Ele Ferrannini

Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)

Erratum to: DiabetologiaDOI 10.1007/s00125-012-2534-0In the text box ‘Properties of currently available glucose-lowering agents that may guide treatment choice in individualpatients with type 2 diabetes mellitus ’ vildagliptin was incor-rectly assigned footnote ‘a’ (Limited use in the USA/Europe)instead of footnote ‘b’ (Not licensed in the USA).

Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement of the American Diabetes Association and the European Association for the Study of Diabetes

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes

In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2). Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR).

Insulin resistance and insulin hypersecretion are established features of obesity. Their prevalence, however, has only been inferred from plasma insulin concentrations. We measured insulin sensitivity (as the whole-body insulin-mediated glucose uptake) and fasting posthepatic insulin delivery rate (IDR) with the use of the euglycemic insulin clamp technique in a large group of obese subjects in the database of the European Group for the Study of Insulin Resistance (1,146 nondiabetic, normotensive Caucasian men and women aged 18-85 yr, with a body mass index (BMI) ranging from 15 to 55 kg.m-2). Insulin resistance, defined as the lowest decile of insulin sensitivity in the lean subgroup (608 subjects with a mean BMI of 29 kg.m-2). Insulin sensitivity declined linearly with BMI at an age- and sex-adjusted rate of 1.2 micromol.min-1.kg FFM-1 per BMI unit (95% confidence intervals = 1.0-1.4). Insulin hypersecretion, defined as the upper decile of IDR, was significantly (P<0.0001) more prevalent (38%) than insulin resistance in the obese group. In the whole dataset, IDR rose as a function of both BMI and insulin resistance in a nonlinear fashion. Neither the waist circumference nor the waist-to-hip ratio, indices of body fat distribution, was related to insulin sensitivity after adjustment for age, gender, and BMI; both, however, were positively associated (P<0.001) with insulin hypersecretion, particularly in women. In nondiabetic, normotensive obese subjects, the prevalence of insulin resistance is relatively low, and is exceeded by the prevalence of insulin hypersecretion, particularly in women with central obesity. In the obese with preserved insulin sensitivity, risk for diabetes, cardiovascular risk, and response to treatment may be different than in insulin resistant obesity.

Endothelial function and dysfunction. Part Ii: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension*

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

Dapagliflozin Monotherapy in Type 2 Diabetic Patients With Inadequate Glycemic Control by Diet and Exercise: A randomized, double-blind, placebo-controlled, phase 3 trial

OBJECTIVE Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose cotransporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner. We evaluated the efficacy and safety of dapagliflozin in treatment-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0–10% (n = 485) were randomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). Patients with A1C 10.1–12% (high-A1C exploratory cohort; n = 73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin. The primary end point was change from baseline in A1C in the main cohort, statistically tested using an ANCOVA. RESULTS In the main cohort, mean A1C changes from baseline at week 24 were −0.23% with placebo and −0.58, −0.77 (P = 0.0005 vs. placebo), and −0.89% (P < 0.0001 vs. placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results. CONCLUSIONS Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes.

How to measure insulin sensitivity

Insulin resistance is common in the general population and tends to cluster with glucose intolerance, dyslipidaemia and high blood pressure. The importance of the insulin-resistant phenotype for the assessment of cardiovascular risk and response to intervention is increasingly being recognized. Therefore, there is a need for an accurate and reproducible method for measuring insulin resistance in vivo. The euglycaemic insulin clamp is currently the best available standard technique. It provides steady-state measures of insulin action and is easily combined with a number of other investigative methods (tracer dilution, limb catheterization, indirect calorimetry, positron emission tomography and nuclear magnetic resonance scans). Whereas homeostatic model assessment uses fasting plasma glucose and insulin concentrations to derive indices of insulin sensitivity and secretion from a mathematical model, other techniques are based on the exogenous infusion of glucose or insulin, or both, either under steady-state (the insulin suppression test) or under dynamic conditions (insulin tolerance test, intravenous glucose-tolerance test with minimal model analysis, and constant infusion of glucose with model assessment). This article recalls the principles of insulin action, with special reference to the concept of clearance and the equivalence of different approaches to estimating this function. Merits and disadvantages of the various techniques are then concisely reviewed, with emphasis on their relative feasibilities and reliabilities. Recent developments and future trends are mentioned. Criteria for choice and some reference data are given to aid the clinical investigator.

Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.

In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on longterm treatment outcomeswithmanyof thesemedications, the 2012publicationwas less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patientcentered care and shared decision making, and this continues to be our position, although therearenowmorehead-to-head trials that showslight variancebetweenagents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient. The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-facemeeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2).

α-Hydroxybutyrate Is an Early Biomarker of Insulin Resistance and Glucose Intolerance in a Nondiabetic Population

Background Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects. Methods Using mass spectrometry, non-targeted biochemical profiling was conducted in a cohort of 399 nondiabetic subjects representing a broad spectrum of insulin sensitivity and glucose tolerance (based on the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing, respectively). Results Random forest statistical analysis selected α-hydroxybutyrate (α–HB) as the top-ranked biochemical for separating insulin resistant (lower third of the clamp-derived MFFM = 33 [12] µmol·min−1·kgFFM −1, median [interquartile range], n = 140) from insulin sensitive subjects (MFFM = 66 [23] µmol·min−1·kgFFM −1) with a 76% accuracy. By targeted isotope dilution assay, plasma α–HB concentrations were reciprocally related to MFFM; and by partition analysis, an α–HB value of 5 µg/ml was found to best separate insulin resistant from insulin sensitive subjects. α–HB also separated subjects with normal glucose tolerance from those with impaired fasting glycemia or impaired glucose tolerance independently of, and in an additive fashion to, insulin resistance. These associations were also independent of sex, age and BMI. Other metabolites from this global analysis that significantly correlated to insulin sensitivity included certain organic acid, amino acid, lysophospholipid, acylcarnitine and fatty acid species. Several metabolites are intermediates related to α-HB metabolism and biosynthesis. Conclusions α–hydroxybutyrate is an early marker for both insulin resistance and impaired glucose regulation. The underlying biochemical mechanisms may involve increased lipid oxidation and oxidative stress.

Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients

OBJECTIVE—To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS—Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20–61 kg/m2). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS—The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27–0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. CONCLUSIONS—Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.