Section 2: Management of Hypertension in Diabetes
All patients with diabetes should have blood pressure measured at the time of diagnosis or initial office evaluation and at each scheduled diabetes visit [36]. Because of the high cardiovascular risk associated with blood pressure pi130/80 mmHg in patients with diabetes, 130/80 mmHg is considered to be the cut point for defining hypertension, rather than 140/90 mmHg, as in the general population. Initial assessment of a hypertensive diabetic patient should include a complete medical history with special emphasis on cardiovascular risk factors and the presence of diabetes complications and other cardiovascular complications.
The measurement of blood pressure should ideally be performed in the supine and standing position. Two or more determinations in each position should be obtained using an appropriately sized cuff; obese patients generally require a large arm cuff and sometimes a thigh cuff to ensure accuracy. Cardiovascular autonomic neuropathy with significant orthostatic changes in blood pressure is common in diabetic subjects; can cause falsely low or high readings, depending on the position of the patient when the blood pressure is taken; and should be considered when treating patients [37].
The diagnosis of hypertension in patients with diabetes should be reserved for those individuals whose blood pressure levels exceed 130/80 mmHg on at least two separate occasions separated by at least 1 week. The physical exam should include height, weight, funduscopic examination, and careful evaluation of arterial circulation. Initial laboratory examination should include serum creatinine, electrolytes, A1C test, fasting lipid profile, and urinary albumin excretion (this can be measured by semiquantitative methods as screening tests, by quantitative methods in timed urine samples, or as albumin-to-creatinine ratio in spot samples).
Dietary management with moderate sodium restriction has been effective in reducing blood pressure in individuals with essential hypertension [38,39]. Several controlled studies have looked at the relationship between weight loss and blood pressure reduction [40,41]. Weight reduction can reduce blood pressure independent of sodium intake and can also improve blood glucose and lipid levels. The loss of 1 kg body wt has resulted in decreases in mean arterial blood pressure of ~1 mmHg [42]. The role of very low calorie diets and pharmacological agents that induce weight loss in the management of hypertension in diabetic patients has not been adequately studied. Some appetite suppressants, both prescription and over-the-counter, may induce increases in blood pressure levels [43,44,45] and therefore must be used with care. One over-the-counter appetite suppressant, phenylpropanolamine, has been associated with an increased risk of hemorrhagic stroke [46] in women and has been taken off the market; however, patients may still have supplies of this drug. Therefore, part of history-taking should include the use of over-the-counter drugs. Given the present evidence, weight reduction should be considered an effective measure in the initial management of mild-to-moderate hypertension, and the results could most likely be extrapolated to the diabetic hypertensive population.
Sodium restriction has not been tested in the diabetic population in controlled clinical trials. However, results from controlled trials in essential hypertension have shown a reduction of ~5 mmHg for systolic and ~2-3 mmHg for diastolic blood pressure, with moderate sodium restriction (from a daily intake of 200 mmol [4,600 mg] to 100 mmol [2,300 mg] of sodium per day). A dose-response effect has been observed with sodium restriction. Reductions in daily sodium intake to levels of 10-20 mmol (230-460 mg) per day have resulted in decreases in systolic blood pressure of 10-12 mmHg [38]. Even when pharmacological agents are used, there is often a better response when there is concomitant salt restriction caused by the aforementioned volume component of hypertension that is almost always present. The efficacy of these measures in diabetic individuals is not known.
Moderately intense physical activity, such as 30-45 min of brisk walking most days of the week, has been shown to lower blood pressure and is recommended in JNC VI [16]. Smoking cessation and moderation of alcohol intake are also recommended by JNC VI to reduce blood pressure [16,47,48].
A number of epidemiological studies suggest an inverse relationship between calcium, magnesium, and potassium intake and blood pressure level [49,50,51]. Most of these studies are cross-sectional, but a few are prospective observational studies. However, none of these studies has analyzed diabetic patients separately from the general hypertension population. Several randomized clinical trials have been published analyzing the effects of calcium supplementation on blood pressure levels. The characteristics of populations studied vary markedly among these studies and include subjects with normal, high-normal, or elevated blood pressure. A meta-analysis of these trials published in 1990 reported a very small blood pressure change (mean reduction in systolic blood pressure 1.8 mmHg and observed reduction in diastolic blood pressure 0.7 mmHg) [50]. There are no randomized clinical trials on magnesium supplementation in diabetic subjects with hypertension.
The purpose of antihypertensive treatment is to reduce the morbidity and mortality from cardiovascular complications (congestive heart failure, coronary artery disease, and stroke) and microvascular complications (nephropathy, neuropathy, and retinopathy). Available studies exploring the effects of pharmacological agents on the course of these complications will be reviewed. All available agents produce a similar reduction in systolic and diastolic blood pressure at the doses available for clinical use (10-15 and 5-10 mmHg in systolic and diastolic blood pressure, respectively). The differences among agents observed in comparative efficacy studies (those observing the blood pressure reduction effects) are usually small [52]. The effects of these differences on the cardiovascular or microvascular outcomes cannot be adequately evaluated. Many studies have been published on the effects of various antihypertensive agents on metabolic parameters, including lipids, glucose levels, and insulin resistance. Whereas these parameters are known risk factors for cardiovascular complications, the relevance of these findings in terms of clinical outcomes is not clear. Relevant studies in this area will be discussed.
Nephropathy. Approximately 20-30% of patients with type 1 diabetes and 10-20% with type 2 diabetes will develop end-stage renal disease (ESRD) [53]. Diabetes now accounts for ~50% of all new patients with ESRD and is the most common cause of this condition in adults. Among African-Americans, the incidence of ESRD is ~5 times that of whites; Native Americans and Asians also have high rates of ESRD. Familial and genetic factors play an important role in the development of this complication. The purpose of clinical interventions is to reduce the morbidity and mortality from this complication. Few interventional studies have used the development of ESRD as a primary outcome because of the long follow-up period that would be required. However, many studies have analyzed the effects of antihypertensive drugs on surrogate markers for renal damage, mainly urinary excretion of several markers of renal damage, albumin in particular. Because there is not always a correlation between surrogate markers and clinical outcomes, studies assessing clinical outcomes or renal function (glomerular filtration rate [GFR] or creatinine clearance) will be emphasized. The design of the clinical outcomes studies available is not always randomized, and the duration of the studies vary markedly; however, significant evidence is available supporting the aggressive management of hypertension in the prevention of advanced renal disease and its mortality. Normotensive patients with advanced diabetic nephropathy show slower progression compared with hypertensive patients [54]. Studies of the impact of antihypertensive treatment on diabetic nephropathy have generally included either type 1 or type 2 patients, but not both. There are also a number of studies of antihypertensive therapy including ACE inhibitors and other drug classes on the progression of nephropathy in patients without hypertension, primarily in type 1 diabetes.
Type 1 Diabetic Patients. A large placebo-controlled clinical trial using the ACE inhibitor captopril (Collaborative Study Group Trial) showed a significant decrease in the progression of diabetic nephropathy in subjects with type 1 diabetes and overt proteinuria (urinary albumin levels >500 mg/24 h) [55]. This study was designed to compare the effects of captopril versus other non-ACE inhibitor antihypertensive agents. A total of 409 patients were studied. Patients were randomized to captopril or placebo. Other antihypertensive drugs were allowed to achieve the desired blood pressure level in both groups. Mean baseline blood pressures were 137/85 mmHg in the captopril group and 140/86 mmHg in the placebo group. A total of 75% of the patients were hypertensive, and 60% were receiving antihypertensive medications at baseline. During treatment, the blood pressure averaged 128-134/77-82 mmHg in the captopril group and 129-136/80-84 mmHg in the placebo group. The great majority of patients in both groups received diuretics, and 15% in the placebo group and 11% in the captopril group received ß-blockers. The rate of decline in renal function in this study was 11% per year in the captopril group and 17% per year in the placebo group. The end points of death, ESRD, or doubling the serum creatinine were reduced by 50% in the captopril group compared with standard antihypertensive treatment. The differences in systolic and diastolic blood pressure levels between the two groups (placebo and captopril) studied were small, suggesting that ACE inhibitors have a renal protective effect independent of their antihypertensive effect. There are studies showing that in patients with microalbuminuria (urinary albumin excretion rate [UAER] 30-300 mg/24 h) and hypertension, ACE inhibitors decrease the progression to overt proteinuria (UAER >300 mg/24 h) [56,57]. Also, in studies of type 1 patients with microalbuminuria without a clinical diagnosis of hypertension, several small clinical trials suggest that ACE inhibitors may be beneficial in delaying or preventing the progression of nephropathy [58,59]. A recent meta-analysis of raw data obtained for 698 patients enrolled in several small trials has shown a statistically significant decrease in progression to macroalbuminuria and in regression of albuminuria [60].
Type 2 Diabetic Patients. A multicenter randomized study in type 2 diabetic patients, the U.K. Prospective Diabetes Study (UKPDS)-Hypertension in Diabetes Study (HDS) [4], evaluated the effects of different levels of blood pressure control on diabetic complications. A total of 1,148 patients were included; 758 were allocated to what was designated tight blood pressure control (goal: blood pressure <150/85 mmHg), and 390 were allocated to less tight control (goal: blood pressure <180/105 mmHg). Practitioners could choose any treatment for the "less tight" group, but were to avoid ACE inhibitors and ß-blockers. The patients allocated to tight control were subsequently randomized to the ACE inhibitor captopril (400 patients) or the ß-blocker atenolol (358 patients). If the target was not met, additional agents were prescribed (loop diuretic, calcium channel blocker, or vasodilator). The baseline blood pressure level was 160/94 mmHg. The patients were followed for a median of 8.4 years. Blood pressure was reduced to 144/82 mmHg in the tight control group and 154/87 mmHg in the less tight control group (P < 0.0001). Tight control was associated with a reduction of 24% in diabetes-related end points, 32% in deaths related to diabetes, and 37% in microvascular end points (nephropathy and advanced retinopathy). Patients assigned to the tight control group had a 29% reduction in the risk of developing urinary albumin levels >50 mg/l at 6 years, but no significant changes were observed in the development of overt proteinuria or increase in plasma creatinine levels between the two groups.
There is little evidence that the use of ACE-inhibitors as prophylactic treatment in type 1 or type 2 patients without microalbuminuria can prevent the development of diabetic nephropathy, although there was a nonsignificant decrease in the development of microalbuminuria in type 2 patients in the MICRO-Heart Outcomes Prevention Evaluation (HOPE) study [61]. It should be noted that this was a cardiovascular risk trial, not a hypertension trial, as a significant portion of the participants did not have hypertension and those who did were managed throughout the study with non-ACE inhibitor medications. The mean blood pressure in this study at baseline was 142/80 mmHg in the ramipril group and 142/79 mmHg in the placebo group. By the end of the study, blood pressure decreased by 1.9 mmHg for systolic and 3.3 mmHg for diastolic in the ramapril group compared with an increase of 0.6 mmHg for systolic and a decrease of 2.3 for diastolic in the placebo group. Even this minimal lowering of blood pressure from the ACE inhibitor may have had some role in producing this result.
Angiotensin receptor blockers (ARBs) have been shown to retard the progression of albuminuria and the development and progression of nephropathy. Losartan, ibesartan, telmesartan, candesartan, eprosartan, and valsartan are effective antihypertensive agents [62,63]. They are not associated with cough, like ACE inhibitors. Angiotensin II receptor blockers have been shown to decrease proteinuria [64,65]. There are now three recent large, placebo-controlled, multicenter trials examining the renoprotective effects of an ARB in hypertensive patients with type 2 diabetes (already on other hypertensive medications), examining either the development or progression of nephropathy (Table 1). Parving et al. [66] studied 590 hypertensive patients with microalbuminuria, comparing irbesartan (at two different doses) versus placebo. Follow-up was for 2 years. They found that in 5.2% of the 300-mg irbsesartan group (P < 0.001) and in 9.7% of the 150-mg irbesartan group (P = 0.08), the primary outcome (time to onset of diabetic nephropathy, defined by persistent albuminuria, with a UAER >200 µg/min and >30% higher than baseline) was achieved, compared with 14.9% of the placebo group. They concluded that irbesartan had a renoprotective effect independent of any blood pressure-lowering effect.
Lewis et al. [67] studied 1,715 hypertensive patients with nephropathy given irbesartan, amlodipine, or placebo. Mean duration of follow-up was 2.6 years. Treatment with irbesartan (300 mg) was associated with a reduction of the risk of the primary composite end point (doubling of serum creatinine, development of ESRD, or death) of 20% compared with the placebo group (P = 0.02) and 23% compared with the amlodipine group (P = 0.006). The risk of doubling serum creatinine was 33% lower compared with the placebo group (P = 0.003) and 37% compared with the amlodipine group (10 mg) (P < 0.001). The relative risk of ESRD was 23% lower in the irbesartan group than in the placebo or amlodipine groups (P = 0.07). These differences were not explained by the blood pressure reduction achieved. There were no significant differences in the rates of death or cardiovascular composite outcomes.
Brenner et al. [68] studied 1,513 hypertensive patients with established nephropathy, comparing losartan (100 mg) with placebo. Mean follow-up was 3.4 years. Patients in the losartan group had a 16% risk reduction in the composite primary end point (doubling of serum creatinine, ESRD, or death) (P = 0.002), a 25% risk reduction in the doubling of serum creatinine (P = 0.006), and a 28% reduction in ESRD (P = 0.002). There was no effect seen for death rate. The composite of mortality and morbidity from cardiovascular causes was similar between the two groups. The benefits exceeded those attributable to changes in blood pressure.
Other Microvascular Complications. In the UKPDS, there was a significant reduction of 34% in the number of patients requiring photocoagulation and showing deterioration of the retinopathy by two or more steps [4]. A 47% reduction in the risk of decreasing vision in both eyes was associated with tight blood pressure control. No differences in blood pressure control were observed between the captopril and the atenolol groups (blood pressure 144/83 and 143/81, respectively). At the end of the study, 78% of the patients assigned to captopril and 65% assigned to atenolol were taking the study medications (P < 0.0001 for captopril vs. atenolol). This difference was attributed to a higher incidence of peripheral vascular problems and bronchial spasm observed with the ß-blocker. No difference in study end points was seen between the ACE inhibitor and the ß-blocker; both were equally effective in reducing the risk of cardiovascular and microvascular complications. An epidemiological analysis of this study showed that each 10-mmHg decrease in mean systolic blood pressure was associated with relative risk reductions of 12% for any complication of diabetes, 15% for deaths related to diabetes, 11% for myocardial infarction, and 13% for microvascular complications [13]. There was no threshold of risk, and the lowest risk occurred in the group with systolic blood pressure <120 mmHg [4,7]. Further evidence of reduction in macrovascular disease in the UKPDS will be discussed in the next section.
In several recent studies using various antihypertensive drug regimens, indications are that the incidence of cardiovascular events can be effectively reduced in patients with diabetes and hypertension. Three studies, the UKPDS-HDS [4,7], the Appropriate Blood Pressure Control in Diabetes (ABCD) trial [6], and the Fosinipril versus Amlodipine Cardiovascular Randomized Events Trial (FACET) [9] included only patients with diabetes. The UKPDS-HDS, the design of which was described in the previous section, was both a study of the effect of tight blood pressure control on microvascular and macrovascular complications of diabetes as well as a comparison of ß-blockers (atenolol) versus an ACE inhibitor (captopril) [4,7]. In addition to the decreases in microvascular disease previously described, the tight control group experienced a 24% drop in total diabetes-related end points (CI 8-30%; P < 0.0046), a 32% decrease in deaths related to diabetes (CI 6-51%; P = 0.019), and a 44% decrease in strokes (CI 11-50%; P = 0.0004). There was no difference within the "tight" control group between patients treated with atenolol and patients treated with captopril. After 9 years of follow-up, 29% of patients on the tight control group required three or more drugs to achieve target blood pressures.
Two studies have compared the efficacy of dihydropyridine calcium channel blockers (DCCBs) and ACE inhibitors on cardiovascular events in diabetic patients with hypertension. In the ABCD trial [6], 470 patients with type 2 diabetes and hypertension (diastolic blood pressure pi90 mmHg) were randomized to nisoldipine (a DCCB) and enalapril (an ACE inhibitor). A similar reduction in blood pressure was observed with both drugs. A slightly higher (but statistically significant) number of patients in the enalapril group received ß-blockers and thiazide diuretics. After 5 years of follow-up, 25 patients in the nisoldipine group had developed fatal or nonfatal myocardial infarction compared with 5 patients in the enalapril group (P = 0.002). The results of this study suggest either that enalapril had a marked protective effect beyond its antihypertensive properties or that nisoldipine has a deleterious effect. Because myocardial infarction was a secondary outcome in this study, these results must be interpreted with caution.
The FACET [9] reported the results of antihypertensive treatment in 380 type 2 diabetic patients with hypertension. Mean follow-up was 2.9 years in the fosinopril (an ACE inhibitor) group and 2.4 years in the amlodipine (a DCCB) group. Cardiovascular events were secondary end points. A total of 27 patients in the amlodipine group and 14 in the fosinopril group developed the combined end point of acute myocardial infarction, stroke, or hospitalization for angina (risk ratio 0.49, 95% CI 0.26-0.95). The number of myocardial infarctions was similar in both groups (13 in the fosinopril group and 11 in the amlodipine group). The differences in outcomes were mainly caused by hospitalization for angina and strokes (more common in the amlodipine group). These two studies suggest that ACE inhibitors may have an advantage over some DCCBs. Interpretation of these studies is controversial and has been the subject of numerous conflicting reviews and commentaries [69,70,71,72,73,74,75].
In addition to the clinical trials specifically in patients with diabetes, several studies in the general population of patients with hypertension have included sufficient patients with diabetes to allow analysis of a subgroup with diabetes. These include studies of drug treatment versus placebo in the treatment of isolated systolic hypertension in older patients, studies comparing outcomes in participants assigned to different blood pressure targets, and trials comparing different drugs.
In a post hoc report of the Systolic Hypertension in Europe trial (Syst-Eur) [3], 492 diabetic patients included in the study were separately analyzed. Patients >60 years of age with systolic hypertension, stratified for center, gender, and cardiovascular complications, were randomized to receive a stepped-care regimen with nitrendipine (as the first step) or placebo. Baseline blood pressure was 175/84 mmHg. After 2 years of follow-up, the blood pressure of patients with diabetes receiving active treatment had decreased by 22.1/6.8 mmHg and by 13.5/2.9 mmHg in the placebo group. Mean differences between the active treatment and placebo groups were 8.6/3.9 mmHg. Cardiovascular mortality and events in the diabetic subjects receiving placebo were approximately twice that of the nondiabetic subjects receiving placebo; however, the rate in the diabetic patients receiving active treatment was similar to that of the nondiabetic patients. A reduction of 70% in cardiovascular mortality, 62% in all cardiovascular events, 69% in strokes, and 57% in cardiovascular events was associated with active treatment in the diabetic group. The relative benefit of antihypertensive treatment was greater in the group of patients with diabetes compared with the nondiabetic group in terms of overall mortality (P = 0.04 diabetic vs. nondiabetic group), cardiovascular mortality (P = 0.02), and all cardiovascular events combined (P = 0.01). The absolute benefit was also markedly greater for the diabetic patients. For example, 19.5 cardiovascular deaths per 1,000 patient-years were prevented in the diabetic group compared with 1.9 per 1,000 patient-years in the nondiabetic group, and 35.6 cardiovascular events per 100 patient-years were prevented in the diabetic group compared with 7.9 in the nondiabetic group. Although this was a placebo-controlled study and not a drug comparison study, the larger reductions in event rates seen in the group treated with nitrendipine-based therapy suggest that DCCBs, or at least nitrendipine, do not have major deleterious cardiovascular effects in older patients with diabetes and isolated systolic hypertension.
The post hoc analysis of the Systolic Hypertension in the Elderly (SHEP) study included 583 subjects with diabetes >60 years of age (12% of all the study patients) [2]. A low-dose thiazide diuretic, chlorthalidone, versus placebo was used, and atenolol or reserpine was used if chlorthalidone alone was not sufficient to control the blood pressure. The goal of the treatment was a reduction in systolic blood pressure of at least 20 mmHg in patients with systolic blood pressure between 160-179 mmHg and a reduction to <160 mmHg in patients with systolic blood pressure >180 mmHg. The actual mean reductions of systolic and diastolic blood pressure were 9.8/2.2 mmHg in the diabetic group and 12.1/4.1 mmHg in the nondiabetic group (n = 4,149). A reduction of 34% (P < 0.05) in cardiovascular events was observed in the diabetic group treated with chlorthalidone compared with the placebo group. This relative reduction was similar to the reduction observed in the group as a whole. These events included major coronary events (fatal and nonfatal myocardial infarction, sudden death, coronary bypass, and angioplasty), cerebrovascular events (stroke, transient ischemic attacks, and carotid endarterectomy), and aortic aneurysm. The rate of coronary artery disease end points in the diabetic group was reduced by 55 vs. 20% in the nondiabetic group (P < 0.05). Because the rate of cardiovascular disease in diabetic patients was twice as high as in nondiabetic patients, the absolute risk reduction in the diabetic group was twice as great in the diabetic group (101 per 1,000 randomized patients).
The Hypertension Optimal Treatment (HOT) trial ([5]) was a large-scale multinational study that included 18,790 patients, 1,501 of whom had diabetes. One-third of the patients were assigned to each of three different levels of hypertension control, with treatment targets of diastolic blood pressure <=90, <=85, and <=80 mmHg. The DCCB felodipine was used as initial treatment, followed by a five-step treatment to achieve the goal blood pressures. The baseline diastolic blood pressure was 105 mmHg. Diabetic patients had a rate of cardiovascular events two to three times higher than the group as a whole for the <=90 and <=85 mmHg groups. In the <=80 mmHg group, the rate of cardiovascular disease events in the diabetic group was lower than in the <=90 mmHg group and approached the lower rate seen in patients without diabetes. In the group as a whole, the lowest incidence of major cardiovascular events was observed at a diastolic pressure of 82.6 mmHg, and the lowest risk of cardiovascular mortality was observed at a diastolic blood pressure of 86.5 mmHg, with no difference among the three groups. Among the diabetic patients, however, the group assigned to a target diastolic blood pressure <=80 mmHg (achieved blood pressure 81 mmHg) showed a marked reduction in major cardiovascular events (51%, P = 0.005) and in cardiovascular mortality (43%, P = 0.016) compared with those patients assigned to a target of <=90 mmHg. The majority of the patients required a combination of at least two drugs (usually felodipine, a DCCB, with an ACE inhibitor, ß-blocker, and/or a diuretic) to achieve the targeted level of blood pressure.
Several recent studies primarily aimed at assessing the relative efficacy of different drug classes on cardiovascular outcomes reported separately on patients with diabetes. The Swedish Trial in Old Patients with Hypertension-2 (STOP Hypertension-2) [11] found a significant decrease in myocardial infarction in patients on ACE inhibitors compared with patients treated with the DCCBs felodipine or isradipine, but not compared with ß-blockers and diuretics. The International Nifedipine (GITS) study -- Intervention as a Goal in Hypertension -- found no difference between therapy based on nifedipine, a DCCB, versus co-amilozide, a thiazide/potassium-sparing diuretic combination [12]. In the Nordic Diltiazem Trial, treatment based on diltiazem hydrochloride, a non-DCCB (NDCCB), was compared with ß-blocker/diuretic-based treatment [13]. This study found a significantly lower risk of stroke for patients treated with diltiazem-based therapy compared with the ß-blocker/diuretic-therapy group but a nonsignificant trend toward higher rates of myocardial infarction, cardiovascular death, and congestive heart failure in the diltiazem group. There were no differences in combined cardiovascular events or mortality. In none of these studies did results differ for participants with diabetes.
In the Captopril Prevention Project (CAPPP), 717 participants with diabetes and treated or untreated hypertension received either the ACE inhibitor captopril or conventional treatment consisting of a ß-blocker, diuretic, or both. The study design was an open randomized prospective trial including a total of 10,985 patients with and without diabetes [10]. After 6.1 years of follow-up, there was a 14% (95% CI 1.0-26.0) lower rate of the combined outcome of fatal and nonfatal stroke, myocardial infarction, or other cardiovascular death among patients with diabetes in the group taking captopril versus those taking diuretics and ß-blockers. In contrast, in the nondiabetic subjects, the only difference in outcomes between groups was an increased relative risk of stroke of 25% (95% CI 1.0-55.0) in the captopril group. Concern has been raised about unbalanced randomization in the nondiabetic group.
Recently, the HOPE study evaluated the effect of an ACE inhibitor, ramipril, on 9,541 patients with a high risk of cardiovascular disease, including 3,378 with diabetes [61]. As previously noted, in this non-hypertensive trial, the blood pressure changes were quite small with ramapril treatment. All-cause and cardiovascular mortality as well as cardiovascular events, including myocardial infarction and stroke, were significantly decreased by ramipril treatment.
Diabetes Care. 2002;25(1) © 2002 American Diabetes Association, Inc.
Cite this: The Treatment of Hypertension in Adult Patients With Diabetes - Medscape - Jan 01, 2002.
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