Janet B. McGill

A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

BACKGROUND Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. METHODS In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. RESULTS Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. CONCLUSIONS The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Role of Orlistat in the Treatment of Obese Patients With Type 2 Diabetes: A 1-year randomized double-blind study

OBJECTIVE Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28–40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS After 1 year of treatment, the orlistat group lost 6.2 ± 0.45% (mean ± SEM) of initial body weight vs. 4.3 ± 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost ≥ 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.

CONSENSUS STATEMENT BY THE AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY ON THE COMPREHENSIVE TYPE 2 DIABETES MANAGEMENT ALGORITHM--2016 EXECUTIVE SUMMARY.

Abbreviations: A1C = hemoglobin A1C AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascular Risk in Diabetes ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ACEI = angiotensinconverting enzyme inhibitor AGI = alpha-glucosidase inhibitor apo B = apolipoprotein B ARB = angiotensin II receptor blocker ASCVD = atherosclerotic cardiovascular disease BAS = bile acid sequestrant BMI = body mass index BP = blood pressure CHD = coronary heart disease CKD = chronic kidney disease CVD = cardiovascular disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 EPA = eicosapentaenoic acid FDA = Food and Drug Administration GLP-1 = glucagon-like peptide 1 HDL-C = high-density-lipoprotein cholesterol LDL-C = low-densitylipoprotein cholesterol LDL-P = low-density-lipoprotein particle Look AHEAD = Look Action for Health in Diabetes NPH = neutral protamine Hagedorn OSA = obstructive sleep apnea SFU = sulfonylurea SGLT-2 = sodium glucose cotrans...

Effects of nortriptyline on depression and glycemic control in diabetes: results of a double-blind, placebo-controlled trial.

Objective Depression is a prevalent and chronic condition in diabetes and is associated with poor glucose regulation and poor compliance with diabetes treatment. This investigation evaluated the effects of nortriptyline on depression and glycemic control to see whether depression in diabetes is treatable and whether restoring mental health contributes to improved medical outcome. Method: Sixty-eight diabetic patients with poor glycemic control, 28 of whom had active major depression (DSM-IIIR), completed a randomized, placebo-controlled, double-blind trial involving 8 weeks of treatment with nortriptyline targeted to therapeutic plasma levels (50-150 ng/ml). Depression improvement was determined with the Beck Depression Inventory; glucose control was measured by glycated hemoglobin levels. Compliance behavior was assessed using medication dispensing devices and glucometers equipped with electronic memory. Results: The reduction in depression symptoms was significantly greater in depressed patients treated with nortriptyline compared with those receiving placebo (-10.2 vs -5.8, p =.03). Nortriptyline was not statistically superior to placebo in reducing glycated hemoglobin of the depressed subjects (p =.5). However, path analysis indicated that the direct effect of nortriptyline was to worsen glycemic control whereas depression improvement had an independent beneficial effect on glycated hemoglobin. These findings were not explained by the relationships of nortriptyline treatment to weight change (r = -0.21, p =.31) or depression improvement to compliance with the protocol for self-monitoring of blood glucose (r = 0.01, p =.97). Conclusions: Major depression in diabetic patients can be effectively treated with nortriptyline at the expense of a direct hyperglycemic effect. Path analysis demonstrated a treatment-independent effect of depression improvement on glycemic control, suggesting that a more ideal antidepressant agent may both restore mental health and improve medical outcome.

Factors Responsible for Impaired Fibrinolysis in Obese Subjects and NIDDM Patients

Accelerated atherosclerosis is the leading cause of death in patients with non-insulin-dependent diabetes mellitus (NIDDM). Impaired endogenous fibrinolytic activity may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi and clot-associated mitogens. This study was conducted to further characterize endogenous fibrinolysis in lean and obese nondiabetic subjects and in NIDDM patients and to identify mechanisms responsible for the alterations identified. Obese and diabetic subjects had threefold elevations of plasma concentrations of plasminogen activator inhibitor type 1 (PAI-1) compared with values in lean control subjects. Despite the lack of significant differences in plasma concentrations of tissue-type plasminogen activator in the obese and diabetic subjects, both basal and stimulated endogenous fibrinolytic activities were decreased. The decreases were associated with increased activity of PAI-1 in plasma, in turn correlated with increased concentrations of immunoreactive insulin and C-peptide. These results are consistent with our previous observations demonstrating direct stimulatory effects of insulin and its precursors on cellular expression of PAI-1 in vitro and observations by others demonstrating decreased basal fibrinolytic activity in NIDDM patients. Impaired endogenous fibrinolytic activity could lead to prolonged or recurrent exposure of luminal surfaces of vessel walls to microthrombi and clot-associated mitogens that may accelerate atherosclerosis in hyperinsulinemic subjects.

The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria ☆

PURPOSE To determine whether angiotensin-converting enzyme (ACE) inhibition with captopril reduces the progression of microalbuminuria to overt proteinuria in normotensive patients with insulin-dependent diabetes mellitus (IDDM). PATIENTS AND METHODS This study was a prospective randomized, double-blind, placebo-controlled trial involving 26 centers in the United States and Canada. One hundred forty-three subjects, 14 to 57 years of age, with IDDM for 4 to 33 years, blood pressure < 140/90 mm Hg in the absence of antihypertensive therapy, and persistent albumin excretion 20 to 200 micrograms/min were randomized to double-blind treatment with captopril 50 mg or placebo BID. Albumin excretion rate (AER), blood pressure, and glycohemoglobin were determined every 3 months, and creatinine clearance (CrCl) and urea excretion were measured every 6 months. RESULTS Within 24 months, 6.0% (4/67) of captopril-treated subjects and 18.6% (13/70) of placebo-treated subjects progressed to clinical proteinuria, defined as AER > 200 micrograms/min and at least 30% above baseline (risk reduction = 67.8%, P = 0.037). AER increased at an annual rate of 11.8% (95% confidence interval [CI] -3.3% to 29.1%) in the placebo group, while it declined by 17.9% (CI -29.6% to -4.3%) in the captopril group (P = 0.004). CrCl decreased by 4.9 mL/min per 1.73 m2 per year in the placebo group, while it remained stable in the captopril group (0.9 mL/min per 1.73 m2 per year, P = 0.039 between groups). Ten subjects required treatment for hypertension; 8 in the placebo group and 2 in the captopril group. There was little correlation between the 24-month changes in mean arterial blood pressure and AER in either group. Glycohemoglobin and urinary urea excretion did not differ between groups. CONCLUSIONS After 24 months of therapy with captopril, compared with placebo, normotensive subjects with IDDM experienced significantly less progression of microalbuminuria to clinical proteinuria, reduced albumin excretion, and preserved CrCl rate. The ACE inhibitor, captopril, was well tolerated.

American Association of Clinical Endocrinologists' Comprehensive Diabetes Management Algorithm 2013 Consensus Statement - Executive Summary

Alan J. Garber, MD, PhD, FACE; Martin J. Abrahamson, MD; Joshua I. Barzilay, MD, FACE; Lawrence Blonde, MD, FACP, FACE; Zachary T. Bloomgarden, MD, MACE; Michael A. Bush, MD; Samuel Dagogo-Jack, MD, FACE; Michael B. Davidson, DO, FACE; Daniel Einhorn, MD, FACP, FACE; W. Timothy Garvey, MD; George Grunberger, MD, FACP, FACE; Yehuda Handelsman, MD, FACP, FACE, FNLA; Irl B. Hirsch, MD; Paul S. Jellinger, MD, MACE; Janet B. McGill, MD, FACE; Jeffrey I. Mechanick, MD, FACE, ECNU, FACN, FACP; Paul D. Rosenblit, MD, PhD, FACE, FNLA; Guillermo E. Umpierrez, MD, FACE; Michael H. Davidson, MD, FACC, FACP, FNLA

Anxiety and Poor Glycemic Control: A Meta-Analytic Review of the Literature

Objective: To determine whether anxiety is associated with poor glycemic control in adults with type 1 or type 2 diabetes. Method: MEDLINE, PubMed, and PsycINFO databases were used to locate studies that measured the association of anxiety with glycemic control. Meta-analytic procedures were used to convert the findings to a common metric, compute effect sizes (ES), and statistically analyze the collective data. Results: The search procedures identified 12 studies, 11 (92 percent) of which satisfied the criteria for inclusion in the meta-analysis. In this overall group, anxiety was not associated with glycemic control (p = 0.19), although the ES was marginally statistically significant (ES = .09, 95 percent CI = 0.04 to 0.14). In studies that determined anxiety from diagnostic interviews, anxiety was associated with hyperglycemia (p = 0.003) and the ES was also statistically significant (ES: 0.25, 95 percent CI = 0.10 to 0.38). Conclusions: The existing literature suggests that anxiety disorders are associated with hyperglycemia in diabetic patients. Additional studies are required to confirm the magnitude of the relationship, to elucidate moderating and causal factors, and to determine whether successful treatment of anxiety improves glycemic control.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY - CLINICAL PRACTICE GUIDELINES FOR DEVELOPING A DIABETES MELLITUS COMPREHENSIVE CARE PLAN - 2015

The American Association of Clinical Endocrinologists/American College of Endocrinology Medical Guidelines for Clinical Practice are systematically developed statements to assist healthcare professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. The presented recommendations may not be appropriate in all situations. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances. Abbreviations: A1C = hemoglobin A1c AACE = American Association of Clinical Endocrinologists ACCORD = Action to Control Cardiovascu...

Evidence of a Strong Association Between Frequency of Self-Monitoring of Blood Glucose and Hemoglobin A1c Levels in T1D Exchange Clinic Registry Participants

OBJECTIVE Despite substantial evidence of the benefit of frequent self-monitoring of blood glucose (SMBG) in type 1 diabetes, certain insurers limit the number of test strips that they will provide. The large database of the T1D Exchange clinic registry provided an opportunity to evaluate the relationship between the number of SMBG measurements per day and HbA1c levels across a wide age range of children and adults. RESEARCH DESIGN AND METHODS The analysis included 20,555 participants in the T1D Exchange clinic registry with type 1 diabetes ≥1 year and not using a continuous glucose monitor (11,641 younger than age 18 years and 8,914 18 years old or older). General linear models were used to assess the association between the number of SMBG measurements and HbA1c levels after adjusting for potential confounding variables. RESULTS A higher number of SMBG measurements per day were associated with non-Hispanic white race, insurance coverage, higher household income, and use of an insulin pump for insulin delivery (P < 0.001 for each factor). After adjusting for these factors, a higher number of SMBG measurements per day was strongly associated with a lower HbA1c level (adjusted P < 0.001), with the association being present in all age-groups and in both insulin pump and injection users. CONCLUSIONS There is a strong association between higher SMBG frequency and lower HbA1c levels. It is important for insurers to consider that reducing restrictions on the number of test strips provided per month may lead to improved glycemic control for some patients with type 1 diabetes.