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 ß-cell function.

Effect of nateglinide on the incidence of diabetes and cardiovascular events.

BACKGROUND: The ability of short-acting insulin secretagogues to reduce the risk of diabetes or cardiovascular events in people with impaired glucose tolerance is unknown. METHODS: In a double-blind, randomized clinical trial, we assigned 9306 participants with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors to receive nateglinide (up to 60 mg three times daily) or placebo, in a 2-by-2 factorial design with valsartan or placebo, in addition to participation in a lifestyle modification program. We followed the participants for a median of 5.0 years for incident diabetes (and a median of 6.5 years for vital status). We evaluated the effect of nateglinide on the occurrence of three coprimary outcomes: the development of diabetes; a core cardiovascular outcome that was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; and an extended cardiovascular outcome that was a composite of the individual components of the core composite cardiovascular outcome, hospitalization for unstable angina, or arterial revascularization. RESULTS: After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P=0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P=0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P=0.16). Nateglinide did, however, increase the risk of hypoglycemia. CONCLUSIONS: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes. (ClinicalTrials.gov number, NCT00097786.)

Effect of valsartan on the incidence of diabetes and cardiovascular events.

BACKGROUND: It is not known whether drugs that block the renin-angiotensin system reduce the risk of diabetes and cardiovascular events in patients with impaired glucose tolerance. METHODS: In this double-blind, randomized clinical trial with a 2-by-2 factorial design, we assigned 9306 patients with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors to receive valsartan (up to 160 mg daily) or placebo (and nateglinide or placebo) in addition to lifestyle modification. We then followed the patients for a median of 5.0 years for the development of diabetes (6.5 years for vital status). We studied the effects of valsartan on the occurrence of three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization. RESULTS: The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P<0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P=0.85). CONCLUSIONS: Among patients with impaired glucose tolerance and cardiovascular disease or risk factors, the use of valsartan for 5 years, along with lifestyle modification, led to a relative reduction of 14% in the incidence of diabetes but did not reduce the rate of cardiovascular events. (ClinicalTrials.gov number, NCT00097786.)

C-reactive protein and features of metabolic syndrome in Brazilian women with previous gestational diabetes.

OBJECTIVE: C-reactive protein (CRP), an inflammatory biomarker, has been associated with the development of diabetes. Gestational diabetes (GDM) predicts type 2 diabetes (T2DM) and may be part of the metabolic syndrome (MS). Few studies have examined the association of CRP, MS and diabetes in women with previous GDM. RESEARCH DESIGN AND METHODS: Women with previous GDM (n=70) and randomly sampled women without previous GDM (n=108) from the one center of the Brazilian Study of Gestational Diabetes participated in the study after 6 years of index pregnancy. Oral glucose tolerance test and anthropometry were performed. CRP levels were measured by the nephelometry. The MS was defined by the ATPIII criteria. RESULTS: There was significant positive linear correlation between CRP levels, fasting insulin (R=0.053) and HOMA IR (0.048) in previous GDM. Mean CRP levels were significantly higher in previous GDM group with abdominal obesity (1.227 95% CI 0.871-1.584 versus 0.597, 95% CI 0.378-0.817; p=0.001) and abnormal glucose tolerance (1.168 95% CI 0.784-1.552 versus 0.657 95% CI 0.455-0.859, p=0.012). There were differences when considering the presence of different MS features, once the previous GDM group reported a significantly higher number of women with low HDL (74.3% versus 55.6%, p=0.016) and abnormal glucose tolerance (45.7% versus 25%, p=0.005) than the group without GDM. On average, the CRP levels were significantly higher in women with previous GDM and MS (0.918 95% CI 0.569; 1.268 versus 0.524 95% CI 0.373; 0.675, p=0.044) than the control group. CONCLUSIONS: The data suggests that the presence of MS in women with previous GDM is associated with high levels of CRP.

[Cardiovascular assessment of diabetic patients]. / Avaliação cardiovascular de pacientes diabéticos em ambulatório universitário.

INTRODUCTION: Type 2 diabetes is a cardiovascular disease. The morbidity and mortality among these patients are primarily due to cardiovascular diseases. There are many guidelines regarding clinical evaluation of cardiovascular disease in those patients. Implementation of these guidelines has been an argued subject. Our objective in this paper is to describe what basal cardiovascular evaluation has been carried out at a specialized university Diabetes Center. SUBJECTS AND METHODS: Data were collected from February to October 2006 of 121 type 2 diabetes individuals who were enrolled at the Diabetes Center of Federal University of São Paulo. We analyzed the type of cardiovascular disease evaluation that they had been submitted in the year that preceded the consultation. RESULTS: We have observed a high prevalence of several other cardiovascular risk factors in this population. The cardiovascular evaluations during this period has shown 36% of the patients had not been submitted to any cardiovascular test, 17% had been submitted to resting electrocardiogram and 27% of the patients had been submitted to exercise test. Rest echocardiogram, pharmacologic stress echocardiogram, myocardial perfusion scintigraphy, and coronary angiography have been carried out in a much lesser ratio. CONCLUSION: Our data has shown the variability and limitations on boarding diagnosing of DAC in university environment patients and point us the necessity of constructing defined and directed directives for the peculiarities of the Brazilian population and health system.

Updated risk factors should be used to predict development of diabetes.

AIMS: Predicting incident diabetes could inform treatment strategies for diabetes prevention, but the incremental benefit of recalculating risk using updated risk factors is unknown. We used baseline and 1-year data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) Trial to compare diabetes risk prediction using historical or updated clinical information. METHODS: Among non-diabetic participants reaching 1year of follow-up in NAVIGATOR, we compared the performance of the published baseline diabetes risk model with a "landmark" model incorporating risk factors updated at the 1-year time point. The C-statistic was used to compare model discrimination and reclassification analyses to demonstrate the relative accuracy of diabetes prediction. RESULTS: A total of 7527 participants remained non-diabetic at 1year, and 2375 developed diabetes during a median of 4years of follow-up. The C-statistic for the landmark model was higher (0.73 [95% CI 0.72-0.74]) than for the baseline model (0.67 [95% CI 0.66-0.68]). The landmark model improved classification to modest (<20%), moderate (20%-40%), and high (>40%) 4-year risk, with a net reclassification index of 0.14 (95% CI 0.10-0.16) and an integrated discrimination index of 0.01 (95% CI 0.003-0.013). CONCLUSIONS: Using historical clinical values to calculate diabetes risk reduces the accuracy of prediction. Diabetes risk calculations should be routinely updated to inform discussions about diabetes prevention at both the patient and population health levels.

Myocardial dysfunction in mitochondrial diabetes treated with Coenzyme Q10.

Maternally-inherited diabetes and deafness (MIDD) has been related to an A to G transition in the mitochondrial tRNA Leu (UUR) gene at the base pair 3243. Although some previous articles have reported that this mutation may be a cause of cardiomyopathy in diabetes, the degree of cardiac involvement and a specific treatment has not been established. Here, we reported a case of a patient with MIDD who developed congestive heart failure and the therapeutic usefulness of Coenzyme Q10 (CoQ10). In our patient, after the introduction of Coenzyme Q10 150 mg/day, there was a gradual improvement on left ventricular function evaluated by echocardiography. The fractional shortening (FS) and ejection fraction (EF) increased from 26 to 34% and from 49 to 64%, respectively. No side effects were noted. Three months after CoQ10 discontinuation, the parameters of systolic function evaluated by echocardiography decreased, suggesting that CoQ10 had a beneficial effect. Identification of diabetes and cardiomyopathy due to mitochondrial gene mutation may have therapeutic implications and Coenzyme Q10 is a possible adjunctive treatment in such patients.

[Metabolic alterations in HIV-associated lipodystrophy syndrome]. / Alterações metabólicas da síndrome lipodistrófica do HIV.

The introduction of highly active antiretroviral therapy (HAART) has reduced morbidity and mortality in patients infected with the human immunodeficiency virus (HIV). However, prolonged treatment with combination regimens can be difficult to sustain because of problems with adherence and toxic effects. Treatment with antiretroviral agents--protease inhibitors in particular--has uncovered a syndrome of abnormal fat redistribution, impaired glucose metabolism, insulin resistance and dyslipidemia, collectively termed lipodystrophy syndrome (SLHIV). Nowadays, no clinical guidelines are available for the prevention or treatment of SLHIV, and its cause have yet to be totally elucidated. This review emphasizes the clinical features and the data from previous studies about the SLHIV taking into account that a better understanding of this syndrome for HIV specialists, cardiologists and endocrinologists is fundamental for the disease control.

Role of the Gly40Ser mutation in the glucagon receptor gene in Brazilian patients with type 2 diabetes mellitus.

INTRODUCTION: A missense mutation in the glucagon receptor gene (Gly40Ser) has been associated with type 2 diabetes mellitus in some populations. AIM: To investigate whether this mutation is associated with type 2 diabetes in Brazilian patients and its functional significance in vivo. METHODOLOGY: One hundred fifteen patients with type 2 diabetes and 115 control subjects were screened by restriction-enzyme digestion with BstE II. The in vivo implications were investigated by 1 mg glucagon intravenous injection and plasma C-peptide (before and after 6 minutes) and glucose measurements (before and after 30, 60, 90, and 120 minutes), and first-phase insulin response (1 + 3 minutes) to intravenous glucose tolerance test. These procedures were performed in two groups of patients with diabetes, which differed only by the presence or absence of the Gly40Ser mutation, and two groups of control subjects. RESULTS: The mutation was detected in two patients with diabetes (1.7%) and in four control subjects (3.5%) (not significant). Patients with diabetes and carriers of Gly40Ser showed basal C-peptide levels significantly lower than noncarriers (0.70 ng/mL versus 1.50 ng/mL, p = 0.008). No differences were found between Gly40Ser carriers and noncarriers in control subjects within the parameters studied. CONCLUSION: Our results show that the Gly40Ser mutation in the glucagon receptor gene is not associated with type 2 diabetes in a Brazilian population. However, a reduction of insulin secretion was observed in Gly40Ser carriers.

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% non-white, 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 <7% was observed in only 26% of patients. Mean HbA1c was higher (p < 0.01) in the North (9.0±2.6%) and Northeast (8.9±2.4%) than in the Midwest (8.1±2%), Southeast (8.4±2.1%) and South regions (8.3±1.9%). Using the cut-off value of HbA1c above the median, age (0.986 (0.983 to 0.989)), white ethnicity (0.931 (0.883 to 0.981)) and being from Midwest region (0.858 (0.745 to 0.989)) were protective factors, while diabetes duration (1.015 (1.012 to 1.018)), use of insulin (1.710 (1.624 to 1.802)) and living in the Northeast region (1.197 (1.085 to 1.321)) were associated with 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.

A novel risk classification paradigm for patients with impaired glucose tolerance and high cardiovascular risk.

We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests.

Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks.

To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled on sulphonylurea monotherapy, 768 patients were randomised to saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg versus placebo added to up-titrated glyburide over 76 weeks (24 weeks plus 52-week extension) in this phase 3, double-blind, placebo-controlled trial; 557 patients completed the study, 142 without being rescued. At 76 weeks, adjusted mean changes from baseline HbA(1C) (repeated measures model) (95% confidence interval) for saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide were 0.11% (-0.05, 0.27), 0.03% (-0.14, 0.19), and 0.69% (0.47, 0.92), respectively (post hoc and nominal p < 0.0001 for saxagliptin 2.5 and 5 mg vs. up-titrated glyburide). Adverse event frequency was similar in all treatment groups; reported hypoglycaemia event rates were 24.2%, 22.9%, and 20.6% with saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide, respectively. Saxagliptin plus glyburide provided sustained incremental efficacy compared with up-titrated glyburide over 76 weeks, and was generally well tolerated.

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 ß-cell function, reflected as increases in homeostasis model assessment (HOMA)-2ß. 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.

Aerobic exercise capacity and pulmonary function in athletes with and without type 1 diabetes.

OBJECTIVE: To compare the aerobic exercise capacity and pulmonary function between athletes with and without type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifty-one adult age-matched individuals were assessed in random order to the maximum volume of O(2) consumption (Vo(2 peak max)) (ml/kg/min), anaerobic threshold (ml/kg/min), peak pulmonary ventilation (Ve), heart rate (beats per min), time to exhaustion (min), forced vital capacity (FEV) (%), forced expiratory volume in the first second (FEV1) (%), total lung capacity (TLC) (%), and lung diffusion capacity for carbon monoxide (DL(CO)) (%). Individuals were 27 with type 1 diabetes: 15 athletes (ADM) and 12 nonathletes (NADM); and 24 healthy individuals: 12 ADM and 12 NADM. Duration of diabetes was 14.6 ± 6.2 and 15.2 ± 6.7 years in ADM and NADM, respectively. RESULTS: Vo(2 peak) (max) was higher in ADM than in NADM (P < 0.001). The anaerobic threshold was lower in subjects with type 1 diabetes than in control subjects (P < 0.001). FEV1 was lower in ADM than in other groups (NADM, athletes control, and nonathletes control, P < 0.001). CONCLUSIONS: Aerobic capacity in subjects with type 1 diabetes with programmed exercise is similar to the capacity of normal athletes despite lower anaerobic threshold and FEV1.

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.An additional source used, as a basis for the new algorithm, was to assess the acceptability of controversial arguments published in international literature, through a panel of renowned Brazilian specialists. Thirty controversial arguments in diabetes have been selected with their respective references, where each argument was assessed and scored according to its acceptability level and personal conviction of each member of the evaluation panel.This methodology was adapted using a similar approach to the one adopted in the recent position statement by the American College of Cardiology on coronary revascularization, of which not only cardiologists took part, but also specialists of other related areas.

Association of lipoprotein lipase D9N polymorphism with myocardial infarction in type 2 diabetes: the genetics, outcomes, and lipids in type 2 diabetes (GOLD) study.

The association of polymorphisms affecting lipid metabolism with the risk of myocardial infarction (MI) in type 2 diabetes mellitus was investigated. The Genetics, Outcomes and Lipids in type 2 Diabetes (GOLD) Study is a prospective, multicenter study, conducted on 990 patients presenting diabetes and MI (n=386), or diabetes without previous manifestation of stroke, peripheral or coronary arterial disease (n=604), recruited from 27 institutions in Brazil. APO A1 (A/G -75 and C/T +83) and APO C3 (C/G 3'UTR) non-coding sequences, CETP (Taq 1B), LPL (D9N), APO E (epsilon2, epsilon3, epsilon4,), PON-1 (Q192R), and two LCAT variants Arg(147)-->Trp and Tyr(171)-->Stop were tested by PCR-RFLP. There was a higher prevalence of LPL DN genotype (19% vs.12%, p=0.03) and a higher frequency of the N allele (11% vs. 7%) among subjects with MI when compared to controls, with an odds ratio of MI for carriers of 9N allele of 2.46 (95% CI=1.79-3.39, p<0.0001). This association was present in men and women, in non-smokers and in hypertensive patients. A logistic regression model including gender, duration of diabetes, systolic blood pressure, HDL-C, left ventricle hypertrophy and D9N polymorphism showed that the latter still remained significantly associated with MI (OR=1.50, 95% CI=1.02-2.25, p=0.049). These findings suggest that D9N polymorphism can be a useful risk marker for myocardial infarction and that further potential candidate genes should be screened for exploratory analysis and for future therapeutic intervention in diabetes.

[In hospital care for diabetic foot: a comparison between the estimated cost and the SUS reimbursement]. / Internações por pé diabético: comparação entre o custo direto estimado e o desembolso do SUS.

This study aimed to analyze costs for treating patients with diabetic foot cared by the public Brazilian Health System (SUS), comparing the estimated cost with the amount of SUS reimbursement. A cohort prospective study carried out in hospitals that provide services for the Unified Health System in Sergipe, involving 109 hospitalization episodes of patients with diabetes and foot ulcers. We follow these patients day by day and estimated the hospital direct cost and the SUS reimbursement. All patients had type 2 diabetes and the majority of ulcers (64.2%) were classified as Wagner 4 or 5. Forty-three (39.4%) healed without amputation and fifty-two (47.7%) healed with amputation. Fourteen (12.8%) patients died. Hospital direct cost ranged from R$ 943.72 to R$ 16,378.85; with an average of R$ 4,461.04. The SUS reimbursement varied from R$ 96.95 to R$ 2,410.18, with an average of R$ 633.97, usually seven times low. Smaller difference between costs occurred in patients from the Beneficent hospital and higher rates occurred in those treated with minor amputation.