Sibutramine plus meal replacement therapy for body weight loss and maintenance in obese patients.

OBJECTIVE: Our objective was to assess the efficacy and safety of sibutramine with a low-calorie diet (LCD) and commercial meal-replacement product in achieving weight loss and weight-loss maintenance in obese patients. RESEARCH METHODS AND PROCEDURES: Eight U.S. centers recruited 148 obese patients for a 3-month comprehensive weight-loss therapy (Phase I) comprising daily sibutramine 10 mg + LCD (two Slim-Fast meal-replacement shakes, one low-calorie meal; total kcal/d = 1200-1500). Patients (N = 113) who lost > or =5% of initial body weight during Phase I were randomized for a 9-month period (Phase II) to daily sibutramine 15 mg + LCD (one meal-replacement shake; two low-calorie meals: total kcal/d approximately 1200-1500) or daily placebo + three low-calorie meals (total kcal/d approximately 1200-1500). Both phases included behavior modification. Efficacy was assessed by body weight change during each phase and by the number of patients at endpoint maintaining > or =80% of the weight they had lost by the end of Phase I. Other outcomes included changes in cardiovascular and metabolic risk factors, adverse events, and vital signs. RESULTS: Mean body weight change during Phase I was -8.3 kg (p < 0.001). Patients randomized to sibutramine in Phase II had an additional -2.5 kg mean weight loss vs. a 2.8-kg increase in the placebo group (p < 0.001). More sibutramine patients maintained > or =80% of their Phase I weight loss at the end of Phase II (85.5% vs. placebo 36.7%, p < 0.001). Most adverse events were mild or moderate in severity, and all serious adverse events were unrelated to sibutramine. DISCUSSION: Sibutramine plus LCD with meal replacements and behavior modification is a safe and effective strategy for achieving and sustaining weight loss in obese patients.

Cardiovascular effects of sibutramine in the treatment of obese adolescents: results of a randomized, double-blind, placebo-controlled study.

BACKGROUND: Adolescent obesity is a major public health problem. Treatment options in addition to behavioral therapy could include pharmacotherapy with sibutramine. OBJECTIVES: Concerns regarding increases in blood pressure and heart rate after sibutramine treatment in some adult patients precipitated the present analysis, which evaluated the cardiovascular safety of sibutramine plus a behavioral therapy program in obese adolescents. PATIENTS AND METHODS: With this 12-month, randomized, double-blind, placebo-controlled trial in 33 US clinics we studied 498 adolescents aged 12 to 16 years with multiethnic backgrounds and BMIs of 28.1 to 46.3 kg/m2. RESULTS: The subjects were randomly assigned to behavioral therapy plus 10 mg of sibutramine or behavioral therapy plus placebo daily. At the end point, there was a mean treatment group difference in BMI of 2.6 kg/m2 in favor of sibutramine. Small mean decreases in blood pressure and pulse rate were seen in both sibutramine and placebo groups at the end point (systolic blood pressure: -2.1 vs -2.1 mmHg; diastolic blood pressure: -0.1 vs -1.1 mmHg; pulse rate: -0.2 vs -1.8 bpm). In both treatment groups, these reductions in vital signs were greater at the end point when BMI reduction was > or = 5% compared with < 5%. CONCLUSIONS: Sibutramine may have some direct cardiovascular effects on obese adolescents. These cardiovascular effects may be balanced by a reduction in BMI, which, in adolescents, seems to be greater than that observed in adults.

Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome.

OBJECTIVE: We sought to test the hypothesis that a fixed-dose combination of trandolapril/verapamil-SR (T/V) is superior to a fixed-dose combination of losartan/hydrochlorothiazide (L/H) on glucose tolerance in hypertensive patients with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: A prospective, randomized, open-label, blinded-end points design was used to assess the effects of a T/V versus L/H combination in patients with IGT and hypertension (n = 240) followed for up to 1 year. Doses were titrated to a systolic blood pressure <130 mmHg. Primary outcome was change from baseline in a 2-h glucose on oral glucose tolerance test (OGTT) at study end (mean [+/-SD] at follow-up, 46.9 +/- 13.5 weeks). Secondary outcomes included changes in insulin sensitivity, office and 24-h ambulatory blood pressure, incidence of new-onset diabetes, lipids, and inflammatory markers. Data are expressed as means +/- SE unless otherwise noted. RESULTS: Changes at study end were noted in 2-h OGTT glucose (T/V -0.21 +/- 0.36 vs. L/H +1.44 +/- 0.36 mmol/l; P < 0.001) and insulin level (-30.13 +/- 38.38 vs. +84.86 +/- 38.33 pmol/l, respectively; P = 0.025). Worsening of insulin resistance occurred by week 12 (T/V 0.000 +/- 0.001 vs. L/H -0.005 +/- 0.001; P = 0.016). A higher incidence of new-onset diabetes (T/V 11.0 vs. L/H 26.6%; P = 0.002) and HbA1c >7% (2.6 vs. 9.6%, respectively; P = 0.05) occurred at study end. CONCLUSIONS: In patients with IGT, normal kidney function, and hypertension, the fixed-dose combination of T/V reduces the risk of new-onset diabetes compared with an L/H-based therapy.

Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from the INternational VErapamil SR-Trandolapril STudy [INVEST]).

Knowledge of predictors of diabetes mellitus (DM) development in patients with coronary artery disease (CAD) who use antihypertensive therapy could contribute to decreasing this adverse metabolic consequence. This is particularly relevant because the standard of care, beta blockers combined with diuretics, may contribute to adverse metabolic risk. The INternational VErapamil SR-trandolapril STudy compared a calcium antagonist-based (verapamil SR) and a beta-blocker-based (atenolol) strategy with trandolapril and/or hydrochlorothiazide added to control blood pressure (BP) in patients with CAD. The 16,176 patients without DM at entry were investigated with regard to newly diagnosed DM during follow-up. Newly diagnosed DM was less frequent in the verapamil SR versus atenolol strategy (7.0% vs 8.2%, hazard ratio 0.85, 95% confidence interval 0.76 to 0.95, p <0.01). Characteristics associated with risk for newly diagnosed DM included United States residence, left ventricular hypertrophy, previous stroke/transient ischemic attack, Hispanic ethnicity, coronary revascularization, hypercholesterolemia, greater body mass index, and higher follow-up systolic BP. Addition of trandolapril to verapamil SR decreased DM risk and addition of hydrochlorothiazide to atenolol increased risk. In conclusion, clinical findings associated with more severe vascular disease and Hispanic ethnicity identify a group at high risk for developing DM, whereas lower on-treatment BP and treatment with verapamil SR-trandolapril attenuated this risk.

Effects of sibutramine treatment in obese adolescents: a randomized trial.

BACKGROUND: Increased prevalence of adolescent obesity requires effective treatment options beyond behavior therapy. OBJECTIVE: To see whether sibutramine reduced weight more than placebo in obese adolescents who were receiving a behavior therapy program. DESIGN: 12-month, 3:1 randomized, double-blind trial conducted from July 2000 to February 2002. SETTING: 33 U.S. outpatient clinics. PARTICIPANTS: 498 participants 12 to 16 years of age with a body mass index (BMI) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex, to the upper limit of 44 kg/m2. INTERVENTIONS: Site-specific behavior therapy plus 10 mg of sibutramine or placebo. Blinded study medication dose was uptitrated to 15 mg or placebo at month 6 if initial BMI was not reduced by 10%. MEASUREMENTS: Body mass index, waist circumference, body weight, fasting lipid and glycemic variables, safety, and tolerability. RESULTS: Seventy-six percent of patients in the sibutramine group and 62% of patients in the placebo group completed the study. The estimated mean treatment group difference at month 12 (linear mixed-effects model) favored sibutramine for change from baseline in BMI (-2.9 kg/m2 [95% CI, -3.5 to -2.2 kg/m2]) and body weight (-8.4 kg [CI, -9.7 to -7.2 kg]) (P < 0.001 for both). The sibutramine group had greater improvements in triglyceride levels, high-density lipoprotein cholesterol levels, insulin levels, and insulin sensitivity (P < or = 0.001 for all). The rate of tachycardia was greater with sibutramine vs. placebo (12.5% vs. 6.2%; difference, 6.3 percentage points [CI, 1.0 to 11.7 percentage points]) but did not lead to increased withdrawal (2.4% vs. 1.5%; difference, 0.9 percentage point [CI, -1.7 to 3.5 percentage points]). LIMITATIONS: The 1-year study duration precluded assessment of long-term weight maintenance and putative health benefits and harms, and 24% and 38% of the sibutramine and placebo groups, respectively, did not complete follow-up. CONCLUSIONS: Sibutramine added to a behavior therapy program reduced BMI and body weight more than placebo and improved the profile of several metabolic risk factors in obese adolescents.

Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous?

BACKGROUND: Because coronary perfusion occurs mainly during diastole, patients with coronary artery disease (CAD) could be at increased risk for coronary events if diastolic pressure falls below critical levels. OBJECTIVE: To determine whether low blood pressure could be associated with excess mortality and morbidity in this population. DESIGN: A secondary analysis of data from the International Verapamil-Trandolapril Study (INVEST), which was conducted from September 1997 to February 2003. SETTING: 862 sites in 14 countries. PATIENTS: 22 576 patients with hypertension and CAD. INTERVENTIONS: Patients from INVEST were randomly assigned to a verapamil sustained-release- or atenolol-based strategy; blood pressure control and outcomes were equivalent. MEASUREMENTS: An unadjusted quadratic proportional hazards model was used to evaluate the relationship between average on-treatment blood pressure and risk for the primary outcome (all-cause death, nonfatal stroke, and nonfatal myocardial infarction [MI]), all-cause death, total MI, and total stroke. A second model adjusted for differences in baseline covariates. RESULTS: The relationship between blood pressure and the primary outcome, all-cause death, and total MI was J-shaped, particularly for diastolic pressure, with a nadir at 119/84 mm Hg. After adjustment, the J-shaped relationship persisted between diastolic pressure and primary outcome. The MI-stroke ratio remained constant over a wide blood pressure range, but at a lower diastolic blood pressure, there were substantially more MIs than strokes. An interaction between decreased diastolic pressure and history of revascularization was observed; low diastolic pressure was associated with a relatively lower risk for the primary outcome in patients with revascularization than in those without revascularization. LIMITATIONS: This is a post hoc analysis of hypertensive patients with CAD. CONCLUSIONS: The risk for the primary outcome, all-cause death, and MI, but not stroke, progressively increased with low diastolic blood pressure. Excessive reduction in diastolic pressure should be avoided in patients with CAD who are being treated for hypertension.

Blood pressure control and cardiovascular outcomes in high-risk Hispanic patients--findings from the International Verapamil SR/Trandolapril Study (INVEST).

BACKGROUND: People of Hispanic origin are the fastest growing ethnic minority in the United States and often have hypertension and other comorbidities which increase the risk associated with coronary artery disease (CAD). METHODS AND RESULTS: An analysis of the 8045 Hispanic patients enrolled in INVEST was conducted, and comparisons were made to the 14,531 non-Hispanic patients. INVEST was a prospective, randomized, open, blinded end point study in CAD patients with hypertension. After 61,835 patient-years of follow-up, treatment with either a verapamil sustained release (SR) or atenolol antihypertensive strategy resulted in greater blood pressure control in Hispanic patients, and Hispanic patients were at significantly lower risk of experiencing a nonfatal myocardial infarction, nonfatal stroke, or death (hazard ratio [HR] 0.87, 95% CI 0.78-0.97). Hispanic ethnicity was associated with an increase (HR 1.19, 95% CI 1.04-1.36), and randomization to the verapamil SR strategy was associated with a decrease (HR 0.85, 95% CI 0.76-0.95), in the risk of new-onset diabetes. Use of trandolapril in the verapamil SR strategy was associated with reduced risk of new-onset diabetes, whereas increasing doses of atenolol and hydrochlorothiazide in the atenolol strategy were associated with increased risk of new-onset diabetes. CONCLUSIONS: The Hispanic cohort of INVEST had better blood pressure control and lower risk of adverse cardiovascular outcomes compared with the non-Hispanic cohort. A verapamil SR strategy is an alternative to an atenolol strategy for the treatment of Hispanic patients with hypertension and CAD and can reduce the risk of new-onset diabetes.

Predictors of adverse outcome among patients with hypertension and coronary artery disease.

OBJECTIVES: We sought to determine predictors for adverse outcomes in hypertensive patients with coronary artery disease (CAD). BACKGROUND: Factors leading to adverse outcomes in hypertensive patients with CAD are poorly understood. The INternational VErapamil-trandolapril STudy (INVEST) compared outcomes in hypertensive patients with CAD that were assigned randomly to either a verapamil sustained-release (SR)- or an atenolol-based strategy for blood pressure (BP) control. Trandolapril and hydrochlorothiazide were used as added agents. During follow-up (61,835 patient-years), BP control and the primary outcome (death, nonfatal myocardial infarction, and nonfatal stroke) were not different between strategies. METHODS: We investigated risk for adverse outcome associated with baseline factors, follow-up BP, and drug treatments using Cox modeling. RESULTS: Previous heart failure (adjusted hazard ratio [HR] 1.96), as well as diabetes (HR 1.77), increased age (HR 1.63), U.S. residency (HR 1.61), renal impairment (HR 1.50), stroke/transient ischemic attack (HR 1.43), smoking (HR 1.41), myocardial infarction (HR 1.34), peripheral vascular disease (HR 1.27), and revascularization (HR 1.15) predicted increased risk. Follow-up systolic BP <140 mm Hg or diastolic BP <90 mm Hg (HRs 0.82 or 0.70, respectively) and trandolapril with verapamil SR (HRs 0.78 and 0.79) were associated with reduced risk. CONCLUSIONS: In hypertensive patients with CAD, increased risk for adverse outcomes was associated with conditions related to the severity of CAD and diminished left ventricular function. Lower follow-up BP and addition of trandolapril to verapamil SR each were associated with reduced risk.

A drug dose model for predicting clinical outcomes in hypertensive coronary disease patients.

To understand the effects of single- and multiple-drug combinations for hypertension on the risk of adverse clinical outcomes, the authors analyzed data from the International Verapamil SR/Trandolapril Study (INVEST). This trial randomized 22,576 hypertensive patients with coronary artery disease to sustained-release verapamil or to atenolol as initial agents, followed by trandolapril or hydrochlorothiazide. Electronically collected prescription data from INVEST during 61,835 patient-years were analyzed using a Cox proportional hazards model with nine covariates (randomization strategy, four average daily dose terms, two ratios measuring the proportion of time the first two drugs in the treatment arm were coprescribed, and two interaction terms). Increasing doses of atenolol and sustained-release verapamil were associated with decreasing risk of the composite primary outcome (death, myocardial infarction, or stroke). Combination therapy with two drugs (verapamil/trandolapril or atenolol/hydrochlorothiazide) reduced the risk of primary outcome compared with monotherapy (verapamil or atenolol), and triple therapy (verapamil/trandolapril/hydrochlorothiazide or atenolol/hydrochlorothiazide/trandolapril) further reduced the risk.

Characteristics of contemporary patients with hypertension and coronary artery disease.

BACKGROUND: Despite a high prevalence of hypertension in the population with CAD, there are limited data describing the clinical characteristics and treatments, as well as their interrelations in these patients. This is particularly true for black and Hispanic patients who have been underrepresented in randomized CAD trials. HYPOTHESIS: There exist racial and ethnic differences that define the characteristics of patients with both coronary artery disease (CAD) and hypertension. METHODS: This report describes the characteristics of Caucasian, Hispanic, and black patients enrolled in the International Verapamil SR/trandolapril Study (INVEST), a prospective trial undertaken exclusively in patients with CAD and hypertension. RESULTS: In all, 10,925 Caucasian, 8,045 Hispanic, and 3,029 black patients are described. An abnormal angiogram or documented myocardial infarction was observed more frequently in Caucasian patients (73%), while angina pectoris was more prevalent in Hispanic patients (87%). Diabetes and left ventricular hypertrophy were most common in black patients (33 and 29%, respectively), while hypercholesterolemia and prior revascularization (coronary artery bypass graft or angioplasty) were most common in Caucasian patients (64 and 41%, respectively). More than 60% of Hispanic and black patients were women--a unique characteristic for randomized CAD trials. Comparing race/ethnic cohorts, there were significant differences for all characteristics. More than 80% of patients in all race/ethnic groups were receiving antihypertensive therapy; however, only fewer than 25% had controlled blood pressure according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. CONCLUSIONS: This high-risk population of hypertensive patients with CAD has been undertreated and does not have well-controlled BP. Race/ethnic differences were observed for clinical characteristics and medication use.

Efficacy and safety of propafenone sustained release in the prophylaxis of symptomatic paroxysmal atrial fibrillation (The European Rythmol/Rytmonorm Atrial Fibrillation Trial [ERAFT] Study).

We report a double-blind, multicenter, multinational, placebo-controlled, and well-controlled trial to prove that the sustained-release (SR) formulation of propafenone is superior to placebo in preventing symptoms of paroxysmal atrial fibrillation (AF). A total of 594 patients were enrolled in the qualifying period of the study and 293 patients were randomized at 53 centers. There were significant increases in the arrhythmia-free periods from day 5 of randomization to the first recurrence of symptomatic atrial arrhythmia in the propafenone SR 325 mg twice daily (p = 0.004) and propafenone SR 425 mg twice daily (p = 0.003) treatment groups compared with placebo. The median arrhythmia-free time was 9 days in the placebo group, 35 days in the propafenone SR 325 mg twice daily group, and 44 days in the propafenone SR 425 mg twice daily group. There was a significant reduction in average heart rate during the first recurrence of symptomatic arrhythmia after day 5 in the low-dose propafenone group compared with placebo. The median treatment failure time from day 5 (arrhythmia recurrence, adverse events, and withdrawals) was prolonged from 8 days in the placebo group to 19 days in the propafenone SR 325 mg twice daily group (p = 0.002) and to 24 days in the propafenone SR 425 mg twice daily group (p = 0.006). The percentage of patients with >/=1 serious adverse event was similar in the propafenone SR treatment groups (propafenone SR 325 mg twice daily, 10.0%; propafenone SR 425 mg twice daily, 11.2%) but lower in the placebo group (1.1%). In conclusion, the SR formulation of propafenone is superior to placebo, well-tolerated, and prevents symptoms of paroxysmal AF.