Saxagliptin for type 2 diabetes

Saxagliptin (Onglyza™) is a potent, selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for improving glycemic control in patients with type 2 diabetes (T2D). By blocking DPP-4, saxagliptin increases and prolongs the effects of incretins, a group of peptide hormones released by intestinal cells after meals, which stimulate glucose-dependent insulin secretion to lower blood glucose. In controlled clinical trials, saxagliptin administered as monotherapy or in combination with metformin, glyburide, or a thiazolidinedione improved glycemic control in a clinically significant manner, reflected by significant decreases in glycated hemoglobin (monotherapy, −0.5%; add-on to metformin, thiazolidinedione, or sulfonylurea, −0.6% to 0.9%; initial combination with metformin, −2.5%), fasting plasma glucose, and postprandial glucose compared with controls. Additionally, saxagliptin improved β-cell function, reflected as increases in homeostasis model assessment (HOMA)-2β. Saxagliptin was generally well tolerated; it did not increase hypoglycemia compared with controls, and was weight neutral. A meta-analysis of Phase II and III trials showed that saxagliptin did not increase the risk of major cardiovascular events. Professional organizations have updated their guidelines for T2D to include a DPP-4 inhibitor as an early treatment option—either as initial therapy in combination with metformin, or as add-on therapy for patients whose glycemia is inadequately controlled by a single oral antidiabetic drug

Facts about the history of the AE&M

Univ Fed Sao Paulo EPM Unifesp, Ctr Pesquisa Clin Diabet, Escola Paulista Med, Sao Paulo, SP, BrazilCtr Diabet Hosp Sirio Libanes, Sao Paulo, SP, BrazilUniv Fed Sao Paulo EPM Unifesp, Ctr Pesquisa Clin Diabet, Escola Paulista Med, Sao Paulo, SP, BrazilWeb of Scienc

Low cardiorespiratory fitness in people at risk for type 2 diabetes: early marker for insulin resistance

<p>Abstract</p> <p>Purpose</p> <p>There is a significant association between insulin resistance and low cardiorespiratory fitness in nondiabetic subjects. In a population with risk factors for type 2 diabetes (T2DM), before they are insulin resistant, we investigated low exercise capacity (VO2max) as an early marker of impaired insulin sensitivity in order to determine earlier interventions to prevent development of insulin resistance syndrome (IRS) and T2DM.</p> <p>Methods</p> <p>Cross-sectional analyses of data on 369 (78 men and 291 women) people at risk for IRS and T2DM, aged 45.6 +/- 10 years (20-65 years) old from the Community Diabetes Prevention Project in Minnesota were carried out. The cardiorespiratory fitness (VO2max) by respiratory gas exchange and bicycle ergometer were measured in our at risk non insulin resistant population and compared with a control group living in the same geographic area. Both groups were equally sedentary, matched for age, gender and BMI.</p> <p>Results</p> <p>The most prevalent abnormality in the study population was markedly low VO2max when compared with general work site screening control group, (n = 177; 137F; 40 M, mean age 40 ± 11 years; BMI = 27.8 ± 6.1 kg/m²). Individuals at risk for IRS and T2DM had a VO2max (22 ± 6 ml/kg/min) 15% lower than the control group VO2max (26 ± 9 ml/kg/min) (p < 0.001). It was foun that VO₂max was inversely correlated with HOMA-IR (r = -0.30, p < 0.0001).</p> <p>Conclusions</p> <p>Decreased VO2max is correlated with impaired insulin sensitivity and was the most prevalent abnormality in a population at risk for IRS and T2DM but without overt disease. This raises the possibility that decreased VO2 max is among the earliest indicators of IRS and T2DM therefore, an important risk factor for disease progression.</p

Algorithm for the treatment of type 2 diabetes: a position statement of Brazilian Diabetes Society

The Brazilian Diabetes Society is starting an innovative project of quantitative assessment of medical arguments of and implementing a new way of elaborating SBD Position Statements. The final aim of this particular project is to propose a new Brazilian algorithm for the treatment of type 2 diabetes, based on the opinions of endocrinologists surveyed from a poll conducted on the Brazilian Diabetes Society website regarding the latest algorithm proposed by American Diabetes Association /European Association for the Study of Diabetes, published in January 2009

Poor glycaemic control in Brazilian patients with type 2 diabetes attending the public healthcare system a cross-sectional study

Objectives: To describe the clinical profile of Brazilian patients with type 2 diabetes attending the public healthcare system and identify factors associated with poor glycaemic control.Design: Cross-sectional study.Setting: 14 centres in five regions of Brazil, including primary care units and outpatient clinics of University Hospitals.Participants: Patients with type 2 diabetes attending outpatient clinics of public healthcare system.Main outcome measured: Glycated haemoglobin (HbA1c), centrally measured by high-performance liquid chromatography (National Glycohemoglobin Standardization Program certified).Results: A total of 5750 patients aged 61 10 years, with 11 8 years of diabetes duration (66% women, 56% nonwhite, body mass index: 28.0 5.3 kg/m(2)) were analysed. Mean HbA1c was 8.6 +/- 2.2%, and median HbA1c was 8.1% (6.9% to 9.9%). HbA1c 8%.Conclusions: the majority of Brazilian patients with type 2 diabetes attending the public healthcare system had HbA1c levels above recommended targets. the recognition of Northeast residents and non-white patients as vulnerable populations should guide future policies and actions to prevent and control diabetes.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundo de Incentivo a Pesquisa (FIPE) of Hospital de Clinicas de Porto Alegre (HCPA)Pfizer PharmaceuticalHosp Clin Porto Alegre, Endocrine Div, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Porto Alegre, RS, BrazilHosp Getulio Vargas, Endocrine Div, Manaus, Amazonas, BrazilUniv Fed Amazonas, Manaus, Amazonas, BrazilFed Univ Para, BR-66059 Belem, Para, BrazilUniversidade Federal de São Paulo, Endocrine Div, São Paulo, BrazilUniversidade Federal de São Paulo, Endocrine Div, São Paulo, BrazilWeb of Scienc

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction &gt;0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p&lt;0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p&lt;0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Evolving Metformin Treatment Strategies in Type-2 Diabetes: From Immediate-Release Metformin Monotherapy to Extended- Release Combination Therapy

Over the last 40 years, metformin has revolutionized the treatment of type-2 diabetes worldwide and is still the most influential oral antidiabetic drug today. International guidelines now recommend that patients with type-2 diabetes are started on metformin therapy as soon as they are diagnosed, as it has been shown to improve long-term clinical outcomes compared with initial management with diet alone, without increasing the risk of developing hypoglycemia or weight gain. the older, immediate-release formulation of metformin does have some limitations, with incidence of gastrointestinal adverse effects restricting the dose in some patients, forming a barrier to treatment adherence, and subsequent glycemic control. However, the second-generation extended-release formulation (met XR) has the potential to overcome these challenges. in this review, we provide an overview of the evidence supporting the use of metformin as the first-line gold standard for type-2 diabetes management and the expansion of its potential roles for the future. We also consider the advantages of met XR, in terms of its tolerability and convenient dose regimen, and review therapeutic options for when disease progression inevitably leads to inadequate control with monotherapy. These therapy options include the synergistic potential of combination strategies with met XR and dipeptidyl peptidase 4 inhibitors, a combination that has also been indicated for early-stage use (at diagnosis) as a potential method for preserving -cell function.AstraZenecaBristol-Myers SquibbUniversidade Federal de São Paulo, Ctr Diabet, São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Diabet, São Paulo, BrazilWeb of Scienc