Alain Golay

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial

BACKGROUND Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients

BACKGROUND We undertook a randomised controlled trial to assess the efficacy and tolerance 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.

Physical Activity and Insulin Sensitivity: The RISC Study

OBJECTIVE— Physical activity is a modifiable risk factor for type 2 diabetes, partly through its action on insulin sensitivity. We report the relation between insulin sensitivity and physical activity measured by accelerometry. RESEARCH DESIGN AND METHODS— This is a cross-sectional study of 346 men and 455 women, aged 30–60 years, without cardiovascular disease and not treated by drugs for diabetes, hypertension, dyslipidemia, or obesity. Participants were recruited in 18 clinical centers from 13 European countries. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Physical activity was recorded by accelerometry for a median of 6 days. We studied the relationship of insulin sensitivity with total activity (in counts per minute), percent of time spent sedentary, percent of time in light activity, and activity intensity (whether the participant recorded some vigorous or some moderate activity). RESULTS— In both men and women, total activity was associated with insulin sensitivity (P < 0.0001). Time spent sedentary, in light activity, and activity intensity was also associated with insulin sensitivity (P < 0.0004/0.01, 0.002/0.03, and 0.02/0.004, respectively, for men/women) but lost significance once adjusted for total activity. Adjustment for confounders such as adiposity attenuated the relationship with total activity; there were no interactions with confounders. Even in the 25% most sedentary individuals, total activity was significantly associated with better insulin sensitivity (P < 0.0001). CONCLUSIONS— Accumulated daily physical activity is a major determinant of insulin sensitivity. Time spent sedentary, time spent in light-activity, and bouts of moderate or vigorous activity did not impact insulin sensitivity independently of total activity.

Lipid peroxidation in skeletal muscle of obese as compared to endurance-trained humans: a case of good vs. bad lipids?

Intra‐myocellular triglycerides (IMTG) accumulate in the muscle of obese and endurance‐trained (ET) humans and are considered a pathogenic factor in the development of insulin resistance, in the former. We postulate that this paradox may be associated with the peroxidation status of the IMTG. IMTG content was the same in the obese and ET subjects. The lipid peroxidation/IMTG ratio was 4.2‐fold higher in the obese subjects. Hence, obesity results in an increased level of IMTG peroxidation while ET has a protective effect on IMTG peroxidation. This suggests a link between the lipid peroxidation/IMTG ratio and insulin resistance.

Glucose-induced Thermogenesis in Nondiabetic and Diabetic Obese Subjects

The glucose-induced thermogenesis (GIT) following a 100-g oral glucose load has been measured by continuous indirect calorimetry in 55 nondiabetic and diabetic obese subjects of various ages and compared with two control groups of 17 young and 13 elderly nonobese subjects. The obese subjects were divided into four groups: group A, normal glucose tolerance; group B, impaired glucose tolerance; group C, diabetes with increased insulin response; group D, diabetes with reduced insulin response. The glucose-induced thermogenesis measured during 3 h represented 8.6 ± 0.7% of the energy content of the load in the young control group. In all obese groups, the glucose-induced thermogenesis was significantly lower than in the young control group, i.e., 6.6 ± 0.9%, 6.4 ± 0.6%, 3.7 ± 0.7%, and 2.2 ± 0.4% in groups A, B, C, and D, respectively. Since the obese diabetics were older than the other groups, their glucose-induced thermogenesis was compared with that of the elderly control group; the latter (5.8 ± 0.3%) was significantly lower (P < 0.05) than that of the young control group. The obese diabetics also had a significantly lower glucose-induced thermogenesis than the elderly control group (P < 0.02 and P < 0.001 for groups C and D, respectively). When corrected for glucosuria and after taking into account the glucosuria and the changes in the glucose space, the corrected glucose-induced thermogenesis (i.e., related to glucose “uptake”), was still significantly reduced in group A versus the young control group (6.6 ± 0.9 versus 8.6 ± 0.7%, P < 0.05), and in group D versus the elderly (matched for age) control group (4.2 ± 0.7 versus 5.8 ± 0.3%, P < 0.05). It is concluded that the postprandial thermogenesis induced by glucose ingestion is decreased in the presence of insulin resistance and/or reduced insulin response to the glucose load in obese subjects. In addition, age itself contributes to decrease glucose-induced thermogenesis.

Obesity and the four facets of impulsivity

OBJECTIVE Obesity is a complex condition involving biological, psychological, sociocultural and environmental components. Impulsivity seems to be a particularly important factor. Whiteside and Lynam recently proposed dividing impulsivity into four separate dimensions: Urgency, lack of Premeditation, lack of Perseverance and Sensation Seeking (associated with a tendency to exaggerate the impact of rewards). The objective of this article is to examine how obesity and eating disorder symptoms may be related to the four facets of impulsivity. METHODS Whiteside and Lynams Impulsive Behavior Scale, the Sensitivity to Punishment and Sensitivity to Reward Questionnaire, the Eating Disorder Examination Questionnaire and the Mizes Anorectic Cognitions Questionnaire were used to explore the association between the cognitive and motivational facets of impulsivity and obesity in 47 overweight or obese persons with eating disorders and 47 normal-weight controls. RESULTS Results suggest that overweight and obese persons have higher levels of Urgency, lack of Perseverance and Sensitivity to Reward. CONCLUSION These results suggest that obese and overweight persons have difficulty inhibiting automatic or dominant behavior and intrusive thoughts and a higher sensitivity to reward. PRACTICE IMPLICATIONS Overweight and obese persons may benefit from psychological interventions targeting self-control problems associated with impulsive eating behaviors.

Effect of beta and alpha adrenergic blockade on glucose-induced thermogenesis in man.

After intravenous glucose/insulin infusion there is an increase in oxygen consumption and energy expenditure that has been referred to as thermogenesis. To examine the contribution of the beta and alpha adrenergic nervous system to this thermogenic response, 12 healthy volunteers participated in three studies: (a) euglycemic insulin (plasma insulin approximately 100 microunits/ml) clamp study (n = 12); (b) insulin clamp study after beta adrenergic blockade with intravenous propranolol for 1 h (n = 12); (c) insulin clamp study after alpha adrenergic blockade with phentolamine for 1 h (n = 5). During the control insulin clamp study total glucose uptake, glucose oxidation and nonoxidative glucose uptake averaged 7.85 +/- 0.47, 2.62 +/- 0.22, and 5.23 +/- 0.51 mg/kg X min. After propranolol infusion, insulin-mediated glucose uptake was significantly reduced, 6.89 +/- 0.41 (P less than 0.02). This decrease was primarily the result of a decrease in glucose oxidation (1.97 +/- 0.19 mg/kg X min, P less than 0.01) without any change in nonoxidative glucose metabolism. Phentolamine administration had no effect on total glucose uptake, glucose oxidation, or nonoxidative glucose disposal. The increments in energy expenditure (0.10 +/- 0.01 vs. 0.03 +/- 0.01 kcal/min) and glucose/insulin-induced thermogenesis (4.9 +/- 0.5 vs. 1.5 +/- 0.5%) were reduced by 70% during the propranolol/insulin clamp study. The increments in energy expenditure (0.12 +/- 0.03 kcal/min) and thermogenesis (5.0 +/- 1.5%) were not affected by phentolamine. These results indicate that activation of the beta adrenergic receptor plays an important role in the insulin/glucose-mediated increase in energy expenditure and thermogenesis. In contrast, the alpha adrenergic receptor does not appear to participate in this response.

Metformin and body weight

Most patients with type 2 diabetes are overweight or obese, overweight or obesity increases the risk of developing type 2 diabetes and obesity per se is strongly associated with multiple cardiometabolic risk factors. However, many antidiabetic treatments increase body weight. The oral antidiabetic agent, metformin, has been evaluated in hundreds of clinical studies in diverse patient populations during approximately five decades of clinical use. This review summarizes the effects of metformin on body weight, with special reference to studies of longer duration (⩾6 months) as both diabetes and obesity are long-term conditions. Approximately half of studies in drug-naive type 2 diabetic patients demonstrated significant weight loss with metformin compared with baseline or comparator drugs, although pooled analyses have suggested no significant effect versus placebo. Similarly, metformin has been shown to induce weight loss in obese nondiabetic populations, although studies of long duration in this population are scarce. Metformin does appear to mitigate the adverse effects of insulin on body weight. The weight-neutral or weight-sparing effects of metformin constitute a therapeutic advantage in diabetes management where other first-line oral antidiabetic treatments often promote clinically significant weight gain.

Randomised controlled trial of a guided self-help treatment on the Internet for binge eating disorder.

Binge eating disorder (BED) is a common and under-treated condition with major health implications. Cognitive behavioural therapy (CBT) self-help manuals have proved to be efficient in BED treatment. Increasing evidence also support the use of new technology to improve treatment access and dissemination. This is the first randomised controlled study to evaluate the efficacy of an Internet guided self-help treatment programme, based on CBT, for adults with threshold and subthreshold BED. Seventy-four women were randomised into two groups. The first group received the six-month online programme with a six-month follow-up. The second group was placed in a six-month waiting list before participating in the six-month intervention. Guidance consisted of a regular e-mail contact with a coach during the whole intervention. Binge eating behaviour, drive for thinness, body dissatisfaction and interoceptive awareness significantly improved after the Internet self-help treatment intervention. The number of objective binge episodes, overall eating disorder symptoms score and perceived hunger also decreased. Improvements were maintained at six-month follow-up. Dropouts exhibited more shape concern and a higher drive for thinness. Overall, a transfer of CBT-based self-help techniques to the Internet was well accepted by patients, and showed positive results for eating disorders psychopathology.

Open questions about metabolically normal obesity

Subsets of obese subjects without any cardiometabolic risk factors have been repeatedly described. This raises questions whether obesity ‘per se’ enhances the risk for cardiovascular or metabolic diseases and whether healthy obese subjects would benefit from a medical treatment. In order to answer these questions, as a first step, an expert consensus should be reached for the definition of metabolic normality. In fact, up to now, different parameters related to the metabolic syndrome and/or to insulin sensitivity have been utilized across studies. Once an agreement is reached, population-based studies should be undertaken to establish the incidence of metabolic normality among obese subjects. Furthermore, many other parameters such as age, sex, race, fat distribution and physical activity should be monitored to obtain results representative of a general population. Longitudinal studies aimed at investigating the evolution of the cardiometabolic profile of healthy obese subjects are also needed. In conclusion, data from the literature strongly suggest that a regular surveillance of the cardiometabolic parameters and a prevention of any further weight gain should be applied to healthy obese individuals, whereas possible benefits of a weight loss treatment are still a matter of debate.