is the combination preferred by the treating physician. Often three or even four drugs are needed. Treatment should be individualized according to concomitant risk factors and diseases and depending on the age and hemodynamic and laboratory parameters of the patient. In order to maximally reduce cardio renal risk, control of lipid and glycemic levels should also be ensured. Keywords: blood pressure; diabetes mellitus; hypertension; treatment American Journal of Hypertension, advance online publication 28 April 2011; doi:10.1038/ajh.2011.77 Hypertension is a powerful risk factor for cardiovascular morbidity and mortality, 1 particuarly in patients with diabetes. Patients with hypertension are at two to three times higher risk of developing diabetes than patients with normal blood pressure (BP). 2 Patients with type 2 diabetes have a two- to fourfold greater risk of death from cardiovascular (CV) causes than those without diabetes. 3,4 The simultaneous presence of hypertension and diabetes is devastating to the CV system. In patients with diabetes BP control is particularly beneficial; 5,6 yet, only ~30% of the patients meet the current target as regards BP. 7 This paper reviews the management of BP in patients with diabetes. Epidemiology The incidence of hypertension in patients with type 2 diabetes is approximately twofold higher than in age-matched subjects without the disease. 8 The definition of hypertension is different in diabetes; in those with diabetes BP levels >130/80 mm Hg are defined as hypertension. 9 Strong linear associations have recently been found to exist between age and body mass index on the one hand and the prevalence of diabetes mellitus and hypertension on the other. 10 The highest prevalence rates of diabetes (50%) and hypertension (72.6%) were found among the oldest patients (>60 years of age) and in those with the highest body mass indexes (>50). 10 1 Department of Internal Medicine D and Hypertension unit, The Chaim Sheba Medical Center, Tel-Hashomer, affiliated to Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; 2 Division of Cardiology, Luke s-roosevelt Hospital and Columbia University, New York, New York, USA. Correspondence: Ehud Grossman (gross-e@zahav.net.il) Received 26 September 2010; first decision 23 October 2010; accepted 19 March 2011. 2011 American Journal of Hypertension, Ltd. In the National Health and Nutrition Examination Survey (NHANES) conducted during the years 1999 2004, the prevalence of hypertension and diabetes simultaneously in the U.S. population was only 2% in the age group 30 54 years, increasing to 12.4% in the age group 65 74 years. 7 Bp Characteristics in Patients with Diabetes Mellitus Patients with diabetes have more isolated systolic hypertension and, because of autonomic neuropathy, they experience less reduction in nocturnal BP and higher baseline heart rates than their counterparts who do not have diabetes. 11 14 In addition, those with diabetes have enhanced variability in BP; they are prone to develop orthostatic hypotension, and their hypertension is more resistant to treatment. 11,15 BP control in these patients presents a great challenge, because the target BP is quite low and the response to treatment is poor. 11 Bp and Target Organ Damage in Diabetes Mellitus Diabetes mellitus is associated with a high risk for CV disease, and is the leading cause of end-stage renal disease (ESRD), 16 blindness, and nontraumatic amputations in western countries. 17 Coronary heart disease (CHD) is far more common in patients with both diabetes and hypertension than in those who have either disease by itself. 3 In the Prospective Cardiovascular Munster (PROCAM) trial, the incidence of CHD during 4 years was 6 per 1,000 in those without hypertension, diabetes, or hyperlipidemia, 14 or 15 per 1,000 in those with hypertension or diabetes, respectively, and as high as 48 per 1,000 when both hypertension and diabetes were present in the same AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 8 863-875 august 2011 863

STATE OF THE ART Hypertension and Diabetes patient. 18 The simultaneous presence of diabetes and hypertension results in more severe cardiomyopathy than would be expected with either hypertension or diabetes mellitus alone. 3 We showed that the prevalence of left ventricular hypertrophy was 72% in patients with both diabetes and hypertension, and only 32% in those with a similar level of hypertension but no diabetes. 19 Hypertension, mainly systolic, is strongly and directly related to stroke in all age groups. 1 The presence of diabetes more than doubles the risk of stroke in patients with hypertension. 20 Lowering the BP in patients with hypertension and diabetes reduces the risk of stroke by 44%. 6 Diabetes mellitus is one of the leading causes of ESRD. 21 Hypertension is a well-defined risk factor for ESRD, and accounts for 27% of all the ESRD cases in the United States, and 33.4% of ESRD cases among African Americans. 21 BP control can slow the progression of renal disease in patients with diabetes. 22 Diabetes mellitus may cause diabetic retinopathy, and hypertension accelerates the development of diabetic retinopathy. 23 What Should Be the Target Bp in Diabetes Mellitus? Current guidelines recommend lowering BP to <130/80 mm Hg in patients with diabetes. 24 27 In patients with type 2 diabetes, several studies have shown the benefit of intensive BP control (Table 1). 6,28 30 In the Hypertension Optimal Treatment study 29 there was evidence that, in patients with both type 2 diabetes and hypertension, lowering BP to the lowest target level (diastolic BP 80 mm Hg) resulted in 51% reduction in major CV events as compared with the group for which the target was 90 mm Hg. These findings were supported by the results from the UK Prospective Diabetes Study (UKPDS 38). 6 In that study, tight control of BP in hypertensive patients with type 2 diabetes (average of 144/82 mm Hg in the tight control group vs. 154/87 mm Hg in the less tight control group) was associated with a reduction of 37% in microvascular-related endpoints and 44% in the risk of stroke events. 6 Further analysis of the UKPDS showed that each 10 mm Hg decrease in systolic BP was associated with 12% reduction in risk of any complication related to type 2 diabetes, without a threshold. 31 In the Appropriate Blood Pressure Control in Diabetes (ABCD) trial intensive BP control had no effect on the primary endpoint, but was associated with improvement in secondary outcomes 32 (Table 1). On the basis of these data, both the American Diabetes Association and the Joint National Committee (JNC) 7 24,25 recommended a target BP <130/80 mm Hg for patients with diabetes and <125/75 mm Hg for those with proteinuria. However, a meticulous review of the literature and results from recent publications cast doubt on the validity of these current recommendations. In the Action in Diabetes and Vascular disease, preterax and diamicorn MR Controlled Evaluation (ADVANCE) trial, active treatment (BP = 136/73 mm Hg) reduced the relative risk of a major macrovascular or microvascular event by 9% as compared to the placebo treatment (BP = 140/73 mm Hg). The authors stated that the study treatment was not affected by the initial BP levels. However, the mean initial BP of the population studied was 145/81 mm Hg and 7,655 (68.5%) patients had a history of current antihypertensive treatment. Analysis of subgroups revealed that, in patients with no history of hypertension, active treatment did not reduce the rate of occurrence of CV events. It is noteworthy that the systolic BP achieved in this trial was >130 mm Hg (136 mm Hg). In other trials that showed the benefits of lowering BP, the systolic BP achieved remained >130 mm Hg (Table 1). The International Verapamil SR-Trandolapril (INVEST) study included 6,400 patients with diabetes who were divided into three groups according to mean systolic BP achieved 33 (Table 1). The authors also evaluated the effect of very low systolic BP (<115 mm Hg). During the INVEST follow up, the rate of primary outcome was 19.8% in the not-controlled group and 12.6% and 12.7% in the usual and tight control groups respectively (P < 0.001 for the not controlled group vs. the other groups) (Table 1). The rate of all-cause mortality was significantly higher in the tight control group than in the usual control group (11% vs. 10.2%; P = 0.035). During the extended follow up, tight control was associated with an increase in mortality rate as compared to usual control (adjusted hazard ratio 1.15 (95% confidence interval 1.01 1.32); P = 0.04). Systolic BP <115 mm Hg was associated with an increase in the risk for mortality. This study has some limitations: it represents observational analysis of a randomized control study, it included only patients with CHD, and the division of the groups was according to the BP achieved. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial investigated whether therapy targeting normal systolic BP (i.e., <120 mm Hg) reduces the rate of occurrence of major CV events in participants with type 2 diabetes who are at high risk for such events. 34 Patients with diabetes were randomly assigned to intensive therapy targeting a systolic BP of <120 mm Hg, or to standard therapy targeting a systolic BP of <140 mm Hg. Despite the 14.2 mm Hg difference in systolic BP between the groups, the rate of primary endpoint was the same. Intensive therapy was associated with lower rate of stroke a prespecified secondary outcome than standard therapy, but serious adverse events attributable to antihypertensive treatment, such as hypotension, bradycardia, hyperkalemia, and renal deterioration occurred more frequently in the intensive-therapy group (3.3%) than in the standard-therapy group (1.3%) (P < 0.001). In a recent additional analysis of the ACCORD trial, it has been shown that intensive BP control 864 august 2011 VOLUME 24 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

Hypertension and Diabetes STATE OF THE ART did not reduce the rate of progression of diabetic retinopathy. 35 The results of these recent studies suggest that there is little, if any, benefit in lowering the BP intensively, even in patients with diabetes, and in fact that too-aggressive a lowering of BP may be dangerous to the patient. The target BP in patients with diabetes has not been established but the previously cited target of <130/80 has not been supported by recent evidence; we recommend a target BP of 135/85 mm Hg. 36 Lower BP levels may be appropriate in selected patients with diabetes who also have proteinuria, 37,38 but this should be documented in prospective trials. How To Achieve Target Bp Nonpharmacologic therapy Nonpharmacologic therapy such as weight loss, low-sodium diet and regular exercise has beneficial effects in patients with hypertension, those with diabetes, and possibly also in those who have both these disorders. 24 However, there is no good study showing that weight loss per se will decrease BP in the long run. The Swedish Obese Subjects (SOS) study assessed changes in CV risk factors over follow-up periods of 2 and 10 years in surgically treated subjects and compared them with findings in matched conventionally treated control subjects. 39 After 2 years, body weight had increased by 0.1% in the control group and had decreased by 23.4% in the surgery group (P < 0.001); after 10 years, body weight had increased by 1.6% in the control group, and decreased by 16.1% in the surgery group (P < 0.001). The incidence rates of diabetes were markedly lower in the surgically treated group than in the control group after both 2 and 10 years, whereas the incidence of hypertension did not differ between the groups over the 2- and 10-year periods. At the 2-year follow-up, systolic BP had increased by 0.5 mm Hg in the control group and decreased by 4.4 mm Hg in the surgery group (P < 0.001), whereas, at the 10-year follow-up, the change in systolic BP was not significantly different between the groups. Therefore some uncertainties remain pertaining to the long-term antihypertensive efficacy of weight loss. However, this strategy should continue to be encouraged, because it may have beneficial effects as regards glycemia and lipid profile. The Dietary Approaches to Stop Hypertension (DASH) study has shown that an appropriate diet can lower BP in subjects without diabetes. 40 This diet may offer an additional nutritional approach to treating hypertension in patients with diabetes. Lifestyle therapy consists of reducing sodium intake to <1,500 mg/day, losing excess weight, increasing the consumption of fruits and vegetables (8 10 servings/day), and low fat dairy products (2 3 servings/day); avoiding excessive alcohol consumption, and increasing physical activity levels. 24 An initial trial of nonpharmacologic therapy for 3 6 months may be reasonable in patients with diabetes in whom BP levels are 130 139/80 89 mm Hg. However, where the BP is 140/90 mm Hg, drug therapy should be initiated along with nonpharmacologic therapy. 24 Drug therapy Blockers of the renin angiotensin aldosterone system (RAAS). Blockers of RAAS, either angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), have become the cornerstone of the management of patients with hypertension plus diabetes. In high-risk patients with diabetes, ACE inhibitors reduced CV-related morbidity and mortality. 28 Both these drugs classes have been shown to have a beneficial effect on surrogate endpoints such as decreasing microalbuminuria, slowing progression from microalbuminuria to macroalbuminuria, and slowing the decline in renal function. 37,38,41 46 Despite the theoretical advantage of blockers of RAAS over other antihypertensive agents, there is no solid evidence that they are indeed superior to other agents in these patients. 6 Nevertheless, they are considered to be the drugs of choice for patients with diabetes because these patients are at a high risk for CV diseases. Unlike ACE inhibitors and ARBs, which reactively stimulate an increase in plasma renin activity, direct renin inhibitors such as aliskiren suppress the effects of renin and lead to a reduction in plasma renin activity. However, additional results from long-term studies are required before aliskiren can be included as an RAAS blocker of choice in patients with hypertension plus diabetes. Blockers of the RAAS may cause hyperkalemia and renal deterioration mainly in patients with diabetes who have bilateral renal artery stenosis or renal failure, and in those with hyporeninemic hypoaldosteronism. These side effects usually occur shortly after drug initiation, and therefore close monitoring of kidney functions and electrolytes is required soon after drug initiation. It is important to note that a small increase in creatinine (up to 20 25%) is acceptable after initiation of therapy with a RAAS blocker, and is even deemed to be nephroprotective. 22 Hyperkalemia and deterioration in renal function can be triggered by unforeseeable factors such as dehydration, the use of concomitant drugs such as nonsteroidal anti-inflammatory drugs and intravenous contrast. Importantly, as the disease and renal failure progress, a dose of an ACE inhibitor that was previously well tolerated may become inappropriate in a given patient. In most patients with hypertension and diabetes, BP is not adequately controlled with any of the RAAS blocker as monotherapy. In the Losartan Intervention For Endpoint reduction in hypertension study (LIFE), only 9% of the patients with diabetes remained on monotherapy with losartan. 47 Indeed, monotherapy with any drug class rarely achieves the target BP in these patients; most often, two or more drugs need to be prescribed together. 22 AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 8 august 2011 865

STATE OF THE ART Hypertension and Diabetes Table 1 List of studies in diabetic hypertensive patients Trial acronym Number of patients Age Studies that evaluated active treatment vs. placebo Follow-up Achieved SBP (mm Hg) Initial SBP (mm Hg) Active Comparator Design Primary endpoint Secondary endpoints SHEP DM 69 583 70 4.5 170 145 155 Double-blind, randomized, placebo-controlled trial comparing chlorthalidone vs. placebo Syst-Eur DM 87 492 70 2 175 153 162 Double-blind, randomized, placebo-controlled trial comparing nitrendipine vs. placebo Syst-China DM 88 98 66.5 3 172 150 156 Double-blind, randomized, placebo-controlled trial comparing nitrendipine vs. placebo IDNT 38,89 1715 59 2.6 159 IRB 140 AML 141 144 Prospective randomized double-blind placebocontrolled trial comparing IRB vs, AML vs. placebo in patients with type 2 diabetic nephropathy RENAAL 37 1513 60 3.4 153 143 145 Prospective, randomized double-blind trial comparing losartan vs. placebo in addition to conventional antihypertensive treatment. ADVANCE 30 11140 66 4.3 145 134 140 Randomized controlled study comparing perindopril + indapamide vs. placebo. Decrease in CV disease 34%, P < 0.05 Decrease in stroke 73%, P = 0.02 Decrease in stroke 45%,P = 0.42 Decrease in the time to the primary composite end point (a doubling of the base-line serum creatinine, the development of endstage renal disease, or death from any cause) 20% vs. placebo (P=0.02) and 23% vs. AML(P=0.006). Decrease in the composite of a doubling of the baseline serum creatinine, endstage renal disease, or death 16% (P = 0.02) Decrease in combined major macro and microvascular events 9%, P = 0.04 Decrease in all CV endpoints 55%, P = 0.09 Decrease in CV mortality 76%, P = 0.01 Decrease in all CV end points 74%, P = 0.03 Decrease in HF with IRB vs. AML 35%, P = 0.004 and vs. placebo 28%, P = 0.048. Decrease in MI with AML vs. placebo 42% (P = 0.021) The time to the first CV composite events did not differ among the three groups. No difference in the composite end point of morbidity and mortality from CV causes. Decrease in HF 32% (P=0.005), decrease in proteinuria (P<0.001), Reduction in the rate of decline in renal function 18% (P=0.01). Decrease in all-cause mortality 14%, P =0.03, Decrease in CV mortality 18%. P =0.03. Decrease in total coronary event 14%, P =0.02, decrease in all renal events 21%, P <0.0001 No difference in total stroke, HF, visual deterioration, neuropathy, cognitive function Table 1 Continued on next page 866 august 2011 VOLUME 24 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

Hypertension and Diabetes STATE OF THE ART Table 1 Continued Trial acronym Number of patients Age Follow-up Achieved SBP (mm Hg) Initial SBP (mm Hg) Active Comparator Design Primary endpoint Secondary endpoints Studies comparing different treatments FACET 90 380 63 2.5 171 157 153 Prospective randomized open-label trial comparing Fosinopril vs. AML ABCD-HT 91 470 57.5 5.3 155 Intensive 132 Moderate 138 STOP2 DM 92 719 75.8 5 195 ACEI group 162 CA group 161 Intensive 132 Moderate 138 Conventional treatment 161 Prospective randomized controlled trial assessing the benefit of intensive vs. moderate BP control in hypertensive patients. This study compared nisoldipine with enalapril as a first-line antihypertensive agent PROBE design study comparing conventional treatment (diuretics and/ or β-blockers).vs. newer drugs (ACEI or CA) in elderly patients. CAPPP DM 93 572 55 6.1 163 155 153 PROBE design comparing captopril vs. conventional treatment (diuretics and/or β-blockers). LIFE DM 47 1,195 67 4.7 177 146 148 Prospective, randomized double-blind trial comparing losartan based to atenolol-based treatment in diabetic hypertensive patients with LVH INSIGHT DM 94 1302 65 4 175 144 145 Prospective, randomized double-blind trial comparing Nifedipine vs. co-amilozide ALLHAT DM 66 13010 66.6 4.9 146.5 AML 136.3 135 Prospective randomized, LIS 137.9 double-blind, activecontrolled trial comparing AML or LIS vs. CHL as first-step antihypertensive therapy. No difference in diabetes control and serum lipids The prevention of CV mortality was similar in the three treatment groups Decrease in combined fatal and nonfatal MI and stroke and other CV deaths, in the captopril vs. conventional therapy group 41%, P = 0.018 Decrease in composite of CV mortality and morbidity (stroke and MI) in the losartan vs. atenolol- based treatment 24%, P = 0.031 Composite end point of incidence of CV death, MI, HF, and stroke No difference; P =1.00 No significant difference in the incidence of fatal CHD and nonfatal MI Decrease in any major vascular event with fosinopril 51% (P = 0.030) Decrease in fatal and nonfatal MI with enalapril vs. nisoldipine 82% (P =0.001) Decrease in fatal and non fatal MI with ACEI vs. CA 49% P = 0.025 Decrease in total mortality 44% P = 0.034 Decrease in all cardiac events 33% P = 0.029. Decrease in CV mortality 37% P =0.028 Decrease in total mortality 39% P = 0.002 in the losartan- vs. atenolol based therapy Decrease in secondary outcomes (all-cause death) in the nifedipine group 24% (P = 0.03) Increase in HF in AML compared to CHL 39% P = 0.001 Table 1 Continued on next page AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 8 august 2011 867

STATE OF THE ART Hypertension and Diabetes Table 1 Continued Trial acronym Number of patients Age Follow-up ASCOT DM 57 5137 63.4 5.5 164.9 136 137 Prospective, randomized controlled trial comparing AML with addition of perindopril as required (AML based) vs. atenolol with addition of thiazide as required (atenolol-based) therapy. ACCOMPLIS DM 82 6946 67.5 2.5 145 131.5 132.7 Prospective, randomized double-blind trial comparing benazepril plus amlodipine vs. benazepril plus hydrochlorothiazide Studies designed to determine target blood pressure in diabetic patients Achieved SBP (mm Hg) Initial SBP (mm Hg) Active Comparator Design Primary endpoint Secondary endpoints HOT DM 29 1505 61.5 3.8 169 144 148 PROBE design to determine target DBP. Felodipine as the first drug. UKPDS 6 1148 56 8.4 160 144 154 Randomized controlled trial assessing the benefit of tight vs. less tight BP control, with either atenolol or captopril. ABCD HT 95 470 57.5 5.3 155 132 138 Prospective randomized controlled trial assessing the benefit of intensive vs. moderate BP control in hypertensive patients. ABCD NT 32 480 59 5.3 137 128 137 Prospective randomized controlled trial assessing the benefit of intensive vs. moderate BP control in normotensive subjects. Non significant decrease in CHD death and nonfatal MI 8% Decrease in composite of the first occurrence of a CV event or death from CV causes 21% P =0.003 Decrease in CV endpoints 51%, P = 0.005 Decrease in stroke 44%, P = 0.013 Decrease in any diabetes related endpoints 24%, P = 0.0046 No effect on nephropathy, neuropathy or retinopathy No change in creatinine clearance Decrease in total CV events and procedures 14% P= 0.0236. Decrease in stroke 25%, P=0.017. Decrease in PAD 48%, P=0.004. Decrease in non cardiac revascularization 57% (P<0.001). Decrease in non revascularization coronary event 27%, P = 0.013, Decrease in revascularization 20% P = 0.024. Decrease in renal endpoint 47%, P<0.001. No difference in other secondary endpoints Intensive therapy reduced total death from 10.7% to 5.5% (P = 0.037) Less progression to microalbuminuria (P = 0.012) and from micro to overt albuminuria (P = 0.028), less progression of diabetic retinopathy (P = 0.019) and less strokes (P = 0.03). Table 1 Continued on next page 868 august 2011 VOLUME 24 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

Hypertension and Diabetes STATE OF THE ART Table 1 Continued Trial acronym Number of patients Age Follow-up INVEST DM 33 6400 66 2.7 5 years extended follow-up for allcause mortality in the US cohort Tight 144 Usual 149 Uncontrolled 159 Achieved SBP (mm Hg) Initial SBP (mm Hg) Active Comparator Design Primary endpoint Secondary endpoints Tight 121.5 Usual 131.2 Uncontrolled 146.1 Observational, secondary analysis of the INVEST a prospective, randomized double-blind trial that compared a CA based to β-blocker based treatment in hypertensive patients with CAD. Outcome was analyzed according to the level of BP control. Tight (SBP <130 mm Hg) vs. usual control (SBP 130 <140 mm Hg) vs. uncontrolled (SBP 140 mm Hg). ACCORD 34 4733 62.2 4.7 139 119 133 Prospective, randomized non blinded trial assessing the benefit of intensive therapy, (SBP <120 mm Hg), vs. standard therapy, (SBP <140 mm Hg). Decrease in the first occurrence of composite of all-cause death, nonfatal MI, or nonfatal stroke in the usual control vs. uncontrolled 32% P < 0.001 No difference in composite of nonfatal MI, nonfatal stroke, or death from CV causes, P = 0.20 Decrease in all-cause mortality, non fatal MI, non fatal stroke, total MI and total stroke in the usual and tight control vs. uncontrolled (P<0.05). During extended followup adjusted increase in all-cause mortality in the tight vs. usual control 15% (P = 0.04). Decrease in rate of stroke 47% (P = 0.01) No difference in other secondary endpoints. ABCD NT,Appropriate Blood Pressure Control in Diabetes Normotensives; ABCD HT, Appropriate Blood Pressure Control in Diabetes Hypertensives; ACCOMPLISH, Avoiding cardiovascular Events through combination Therapy in Patients Living with Systolic Hypertension; ACCORD, The Action to Control Cardiovascular Risk in Diabetes; ACEI, Angiotensin converting enzyme inhibitor; ADVANCE, Action in Diabetes and Vascular disease, preterax and diamicorn MR Controlled Evaluation; ALLHAT, Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial; AML, amlodipine; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; BP, blood pressure; CA, calcium antagonists; CAD, coronary artery disease; CAPPP, Captopril Prevention Project; CHD, coronary heart disease, CHL, chlorthalidone; CV, cardiovascular; DBP, diastolic blood pressure; DM, diabetes mellitus; FACET, Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial; HF, heart failure; HOT, hypertension optimal treatment; IDNT, Irbesartan Diabetic Nephropathy Trial; INSIGHT, International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment, INVEST, The International Verapamil SR-Trandolapril; IRB, Irbesartan; LIFE, Losartan Intervention For Endpoint reduction in hypertension study; LIS, lisinopril; LVH, left ventricular hypertrophy; MI, myocardial infarction; PAD, peripheral arterial disease; PROBE, Prospective, Randomized, Open with Blinded Endpoint evaluation; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; SBP, systolic blood pressure; SHEP, Systolic Hypertension in the Elderly Program, STOP 2, Swedish Trial in Old Patients with Hypertension-2; Syst-China, systolic hypertension in China; Syst-Eur, systolic hypertension in Europe; UKPDS, UK Prospective Diabetes Study. AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 8 august 2011 869

STATE OF THE ART Hypertension and Diabetes Combinations of RAAS blockers. Combination therapy with ACE inhibitors and ARBs can block the RAAS better than any of them alone. This combination has little, if any additive effect, on BP, but may be synergistic with regard to reducing microalbuminuria. 48 However the recent large clinical study The Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET) showed that, in high-risk patients, the combination of the ARB, telmisartan, with the ACE inhibitor, ramipril, was more effective than ramipril alone in reducing BP; however, it did not reduce the primary endpoints and was associated with an increased risk of hypotension, syncope, and renal failure. 49,50 Therefore combination therapy with an ARB and an ACE inhibitor is not recommended in patients with diabetes plus hypertension. Unlike combination therapy involving an ACE inhibitor and an ARB, the administration of aliskiren along with the ARB, losartan, was effective in reducing albuminuria and maintaining renal function. 51 Further studies are needed to confirm the efficacy of this combination treatment involving aliskiren and ARB in reducing CV endpoints. Calcium antagonists. Calcium antagonists are efficacious antihypertensive agents, and have been shown to be at least as beneficial in patients with diabetes plus hypertension as conventional therapy. 52 Non-dihydropyridine calcium antagonists such as verapamil and diltiazem seem, at least in monotherapy, to be superior to dihydropyridines, because they have been shown to decrease proteinuria more efficiently than the dihydropyridines, and almost to the same extent achieved by ACE inhibitors. 53 However, most of the long-term clinical trials in hypertension that showed the benefit of calcium antagonists used the dihydropyridine drug, amlodipine(table 1). 54 56 We showed that, as compared to conventional therapy in patients with diabetes plus hypertension, calcium antagonists produced similar effects on CHD, less reduction in the risk of congestive heart failure, and a somewhat greater reduction in the risk of stroke. 52 Similarly, when compared to RAAS blockers, calcium antagonists were less effective in preventing heart failure, but the two classes of drugs had similar beneficial effects as regards risk of stroke, CHD, and total mortality. In patients with diabetes mellitus plus hypertension in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), amlodipine-based treatment reduced the incidence of total CV events and procedures by 14% as compared to the atenolol-based regimen. 57 Calcium antagonists are very effective in lowering BP as well as variability in BP, regardless of comorbidities, concomitant medications, salt intake, race, age, diet, activity of RAAS. Also, they are metabolically neutral and well tolerated. In order to achieve a target value of BP, a calcium antagonist is commonly needed. β-blockers. As a general rule, β-blockers should not be used as first-line therapy in patients with diabetes plus hypertension, but may be useful as add-ons in selected patients. Sympathetic activity is commonly enhanced in diabetes and CHD is often present; both these conditions are favorably influenced by a β-blocker. In a recent meta-analysis, Law et al. showed that β-blockers have a special effect (over and above that relating to BP reduction) in preventing recurrent CHD events in patients with a history of CHD. 58 In the UKPDS study, 59 outcomes were similar when patients were randomized either to a β-blocker or to an ACE inhibitor. However, in this study, risk of CHD was not shown to be significantly reduced by either one of the two drug classes. β-blockers are not considered ideal for use in patients with diabetes plus hypertension because of their unfavorable effect on endocrine metabolism. β-blockers have been shown to increase triglycerides, lower high-density lipoprotein cholesterol, worsen insulin resistance, lead to a systemic weight gain, and mask hypoglycemia. 60 63 As a class, β-blockers have never been shown to reduce the rate of occurrence of heart attacks and strokes in uncomplicated hypertension. 64 In the ASCOT study, an atenolol-based regimen prevented fewer CV events than an amlodipine-based regimen in the whole group as well as in a subset of patients with diabetes. 54,57 As a general rule, the use of β-blockers in patients with diabetes should be restricted to those in whom there are indications for this drug class. These indications include symptoms of sympathetic excess or tachycardia, the presence of CHD, or the need for an add-on therapy for uncontrolled hypertension. Diuretics. Thiazide diuretics have been, are, and will be a major component of the antihypertensive drug arsenal. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 56,65 chlorthalidone was shown to be superior to the α-blocker doxazosin mesylate in preventing stroke, and to the ACE inhibitor lisinopril in preventing stroke in black patients. In 13,100 patients with diabetes who participated in the ALLHAT, chlorthalidone was shown to be as effective as a calcium antagonist and an ACE inhibitor in reducing CV-related morbidity and mortality. 66 Several placebo-controlled studies have shown the efficacy of diuretics in reducing CV-related morbidity and mortality in the elderly. 67,68 In the Systolic Hypertension in the Elderly Program (SHEP), 67 in elderly patients (age >60 years) with isolated systolic hypertension, chlorthalidone reduced the rate of total stroke by 36%, the rate of major CV events by 32%, and the rate of all-cause mortality by 13%. The beneficial effects of chlorthalidone were the same in patients with or without diabetes. 69 In the recent Hypertension in the Very Elderly Trial (HYVET) 68 indapamide a thiazide like diuretic reduced the rate of stroke, CHD, heart failure, and all-cause mortality in very elderly hypertensive patients. It would therefore appear that, at least in elderly patients, chlorthalidone or indapamide 870 august 2011 VOLUME 24 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

Hypertension and Diabetes STATE OF THE ART should remain optional choices. However, diuretics have been well documented to have negative effects on endocrine metabolism relating to insulin resistance and electrolytes. 70,71 Loop diuretics may have fewer diabetogenic effects than thiazides, but there is little reason for their use in patients with diabetes unless the increase in creatinine dictates the decision to prescribe it. Thiazides may induce hyponatremia, which appears to be particularly common in elderly women. 72 This side effect can be prevented by the use of a low-medium dose of diuretic and by instructing patients to limit their fluid intake. Hyperuricemia and gout are common clinical complications in the patient with diabetes. Thiazide diuretics increase uric acid levels, and their indiscriminant use may trigger an attack of gout in a susceptible patient. The unfavorable effects of diuretics on glucose metabolism were not translated into increased cardiovascular morbidity and mortality during the follow up of a few years. 73 Recently, a long follow-up (15 years) of the SHEP study showed that the diabetogenic effect of thiazide had no impact on cardiovascular morbidity and mortality. 74 As with most drug classes used in hypertension, the long-term safety of diuretics remains uncertain. Therefore, in patients with diabetes plus hypertension, diuretics should be used in low doses and in combination with other drugs such as ACE inhibitors and ARBs only. Aldosterone antagonists. Aldosterone antagonists such as spironolactone and eplerenone can be exceedingly helpful in selected patients. 75,76 These drugs have been shown to reduce target organ disease and surrogate endpoints such as microproteinuria and left ventricular hypertrophy. 77 The addition of spironolactone to a regimen that includes maximal ACE inhibition affords greater renoprotection than the addition of the ARB losartan in diabetic nephropathy. 78 Spironolactone is particularly effective in patients with hypertension in whom serum potassium is low (<4 mmol/l) and in those with aldosterone breakthrough. 76,79 Eplerenone has a cleaner adverseeffect profile as compared to spironolactone, in that it does not seem to cause gynecomastia. 80 However, given that patients with diabetes plus hypertension are prone to hyperkalemia (hyporeninemic hypoaldosteronism, renal impairment, and/ or ACE inhibitor/arb treatment), these drugs should be used cautiously and in low doses only; potassium and creatinine will have to be monitored frequently. α-blockers. α-blockers have been shown to exert a favorable effect on metabolic endocrine parameters. Despite these seemingly favorable surrogate endpoint effects of alpha-blockers, the ALLHAT study has documented the superiority of chlorthalidone in preventing CHD and congestive heart failure. 65 As a class, α-blockers drugs should no longer be used for initial therapy in uncomplicated hypertension. However, they may be useful agents as third- or fourth-step therapy, and in patients with symptoms of prostatism. Combination therapy As discussed earlier in this paper, it is very difficult to achieve BP targets with monotherapy, and most patients require a combination of two or three drugs to get to target. Therefore the main question should be which combination is preferable? A blocker of the RAAS, either an ACE inhibitor or an ARB, represents the cornerstone of the antihypertensive arsenal for patients with diabetes plus hypertension. As a second step, the American Diabetes Association suggests a low dose of a thiazide diuretic. 24 However, the recent Avoiding cardiovascular Events through combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that a combination therapy with the ACE inhibitor, benazepril, and hydrochlorothiazide was less effective in lowering the risk of the predefined primary endpoints than the combination therapy with benazepril and amlodipine. 55 Moreover, combination therapy with benazepril plus amlodipine attenuated the progression of nephropathy to a greater extent as compared to benazepril plus hydrochlorothiazide. 81 In 6,946 patients with diabetes who were included in the ACCOMPLISH trial, combination therapy with benazepril plus amlodipine was more effective than therapy with benazepril plus hydrochlorothiazide in reducing the rate of primary endpoints (hazard ratio: 0.79, 95% confidence interval: 0.68 0.92, P = 0.003). 82 In the light of the ACCOMPLISH trial results, we suggest that, primarily, a calcium antagonist should be prescribed in addition to a RAAS blocker unless there is a clear indication for diuretics, such as a history of congestive heart failure. In many patients, triple therapy is required and, in general, it will consist of a blocker of RAAS, a calcium antagonist, and a low-dose thiazide diuretic. A β-blocker can be used in patients with CHD or congestive heart failure, or in patients with rapid heart rate. Aldosterone antagonists should be considered in patients with low serum potassium levels (<4 mmol/l) (Figure 1). In order to prevent hyperkalemia, a thiazide diuretic should be continued and serum potassium should be monitored frequently, especially in patients with chronic renal failure. Additional add-on therapies in patients on quadruple drug therapy are α-blockers and/or anti-adrenergic agents. As mentioned earlier combination therapy with an ACE inhibitor and an ARB is not recommended. However, in patients with microalbuminuria or diabetic nephropathy who do not respond to a combination therapy that includes a maximal dose of a RAAS blocker, the addition of the renin inhibitor, aliskiren, should be considered. In order to limit the number of medications used and to improve compliance, fixed-dose combinations of drugs may be helpful. AMERICAN JOURNAL OF HYPERTENSION VOLUME 24 NUMBER 8 august 2011 871

STATE OF THE ART Hypertension and Diabetes BP > 135/85 BP < 135/85 Continue monotherapy Continue therapy HR >80 beats/min add β-blocker Treatment of the diabetic-hypertensive ACEI/ARB BP < 135/85 Continue therapy BP > 135/85 Add CA BP < 135/85 K 4 mmol/l add spironolactone BP > 135/85 Add diuretic BP > 135/85 HR <60, K >4 mmol/l add α-blocker Figure 1 Suggested approach to controlling blood pressure in patients with diabetes who have normal renal function and no ischemic heart disease or congestive heart failure. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CA, calcium antagonists; HR, heart rate; K, potassium. Resistant hypertension Patients who have diabetes alongside hypertension are more resistant to antihypertensive treatment than those with hypertension alone. Also, given that the target BP in patients having both diseases simultaneously is lower than in those with hypertension alone, the rate of BP control is generally lower in patients with diabetes plus hypertension. In the ACCOMPLISH trial, ~75% of the patients achieved the BP target, whereas only ~45% of the patients with diabetes achieved the BP target. When resistant hypertension is suspected, 24-h ambulatory BP monitoring should be performed to exclude a white-coat effect. If 24-h ambulatory BP monitoring confirms the diagnosis of resistant hypertension, treatable secondary causes such as renal artery stenosis, primary hyperaldosteronism, pheochromocytoma, sleep apnea and drug-induced hypertension should be excluded. After excluding secondary causes, weight loss, sodium restriction, and regular physical exercise should be encouraged. We recommend intensification of treatment, where necessary, mainly by increasing the diuretic dose and adding an aldosterone antagonist if required. Very elderly patients The combination of diabetes and hypertension is common in the elderly, and the rate of CV events is higher in this age group. The recent HYVET showed that very elderly patients can benefit from lowering of BP; however, only a small fraction (<7%) of the patients in this study had diabetes. A recent analysis of the results of ADVANCE trial by age showed that the administration of perindopril-indapamide lowers BP safely and reduces the risk of major adverse clinical outcomes in patients 75 years of age. 83 Moreover, the absolute benefit was greater in patients 75 years of age than in those <65 of age. It is clear that the treatment of elderly patients with diabetes plus hypertension requires extra care as regards the selection of drugs, because these patients tend to have orthostatic hypotension and are more prone to developing adverse events. It is preferable to use lower doses, titrate treatment more closely, and monitor the patient by measuring BP in the standing position as well. Adjunct therapy Control of lipid and glycemic levels. When event rates are scrutinized in patients with diabetes among the cohorts in randomized trials, 84 it becomes increasingly clear that statins are efficacious in reducing the rate of occurrence of adverse events in this highrisk population. Simvastatin has been shown to reduce the rate of CHD by ~50% in this group as compared to placebo. In the CARDS study, 2,838 patients with diabetes with a mean low-density lipoprotein (LDL) at baseline of 118 mg/ dl were later randomized to receive either atorvastatin or placebo. 85 After a median follow up period of ~4 years, there was a 37% reduction in the primary endpoint. The rate of occurrence of strokes was reduced by 48%, and that of total mortality by 27%. The study was halted early because the benefits of atorvastatin therapy in patients with type 2 diabetes were established. The recent guidelines of the American Diabetes Association state that lipid-lowering therapy should be used regardless of baseline LDL cholesterol levels, in all patients >40 years of age with type 2 diabetes and one or more CV risk factors including hypertension. 24 In low-risk patients, statin should be prescribe if LDL cholesterol is >100 mg/dl. In individuals without overt CV disease, the primary goal is LDL <100 mg/dl, whereas in those with overt CV disease the goal is LDL <70 mg/dl. Glycemic control in type 2 diabetes is important mainly for preventing microvascular complications. 86 Glucose control with metformin therapy appears to decrease the risk of diabetes-related endpoints in patients with diabetes, and is associated with less weight gain and fewer hypoglycemic events 872 august 2011 VOLUME 24 NUMBER 8 AMERICAN JOURNAL OF HYPERTENSION

Hypertension and Diabetes STATE OF THE ART as compared to therapy with insulin and sulphonylureas. 5 Therefore metformin is considered to be the first-line pharmacological therapy of choice in patients with type 2 diabetes. The goal of glycemic control is to achieve hemoglobin A 1c (HbA 1c ) <7%. Summary The simultaneous presence of hypertension and diabetes is devastating to the CV system. Lowering the BP in patients with diabetes is particularly beneficial. The results of recent studies suggest that the target BP in patients with diabetes should be 135/85 mm Hg. Lower BP levels may be appropriate in patients with diabetes plus proteinuria and in those at risk for stroke. Nonpharmacologic therapy such as weight loss, low-sodium diet, and regular physical exercise should be encouraged in all patients. Blockers of RAAS, either ACE inhibitors or ARBs, have become a cornerstone in the management of patients with diabetes plus hypertension. Most patients require combination therapy to control their BP. Combination therapy with an RAAS blocker and a calcium antagonist is superior to the traditional therapy with an RAAS blocker and a diuretic. A thiazide diuretic should be added when BP is not well controlled in patients on combination therapy. When BP is not well controlled even with combination therapy with all these three types of drugs, the addition of a β- or α-blocker or an aldosterone antagonist should be considered, based on hemodynamic and laboratory parameters. In order to maximally reduce cardio-renal risk, control of lipid and glycemic levels should also be achieved. Disclosure: The authors declared no conflict of interest. 1. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R; Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360:1903 1913. 2. 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