Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group

BACKGROUND: We undertook a randomised controlled trial to assess the efficacy and tolerability of orlistat, a gastrointestinal lipase inhibitor, in promoting weight loss and preventing weight regain in obese patients over a 2-year period. METHODS: 743 patients (body-mass index 28-47 kg/m2), recruited at 15 European centres, entered a 4-week, single-blind, placebo lead-in period on a slightly hypocaloric diet (600 kcal/day deficit). 688 patients who completed the lead-in were assigned double-blind treatment with orlistat 120 mg (three times a day) or placebo for 1 year in conjunction with the hypocaloric diet. In a second 52-week double-blind period patients were reassigned orlistat or placebo with a weight maintenance (eucaloric) diet. FINDINGS: From the start of lead-in to the end of year 1, the orlistat group lost, on average, more bodyweight than the placebo group (10.2% [10.3 kg] vs 6.1% [6.1 kg]; LSM difference 3.9 kg [p<0.001] from randomisation to the end of year 1). During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo (p<0.001). Patients switched from placebo to orlistat lost an additional 0.9 kg during year 2, compared with a mean regain of 2.5 kg in patients who continued on placebo (p<0.001). Total cholesterol, low-density lipoprotein (LDL) cholesterol, LDL/high-density lipoprotein ratio, and concentrations of glucose and insulin decreased more in the orlistat group than in the placebo group. Gastrointestinal adverse events were more common in the orlistat group. Other adverse symptoms occurred at a similar frequency during both treatments. INTERPRETATION: Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period. The use of orlistat beyond 2 years needs careful monitoring with respect to efficacy and adverse events.     

Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial

CONTEXT: Orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, may promote weight loss and reduce cardiovascular risk factors. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention is more effective than placebo plus diet for weight loss and maintenance over 2 years. DESIGN: Randomized, double-blind, placebo-controlled study conducted from October 1992 to October 1995. SETTING AND PARTICIPANTS: Obese adults (body mass index [weight in kilograms divided by the square of height in meters], 30-43 kg/m2) evaluated at 18 US research centers. INTERVENTION: Subjects received placebo plus a controlled-energy diet during a 4-week lead-in. On study day 1, the diet was continued and subjects were randomized to receive placebo 3 times a day or orlistat, 120 mg 3 times a day, for 52 weeks. After 52 weeks, subjects began a weight-maintenance diet, and the placebo group (n = 133) continued to receive placebo and orlistat-treated subjects were rerandomized to receive placebo 3 times a day (n = 138), orlistat, 60 mg (n = 152) or 120 mg (n = 153) 3 times a day, for an additional 52 weeks. MAIN OUTCOME MEASURES: Body weight change and changes in blood pressure and serum lipid, glucose, and insulin levels. RESULTS: A total of 1187 subjects entered the protocol, and 892 were randomly assigned on day 1 to double-blind treatment. For intent-to-treat analysis, 223 placebo-treated subjects and 657 orlistat-treated subjects were evaluated. During the first year orlistat-treated subjects lost more weight (mean +/- SEM, 8.76+/-0.37 kg) than placebo-treated subjects (5.81+/-0.67 kg) (P<.001). Subjects treated with orlistat, 120 mg 3 times a day, during year 1 and year 2 regained less weight during year 2 (3.2+/-0.45 kg; 35.2% regain) than those who received orlistat, 60 mg (4.26+/-0.57 kg; 51.3% regain), or placebo (5.63+/-0.42 kg; 63.4% regain) in year 2 (P<.001). Treatment with orlistat, 120 mg 3 times a day, was associated with improvements in fasting low-density lipoprotein cholesterol and insulin levels. CONCLUSIONS: Two-year treatment with orlistat plus diet significantly promotes weight loss, lessens weight regain, and improves some obesity-related disease risk factors.     

Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus

An initial improvement in glycemic control is often followed by gradual deterioration of glycemia during insulin treatment of patients with noninsulin-dependent diabetes mellitus (NIDDM). We examined the causes of such worsening in a 12-month follow-up analysis of 100 insulin-treated NIDDM patients in the Finnish Multicenter Insulin Therapy Study who were treated with either combination therapy with insulin or insulin alone. In the entire study group, glycemic control averaged 9.7 +/- 0.2% at 0 months and 8.0 +/- 0.1%, 8.0 +/- 0.1%, 8.2 +/- 0.1%, and 8.5 +/- 0.2% at 3, 6, 9, and 12 months (P < 0.001 for each time point vs. 0 months). Glycemic control at 12 months was significantly worse than that at 3 (P < 0.001), 6 (P < 0.001), and 9 months (P < 0.02). Baseline body mass index was the most significant predictor of deterioration in glycemic control. During 1 yr, hemoglobin A1c decreased almost 3-fold more (by 1.7 +/- 0.2%; P < 0.001 vs. 0 months) in patients whose baseline weight was below the mean baseline body mass index of 28.1 kg/m2 (nonobese patients) than in those whose weight exceeded 28.1 kg/m2 (obese patients; 0.5 +/- 0.2%; P = NS vs. 0 months; P < 0.01 vs. obese patients). Glycemic control improved similarly over 1 yr in the nonobese subjects and deteriorated similarly in the obese patients regardless of their treatment regimen. Insulin doses, per body weight, were similar in the nonobese and obese patients. The nonobese patients consistently gained less weight during 12 months of combination therapy with insulin (3.5 +/- 0.6 kg at 12 months) than during insulin therapy alone (5.1 +/- 0.6 kg; P < 0.05). The treatment regimen did not influence weight gain in the obese group, who gained 4.4 +/- 1.0 kg during combination therapy with insulin and 4.5 +/- 1.1 kg during insulin therapy alone. We reached the following conclusions: 1) after an initial good response, glycemic control deteriorates more in obese than in nonobese patients with NIDDM; 2) in obese patients, weight gain per se cannot explain the poor glycemic response to combination or insulin therapy, but it may induce a disproportionately large increase in insulin requirements because of greater insulin resistance in the obese than in the nonobese; 3) in nonobese patients, glycemic control improves equally during 1 yr with combination therapy with insulin and insulin alone, but combination therapy with insulin is associated with less weight gain than treatment with insulin alone; 4) weight gain appears harmful, as it is associated with increases in blood pressure and low density lipoprotein cholesterol.     

Continuous assay for acid phosphatase using 1-naphthyl phosphate as a substrate

The sequential effects of an American Heart Association (AHA) Step 1 diet and subsequent weight loss on lipoprotein lipids in obese [body mass index (in kg/m2) > 27], postmenopausal women (n = 48) were determined. Subjects followed a euenergetic AHA Step 1 diet for 2 mo, followed by a weight-loss diet (deficit of 1.0-1.5 MJ/d) for 6 mo. The AHA diet lowered concentrations of total (7%), low-density-lipoprotein (LDL) (6%), and high-density-lipoprotein (HDL) (14%) cholesterol (P < 0.01). Weight loss (-5.6 +/- 0.7 kg; P < 0.01) increased plasma triacylglycerol concentrations (9%; P < 0.01) and increased HDL-cholesterol concentrations (8%; P < 0.01) compared with changes after the AHA diet, but there were no changes in total or LDL cholesterol. The combined AHA diet and weight-loss interventions lowered triacylglycerol (10%) and total (6%), LDL (6%), and HDL (7%) cholesterol. These changes correlated indirectly with the baseline concentration for each lipid. When the women were divided on the basis of initial LDL-cholesterol concentration, the AHA diet and weight-loss interventions reduced (P < 0.01) triacylglycerol (19%), total cholesterol (13%), and LDL cholesterol (14%) in the women with hypercholesterolemia but not in normocholesterolemic or midly hypercholesterolemic women. Thus, an AHA Step 1 diet and subsequent weight loss improve lipoprotein lipid profiles of obese, postmenopausal women with hypercholesterolemia. However, because it lowers HDL cholesterol, a low-fat diet without substantial weight loss may not be beneficial for improving lipoprotein lipid risk factors for coronary artery disease in obese, postmenopausal women with normal lipid profiles.     

Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study

OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy.     

Reduction of obesity and improvement in metabolic parameters by inhibition of intestinal lipases: current results with orlistat

Until recently, obesity did not play a major role in considerations of physicians and public health authorities. The impact of health-threatening overweight was so far considered only as a risk factor for various other serious illnesses, such as hypertension, diabetes mellitus, hyperuricemia, elevated blood lipid levels and of vascular diseases of the heart, the brain and the kidneys. Recently however, obesity has been rated by the WHO as an unique disease, resulting in elevated morbidity and mortality. It is of constantly increasing importance because of the raising number of obese individuals in all industrial countries. In Austria an incidence of 8.5% of the adult population is estimated to be obese with a BMI > 30. Though the established concept for treatment of overweight consists of reduction of the caloric intake by diet, there is an obvious need for drugs making dieting easier acceptable to obese patients for prolonged periods. Orlistat is the first representative of a new class of such drugs, inhibiting intestinal acting lipase thus reducing the intestinal absorption of triglycerides; it contributes, therefore, to a reduced calorie intake. Preliminary results of treatment studies with Orlistat are presented, demonstrating its efficacy in inducing weight loss and improving metabolic parameters with tolerable intestinal side effects. After finalization of international studies, demonstrating efficacy and tolerability, orlistat has been registered in Austria in September 1998.     

Lipoprotein(a) in android obesity and NIDDM

OBJECTIVE: To assess the level of serum lipoprotein(a) [Lp(a)] in nonobese and obese NIDDM subjects with android body distribution. RESEARCH DESIGN AND METHODS: Serum Lp(a) levels were measured in 30 long-standing NIDDM patients (duration of diabetes 12.5 +/- 3 years, mean +/- SD), with 15 of the patients being obese of android distribution (BMI > 30 kg/m2 and waist-to-hip ratio > 0.8). In addition, there were 15 android obese nondiabetic subjects and 10 healthy subjects serving as the control group. RESULTS: All groups of patients in this study (diabetic, obese, and obese diabetic) showed significantly higher levels of Lp(a) than the healthy control group. Lp(a) concentrations were significantly higher in NIDDM patients with android type of obesity than in nondiabetic androids (24.1 +/- 5.6 vs. 14.8 +/- 2.4 mg/dl, P < 0.001). Significantly greater levels of Lp(a) were found in nonobese subjects with diabetes when compared with obese subjects without diabetes (22.3 +/- 4.1 vs. 14.8 +/- 2.4 mg/dl, P < 0.001). Furthermore, Lp(a) serum concentrations were not dependent on the degree of glycemic control (controlled NIDDM 23.6 +/- 5.0 vs. uncontrolled NIDDM 21.4 +/- 2.7 mg/dl, NS), but were much greater in subjects with diabetes complicated by vascular disease (complicated 26.3 +/- 5.0 vs. uncomplicated 20.5 +/- 2.7 mg/dl, P < 0.001). No correlation was found between Lp(a) and other lipid parameters in this study. CONCLUSIONS: Lp(a) levels are significantly elevated in both android-obese and nonobese NIDDM patients regardless of the degree of glycemic control. Lp(a) is an independent risk factor showing greater elevations in those subjects complicated with diabetic vascular diseases.     

Small weight loss on long-term acarbose therapy with no change in dietary pattern or nutrient intake of individuals with non-insulin-dependent diabetes

OBJECTIVES: To see if the long-term treatment of non-insulin dependent diabetes (NIDDM) with the alpha-glucosidase inhibitor acarbose affects food intake and body weight. DESIGN: Randomized, double-blind, placebo-controlled, parallel design clinical trial of 12 months duration. SUBJECTS: Subjects with NIDDM in four treatment strata: 77 on diet alone, 83 also treated with metformin, 103 also treated with sulfonylurea and 91 also treated with insulin. MEASUREMENTS: Two 3 day diet records were obtained before randomization to acarbose or placebo therapy, and additional 3 day diet records were obtained at 3, 6, 9 and 12 months after randomization. Body weight was also measured at these times. RESULTS: Of the 354 subjects randomized, 279 (79%) completed at least 9 months of therapy and, of these, 263 (94%) provided at least one diet record during the baseline period and two diet records during the treatment period. After one year, subjects on acarbose had lost 0.46 +/- 0.28 kg, which differed significantly from the 0.33 +/- 0.25 kg weight gain on placebo (P = 0.027). The difference in weight change between acarbose and placebo did not differ significantly in the different treatment strata. Being in the study had significant effects on diet, including a reduction in energy intake from 1760-1700 Kcal/d (P < 0.05), a reduction in simple sugars intake from 18.5-17.4% of energy (P < 0.001), and reductions in the number of different foods consumed (33-30, P < 0.001) and the number of meals eaten per day (4.7-4.3, P < 0.001). However, compared to placebo treatment, acarbose had no effect on energy intake, nutrient intakes, or dietary patterns. CONCLUSIONS: In subjects with NIDDM on weight-maintaining diets, long-term acarbose therapy results in a small weight loss, but has no effect on energy or nutrient intakes. The weight loss induced by acarbose may be due partly to reduced doses of concomitant oral agents and insulin and partly to energy loss due to increased colonic fermentation.     

Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group

To assess the effects of troglitazone monotherapy on glycemic control in patients with type 2 diabetes mellitus, we carried out a 6-month, randomized, double-blind, placebo-controlled study in 24 hospital and outpatient clinics in the United States and Canada. Troglitazone 100, 200, 400, or 600 mg or placebo once daily with breakfast was administered to 402 patients with type 2 diabetes with fasting serum glucose (FSG) > 140 mg/dL, glycosylated hemoglobin (HbA1c) > 6.5%, and fasting C-peptide > or = 1.5 ng/mL. Prior oral hypoglycemic therapy was withdrawn in patients who received it before the study. FSG, HbA1c, C-peptide, and serum insulin were evaluated at baseline and the end of the study. Analysis was performed on two subsets of patients based on prestudy therapy: Patients treated with diet and exercise only before the study (22% of patients), and those who had been receiving sulfonylurea therapy (78% of patients). Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG and HbA1c at month 6 compared with placebo-treated patients (FSG: -51 and -60 mg/dL, respectively; HbA1c: -0.7 and -1.1%, respectively). In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P < 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P < 0.05) decreases in mean FSG with 200-600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). Significant (P < 0.05) decreases in mean HbA1c occurred with 400 and 600 mg troglitazone therapy at month 6 (-0.8 and -1.2%, respectively) compared with placebo in this same subset. Significant (P < 0.05) decreases in triglycerides and free fatty acids occurred with troglitazone 400 and 600 mg, and increased high-density lipoprotein occurred with 600 mg troglitazone. We conclude that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with type 2 diabetes. Troglitazone 600 mg monotherapy is efficacious for patients who are newly diagnosed and have never received pharmacological intervention for diabetes.     

No relationship between carbohydrate intake and effect of acarbose on HbA1c or gastrointestinal symptoms in type 2 diabetic subjects consuming 30-60% of energy from carbohydrate

OBJECTIVE: To determine the relationship between carbohydrate intake and the effect of acarbose on HbA1c in subjects with type 2 diabetes treated with acarbose alone, acarbose plus sulfonylurea, acarbose plus metformin, or acarbose plus insulin. RESEARCH DESIGN AND METHODS: We conducted a double-blind randomized placebo-controlled study in which subjects with diabetes in four treatment strata (77 on diet alone, 83 treated with metformin, 103 treated with sulfonylurea, and 91 treated with insulin) were randomized to treatment with placebo or acarbose for 12 months. Before randomization, and 3, 6, 9, and 12 months after randomization, fasting blood was obtained for HbA1c, and 3-day diet records were collected. Subjects who completed at least 6 months of acarbose therapy and provided at least three 3-day diet records were included. RESULTS: In the 114 subjects included in this analysis, carbohydrate intake varied from approximately 30-60% of energy There was no significant relationship between carbohydrate intake and change in HbA1c in any of the four treatment strata (diet: n=26, r=0.35, P=0.076; metformin: n=27, r=0.26, P=0.19; sulfonylurea: n=35, r=0.24, P=0.16; insulin: n=25, r=-0.27, P=0.19). In the 80 subjects consuming <50% of energy from carbohydrate, the fall in HbA1c (7.83 +/-0.17% at baseline to 6.72+/-0.13% on acarbose, P < 0.001) was no different from that of the 34 subjects consuming >50% of energy from carbohydrate (7.55+/-0.25% at baseline to 6.66+/-0.23% on acarbose, P < 0.001). There was no difference in carbohydrate intake between those who dropped out of the study because of gastrointestinal side effects and those who did not, and there was no relationship between severity of symptoms and the composition of the diet. CONCLUSIONS: In subjects with type 2 diabetes consuming 30-60% of energy from carbohydrate, the effect of acarbose on HbA1c and gastrointestinal symptoms was not related to carbohydrate intake. Because most people consume at least 30% of energy from carbohydrate, we conclude that no special diet is needed for acarbose to be effective in improving blood glucose control in the treatment of type 2 diabetes.     

Modification of postprandial hyperglycemia with insulin lispro improves glucose control in patients with type 2 diabetes

OBJECTIVE: Insulin lispro is a rapid-acting analog of human insulin that can be used to target the postprandial rise in plasma glucose. We designed an open-label randomized crossover study of type 2 diabetic patients with secondary failure of sulfonylurea therapy to determine whether improvement of postprandial hyperglycemia would affect total daily glucose control. RESEARCH DESIGN AND METHODS: Twenty-five type 2 diabetic patients who were poorly controlled on a maximum dose of sulfonylureas were studied in a university hospital clinical research center. In one arm of the study, patients continued therapy with maximum-dose sulfonylureas. In the other arm, patients used a combination therapy with insulin lispro before meals and sulfonylureas. After 4 months, patients were crossed over to the opposite arm. Fasting plasma glucose (FPG) and 1- and 2-h postprandial glucose (after a standardized meal), HbA1c, total, HDL, and LDL cholesterol, and triglyceride levels were measured at the end of each arm of the study. RESULTS: Insulin lispro in combination with sulfonylurea therapy significantly reduced 2-h postprandial glucose concentrations compared with sulfonylureas alone, from 18.6 to 14.2 mmol/l (P < 0.0001), and incremental postprandial glucose area from 617.8 to 472.9 mmol.min.1-1 (P < 0.0007). FPG levels were decreased from 10.9 to 8.5 mmol/l (P < 0.0001), and HbA1c values were reduced form 9.0 to 7.1% (P < 0.0001). Total cholesterol was significantly decreased in the lispro arm from 5.44 to 5.10 mmol/l (P < 0.02). HDL cholesterol concentrations were increased in the lispro arm from 0.88 to 0.96 mmol/l (P < 0.01). The patients weighed significantly more after lispro therapy than after sulfonylureas alone, but the difference was small in absolute terms (sulfonylurea therapy alone, 90.6 kg; lispro therapy, 93.8 kg; P < 0.0001). Two episodes of hypoglycemia (glucose concentrations, < 2.8 mmol/l) were reported by the patients while using lispro. CONCLUSIONS: Previously, it has not been possible to address the effect of treatment of postprandial hyperglycemia specifically. We have now shown that the treatment of postprandial hyperglycemia with insulin lispro markedly improves overall glucose control and some lipid parameters in patients with type 2 diabetes.     

High-fat versus high-carbohydrate enteral formulae: effect on blood glucose, C-peptide, and ketones in patients with type 2 diabetes treated with insulin or sulfonylurea

Recently, two commercial enteral formulae for diabetic patients have been made available in Spain: a high-complex-carbohydrate, low-fat formulation (HCF) and a low-carbohydrate formulation (RCF). This study compares the effects of the two enteral nutritional formulae in patients with non-insulin-dependent diabetes mellitus (type 2 diabetes) treated with sulfonylurea or insulin. Fifty-two type 2 diabetes patients were randomly assigned to receive one of the two enteral formulae. Test enteral formula breakfast (250 cc) were consumed at approximately 0900 h after routine medications (insulin or oral agents) had been taken. Venous blood samples were obtained during fasting, before medication, and at 30 and 120 min after the start of the meal. The glycemic response of patients to the HCF was significantly greater than to RCF, but lower than in the sulfonyl type 2 diabetes treated groups. The incremental glucose response was within acceptable levels except in insulin treatment type 2 diabetes patients given HCF. Glucose, insulin, and C-peptide responses were higher in HCF than RCF groups. Two-factor analysis of variance on mean increments of blood glucose and C-peptide from basal levels to 30 min show the type of enteral nutrition as the main factor (P = 0.0010 and P = 0.0005, respectively). The RCF formula supplies 50.0% of energy as fat and 33.3% as carbohydrates, so it may be a ketogenic diet. It was found that both ketone bodies were higher after RCF than after HCF ingestion, but without statistical significance. We conclude that the partial replacement of complex digestible carbohydrates with monounsaturated fatty acids in the enteral formulae for supplementation of oral diet may improve glycemic control in patients with type 2 diabetes. The long-term effects of enteral diets high in monounsaturated fatty acids need further evaluation in patients with type 2 diabetes.     

Troglitazone, an insulin action enhancer, improves glycaemic control and insulin sensitivity in elderly type 2 diabetic patients

The management of Type 2 diabetes mellitus with currently available oral agents may be complicated in the elderly by an increased frequency of side-effects. The effects of troglitazone, an insulin action enhancer, were studied in elderly patients with Type 2 diabetes in a double-blind, parallel-group, placebo-controlled trial. A total of 229 patients (41% male), mean age 75 (range 69-85) years, with two fasting capillary blood glucose values > or =7 and < or =15 mmol l(-1) (and within 4.0 mmol l(-1) of each other) and previously treated with either diet alone (30%) or oral hypoglycaemic agents, were randomized to placebo or troglitazone 400 mg once daily or 200 mg twice daily, or 800 mg once daily or 400 mg twice daily, for 12 weeks. After 12 weeks' treatment, fasting serum glucose was significantly lower in troglitazone-treated patients (troglitazone, adjusted geometric mean 9.4-10.4 mmol l(-1) vs placebo 12.7 mmol l(-1), p < 0.001). Adjusted geometric mean fructosamine was also lower in troglitazone-treated patients by 5 to 15% compared to placebo (P < 0.05 at all doses except 400 mg od). There was no significant difference between troglitazone doses for improvement in glycaemic control. Troglitazone lowered adjusted geometric mean fasting plasma insulin by 27-34% compared to placebo (P < 0.001) and insulin sensitivity (HOMA-S) improved by 9-15% in all troglitazone dose groups (p < 0.001). Troglitazone also lowered serum non-esterified fatty acids and triglyceride. Adverse event incidence in troglitazone-treated patients was similar to that in patients treated with placebo. No weight gain or symptomatic hypoglycaemia was recorded at any of the doses studied. Troglitazone is effective and well tolerated in elderly patients with Type 2 diabetes mellitus, providing improved glycaemic control in the absence of weight gain.     

Type 2 diabetes: glycemic targets and oral therapies for older patients

In older patients with type 2 diabetes, life expectancy and the presence of microvascular complications determine the appropriate intensity of glucose control. The available antidiabetic agents offer many options for achieving glycemic targets, based on the needs of the individual patient. New stimulators of insulin secretion include glimepiride (a sulfonylurea) and repaglinide (a meglitinide). The biguanide metformin is especially useful in obese, insulin-resistant patients. Alpha-glucosidase inhibitors such as acarbose and miglitol act locally in the GI tract to reduce postprandial excursion in glucose levels. The insulin-sensitizing drug troglitazone enhances insulin-mediated glucose disposal. When troglitazone is used, careful monitoring of patients' liver function is required.     

Formulation and in vitro and in vivo availability of diclofenac sodium enteric-coated beads

OBJECTIVE: The beneficial effects of weight loss with a very-low-calorie diet (VLCD) on cardiovascular risk factors have been reported at the end of energy restriction. As the effects, especially on blood pressure, may not remain constant during weight maintenance, we studied the longer-term effects of weight loss on 24h ambulatory blood pressure (ABP), lipids, glucose and insulin. DESIGN: Prospective study of a 17-week weight loss programme containing an eight-week VLCD period and follow-up visit at one-year. SUBJECTS: Twenty-nine moderately obese, normotensive or mildly hypertensive women. The mean +/- s.d. body mass index (BMI) was 36.0 +/- 2.6 kg/m2 and mean age 40.3 +/- 8.3 y. RESULTS: In the last week of the VLCD, the mean (s.d.) weight loss was 12.4 +/- 3.3 kg (P < 0.001), at the end of the programme 15.1 +/- 4.4 kg (P < 0.001 vs baseline), and at one-year follow-up 10.7 +/- 7.6 kg (P < 0.001 vs baseline). Mean 24 h ABP decreased 8.0/4.6 mmHg (P < 0.001 for both) on the last week of the VLCD, at the end of the programme, the systolic ABP decrease was 4.7 mmHg (P < 0.01 vs baseline) and diastolic 2.1 mmHg (not statistically significant (NS) vs baseline). At one-year follow-up, the mean systolic ABP decrease was 4.1 mmHg (P < 0.01 vs baseline) and mean diastolic 3.0 mmHg (P < 0.05 vs baseline). Sodium excretion decreased 55 mmol/24 h in the last VLCD week (P < 0.01) and returned to baseline after that. At the one-year follow-up, beneficial changes, compared with baseline, were observed in mean serum glucose (-0.28 mmol/l, P < 0.05), triglyceride (-0.35 mmol/l, P < 0.01) and HDL cholesterol (+0.16 mmol/l, P < 0.001). CONCLUSIONS: This weight loss programme with a VLCD enabled obese subjects to lose weight and decrease cardiovascular risks. Despite some regain in weight during follow-up, the beneficial effects were overall maintained over the year. Sodium intake tended to increase during follow-up. Information on sodium restriction should be included in weight loss programmes.     

Cloning and functional expression of a human liver organic cation transporter

OBJECTIVE: The triglyceride-lowering effects of omega-3 fats and HDL cholesterol-raising effects of exercise may be appropriate management for dyslipidemia in NIDDM. However, fish oil may impair glycemic control in NIDDM. The present study examined the effects of moderate aerobic exercise and the incorporation of fish into a low-fat (30% total energy) diet on serum lipids and glycemic control in dyslipidemic NIDDM patients. RESEARCH DESIGN AND METHODS: In a controlled, 8-week intervention, 55 sedentary NIDDM subjects with serum triglycerides > 1.8 mmol/l and/or HDL cholesterol < 1.0 mmol/l were randomly assigned to a low-fat diet (30% daily energy intake) with or without one fish meal daily (3.6 g omega-3/day) and further randomized to a moderate (55-65% VO2max) or light (heart rate < 100 bpm) exercise program. An oral glucose tolerance test (75 g), fasting serum glucose, insulin, lipids, and GHb were measured before and after intervention. Self-monitoring of blood glucose was performed throughout. RESULTS: In the 49 subjects who completed the study, moderate exercise improved aerobic fitness (VO2max) by 12% (from 1.87 to 2.07 l/min, P = 0.0001). Fish consumption reduced triglycerides (0.80 mmol/l, P = 0.03) and HDL3 cholesterol (0.05 mmol/l, P = 0.02) and increased HDL2 cholesterol (0.06 mmol/l, P = 0.01). After adjustment for age, sex, and changes in body weight, fish diets were associated with increases in GHb (0.50%, P = 0.05) and self-monitored glucose (0.57 mmol/l, P = 0.0002), which were prevented by moderate exercise. CONCLUSIONS: A reduced fat diet incorporating one daily fish meal reduces serum triglycerides and increases HDL2 cholesterol in dyslipidemic NIDDM patients. Associated deterioration in glycemic control can be prevented by a concomitant program of moderate exercise.     

Effect of 2 types of diet changes on dietary habits, body weight and cholesterol levels in high risk cardiovascular patients

Several non-pharmacological interventions such as weight reduction in obese subjects or diet alteration in subjects having hypercholesterolemia have been shown to be effective in therapeutic trials. Our aim was to test the value of two different ways of teaching patients about their diet. From March 1, 1993, to May 30, 1994, 300 consecutive patients seen in a one-day care hospital were randomised into two groups. The 2 inclusion criteria were: 1) body mass index > 27 kg/m2 in men and > to 25 kg/m2 in women and/or 2) presence of a hypercholesterolemia defined by a total cholesterol > 6.5 mmol/l. Patients in the first group (C) were educated in a 20 to 50 minutes consultation tailored to their needs. Patients in the second group (CC) were given in addition a one-hour course about diet. The goal of the diet was to loss at least 3 kg of body weight and/or to have a cholesterol value below 6.5 mmol/l without treatment. All Patients were followed-up by the same 3 dietician nurses. An out-patient visit was planned at 3 months, and a recall letter was sent to the patients who missed their appointments. Among the 300 patients, 169 (55%) were seen at the 3-month outpatient visit. This proportion did not differ between the 2 groups. Knowledge on diet was assessed by the same 33-item self-administered questionnaire. At baseline scores were comparable between groups (16 vs 17). Scores improved more in the CC than in the C group both at the end of the teaching question (27 vs 23 in the CC and C group respectively, p < 0.001), and at 3 months (25 vs 23 in the CC and C group respectively; p < 0.001). Total cholesterol decreased below 6.5 mmol/l in 28% of the patients with dyslipidemia and a weight loss > 3 kg was observed in 32% of the obese subjects, but improvement did not differ between the 2 groups. We conclude that a specific one-hour course on diet is able to improve knowledge of patients more than a consultation alone, but that better knowledge did not result in improved alteration of risk factors at 3 months.     

Differences in the metabolism of postprandial lipoproteins after a high-monounsaturated-fat versus a high-carbohydrate diet in patients with type 1 diabetes mellitus

There is little information comparing the effects of a high-monounsaturated (Mono)-fat versus a high-carbohydrate (CHO) diet in patients with type 1 diabetes mellitus. In the present study, the effects of these diets on a number of metabolic parameters were compared. Seventeen normolipidemic, nonobese patients with type 1 diabetes were provided with the diets for 4 weeks each in a randomized, crossover design. The percentages of Mono fat of the two diets were 25 Mono versus 9 CHO, with a corresponding total fat content of 40% versus 24% and a total CHO content of 45% versus 61%. At the end of each dietary period, parameters of glycemic control, coagulation factors, and fasting and postprandial lipoproteins were assessed. There were no differences in weight, glycemia, insulin dose, fasting lipid profile, or coagulation factors between the two diets. However, the metabolism of postprandial lipoproteins after a fat load differed; viz, after the Mono diet compared with the CHO diet, mean plasma triglyceride levels over 10 hours were higher (P=.0025, by repeated-measures ANOVA). The levels of triglyceride (P=.0045) and retinyl esters (P=.0046) in chylomicrons (Sf>400) and chylomicron remnants (Sf 100 to 400) (P=.0047 and P=.043, respectively), and the total particle number (apolipoprotein B levels) in chylomicron remnants (P=.001) and small, very low density lipoprotein (Sf 20 to 100, P=.016) were also higher. Our data suggest that in patients with type 1 diabetes, a CHO diet might be preferable to a Mono diet, since adherence to the former results in a lower number of circulating postprandial lipoprotein particles that are potentially atherogenic.     

Differences in corticotropin-releasing hormone-stimulated adrenocorticotropin and cortisol before and after weight loss

Little is known about the effects of intentional weight loss on the function of the hypothalamic-pituitary-adrenal (HPA) axis of obese individuals. We studied the HPA axis of 34 healthy obese women (body mass index, 40.2 +/- 7.9 kg/m2) before and after a 21.0 +/- 7.9-kg weight loss induced by a 26-week weight loss program that included 12 weeks of a 3350 kJ/day (800 Cal/day) liquid formula diet, 6 weeks of gradual refeeding, and 6 weeks of caloric stabilization at 5020-6280 kJ/day (1200-1500 Cal/day). Obese subjects were evaluated twice: before caloric restriction and during the last 3 weeks of caloric stabilization with a 3-h evening 1 microg/kg ovine CRH (oCRH) stimulation test. CRH-stimulated ACTH and cortisol values were compared to those of a control group of 12 normal weight women. Before caloric restriction, both ACTH and cortisol responses to oCRH were similar in obese women and normal weight controls. Weight loss did not significantly alter the ACTH response to oCRH; however, the total plasma cortisol response to oCRH decreased significantly with weight loss (area under the curve, 96,320 +/- 21,040 nmol/L x min before weight loss; 82,450 +/- 22,460 nmol/L x min after weight loss; P < 0.001). Cortisol-binding globulin also decreased significantly after weight loss (2,270 +/- 1,050 nmol/L) compared either to values obtained before weight loss (3,590 +/- 1,360 nmol/L; P < 0.001) or to those of normal weight controls (3,910 +/- 1,400 nmol/L; P < 0.001). Assay for plasma free cortisol, either before or 180 min after oCRH treatment, showed no significant changes in cortisol responses resulting from weight loss. As plasma free cortisol was not altered by weight reduction, the decrease in the total cortisol response to oCRH after weight loss appears to be secondary to significant decreases in cortisol-binding globulin. We conclude that when obese women lose large amounts of weight with a 3350 kJ/day, very low energy diet, such weight reduction does not significantly affect the HPA axis.