Raymond O. Estacio

The Effect of Nisoldipine as Compared with Enalapril on Cardiovascular Outcomes in Patients with Non-Insulin-Dependent Diabetes and Hypertension

BACKGROUND It has recently been reported that the use of calcium-channel blockers for hypertension may be associated with an increased risk of cardiovascular complications. Because this issue remains controversial, we studied the incidence of such complications in patients with non-insulin-dependent diabetes mellitus and hypertension who were randomly assigned to treatment with either the calcium-channel blocker nisoldipine or the angiotensin-converting-enzyme inhibitor enalapril as part of a larger study. METHODS The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial is a prospective, randomized, blinded trial comparing the effects of moderate control of blood pressure (target diastolic pressure, 80 to 89 mm Hg) with those of intensive control of blood pressure (diastolic pressure, 75 mm Hg) on the incidence and progression of complications of diabetes. The study also compared nisoldipine with enalapril as a first-line antihypertensive agent in terms of the prevention and progression of complications of diabetes. In the current study, we analyzed data on a secondary end point (the incidence of myocardial infarction) in the subgroup of patients in the ABCD Trial who had hypertension. RESULTS Analysis of the 470 patients in the trial who had hypertension (base-line diastolic blood pressure, > or = 90 mm Hg) showed similar control of blood pressure, blood glucose and lipid concentrations, and smoking behavior in the nisoldipine group (237 patients) and the enalapril group (233 patients) throughout five years of follow-up. Using a multiple logistic-regression model with adjustment for cardiac risk factors, we found that nisoldipine was associated with a higher incidence of fatal and nonfatal myocardial infarctions (a total of 24) than enalapril (total, 4) (risk ratio, 9.5; 95 percent confidence interval, 2.7 to 33.8). CONCLUSIONS In this population of patients with diabetes and hypertension, we found a significantly higher incidence of fatal and nonfatal myocardial infarction among those assigned to therapy with the calcium-channel blocker nisoldipine than among those assigned to receive enalapril. Since our findings are based on a secondary end point, they will require confirmation.

Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes

In eight patients exhibiting chemical diabetes mellitus with a poststimulative hypoglycemia, we observed that the pattern of the oral glucose tolerance test (OGTT) was improved when indigestible fiber was added to the oral glucose load. As compared with a standard OGTT, the peak blood glucose, expressed as per cent change from baseline, was particularly blunted by pectin or by cellulose phosphate but remained unchanged with cellulose supplementation. The time interval required to reach the blood glucose peak was significantly prolonged with pectin. The rate of blood glucose rise was reduced to a greater extent by pectin than by cellulose phosphate, which in turn was more efficient than cellulose. The blood glucose nadir expressed as per cent change from baseline was blunted by pectin, while the results were not significantly different after addition of either cellulose phosphate or cellulose. On the other hand, the plasma immunoreactive insulin did not show any significant change whether the glucose was given with or without one of the aforementioned types of fiber. From these results, it is concluded that an additional fiber intake may be of interest in the management of chemical diabetes. The use of pectin may diminish the poststimulative hypoglycemia.

Reduction in the Incidence of Acute Myocardial Infarction Associated With a Citywide Smoking Ordinance

Background— Secondhand smoke exposure increases the risk of acute myocardial infarction (AMI). One study (Helena, Mont) examined the issue and found a decrease in AMI associated with a smoke-free ordinance. We sought to determine the impact of a smoke-free ordinance on AMI admission rates in another geographically isolated community (Pueblo, Colo). Methods and Results— We assessed AMI hospitalizations in Pueblo during a 3-year period, 1.5 years before and 1.5 years after implementation of a smoke-free ordinance. We compared the AMI hospitalization rates among individuals residing within city limits, the area where the ordinance applied, versus those outside city limits. We also compared AMI rates during this time period with another geographically isolated but proximal community, El Paso County, Colo, that did not have an ordinance. A total of 855 patients were hospitalized with a diagnosis of primary AMI in Pueblo between January 1, 2002, and December 31, 2004. A reduction in AMI hospitalizations was observed in the period after the ordinance among Pueblo city limit residents (relative risk [RR]=0.73, 95% confidence interval [CI] 0.63 to 0.85). No significant changes in AMI rates were observed among residents outside city limits (RR=0.85, 95% CI 0.63 to 1.16) or in El Paso County during the same period (RR=0.97, 95% CI 0.89 to 1.06). The reduction in AMI rate within Pueblo differed significantly from changes in the external control group (El Paso County) even after adjustment for seasonal trends (P<0.001). Conclusions— A public ordinance reducing exposure to secondhand smoke was associated with a decrease in AMI hospitalizations in Pueblo, Colo, which supports previous data from a smaller study.

Intensive Blood Pressure Control Reduces the Risk of Cardiovascular Events in Patients With Peripheral Arterial Disease and Type 2 Diabetes

Background—Peripheral arterial disease (PAD) and diabetes are both associated with a high risk of ischemic events, but the role of intensive blood pressure control in PAD has not been established. Methods and Results—The Appropriate Blood Pressure Control in Diabetes study followed 950 subjects with type 2 diabetes for 5 years; 480 of the subjects were normotensive (baseline diastolic blood pressure of 80 to 89 mm Hg). Patients randomized to placebo (moderate blood pressure control) had a mean blood pressure of 137±0.7/81±0.3 mm Hg over the last 4 years of treatment. In contrast, patients randomized to intensive treatment with enalapril or nisoldipine had a mean 4-year blood pressure of 128±0.8/75±0.3 mm Hg (P <0.0001 compared with moderate control). PAD, which is defined as an ankle-brachial index <0.90 at the baseline visit, was diagnosed in 53 patients. In patients with PAD, there were 3 cardiovascular events (13.6%) on intensive treatment compared with 12 events (38.7%) on moderate treatment (P =0.046). After adjustment for multiple cardiovascular risk factors, an inverse relationship between ankle-brachial index and cardiovascular events was observed with moderate treatment (P =0.009), but not with intensive treatment (P =0.91). Thus, with intensive blood pressure control, the risk of an event was not increased, even at the lowest ankle-brachial index values, and was the same as in a patient without PAD. Conclusions—In PAD patients with diabetes, intensive blood pressure lowering to a mean of 128/75 mm Hg resulted in a marked reduction in cardiovascular events.

Urinary Albumin Excretion as a Predictor of Diabetic Retinopathy, Neuropathy, and Cardiovascular Disease in NIDDM

OBJECTIVE The relationship between urinary albumin excretion (UAE) and diabetic complications in NIDDM has not been studied in a large American population. The demonstrated relationship between increased UAE and the development of retinopathy, nephropathy, and neuropathy in IDDM makes this an important issue to also be studied in NIDDM patients. RESEARCH DESIGN AND METHODS A large population study of 947 NIDDM patients living predominantly in a metropolitan area was undertaken. Three categories of UAE, namely, normal albuminuria (< 20 μg/min), microalbuminuria (20–200 μg/min), and overt albuminuria (>200 μg/min) were compared with 1) retinopathy as assessed by stereoscopic fundus photographs; 2) cardiovascular disease as assessed by a history of cardiac disease or stroke; ischemic changes on exercise treadmill testing; Q wave myocardial infarction; Estes, Sokolow, or Cornell criteria for left ventricular hypertrophy; positive Rose questionnaire for angina; and an abnormal Doppler exam for peripheral vascular disease; and 3) neuropathy as assessed by neurological symptom and disability scores, autonomic function testing, and quantitative sensory exams involving thermal and vibratory sensation. Selected patient characteristics were then evaluated to determine their effects on the presence of diabetic complications using univariate analyses. Multiple logistic regression analyses were then performed to determine the independent effect of UAE on these diabetic complications. RESULTS χ2 analyses revealed that UAE was significantly associated with the presence of retinopathy (P < 0.001), neuropathy (P < 0.001), and cardiovascular disease (P < 0.001). In the multiple logistic regression analyses, UAE had strong independent associations with retinopathy, neuropathy, and cardiovascular disease. CONCLUSIONS Thus, increasing UAE in this large NIDDM population in the U.S. was associated with an increased prevalence of diabetic retinopathy, neuropathy, and cardiovascular disease. This suggests that UAE may be more than an indicator of renal disease in NIDDM patients and, in fact, may reflect a state of generalized vascular damage occurring throughout the body. Prospective studies in NIDDM patients are needed to determine the predictive effect of UAE and the effect of decreasing UAE on future diabetic micro- and macrovascular complications.

Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial

As the population ages, the incidence of type 2 diabetes will increase as will the incidence of concomitant vascular complications. Hypertension substantially increases the risk of cardiovascular disease in patients with diabetes. Results from the recent Appropriate Blood Pressure Control in Diabetes (ABCD) trial demonstrated an advantage of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) over a long-acting calcium antagonist (nisoldipine) with regard to the incidence of cardiovascular events over a 5-year follow-up period in hypertensive persons with type 2 diabetes. This trial was a prospective, randomized, blinded study comparing the effects of moderate blood pressure control (target diastolic pressure 80-89 mm Hg) with those of intensive control (target diastolic pressure 75 mm Hg) on the incidence and progression of diabetic vascular complications. The study also compared nisoldipine with enalapril as first-line antihypertensive therapy in terms of prevention and progression of complications of diabetes. In 470 hypertensive patients, the incidence of fatal and nonfatal myocardial infarctions was significantly (p = 0.001) higher among those receiving nisoldipine (n = 25) compared with those receiving enalapril (n = 5). Comparison with previous studies suggests that the difference observed between nisoldipine and enalapril resulted from a beneficial effect of enalapril rather than a deleterious effect from nisoldipine. Since these findings in the ABCD trial are based on a secondary endpoint, they require confirmation. Nevertheless, they suggest that ACE inhibitors should be the initial antihypertensive medication used in patients with type 2 diabetes and hypertension.

The Association Between Diabetic Complications and Exercise Capacity in NIDDM Patients

OBJECTIVE Exercise capacity has been used as a noninvasive parameter for predicting cardiovascular events. It has been demonstrated previously in NIDDM patients that several risk factors (i.e., obesity, smoking, hypertension, and African-American race) are associated with an impaired exercise capacity. We studied 265 male and 154 female NIDDM patients who underwent graded exercise testing with expired gas analyses to determine the possible influences of diabetic neuropathy, nephropathy, and retinopathy on exercise capacity. RESEARCH DESIGN AND METHODS Univariate and multiple linear regression analyses were performed to determine the relationship between diabetic neuropathy, urinary albumin excretion (UAE), and retinopathy with respect to peak oxygen consumption (Vo2). Neuropathy was assessed by neurological symptom and disability scores, autonomic function testing, and quantitative sensory exams involving thermal and vibratory sensation. Three categories of UAE were used: normal albuminuria (<20 μg=min), microalbuminuria (20–200 μg/min), and overt albuminuria (>200 μg/min). Retinopathy was assessed by stereoscopic fundus photographs. Multiple linear regression analyses were then performed controlling for age, sex, length of diagnosed diabetes, duration of hypertension, race and ethnicity, GHb, BMI, and smoking to determine whether there was an independent effect of these diabetic complications on exercise capacity. RESULTS Univariate analyses revealed that the presence of diabetic retinopathy (P = 0.03), neuropathy (P = 0.002), microalbuminuria (P = 0.04), and overt albuminuria (P = 0.06) were associated with a lower peak Vo2. Multiple linear regression analyses were performed to determine independent relationships with peak Vo2. The results revealed that increasing retinopathy stage (Parameter estimate [PE] = −0.59 ± 0.3 ml · kg−1 · min−1; P = 0.026) and increasing UAE stage (PE = −0.62 ± 0.3 ml · kg−1 · min−1; P = 0.044) were associated with a decrease in peak Vo2. CONCLUSIONS In the present study of NIDDM subjects, a significant independent association was demonstrated between diabetic nephropathy and retinopathy with exercise capacity. These results were obtained controlling for age, sex, length of diagnosed diabetes, hypertension, race, and BMI. Thus the findings in this large NIDDM population without a history of coronary artery disease indicate a potential pathogenic relationship between microvascular disease and exercise capacity.

Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trial

The hypertensive and normotensive Appropriate Blood Pressure Control in Diabetes (ABCD) studies were prospective, randomized, interventional clinical trials with 5 years of follow-up that examined the role of intensive versus standard blood pressure control in a total of 950 patients with type 2 diabetes mellitus. In the hypertensive ABCD study, a significant decrease in mortality was detected in the intensive blood pressure control group when compared with the standard blood pressure control group. There was also a marked reduction in the incidence of myocardial infarction when patients were randomly assigned to initial antihypertensive therapy with angiotensin-converting-enzyme inhibition rather than calcium channel blockade. The results of the normotensive ABCD study included associations between intensive blood pressure control and significant slowing of the progression of nephropathy (as assessed by urinary albumin excretion) and retinopathy, and fewer strokes. In both the hypertensive and normotensive studies, mean renal function (as assessed by 24 h creatinine clearance) remained stable during 5 years of either intensive or standard blood pressure intervention in patients with normoalbuminuria (<30 mg/24 h) or microalbuminuria (30–300 mg/24 h) at baseline. By contrast, the rate of creatinine clearance in patients with overt diabetic nephropathy (>300 mg/24 h; albuminuria) at baseline decreased by an average of 5 ml/min/year in spite of either intensive or standard blood pressure control. Analysis of the results of 5 years of follow-up revealed a highly significant correlation of all-cause and cardiovascular mortality with left ventricular mass and severity of albuminuria.

Clinical Factors Associated With Urinary Albumin Excretion in Type II Diabetes

Clinical factors associated with urinary albumin excretion (UAE) in type II diabetes are less well known than in type I diabetes. To examine the factors associated with UAE in type II diabetes, 933 Appropriate Blood Pressure Control in Diabetes Trial patients were classified according to UAE status: normoalbuminuria (< 20 micrograms/min), microalbuminuria (20 to 200 micrograms/min), and macroalbuminuria (> 200 micrograms/min). The class of UAE was then correlated with various clinical factors. Using univariate analyses, Hispanic ethnicity, African-American race, male gender, poor glycemic control, insulin use, long duration of diabetes, dyslipidemia, diastolic and systolic hypertension, smoking, and obesity were significantly correlated with microalbuminuria and macroalbuminuria. Using multivariate logistic regression analyses controlling for diabetes duration, glycosylated hemoglobin, gender, and race, the most significant predictors of microalbuminuria and macroalbuminuria were systolic hypertension, body mass index, high-density lipoprotein cholesterol, insulin use, and smoking pack-years. Of these factors, several are potentially reversible with aggressive intervention.

Appropriate Blood Pressure Control in NIDDM (ABCD) Trial

Summary The ABCD (Appropriate Blood Pressure Control in Diabetes) Trial is a large, prospective, randomized clinical trial of 950 patients with non-insulin-dependent diabetes mellitus (NIDDM) designed to compare the effects of intensive blood pressure control with moderate control on the prevention and progression of diabetic nephropathy, retinopathy, cardiovascular disease, and neuropathy in NIDDM. The secondary objective is to determine equivalency of the effects of a calcium channel blocker (nisoldipine) and an angiotensin-converting-enzyme inhibitor (enalapril) as a first-line antihypertensive agent in the prevention and/or progression of these diabetic vascular complications. The study consists of two study populations aged 40–74 years, 470 hypertensive patients (diastolic blood pressure of ≥ 90.0 mmHg at time of randomization) and 480 normotensive patients (diastolic blood pressure of 80.0 mmHg at time of randomization). The study duration is 5 years and is scheduled to end in May of 1998. Patients are randomized to receive either intensive antihypertensive drug therapy or moderate antihypertensive drug therapy. Patients are also randomized to nisoldipine or enalapril, with open-label medications added if further blood pressure control is necessary. The primary outcome measure is glomerular filtration rate as assessed by 24-h creatinine clearance. Secondary outcome measures are urinary albumin excretion, left ventricular hypertrophy, retinopathy, and neuropathy. Cardiovascular morbidity and mortality will also be evaluated. Given the data showing the impact of hypertension on complications in NIDDM, the ABCD Trial is designed to determine if intensive antihypertensive therapy will be more efficacious than moderate antihypertensive therapy on the outcome of diabetic complications in NIDDM. [Diabetologia (1996) 39: 1646–1654]