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Ford E.S.,Centers for Disease Control and Prevention | Cowie C.C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Li C.,Centers for Disease Control and Prevention | Handelsman Y.,Metabolic Institute of America | Bloomgarden Z.T.,Mount Sinai School of Medicine
Journal of Diabetes | Year: 2011

Background: Conditions that affect erythrocyte turnover affect HbA1c concentrations. Although many forms of anemia are associated with lowering of HbA1c, iron deficiency tends to increase HbA1c. We examined the effect of iron and hemoglobin (Hb) status on HbA1c and on the relationship between concentrations of fasting glucose and HbA1c in a national sample of adults in the US. Methods: Cross-sectional data from 8296 adults aged ≥20years who participated in NHANES 1999-2002 were used. Results: The prevalence of low Hb (defined as <120 and <118g/L in women aged 20-69 and ≥70years, respectively, and <137, <133, and <124g/L in men aged 20-49, 50-69, and ≥70years, respectively) was 5.5%. There was a significant positive correlation between Hb concentrations and HbA1c concentrations after adjusting for age, gender, and race or ethnicity, with HbA1c rising from a mean of 5.28% among participants with Hb <100g/L to 5.72% among participants with Hb ≥170g/L. The adjusted mean concentrations of HbA1c were 5.56% and 5.46% among participants with and without iron deficiency, respectively (P=0.095). However, there was no evidence of differences in the relationship between fasting glucose and HbA1c when groups of anemic and non-anemic individuals with and without iron deficiency were examined individually. Conclusions: Caution should be used when diagnosing diabetes and prediabetes among people with high or low Hb when the HbA1c level is near 6.5% or 5.7%, respectively, as changes in erythrocyte turnover may alter the test result. However, the trend for HbA1c to increase with iron deficiency does not appear to require screening for iron deficiency in ascertaining the reliability of HbA1c in the diagnosis of diabetes and prediabetes in a given individual. © 2011 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.


Zinman B.,Samuel Lunenfeld Research Institute | Philis-Tsimikas A.,Scripps Whittier Diabetes Institute | Cariou B.,Nantes University Hospital Center | Handelsman Y.,Metabolic Institute of America | And 4 more authors.
Diabetes Care | Year: 2012

OBJECTIVE - To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patientswith type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS - In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7-10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast plasma glucose (PG) of 3.9-4.9 mmol/L. The primary end point was confirmation of noninferiority of degludec to glargine in A1C reduction after 52 weeks in an intent-to-treat analysis. RESULTS - In all, 1,030 participants (mean age 59 years; baseline A1C 8.2%) were randomized (degludec 773, glargine 257). Reduction in A1C with degludec was similar (noninferior) to that with glargine (1.06 vs. 1.19%), with an estimated treatment difference of degludec to glargine of 0.09% (95% CI -0.04 to 0.22). Overall rates of confirmed hypoglycemia (PG <3.1 mmol/L or severe episodes requiring assistance) were similar, with degludec and glargine at 1.52 versus 1.85 episodes/patient-year of exposure (PYE). There were few episodes of nocturnal confirmed hypoglycemia in the overall population, and these occurred at a lower rate with degludec versus glargine (0.25 vs. 0.39 episodes/PYE; P = 0.038). Similar percentages of patients in both groups achieved A1C levels <7% without hypoglycemia. End-of-trial mean daily insulin doses were 0.59 and 0.60 units/kg for degludec and glargine, respectively. Adverse event rates were similar. CONCLUSIONS - Insulins degludec and glargine administered once daily in combination with OADs provided similar long-term glycemic control in insulin-naive patients with type 2 diabetes, with lower rates of nocturnal hypoglycemia with degludec. © 2012 by the American Diabetes Association.


Rodbard H.W.,Endocrine and Metabolic Consultants | Cariou B.,Nantes University Hospital Center | Zinman B.,Samuel Lunenfeld Research Institute | Handelsman Y.,Metabolic Institute of America | And 4 more authors.
Diabetic Medicine | Year: 2013

Aims: The aim of this study was to compare long-term safety and efficacy of the basal insulin analogue degludec with glargine in insulin-naive subjects with Type 2 diabetes. Methods: This open-label trial included a 52-week core period followed by a 52-week extension. Participants were randomized 3:1 to once-daily degludec or glargine, administered with metformin ± dipeptidyl peptidase-4 inhibitors. Basal insulin was titrated to target pre-breakfast plasma glucose 3.9-4.9 mmol/l. Results: At end of treatment (104 weeks), mean HbA1c reductions were similar for degludec and glargine; estimated treatment difference between degludec and glargine was 1 mmol/mol (95% CI -1 to 3) [0.07% (95% CI -0.07 to 0.22)], P = 0.339 in the extension trial set (degludec 551, glargine 174), comprising subjects who completed core trial and continued into the extension trial. Overall confirmed hypoglycaemia rates (1.72 vs. 2.05 episodes/patient-year), rates of adverse events possibly or probably related to trial product (0.19 events/patient-year), weight gain (2.7 vs. 2.4 kg) and mean daily insulin doses (0.63 U/kg) were similar between treatments in the safety analysis set (degludec 766, glargine 257) comprising all treated subjects. Rates of nocturnal confirmed hypoglycaemia (0.27 vs. 0.46 episodes/patient-year; P = 0.002) and severe hypoglycaemia (0.006 vs. 0.021 episodes/patient-year, P = 0.023) were significantly lower with degludec for the safety analysis set (analysis based on intention-to-treat full analysis set comprising all randomized subjects). Conclusions: In Type 2 diabetes, insulin degludec in combination with oral anti-diabetic drugs, safely and effectively improves long-term glycaemic control, with a significantly lower risk of nocturnal hypoglycaemia as compared with glargine. © 2013 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.


Mathieu C.,Catholic University of Leuven | Rodbard H.W.,Endocrine and Metabolic Consultants | Cariou B.,Nantes University Hospital Center | Handelsman Y.,Metabolic Institute of America | And 4 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

Aim: Two treatment strategies were compared in patients with type 2 diabetes (T2DM) on basal insulin requiring intensification: addition of once-daily (OD) liraglutide (Lira) or OD insulin aspart (IAsp) with largest meal. Methods: Subjects completing 104weeks (52-week main trial BEGIN ONCE-LONG + 52-week extension) on insulin degludec (IDeg) OD + metformin with HbA1c≥7.0% (≥53mmol/mol) were randomized to IDeg+Lira [n=88, mean HbA1c: 7.7% (61mmol/mol)] or IDeg+IAsp (n=89, mean HbA1c: 7.7%) for 26weeks, continuing metformin. Subjects completing 104weeks with HbA1c <7.0% continued IDeg+metformin in a third, non-randomized arm (n=236). Results: IDeg+Lira reduced HbA1c (-0.74%-points) significantly more than IDeg+IAsp (-0.39%-points); estimated treatment difference (ETD) (IDeg+Lira-IDeg+IAsp) -0.32%-points (95% CI -0.53; -0.12); p=0.0024. More IDeg+Lira (49.4%) than IDeg+IAsp (7.2%) subjects achieved HbA1c <7.0% without confirmed hypoglycaemia [plasma glucose <3.1mmol/l (<56mg/dl) or severe hypoglycaemia) and without weight gain; estimated odds ratio (IDeg+Lira/IDeg+IAsp) 13.79 (95% CI 5.24; 36.28); p<0.0001. IDeg+Lira subjects had significantly less confirmed and nocturnal confirmed hypoglycaemia, and significantly greater weight loss (-2.8kg) versus IDeg+IAsp (+0.9kg); ETD (IDeg+Lira-IDeg+IAsp) -3.75kg (95% CI -4.70; -2.79); p<0.0001. Other than more gastrointestinal side effects with IDeg+Lira, no safety differences occurred. Durability of IDeg was established in the non-randomized arm, as mean HbA1c remained <7.0% [mean 6.5% (48mmol/mol) at end-of-trial]. Conclusions: IDeg+Lira improved long-term glycaemic control, with weight loss and less hypoglycaemia versus adding a single daily dose of IAsp in patients with T2DM inadequately controlled with IDeg+metformin. © 2014 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.


Staels B.,Institute Pasteur Of Lille | Handelsman Y.,Metabolic Institute of America | Fonseca V.,Tulane University
Current Diabetes Reports | Year: 2010

Bile acids are generated in the liver and are traditionally recognized for their regulatory role in multiple metabolic processes including bile acid homeostasis, nutrient absorption, and cholesterol homeostasis. Recently, bile acids emerged as signaling molecules that, as ligands for the bile acid receptors farnesoid X receptor (FXR) and TGR5, activate and integrate multiple complex signaling pathways involved in lipid and glucose metabolism. Bile acid sequestrants are pharmacologic molecules that bind to bile acids in the intestine resulting in the interruption of bile acid homeostasis and, consequently, reduction in low-density lipoprotein cholesterol levels in hypercholesterolemia. Bile acid sequestrants also reduce glucose levels and improve glycemic control in persons with type 2 diabetes mellitus (T2DM). This article examines the mechanisms by which bile acid-mediated activation of FXR and TGR5 signaling pathways regulate lipid and glucose metabolism and the potential implications for bile acid sequestrant-mediated regulation of lipid and glucose levels in T2DM.


Fonseca V.A.,Tulane University | Handelsman Y.,Metabolic Institute of America | Staels B.,University of Lille Nord de France | Staels B.,French Institute of Health and Medical Research | Staels B.,Institute Pasteur Of Lille
Diabetes, Obesity and Metabolism | Year: 2010

Simultaneous control of blood glucose and other risk factors such as hypertension and dyslipidaemia is essential for reducing the risk of complications associated with type 2 diabetes mellitus (T2DM). As relatively few patients with T2DM have their risk factors managed to within the limits recommended by the American Diabetes Association, American College of Endocrinology or National Cholesterol Education Program Adult Treatment Panel III guidelines, treatment that can simultaneously control more than one risk factor is of therapeutic benefit. Clinical studies have shown that bile acid sequestrants have glucose-lowering effects in addition to their low-density lipoprotein cholesterol-lowering effects in patients with T2DM. The bile acid sequestrant colesevelam hydrochloride is approved as an adjunct to antidiabetes therapy for improving glycaemic control in adults with T2DM. This review examines data from three phase III clinical trials that evaluated the glucose- and lipid-lowering effects of colesevelam when added to the existing antidiabetes treatment regimen of patients with T2DM. © 2010 Blackwell Publishing Ltd.


Leiter L.A.,Li Ka Shing Knowledge Institute | Carr M.C.,Glaxosmithkline | Stewart M.,Glaxosmithkline | Jones-Leone A.,Glaxosmithkline | And 3 more authors.
Diabetes Care | Year: 2014

OBJECTIVE To evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and/or oral antihyperglycemic medications.RESEARCH DESIGN AND METHODS In this phase III, randomized, double-blind, multicenter, 52-week study, the primary study end point was HbA1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and categorized as mild, moderate, or severe (≥60 to ≤89, ≥30 to ≤59, and ≥15 to ≤29 mL/min/1.73 m2, respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety.RESULTS Baseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m2, HbA1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (20.83% vs. 20.52%, P = 0.0003). Decreases in HbA1c, FPG, and weight were seen through week 52. Time to hyperglycemic rescue through week 52was significantly longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments were similar between groups, and most adverse events (AEs) were mild or moderate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and vomiting, 1.6%, 1.2%, respectively.CONCLUSIONS Once-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy. © 2014 by the American Diabetes Association.


Handelsman Y.,Metabolic Institute of America
Journal of Managed Care Medicine | Year: 2013

Obesity is a major risk factor for developing type 2 diabetes and cardiovascular disease and is epidemic in the United States. Targeting this major public health problem requires lifestyle modifications and many times pharmacotherapy or bariatric surgery. Two new products for long-term use for weight management were recently approved and will hopefully be a step forward in helping significantly overweight individuals.


Handelsman Y.,Metabolic Institute of America
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | Year: 2010

To assess the effect of the bile acid sequestrant colesevelam hydrochloride in patients with hypercholesterolemia and prediabetes. In this 16-week, randomized, double-blind study, adults with untreated prediabetes (2-hour postoral glucose tolerance test [OGTT] glucose > or =140 to 199 mg/dL, fasting plasma glucose [FPG] > or =110 to 125 mg/dL, or both), low-density lipoprotein cholesterol (LDL-C) > or =100 mg/dL, and triglycerides <500 mg/dL were randomly assigned to receive colesevelam (3.75 g/d) or placebo. The primary end point was percent change in LDL-C from baseline to week 16 with last observation carried forward. Secondary end points included change in FPG, hemoglobin A1c (A1C), and 2-hour post-OGTT glucose level from baseline to week 16 and attainment of LDL-C and FPG targets. In total, 216 patients were randomized (colesevelam, 108; placebo, 108). In comparison with placebo, colesevelam significantly reduced LDL-C (mean treatment difference, -15.6%), non-high-density lipoprotein cholesterol (-9.1%), total cholesterol (-7.2%), apolipoprotein B (-8.1%) (P<.001 for all the foregoing), FPG (median, -2.0 mg/dL; P = .02), and A1C (mean, -0.10%; P = .02). Colesevelam did not significantly change 2-hour post-OGTT glucose (-1.9 mg/dL; P = .75) or high-density lipoprotein cholesterol (-0.5%; P = .80). In addition, colesevelam significantly increased triglyceride levels relative to placebo (median, 14.3%; P<.001). The proportion of patients achieving target levels with colesevelam versus placebo, respectively, was as follows: LDL-C <100 mg/dL (29% versus 11%; P<.001), A1C <6.0% (37% versus 25%; P = .05), FPG <110 mg/dL (48% versus 56%; P = .97), and normalization of glucose (FPG <100 mg/dL [40% versus 23%; P = .06]). Colesevelam had a weight-neutral effect and was well tolerated. Colesevelam is an option for managing the lipid profile and normalizing glucose levels in patients with hypercholesterolemia and prediabetes. Further study is warranted to determine whether colesevelam slows or prevents progression of prediabetes to type 2 diabetes.


Handelsman Y.,Metabolic Institute of America
Journal of Managed Care Medicine | Year: 2013

Type 2 diabetes, and resulting cardiovascular disease, continues to be an epidemic problem in the U.S. To fight this epidemic, prevention and treatment needs to be focused on all risk factors present in patients. The newer agents that target the incretin system have a role in managing glucose without significant adverse effects.

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