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André J Scheen1,2 1Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, Liège University, Liège, Belgium; 2Clinical Pharmacology Unit, CHU Liège, Center for Interdisciplinary Research on Medicines (CIRM), Liège University, Liège, BelgiumCorrespondence: André J Scheen Email andre.scheen@chuliege.beAbstract: Metformin remains the first pharmacological choice for treating hyperglycemia in type 2 diabetes (T2DM) in most international guidelines. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are increasingly used as add-on therapy. T2DM pathophysiology is different in Asian and non-Asian (mainly Caucasian) patients. The aim of this systematic review is to compare the efficacy of SGLT2is vs placebo added to metformin in randomized controlled trials (RCTs: range 12– 52 weeks) in Asian versus non-Asian patients with T2DM. The primary endpoint is the reduction in glycated hemoglobin (HbA1c) from baseline and key secondary endpoints are reductions in fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Systematic literature search collected 7 RCTs (3 with 2 doses) in Asian patients (10 analyses, n=1164, iSGLT2: canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, tofogliflozin)) and 10 RCTs (6 with two doses) in non-Asian patients (16 analyses, n=2482, iSGLT2: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin). Baseline values of HbA1c (7.98± 0.19 vs 7.89± 0.27%), FPG (8.80 ± 0.46 vs 9.11± 0.49 mmol/l) and SBP (128.4± 1.6 vs 130.2± 3.1 mmHg) were not significantly different in Asian vs non-Asian patients, but BW was lower in Asian patients (71.6± 4.8 vs 88.0± 2.5 kg, p< 0.001). The placebo-adjusted weighed mean differences (WMD, 95% CI) were similar in Asian versus non-Asian patients regarding the reductions in HbA1c − 0.60 (− 0.68, − 0.53) % versus − 0.54 (− 0.59, − 0.49) % (p=0.568), FPG − 1.37 (− 1.53, − 1.22) mmol/l vs − 1.37 (− 1.47, − 1.27) mmol/l (p=0.627), BW when expressed in percentage of baseline BW − 2.23 (− 2.55, − 1.90) % vs − 2.16 (− 2.37, − 1.96) % (p=0.324), and SBP − 4.53 (− 5.53, − 3.53) mmHg vs − 4.06 (− 4.83, − 3.29) mmHg) (p=0.223). In conclusion, clinical efficacy of SGLT2i, as an add-on treatment to metformin monotherapy in patients with T2DM, is similar in Asian versus non-Asian patients, despite known ethnic differences in phenotype and pathophysiology of T2DM.Keywords: blood pressure, body weight, combined therapy, glucose control, HbA1c, oral antidiabetic drug

Benoit Pétré,1 André J Scheen,2 Olivier Ziegler,3 Anne-Françoise Donneau,1 Nadia Dardenne,1 Eddy Husson,1 Adelin Albert,1 Michèle Guillaume1 1Department of Public Health, University of Liège, Liège, Belgium; 2Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman, University of Liège, Liège, Belgium; 3Department of Diabetes, Metabolic Diseases and Nutrition, Nancy University Hospital, Nancy, France Background and objective: Despite the strength and consistency of the relationship between body mass index (BMI) and quality of life (QoL), a reduction in BMI does not necessarily lead to an improvement in QoL. Between-subject variability indicates the presence of mediators and moderators in the BMI–QoL association. This study aimed to examine the roles of body image discrepancy (BID) and subjective norm (SN) as potential mediators and moderators. Subjects and methods: In 2012, 3,016 volunteers (aged ≥18 years) participated in a community-based survey conducted in the French-speaking region of Belgium. Participation was enhanced using a large multimedia campaign (which was supported by a large network of recruiters) that employed the nonstigmatizing slogan, “Whatever your weight, your opinion will count”. Participants were invited to complete a web-based questionnaire on their weight-related experiences. Self-reported measures were used to calculate each participant’s BMI, BID, SN, and QoL (a French obesity-specific QoL questionnaire was used to calculate the participants’ physical dimension of QoL scores [PHY-QoL], psychosocial dimension of QoL scores [PSY/SOC-QoL], and their total scores). The covariates included gender, age, subjective economic status, level of education, household size, and perceived health. The mediation/moderation tests were based on Hayes’ method. Results: Tests showed that the relationships between BMI and PHY-QoL, PSY/SOC-QoL, and TOT-QoL were partially mediated by BID in both males and females and by SN in females. Moreover, BID was a moderator of the relationship between BMI and PSY/SOC-QoL in males and females. SN was a moderator of the relationship between BMI and PSY/SOC-QoL in males and between BMI and total scores in males (when used without BID in the models). Conclusion: BID and SN should be considered as important factors in obesity management strategies. The study shows that targeting BMI only is not sufficient to improve the QoL of overweight and obese subjects, and that other variables, including perceptual factors, should be considered. Keywords: obesity, quality of life, mediators and moderators, body image

Dipeptidyl peptidase 4 (DPP-4) inhibitors (commonly referred to as gliptins) are a novel class of oral antihyperglycaemic agents with demonstrated efficacy in the treatment of type 2 diabetes mellitus (T2DM). Preclinical data and mechanistic studies have indicated a possible beneficial action on blood vessels and the heart, via both glucagon-like peptide 1 (GLP-1)-dependent and GLP-1-independent effects. DPP-4 inhibition increases the concentration of many peptides with potential vasoactive and cardioprotective effects. Clinically, DPP-4 inhibitors improve several risk factors in patients with T2DM. They improve blood glucose control (mainly by reducing postprandial glycaemia), are weight neutral (or even induce modest weight loss), lower blood pressure, improve postprandial lipaemia, reduce inflammatory markers, diminish oxidative stress, and improve endothelial function. Some positive effects on the heart have also been described in patients with ischaemic heart disease or congestive heart failure, although their clinical relevance requires further investigation. Post-hoc analyses of phase II-III, controlled trials suggest a possible cardioprotective effect with a trend for a lower incidence of major cardiovascular events with gliptins than with placebo or active agents. However, the actual relationship between DPP-4 inhibition and cardiovascular outcomes remains to be proven. Major prospective clinical trials with predefined cardiovascular outcomes and involving various DPP-4 inhibitors are now underway in patients with T2DM and a high-risk cardiovascular profile. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes mellitus (T2DM) are generally treated with many pharmacological compounds and are exposed to a high risk of drug-drug interactions. Indeed, blood glucose control usually requires a combination of various glucose-lowering agents, and the recommended global approach to reduce overall cardiovascular risk generally implies administration of several protective compounds, including HMG-CoA reductase inhibitors (statins), antihypertensive compounds and antiplatelet agents. New compounds have been developed to improve glucose-induced beta-cell secretion and glucose control, without inducing hypoglycaemia or weight gain, in patients with T2DM. Dipeptidylpeptidase-4 (DPP-4) inhibitors are novel oral glucose-lowering agents, which may be used as monotherapy or in combination with other antidiabetic compounds, metformin, thiazolidinediones or even sulfonylureas. Sitagliptin, vildagliptin and saxagliptin are already on the market, either as single agents or in fixed-dose combined formulations with metformin. Other compounds, such as alogliptin and linagliptin, are in a late phase of development. This review summarizes the available data on drug-drug interactions reported in the literature for these five DDP-4 inhibitors: sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin. Possible pharmacokinetic interferences have been investigated between each of these compounds and various pharmacological agents, which were selected because there are other glucose-lowering agents (metformin, glibenclamide [glyburide], pioglitazone/rosiglitazone) that may be prescribed in combination with DPP-4 inhibitors, other drugs that are currently used in patients with T2DM (statins, antihypertensive agents), compounds that are known to interfere with the cytochrome P450 (CYP) system (ketoconazole, diltiazem, rifampicin [rifampin]) or with P-glycoprotein transport (ciclosporin), or agents with a narrow therapeutic safety window (warfarin, digoxin). Generally speaking, almost no drug-drug interactions or only minor drug-drug interactions have been reported between DPP-4 inhibitors and any of these drugs. The gliptins do not significantly modify the pharmacokinetic profile and exposure of the other tested drugs, and the other drugs do not significantly alter the pharmacokinetic profile of the gliptins or exposure to these. The only exception concerns saxagliptin, which is metabolized to an active metabolite by CYP3A4/5. Therefore, exposure to saxagliptin and its primary metabolite may be significantly modified when saxagliptin is coadministered with specific strong inhibitors (ketoconazole, diltiazem) or inducers (rifampicin) of CYP3A4/5 isoforms. The absence of significant drug-drug interactions could be explained by the favourable pharmacokinetic characteristics of DPP-4 inhibitors, which are not inducers or inhibitors of CYP isoforms and are not bound to plasma proteins to a great extent. Therefore, according to these pharmacokinetic findings, which were generally obtained in healthy young male subjects, no dosage adjustment is recommended when gliptins are combined with other pharmacological agents in patients with T2DM, with the exception of a reduction in the daily dosage of saxagliptin when this drug is used in association with a strong inhibitor of CYP3A4/A5. It is worth noting, however, that a reduction in the dose of sulfonylureas is usually recommended when a DPP-4 inhibitor is added, because of a pharmacodynamic interaction (rather than a pharmacokinetic interaction) between the sulfonylurea and the DPP-4 inhibitor, which may result in a higher risk of hypoglycaemia. Otherwise, any gliptin may be combined with metformin or a thiazolidinedione (pioglitazone, rosiglitazone), leading to a significant improvement in glycaemic control without an increased risk of hypoglycaemia or any other adverse event in patients with T2DM. Finally, the absence of drug-drug interactions in clinical trials in healthy subjects requires further evidence from large-scale studies, including typical subjects with T2DM - in particular, multimorbid and geriatric patients receiving polypharmacy. [ABSTRACT FROM AUTHOR]

Background: Rimonabant, a selective cannabinoid type 1 receptor blocker, reduces bodyweight and improves cardiovascular and metabolic risk factors in non-diabetic overweight or obese patients. The aim of the RIO-Diabetes trial was to assess the efficacy and safety of rimonabant in overweight or obese patients with type 2 diabetes that was inadequately controlled by metformin or sulphonylureas.Methods: 1047 overweight or obese type 2 diabetes patients (body-mass index 27-40 kg/m2) with a haemoglobin A1c (HbA1c) concentration of 6.5-10.0% (mean 7.3% [SD 0.9] at baseline) already on metformin or sulphonylurea monotherapy were given a mild hypocaloric diet and advice for increased physical activity, and randomly assigned placebo (n=348), 5 mg/day rimonabant (360) or 20 mg/day rimonabant (339) for 1 year. Two individuals in the 5 mg/day group did not receive double-blind treatment and were thus not included in the final analysis. The primary endpoint was weight change from baseline after 1 year of treatment. Analyses were done on an intention-to-treat basis. This trial is registered at ClinicalTrials.gov, number NCT00029848.Findings: 692 patients completed the 1 year follow-up; numbers in each group after 1 year were much the same. Weight loss was significantly greater after 1 year in both rimonabant groups than in the placebo group (placebo: -1.4 kg [SD 3.6]; 5 mg/day: -2.3 kg [4.2], p=0.01 vs placebo; 20 mg/day: -5.3 kg [5.2], p<0.0001 vs placebo). Rimonabant was generally well tolerated. The incidence of adverse events that led to discontinuation was slightly greater in the 20 mg/day rimonabant group, mainly due to depressed mood disorders, nausea, and dizziness.Interpretation: These data indicate that 20 mg/day rimonabant, in combination with diet and exercise, can produce a clinically meaningful reduction in bodyweight and improve HbA1c and a number of cardiovascular and metabolic risk factors in overweight or obese patients with type 2 diabetes inadequately controlled by metformin or sulphonylureas. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a major health problem associated with excess morbidity and mortality. As the prevalence of this metabolic disorder is rapidly increasing and current treatment fails to stabilise the disease in most patients, prevention should be considered as a key objective in the near future. People who develop type 2 diabetes pass through a phase of impaired glucose tolerance (IGT). Defects in the action and/or secretion of insulin are the two major abnormalities leading to development of glucose intolerance. Any intervention in the impaired glucose tolerance phase that reduces resistance to insulin or protects the beta-cells, or both, should prevent or delay progression to diabetes.Acarbose, miglitol and voglibose act by competitively inhibiting the alpha-glucosidases, a group of key intestinal enzymes involved in the digestion of carbohydrates. They decrease both postprandial hyperglycaemia and hyperinsulinaemia, and thereby may improve sensitivity to insulin and release the stress on beta-cells. These compounds do not induce hypoglycaemia and have a good safety profile, although gastrointestinal adverse effects may limit long-term compliance to therapy.The recent placebo-controlled prospective STOP-noninsulin-dependent diabetes mellitus (STOP-NIDDM) trial demonstrated that acarbose 100mg three times daily reduces the risk of developing type 2 diabetes in patients with IGT (relative risk reduction of 25% after a mean follow-up of 3.3 years). The 6-year Early Diabetes Intervention Trial (EDIT), comparing the effect of acarbose 50mg three times daily to that of metformin, showed a trend to a positive effect of acarbose compared with placebo, in a mid-term 3-year analysis, which should be confirmed in the final analysis.To our knowledge, no such prevention intervention trials have been or are currently being performed with miglitol or voglibose. In conclusion, because of its absence of toxicity and its particular mechanism of action on gastrointestinal tract and indirect consequences on both insulin action and beta-cell function, acarbose may be used to prevent type 2 diabetes. If the ongoing EDIT trial confirms the positive results of the recent STOP-NIDDM trial, acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of diabetes in patients with IGT. However, the best dosage of acarbose for this specific indication remains to be specified, especially when all three important parameters, efficacy, tolerance and cost, are taken into consideration. [ABSTRACT FROM AUTHOR]

Abdominal obesity, especially visceral adipose tissue (VAT), increases the incidence of a cluster of metabolic disturbances (the so-called metabolic syndrome), type 2 diabetes, and associated cardiovascular risk. Not only is abdominal obesity a marker of a dysmetabolic profile, but VAT also appears to be a causal factor for morbidity and premature mortality, both by classic mechanisms (ie, dyslipidemia, hypertension, and glucose dysmetabolism), as well as less conventional mechanisms (ie, low adiponectin levels and high proinflammatory cytokine levels that promote insulin resistance and endothelial dysfunction). Because abdominal obesity is increasingly seen in young people, early intervention is mandatory to stop the cycle that leads to cardiometabolic risk. Obesity should be considered a chronic disease of multifactorial etiology,and treatment must be maintained for life DLfirst with lifestyle interventions (energy-reduced diet and increased physical activity) and then with pharmacologic approaches (eg, orlistat, sibutramine, or rimonabant), when necessary. Beneficial metabolic effects may result from even moderate weight loss and are attributed primarily to a predominant reduction in VAT. Finally, special attention should be paid to possible additional positive effects beyond weight reduction, as especially demonstrated with the CB1 antagonist rimonabant. [ABSTRACT FROM AUTHOR]

Background: In animal models, cannabinoid-1 receptor (CB1) blockade produces a lean phenotype, with resistance to diet-induced obesity and associated dyslipidaemia. We assessed the effect of rimonabant, a selective CB1 blocker, on bodyweight and cardiovascular risk factors in overweight or obese patients.Methods: patients with body-mass index 30 kg/m2 or greater, or body-mass index greater than 27 kg/m2 with treated or untreated dyslipidaemia, hypertension, or both, were randomised to receive double-blind treatment with placebo, 5 mg rimonabant, or 20 mg rimonabant once daily in addition to a mild hypocaloric diet (600 kcal/day deficit). The primary efficacy endpoint was weight change from baseline after 1 year of treatment in the intention-to-treat population.Findings: Weight loss at 1 year was significantly greater in patients treated with rimonabant 5 mg (mean -3.4 kg [SD 5.7]; p=0.002 vs placebo) and 20 mg (-6.6 kg [7.2]; p<0.001 vs placebo) compared with placebo (-1.8 kg [6.4]). Significantly more patients treated with rimonabant 20 mg than placebo achieved weight loss of 5% or greater (p<0.001) and 10% or greater (p<0.001). Rimonabant 20 mg produced significantly greater improvements than placebo in waist circumference, HDL-cholesterol, triglycerides, and insulin resistance, and prevalence of the metabolic syndrome. The effects of rimonabant 5 mg were of less clinical significance. Rimonabant was generally well tolerated with mild and transient side effects.Interpretation: CB1 blockade with rimonabant 20 mg, combined with a hypocaloric diet over 1 year, promoted significant decrease of bodyweight and waist circumference, and improvement in cardiovascular risk factors. [ABSTRACT FROM AUTHOR]