Ibipinabant attenuates β-cell loss in male Zucker diabetic fatty rats independently of its effects on body weight

Aim: To test the antidiabetic efficacy of ibipinabant, this new cannabinoid receptor 1 (CB1) antagonist was compared with food‐restriction‐induced weight loss, rosiglitazone (4 mg/kg) and rimonabant (3 and 10 mg/kg), using parameters of glycaemic control in male Zucker diabetic fatty (ZDF) rats. Methods: Body weight, food and water intake, fasted and non‐fasted glucose and insulin, glucose tolerance and glycosylated haemoglobin (HbA1c) were all assessed over the course of the 9‐week study. Pancreatic insulin content and islet area were also evaluated. Results: At the end of the study, vehicle‐treated ZDF rats were severely hyperglycaemic and showed signs of β‐cell decline, including dramatic reductions in unfasted insulin levels. Ibipinanbant (10 mg/kg) reduced the following relative to vehicle controls: fasting glucose (?61%), glucose excursion area under the curve (AUC) in an oral glucose tolerance test (OGTT, ?44%) and HbA1c (?50%). Furthermore, non‐fasting insulin, islet area and islet insulin content were all increased (71, 40 and 76%, respectively) relative to vehicle controls by the end of the study. All of these effects were similar to those of rimonabant and rosiglitazone, where ibipinabant was slightly more effective than rimonabant at the lowest dose and somewhat less effective than rosiglitazone at all doses. These antidiabetic effects appear independent of weight loss because none of the parameters above were consistently improved by the comparable weight loss induced by food restriction. Conclusions: Ibipinabant may have weight loss‐independent antidiabetic effects and may have the potential to attenuate β‐cell loss in a model of progressive β‐cell dysfunction.     

Long‐term changes in blood pressure following orlistat and sibutramine treatment: a meta‐analysis

Previous meta‐analyses investigating blood pressure effects of anti‐obesity drugs have included studies using non‐licensed doses, but not data from head‐to‐head studies. Furthermore, although diabetes is an important comorbidity in obesity, variation in blood pressure effects across diabetes status has not been investigated. The objective of this study was to estimate the effects on systolic (SBP) and diastolic blood pressure (DBP) of orlistat and sibutramine. Medline, EMBASE, the Cochrane controlled trials register and reference lists of identified articles from 1990 to February 2009 were searched. All placebo‐controlled randomized controlled trials of 12‐month duration or randomized head‐to‐head studies of any duration on adults using standard doses were included. Studies/study arms were excluded if they only evaluated weight maintenance after weight loss. Randomized controlled trials were identified, subjected to inclusion and exclusion criteria, and reviewed. Random effects models were used for assessment of weighted mean differences. Eighteen placebo‐controlled (12 orlistat, 5540 patients; 6 sibutramine, 1495 patients) and four head‐to‐head trials (348 patients) met the inclusion criteria. Three orlistat and three sibutramine studies examined overweight subjects with type 2 diabetes (T2DM), as did two head‐to‐head trials. Mean baseline SBP ranged from 119 to 153 mmHg, and mean DBP from 69 to 98 mmHg. Overall, the placebo‐controlled SBP change was −1.9 (95% CI; −2.7, −1.1) mmHg for orlistat, and 0.5 (−1.1, 2.1) mmHg for sibutramine. The corresponding values for DBP were −1.5 (−2.2, −0.8) and 1.7 (0.7, 2.6). Compared with patients without diabetes, diabetic patients treated with orlistat experienced smaller and non‐significant reductions of SBP (−0.9; −2.6, 0.7 vs. −2.2; −3.0, −1.3) and DBP (−1.0; −2.4, 0.3 vs. −1.6; −2.4, −0.8). For sibutramine, higher on‐treatment elevations in SBP (1.6; −1.3, 4.5 vs. 0.1; −1.8, 2.0) and DBP (2.4; 0.6, 4.1 vs. 1.4; 0.3, 2.5) were seen in patients with vs. without diabetes. In head‐to‐head trials, the overall differences between sibutramine and orlistat were small and non‐significant for both SBP (1.0; −2.3, 4.3) and DBP (−0.2; −2.9, 2.5). In conclusion, in the studies using approved sibutramine doses, the drug caused significant elevations in DBP, while the overall SBP effect was near null. Moreover, absence of a blood pressure‐lowering effect of orlistat ad a higher DBP elevation by sibutramine were observed for persons with diabetes. Head‐to‐head studies indicated that an indirect comparison of placebo‐adjusted blood pressure effects may overestimate the adverse effects associated with sibutramine, but these studies were small, of shorter duration and of lower quality.     

Orlistat 120 mg improves glycaemic control in type 2 diabetic patients with or without concurrent weight loss

Background: Both obesity and type 2 diabetes are associated with increased morbidity and mortality. Published data suggest that orlistat 120 mg, a lipase inhibitor used to treat obesity, may improve glycaemic parameters through weight loss–independent effects. Aim: To investigate the effect of orlistat 120 mg on weight loss, and assess whether changes in glycaemic parameters [fasting plasma glucose (FPG) and haemoglobin A_1c (HbA_1c)] are independent of weight loss. Methods: This retrospective analysis of pooled data from seven multicentre, double‐blind, placebo‐controlled studies involved overweight or obese patients with type 2 diabetes (aged 18–70 years). Patients were required to have a body mass index of 27–43 kg/m², HbA_1c of 6.5 to <13%, and stable weight for ≥3 months. Subjects received orlistat 120 mg tid or placebo for 6 or 12 months. Results: A total of 2550 overweight or obese patients with type 2 diabetes were enrolled and randomized to treatment with orlistat 120 mg tid (n = 1279) or placebo (n = 1271). For the whole population, patients treated with orlistat 120 mg had significantly greater mean decreases in FPG compared with placebo‐treated patients (?1.39 mmol/l vs. ?0.47 mmol/l; p < 0.0001). In addition, orlistat 120 mg provided significantly larger mean decreases in HbA_1c compared with placebo (?0.74% vs. ?0.31%; p < 0.0001). For patients with minimal weight loss (≤1% of baseline body weight), orlistat 120 mg still provided a significantly greater decrease in the least squares mean value for both FPG (?0.83 mmol/l vs. ±0.02 mmol/l; p = 0.0052) and HbA_1c?0.29% vs. ±0.14%; p = 0.0008). This suggested that the improvement of glycaemic control with orlistat 120 mg was independent of weight loss. Using linear regression analysis, improvement in glycaemic control (FPG and HbA_1c) with orlistat 120 mg was less strongly correlated with weight loss than for placebo. Conclusion: Orlistat 120 mg appears to improve glycaemic control more than would be predicted by weight loss alone in overweight or obese patients with type 2 diabetes. Postulated mechanisms underlying this effect include an improvement of insulin sensitivity, a slower and incomplete digestion of dietary fat, reduction of postprandial plasma non‐esterified fatty acids, decreased visceral adipose tissue, and stimulation of glucagon‐like peptide‐1 secretion in the lower small intestine.     

Diabesity

Weight reduction has been shown to improve glycemic control and cardiovascular risk factors associated with insulin resistance in obese individuals with type 2 diabetes mellitus. Therapeutic options for these patients include promoting weight loss (non-pharmacologic and pharmacologic treatment) and improving glycemic control, as well as treating common associated risk factors such as arterial hypertension and dyslipidemias. This article provides an overview of anti-obesity drugs used in the treatment of obese individuals with type 2 diabetes. The most widely investigated drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in many co-morbidities, among them, type 2 diabetes. Clinical trials with these anti-obesity medications in cohorts of obese diabetic patients have been reviewed as well as cathecolaminergic agents (diethylpropion [amfepramone], fenproporex, mazindol, ephedrine-caffeine combination), serotoninergic drugs (fenfluramine, dexfenfluramine, fluoxetine), and other drugs that have some action on weight loss (the antidiabetic agent metformin, anti-epileptic agents topiramate and zonisamide, and the antidepressive bupropion [amfebutamone]). These trials show variable benefits in terms of effects on glucose profiles.     

Diabesity: therapeutic options

A pathogenic relationship exists between type 2 diabetes and obesity. Over the last decade, the escalation in diabetes cases has paralleled the rapid increase in obesity rates, constituting a global health crisis. Environmental risk factors attributed to the global increase in obesity include the consumption of high‐calorie, high‐fat foods and inadequate physical activity. Obese individuals may also have a genetic predisposition for obesity. Both diabetes and obesity confer an elevated risk of developing a range of complications and comorbidities, including cardiovascular disease, hypertension and stroke, which can complicate disease management. This review examines the aetiology of the linkages between diabetes and obesity and the range of available therapies. Recent clinical evidence substantiating the efficacy and safety of incretin‐based antidiabetic therapies is analysed, in addition to data on antiobesity therapeutic strategies, such as antiobesity agents, behaviour modification and bariatric surgery. Glucose control is often accompanied by weight‐neutral or modest weight reduction effects with DPP‐4 inhibitor treatment (sitagliptin, vildagliptin, saxagliptin) and weight loss with GLP‐1 receptor agonist therapy (exenatide, liraglutide). Studies of antiobesity agents including orlistat, sibutramine and rimonabant have shown attrition rates of 30–40%, and the long‐term effects of these agents remain unknown. Bariatric surgical procedures commonly performed are laparoscopic adjustable banding of the stomach and the Roux‐en‐Y gastric bypass, and have produced type 2 diabetes remission rates of up to 73%. Therapeutic strategies that integrate glycaemic control and weight loss will assume greater importance as the prevalence of diabetes and obesity increase.     

Effects of combination of sibutramine and l-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus l-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA_1c] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus l-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA_1c, fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus l-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA_1c, fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus l-carnitine compared with sibutramine alone. Sibutramine plus l-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect.     

Non‐insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes‐related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA_1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon‐like peptide‐1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium‐glucose co‐transporter‐2 and dual sodium‐glucose co‐transporter‐2 and ‐1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis‐related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.     

Strong association between insulin resistance in liver and skeletal muscle in non‐diabetic subjects

Objective To examine the association between insulin resistance in skeletal muscle and liver in non‐diabetic subjects. Research design and methods A total of 182 Mexican American subjects without Type 2 diabetes underwent an oral glucose tolerance test and euglycaemic–hyperinsulinaemic clamp performed with ³[H]glucose. Insulin sensitivity in skeletal muscle was measured as the insulin‐stimulated rate of total glucose disposal during the insulin clamp divided by steady‐state plasma insulin concentration (TGD/SSPI). Hepatic insulin resistance was measured as the product of basal hepatic glucose production and fasting plasma insulin concentration (HGP × FPI). Results Hepatic insulin resistance was strongly correlated (r = 0.68, P < 0.0001) with skeletal muscle insulin resistance. Thirty‐eight per cent of subjects had increased insulin resistance in both liver and skeletal muscle, while 39% were insulin sensitive in both skeletal muscle and liver. Twenty‐three per cent of subjects were discordant for muscle and hepatic insulin resistance (P < 0.0001). Subjects with increased skeletal muscle insulin resistance had a higher 2‐h plasma glucose concentration, greater incremental area under the plasma glucose concentration curve, lower fasting plasma insulin concentration and lower rate of basal hepatic glucose production compared with subjects with increased insulin resistance in liver. Conclusion In non‐diabetic subjects, insulin resistance in skeletal muscle is an important determinant of the fasting and 2‐h plasma glucose concentrations and strongly correlates with hepatic insulin resistance.     

Lowering plasma glucose concentration by inhibiting renal sodium–glucose cotransport

Maintaining normoglycaemia not only reduces the risk of diabetic microvascular complications but also corrects the metabolic abnormalities that contribute to the development and progression of hyperglycaemia, that is insulin resistance and beta‐cell dysfunction. Progressive beta‐cell failure, in addition to side effects associated with many current antidiabetic agents, for example hypoglycaemia and weight gain, presents major obstacles to the achievement of the recommended goal of glycaemic control in patients with type 2 diabetes mellitus (T2DM). Thus, novel effective therapies are needed for optimal glucose control in subjects with T2DM. Most recently, specific inhibitors of the renal sodium–glucose cotransporter 2 (SGLT2) have been developed to produce glucosuria and lower the plasma glucose concentration. Because of the iR unique mechanism of action, which is independent of insulin secretion and insulin action, these agents are effective in lowering the plasma glucose concentration in all stages of the disease and can be combined with all other antidiabetic agents. In this review, we will summarize the available data concerning the mechanism of action, efficacy and safety of this novel class of antidiabetic agents.     

Stabilizing effect of exenatide in a patient with C‐peptide‐negative diabetes mellitus

Background Exenatide is an incretin mimetic licensed for treatment of Type 2 diabetes poorly controlled despite maximally tolerated doses of oral therapy. Similar in structure to the natural incretin hormone glucagon‐like peptide 1 (GLP‐1), it helps restore underlying pathophysiological abnormalities. Case report We report the successful use of exenatide, combined with insulin, in a 66‐year‐old woman initially diagnosed with Type 2 diabetes in 1989 but now exhibiting a Type 1 phenotype. Diet, lifestyle advice and oral glucose‐lowering agents were commenced but persisting poor control necessitated insulin therapy in 2005. She later presented twice in diabetic ketoacidosis, suggesting conversion to a Type 1 phenotype (postprandial C‐peptide < 94 pmol/l). Despite differing insulin regimens, control remained poor with frequent hyperglycaemic and hypoglycaemic excursions, severely impairing quality of life. Whilst an inpatient in 2007 [glycated haemoglobin (HbA_1c) 10.2%, body mass index (BMI) 31.5 kg/m²] exenatide was commenced in an attempt to stabilize glycaemic control. Dramatic improvements were seen and continued. Eight months later, HbA_1c had fallen by 2% with an 8‐kg weight loss and 10‐unit reduction in daily insulin dose. Quality of life dramatically improved. C‐peptide remains undetectable. Conclusions This patient with features of both Type 1 and Type 2 diabetes benefited greatly from exenatide with insulin therapy. The improvement seen in glycaemic control could not be attributable to enhanced insulin secretion but could be as a result of a combination of the other incretin effects (postprandial glucagon suppression, delayed gastric emptying and weight loss secondary to increased satiety) all improving insulin sensitivity, reducing insulin dose and smoothing control.     

Effect of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes mellitus: a systematic review and meta‐analysis of randomized controlled trials

Orlistat is an effective adjunctive treatment to lifestyle modifications in the treatment of obesity. While the majority of current evidence is on the effect of orlistat in obese patients without diabetes, some studies suggest that patients who are obese and have diabetes mellitus lose more weight and have greater improvements in diabetic outcomes when treated with orlistat plus a lifestyle intervention than when treated by lifestyle interventions alone. The aim of this study was to review the evidence of the effects of orlistat on glycaemic control in overweight and obese patients with type 2 diabetes. A systematic review of randomized controlled trials of orlistat in people with type 2 diabetes reporting diabetes outcomes in studies published between January 1990 and September 2013 was conducted. We searched for articles published in English in MEDLINE and EMBASE. Inclusion criteria included all randomized controlled trials of orlistat carried out on adult participants with a body mass index of 25 kg m^?2 or over diagnosed with type 2 diabetes, which reported weight change and at least one diabetic outcome. A total of 765 articles were identified out of which 12 fulfilled the inclusion criteria. The overall mean weight reduction (3, 6 and 12 months) in the orlistat group was ?4.25 kg (95% CI: ?4.5 to ?3.9 kg). The mean weight difference between treatment and control groups was ?2.10 kg (95% CI: ?2.3 to ?1.8 kg, P < 0.001), the mean HbA1c difference was ?6.12 mmol mol^?1 (95% CI: ?10.3 to ?1.9 mmol mol^?1, P < 0.004) and the mean fasting blood glucose difference was ?1.16 mmol L^?1 (95% CI: ?1.4 to ?0.8 mmol L^?1, P < 0.001). Treatment with orlistat plus lifestyle intervention resulted in significantly greater weight loss and improved glycaemic control in overweight and obese patients with type 2 diabetes compared with lifestyle intervention alone.     

Discontinuation due to adverse events in randomized trials of orlistat, sibutramine and rimonabant: a meta-analysis

The objective of this article was to estimate the risk of discontinuation due to adverse events in trials of orlistat, sibutramine and rimonabant. Medline, EMBASE, the Cochrane controlled trials register and reference lists of identified articles were searched from 1990 to May 2008. All randomized placebo-controlled trials of 12–24 months of duration on adults using licensed doses were included. Studies/study arms were excluded if they evaluated weight maintenance after weight loss. Trials were identified, subjected to inclusion and exclusion criteria and reviewed. Data on participants, interventions and discontinuation were extracted and trials rated for quality based on established criteria. A random effects model was used to estimate pooled risk ratios, risk differences and number needed to harm (NNH). A total of 28 trials met the inclusion criteria (16 orlistat, 7 sibutramine and 5 rimonabant). The risk ratios for discontinuation due to adverse events were significantly elevated for rimonabant (2.00; 1.66–2.41) and orlistat (1.59; 1.21–2.08), but not sibutramine (0.98, 0.68–1.41). Compared with placebo, the risk difference was the largest for rimonabant (7%, 5–9%; NNH 14, 11–19), followed by orlistat (3%, 1–4%; NNH 39, 25–83), while no significant difference was seen for sibutramine (0.2%, −3 to 4%; NNH 500). The most common adverse events leading to withdrawal were gastrointestinal for orlistat (40%) and psychiatric for rimonabant (47%). Corresponding information was unavailable for sibutramine. In conclusion, available weight loss drugs differ markedly regarding risk of discontinuation due to adverse events, as well as in underlying causes of these events. Given the large number of patients eligible for treatment, the low NNH for rimonabant is a concern.     

Weight gain during insulin therapy in patients with type 2 diabetes mellitus

In patients with diabetes, the benefits of tight glycemic control are unequivocal--delayed onset and progression of complications such as retinopathy, nephropathy, and neuropathy. However, intensive therapy with insulin and some oral antidiabetic agents come at the price of weight gain, a condition that can prevent attainment of tight glycemic goals and probably limits success of treatment. Insulin-related weight gain has been attributed to anabolic effects of insulin, appetite increases, and reduction of glycosuria. Use of metformin in combination with insulin is commonly recommended as a way to limit weight gain in patients with type 2 diabetes, and other new oral therapies and insulin analogs may also provide weight-control advantages. Lifestyle interventions (patient education about diet and exercise) promote weight loss in the short-term, but have not sustained weight control over long-term intervals. For lasting weight control, such interventions may need to continue throughout the course of treatment. Likewise, weight-loss agents, such as sibutramine and orlistat promote short-term weight loss, but no follow-up studies have yet demonstrated that this loss can be maintained for 5 years or longer. Bariatric surgery is the only treatment recognized to have lasting effects on weight control, but its use is limited at present to those who are morbidly obese.     

Comparing hormonal and symptomatic responses to experimental hypoglycaemia in insulin‐ and sulphonylurea‐treated Type 2 diabetes

Aims Patients with diabetes rely on symptoms to identify hypoglycaemia. Previous data suggest patients with Type 2 diabetes develop greater symptomatic and hormonal responses to hypoglycaemia at higher glucose concentrations than non‐diabetic controls and these responses are lowered by insulin treatment. It is unclear if this is as a result of insulin therapy itself or improved glucose control. We compared physiological responses to hypoglycaemia in patients with Type 2 diabetes patients treated with sulphonylureas (SUs) or insulin (INS) with non‐diabetic controls (CON). Methods Stepped hyperinsulinaemic hypoglycaemic clamps were performed on 20 subjects with Type 2 diabetes, 10 SU‐treated and 10 treated with twice‐daily premixed insulin, and 10 age‐ and weight‐matched non‐diabetic controls. Diabetic subjects were matched for diabetes duration, glycated haemoglobin (HbA_1c) and hypoglycaemia experience. We measured symptoms, counterregulatory hormones and cognitive function at glucose plateaux of 5, 4, 3.5, 3 and 2.5 mmol/l. Results Symptomatic responses to hypoglycaemia occurred at higher blood glucose concentrations in SU‐treated than INS‐treated patients [3.5 (0.4) vs. 2.6 (0.5) mmol/l SU vs. INS; P = 0.001] or controls [SU vs. CON 3.5 (0.4) vs. 3.0 (0.6) mmol/l; P = 0.05]. They also had a greater increase in symptom scores at hypoglycaemia [13.6 (11.3) vs. 3.6 (6.1) vs. 5.1 (4.3) SU vs. INS vs. CON; P = 0.017]. There were no significant differences in counterregulatory hormone responses or impairment of cognitive function among groups. Conclusions Sulphonylurea‐treated subjects are more symptomatic of hypoglycaemia at a higher glucose level than insulin‐treated subjects. This may protect them from severe hypoglycaemia but hinder attainment of glycaemic goals.     

Near-normoglycaemic remission in African-Americans with Type 2 diabetes mellitus is associated with recovery of beta cell function.

AIMS: To prospectively determine the frequency of remission and possible mechanism of beta cell recovery in non-Whites with Type 2 diabetes mellitus in the setting of intensive glycaemic regulation using pharmacological agents. METHODS: Twenty-six consecutive, newly diagnosed African-American, Type 2 diabetic patients presenting primarily for severe hyperglycaemia (31.0+/-12.8 mmol/l) were followed for at least 1 year. Initial hospitalization included treatment with insulin, fluids and electrolytes. Outpatient intensive glycaemic regulation included insulin or glibenclamide, diabetes education and diet that altered nutrient content. Plasma glucose and C-peptide responses to an oral glucose tolerance test and HbA1c were measured at < 14, 15-56 and 57-112 days after presentation. Remission was defined as a HbA1c < or = 6.3% and fasting plasma glucose < 6.9 mmol/l, 3 months after discontinuing all pharmacological agents. RESULTS: Eleven of 26 patients (42.3%) developed remission after a mean of 83 days of pharmacological treatment and remained in remission during follow-up for 248-479 days; one relapsed after 294 days. Fifteen patients who did not develop a remission and were followed for 168-468 days, required continuing pharmacological therapy to be well-controlled. (mean HbA1c = 7.1%). There was no significant difference in age, sex, plasma glucose at presentation, initial glycaemic regulation, final body mass index, magnitude of weight change or pharmacological agents used for treatment between the two groups. Plasma C-peptide response to oral glucose was initially (< 14 days) suppressed in all subjects and subsequently increased. The increase was significantly greater in those who underwent a remission than those who did not. Neither significant weight loss nor severe hypoglycaemia was observed in either group during intensive treatment. CONCLUSIONS: Forty-two per cent of newly diagnosed, unselected African-Americans with Type 2 diabetes, treated intensively using pharmacological agents, education and diet developed near-normoglycaemic remission. Remission was associated with a greater recovery of glucose-stimulated insulin secretion suggesting that therapies directed at promoting beta cell recovery and preservation are potentially useful approaches to the treatment of Type 2 diabetes mellitus.     

The prevalence of retinopathy in impaired glucose tolerance and recent‐onset diabetes in the Diabetes Prevention Program

Aims Retinopathy is considered the complication most closely associated with and characteristic of diabetes mellitus. Hyperglycaemia below levels diagnostic of diabetes, so called pre‐diabetes, is associated with a low prevalence of ‘diabetic’ retinopathy. However, few longitudinal studies of non‐diabetic populations have performed repeated measures of glycaemia and screened for retinopathy to determine its occurrence in the non‐diabetic population and the onset of retinopathy in new‐onset diabetic patients. We determined the prevalence of retinopathy characteristically seen in diabetes in persons with impaired glucose tolerance and in patients with new‐onset diabetes of known duration in the Diabetes Prevention Program (DPP) cohort. Methods The DPP recruited persons with elevated fasting glucose (5.3–6.9 mmol/l) and impaired glucose tolerance, and no history of diagnosed diabetes, other than gestational diabetes not persisting after pregnancy. Seven‐field, stereoscopic fundus photography was completed a mean of 3.1 years after the development of diabetes in 594 of 878 participants who had developed diabetes during the DPP, and in a random sample of 302 participants who remained non‐diabetic. Results Retinopathy consistent with diabetic retinopathy was detected in 12.6 and 7.9% of the diabetic and non‐diabetic participants, respectively (P = 0.03, comparing prevalence in the two groups). Systolic blood pressure and HbA_1c were higher at baseline in the diabetic participants who had retinopathy compared with the diabetic participants without retinopathy. Conclusions Retinopathy characteristic of diabetes is present in persons with elevated fasting glucose and impaired glucose tolerance and no known history of diabetes. The prevalence of retinopathy is significantly higher in persons who develop diabetes, even within 3 years of diagnosis.     

Orlistat in the treatment of overweight or obese Chinese patients with newly diagnosed Type 2 diabetes.

AIMS: Orlistat promotes weight loss in overweight and obese patients with Type 2 diabetes receiving hypoglycaemic treatment, but has not been investigated in patients with newly diagnosed and previously untreated Type 2 diabetes. We evaluated the efficacy of 24 weeks' treatment with orlistat, combined with a mildly reduced-calorie diet, on weight loss and glycaemic control in overweight and obese patients with newly diagnosed and previously untreated Type 2 diabetes. METHODS: A total of 249 Chinese patients (body mass index 25-40 kg/m2) with recently diagnosed Type 2 diabetes were randomized to placebo (n=124) or orlistat 120 mg (n=125) three times daily; all patients followed a mildly reduced-calorie diet. Patients had HbA1c 6.5-8.5% (mean 7.3%) and had never received any glucose-lowering medication. RESULTS: Orlistat-treated patients achieved significantly greater weight loss at the study end than placebo-treated patients (-5.4 vs. -2.4 kg; P<0.0001). More orlistat than placebo patients lost>or=5% (60.5 vs. 26.8%; P<0.0001) and >or=10% of their body weight (20.2 vs. 4.9%; P=0.0002). A significantly greater decrease in HbA(1c) from baseline was obtained with orlistat than placebo (-1.0 vs. -0.6%; P=0.0008). Orlistat-treated patients achieved a significantly greater decrease in fasting plasma glucose (-1.3 vs. -0.5 mmol/l; P=0.0003) and in the 2-h oral glucose tolerance test (-4.1 vs. -1.4 mmol/l; P<0.0001) than placebo recipients. Also, more orlistat- than placebo-treated patients improved from diabetic status to normal or impaired glucose tolerance (44.3 vs. 32.5%; P=0.0763) after 24 weeks. Orlistat also produced improvements in lipid profiles and waist circumference. CONCLUSIONS: In combination with a mildly reduced-calorie diet, orlistat significantly reduces body weight, and improves glycaemic control and several cardiovascular risk factors in overweight and obese Chinese patients with newly diagnosed Type 2 diabetes.     

Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults

BACKGROUND: Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption by approximately 30%, promotes weight loss, and may reduce the risk of developing impaired glucose tolerance and type 2 diabetes in obese subjects. OBJECTIVE: To test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance status and prevents worsening of diabetes status more effectively than placebo. METHODS: We pooled data from 675 obese (body mass index, 30-43 kg/m2) adults at 39 US and European research centers in 3 randomized, double-blind, placebo-controlled multicenter clinical trials. Subjects received placebo plus a low-energy diet during a 4-week lead-in period. On study day 1, the diet was continued, and subjects were randomized to receive placebo 3 times a day (n=316) or treatment with orlistat, 120 mg 3 times a day (n=359), for 104 weeks. A standard 3-hour oral glucose tolerance test was performed on day 1 and at the end of treatment. MAIN OUTCOME MEASURES: The categorical assessment of glucose tolerance status (normal, impaired, diabetic) and changes in status from randomization to end of treatment were the primary efficacy measures. The secondary measures were fasting and postchallenge glucose and insulin levels. RESULTS: The mean length of follow-up was 582 days. Subjects who were treated with orlistat lost more weight (mean +/- SEM, 6.72 +/- 0.41 kg from initial weight) than subjects who received placebo (3.79+/-0.38 kg; P<.001). A smaller percentage of subjects with impaired glucose tolerance at baseline progressed to diabetic status in the orlistat (3.0%) vs placebo (7.6%) group. Conversely, among subjects with impaired glucose tolerance at baseline, glucose levels normalized in more subjects after orlistat treatment (71.6%) vs placebo (49.1%; P=.04). CONCLUSIONS: The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of impaired glucose tolerance and type 2 diabetes.     

Extra‐glycaemic properties of empagliflozin

Type 2 diabetes is a complex and multifaceted disease requiring an individualized approach. A special attention, in treating the patients, should be devoted to the presence of comorbidities like overweight or obesity and arterial hypertension. Among the available anti‐hyperglycaemic agents, several are associated with side effects like hypoglycaemia and weight gain. An increasing interest is reported in sodium‐glucose co‐transporter‐2 inhibitors, a relatively novel class of glucose‐lowering drugs that act independently of insulin, provide benefits beyond glucose‐lowering actions and show a better tolerability compared with traditional medications for type 2 diabetes. This review tries to offer a balanced view on the main extra‐glycaemic effects of empagliflozin, also mentioning clinical data obtained with other sodium‐glucose co‐transporter‐2 inhibitors; the role of the proximal tubule in the pathophysiology of diabetic nephropathy and the potential nehroprotection exerted by this compound are also briefly discussed. Copyright © 2015 John Wiley & Sons, Ltd.     

Head-to-head studies evaluating efficacy of pharmaco-therapy for obesity: a systematic review and meta-analysis

Randomized controlled trials (RCTs) directly comparing weight loss drugs approved in the European Union were reviewed and the results analysed by meta-analysis. Eight RCTs including 885 patients were found comparing weight loss of orlistat and sibutramine, while no study including rimonabant was found. The median study duration was 7 months (range 3–12). Four of the seven studies comparing sibutramine and orlistat mono-therapy showed that sibutramine was significantly more efficacious for weight loss, while the remaining three showed equivalence. The weighted mean difference in weight loss was 2.2 kg (95% CI 0.5–3.9) favouring sibutramine. Three studies investigated orlistat and sibutramine as combination therapy, and two found it to be significantly better than orlistat alone, but not better than sibutramine alone. Based on these head-to-head RCT data, sibutramine appears to be significantly more efficacious for achieving weight loss than orlistat. This is concordant with indirect evidence from previous meta-analyses, where the respective compounds were compared with placebo. Only four studies reported attrition, and the pooled risk ratio was 0.6 (0.3–1.4) indicating lower dropout for sibutramine. This information together with an understanding of the clinical properties of each drug should help to guide the prescribing physician in the selection of adequate drug therapy for obesity.