This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there are no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician. AACE/ACE Task Force on Integration of Insulin Pumps and Continuous Glucose Monitoring in the Management of Patients With Diabetes Mellitus Chair George Grunberger, MD, FACP, FACE Task Force Members Yehuda Handelsman, MD, FACP, FNLA, MACE Zachary T. Bloomgarden, MD, MACE Vivian A. Fonseca, MD, FACE Alan J. Garber, MD, PhD, FACE Richard A. Haas, MD, FACE Victor L. Roberts, MD, MBA, FACP, FACE Guillermo E. Umpierrez, MD, CDE, FACP, FACE Abbreviations: AACE = American Association of Clinical Endocrinologists ACE = American College of Endocrinology A1C = glycated hemoglobin BGM = blood glucose monitoring CGM = continuous glucose monitoring CSII = continuous subcutaneous insulin infusion DM = diabetes mellitus FDA = Food & Drug Administration MDI = multiple daily injections T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus SAP = sensor-augmented pump SMBG = self-monitoring of blood glucose STAR 3 = Sensor-Augmented Pump Therapy for A1C Reduction phase 3 trial.

While patients with type 2 diabetes mellitus have significantly higher risks of a first coronary heart disease (CHD) event, only 3 randomized trials have been published on the use of aspirin for primary prevention in such patients. The Early Treatment of Diabetic Retinopathy Study (ETDRS) tested the effects of aspirin in patients with type 2 diabetes and retinopathy on the prespecified endpoints of cardiovascular events and mortality. Although aspirin produced benefits, nearly half of the subjects had a prior cardiovascular event at randomization ( 1. Aspirin effects on mortality and morbidity in patients with diabetes mellitus: early treatment diabetic retinopathy study report 14. ETDRS Investigators. JAMA. 1992; 268: 1292-1300 Crossref PubMed Scopus (515) Google Scholar , 2. Desai D. Ahmed H.M. Michos E.D. Preventing cardiovascular disease in patients with diabetes: use of aspirin for primary prevention. Curr Cardiol Rep. 2015; 17: 566 Crossref PubMed Scopus (4) Google Scholar ). The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial failed to demonstrate any significant effect of aspirin on clinical cardiovascular disease in patients with type 2 diabetes, and a subsequent 10-year follow up also indicated an increased risk for gastrointestinal (GI) bleeding ( 3. Ogawa H. Nakayama M. Morimoto T. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes. JAMA. 2008; 300 (et al): 2134-2141 Crossref PubMed Scopus (691) Google Scholar , 4. Saito Y. Okada S. Ogawa H. Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus 10-year follow-up of a randomized controlled trial. Circulation. 2017; 135 (et al): 659-670 Crossref PubMed Scopus (107) Google Scholar ). The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial also showed no significant benefits of aspirin in patients with type 2 diabetes and symptomatic peripheral artery disease ( 5. Belch J. MacCuish A. Campbell I. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and anti-oxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ. 2008; 337 (et al): a1840 Crossref PubMed Scopus (580) Google Scholar ).

The authors thank the reader for pointing out inconsistencies between the executive summary of the 2018 American Association of Clinical Endocrinologists Type 2 Diabetes Management Algorithm and the prescribing information of various glucagon-like peptide 1 receptor agonists. The authors agree that it is incorrect to state that all of these agents are contra-indicated in stage 4 and 5 chronic kidney disease and have requested that an erratum be issued with the paper.

OBJECTIVE The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. RESULTS The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). CONCLUSION This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. ABBREVIATIONS 4S = Scandinavian Simvastatin Survival Study A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists AAP = American Academy of Pediatrics ACC = American College of Cardiology ACE = American College of Endocrinology ACS = acute coronary syndrome ADMIT = Arterial Disease Multiple Intervention Trial ADVENT = Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study AHA = American Heart Association AHRQ = Agency for Healthcare Research and Quality AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial ASCVD = atherosclerotic cardiovascular disease ATP = Adult Treatment Panel apo = apolipoprotein BEL = best evidence level BIP = Bezafibrate Infarction Prevention trial BMI = body mass index CABG = coronary artery bypass graft CAC = coronary artery calcification CARDS = Collaborative Atorvastatin Diabetes Study CDP = Coronary Drug Project trial CI = confidence interval CIMT = carotid intimal media thickness CKD = chronic kidney disease CPG(s) = clinical practice guideline(s) CRP = C-reactive protein CTT = Cholesterol Treatment Trialists CV = cerebrovascular CVA = cerebrovascular accident EL = evidence level FH = familial hypercholesterolemia FIELD = Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial HATS = HDL-Atherosclerosis Treatment Study HDL-C = high-density lipoprotein cholesterol HeFH = heterozygous familial hypercholesterolemia HHS = Helsinki Heart Study HIV = human immunodeficiency virus HoFH = homozygous familial hypercholesterolemia HPS = Heart Protection Study HPS2-THRIVE = Treatment of HDL to Reduce the Incidence of Vascular Events trial HR = hazard ratio HRT = hormone replacement therapy hsCRP = high-sensitivity CRP IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial IRAS = Insulin Resistance Atherosclerosis Study JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin LDL-C = low-density lipoprotein cholesterol Lp-PLA2 = lipoprotein-associated phospholipase A2 MACE = major cardiovascular events MESA = Multi-Ethnic Study of Atherosclerosis MetS = metabolic syndrome MI = myocardial infarction MRFIT = Multiple Risk Factor Intervention Trial NCEP = National Cholesterol Education Program NHLBI = National Heart, Lung, and Blood Institute PCOS = polycystic ovary syndrome PCSK9 = proprotein convertase subtilisin/kexin type 9 Post CABG = Post Coronary Artery Bypass Graft trial PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial QALY = quality-adjusted life-year ROC = receiver-operator characteristic SOC = standard of care SHARP = Study of Heart and Renal Protection T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus TG = triglycerides TNT = Treating to New Targets trial VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VLDL-C = very low-density lipoprotein cholesterol WHI = Women's Health Initiative.

OBJECTIVEPatients with type 2 diabetes have an increased risk of fragility fractures; the cause is unclear but is likely multifactorial. Some diabetes treatments induce bone loss, accentuating underlying skeletal fragility and increasing fracture risk. This subgroup analysis aimed to compare long-term effects of liraglutide and glimepiride on bone mineral density (BMD) in patients with type 2 diabetes.METHODSLEAD-3, a 52-week, double-blind, active-control, phase III, multicenter trial, investigated the efficacy of liraglutide (1.2 and 1.8 mg/day) versus glimepiride monotherapy in type 2 diabetes. A 52-week, open-label extension followed, in which participants remained on randomized therapy. A subgroup of participants underwent BMD measurement by dual-energy X-ray absorptiometry at baseline, 52, and 104 weeks. The main outcome measure was change from baseline in total body BMD at 52 and 104 weeks, assessed by analysis of covariance.RESULTSA total of 746 patients with type 2 diabetes aged 19 to 79 years were randomized into the main trial. Of these, 61 patients (20 assigned to liraglutide 1.8 mg/day, 23 to liraglutide 1.2 mg/day, 18 to glimepiride 8 mg/day) had BMD measurements. Baseline age, body mass index, diabetes duration, glycated hemoglobin, and total BMD were similar across treatment groups. There was no apparent difference in mean total BMD change from baseline in patients receiving liraglutide 1.8 or 1.2 mg/day or glimepiride 8 mg/day at 52 or 104 weeks.CONCLUSIONIn this small subgroup analysis, liraglutide monotherapy did not negatively affect total BMD in a 2-year prospective study, suggesting it may not exacerbate the consequences of bone fragility.

Incretin-based therapies are important addition to our armamentarium for the treatment of type 2 diabetes (T2DM). There are six Glucagon-like peptide-1 receptor agonists (GLP-1RAs) which have received regulatory approval for clinical use. The short-acting GLP-1RAs include exenatide twice daily, liraglutide once daily, and lixisenatide once daily. The approved long-acting GLP-1RAs are administered weekly and are exenatide, albiglutide, and dulaglutide. Although all of these therapies lower hemoglobin A1C (HbA1C), there also are unique features of GLP-1RAs that have been made manifest from clinical trial data with regard to weight-loss efficacy, fasting and post-prandial glucose control, cardiovascular safety and protection, and gastrointestinal and injection adverse effects. It is imperative to consider these features when tailoring the choice of a GLP-1RA to patient specific characteristics.

Recent studies have suggested that there is more than one pharmacological approach to glycaemic control in patients with type 2 diabetes and that insulin may not always be the best approach to achieve control in such patients. Conventional wisdom has always held that insulin, owing to its unlimited potential for lowering blood sugar in patients with severe hyperglycaemia, was a superior therapeutic agent compared with other agents with more limited glycaemic efficacy. Insulin was therefore the accepted, and often the preferred, agent for patients with poorly controlled diabetes. This conclusion, however, overlooks two major characteristics regarding all injectable insulins, even modern insulin analogues. First, analogues do not exactly match the physiology of insulin secretion by the non-diabetic pancreas. As a result, their pharmacodynamic action profiles do not match prandial glucose excursions in patients and thus create an excess risk of hypoglycaemia. Human insulin and older types of animal insulin have a far greater potential for hypoglycaemic reactions than do modern insulin analogues, but even the latter clearly have residual hypoglycaemic potential [1]. Excess hypoglycaemia leads to undesirable outcomes, such as poor glycaemic control, weight gain from defensive eating and a greater number of emergency room visits and hospitalizations for treatment [2]. Second, in the presence of well defined standards for glycaemic control, attempts to achieve those targets in clinical practice with commercially available insulins typically incur excess rates of hypoglycaemia, which are intolerable to patients and which therefore limit the degree of glycaemic control attainable. Such limitations may be the result of actual experience in any given patient, or they may result from fear of hypoglycaemia on the part of the patient or the physician, or both. As a result, in almost all modern trials, even with the newest injectable insulin analogues, the majority of patients with type 2 diabetes fail to achieve the modest goals for glycaemic control of the American Diabetes Association [glycated haemoglogin (HbA1c) <7.0%]. Owing to the lack of alternative therapies that are effective in helping more advanced degrees of pancreatic insufficiency and hyperglycaemia, injectable basal insulin was often used in patients failing one or more oral agents and its adverse reactions tolerated, despite its many failings and inadequacies. Within the last decade, several new classes of antidiabetic therapies have appeared that produce superior glycaemic

This document represents the official position of the American Association of Clinical Endocrinologists and the American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice are systematically developed statements to assist health-care 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.

The aim of the present study was to compare the long‐term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52‐week main trial and a 26‐week extension). Patients were randomized to once‐daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre‐breakfast plasma glucose values of 3.9–4.9 mmol/l (70–88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.

Metabolic syndrome is not a disease per se, but is a term that highlights traits that may have an increased risk of disease, approximately 2-fold for cardiovascular disease and 5-fold or more for type 2 diabetes mellitus. Obesity and insulin resistance are believed to be at the core of most cases of metabolic syndrome, although further research is required to truly understand the pathophysiology behind the syndrome and the gene-environment interactions that increase susceptibility. The mainstay of treatment remains lifestyle changes with exercise and diet to induce weight loss and pharmacologic intervention to treat atherogenic dyslipidemia, hypertension, and hyperglycemia.

Insulin degludec (IDeg) is a new basal insulin with an ultra-long and stable glucose-lowering effect. A previous meta-analysis showed that IDeg was associated with lower rates of confirmed (plasma glucose [PG] <3.1 mmol/L or severe requiring assistance) and nocturnal confirmed hypoglycemia vs. insulin glargine (IGlar) in patients with type 2 diabetes (T2D). We performed a post-hoc meta-analysis using an alternative definition of hypoglycemia. This patient-level meta-analysis included all 5 phase 3a, randomized, treat-to-target trials comparing once-daily IDeg (n=2262) and IGlar (n=1110) in T2D. Trials were open label and 26 or 52 weeks. Confirmed hypoglycemia comprised severe episodes requiring assistance or PG <2.3 mmol/L; nocturnal-confirmed hypoglycemia included confirmed episodes with an onset between 12:01 am and 5:59 am. There was a significant 33% lower rate of overall confirmed hypoglycemia for IDeg vs. IGlar for the full meta-analysis population (rate ratio [RR] IDeg/IGlar: 0.67 [0.56; 0.82], p<0.0001) and a significant 45% lower rate in a subset of patients (IDeg: n=1290; IGlar: n=632) who were insulin naïve prior to trial entry (RR: 0.55 [0.39; 0.76], p<0.001). IDeg was also associated with a 27% lower rate of nocturnal confirmed hypoglycemia vs. IGlar in the full population (RR: 0.73 [0.53; 1.01], p=0.06). Lower rates of overall and nocturnal-confirmed hypoglycemia were observed for IDeg compared with IGlar in patients with T2D, regardless of whether a PG concentration of <3.1 mmol/L or <2.3 mmol/L is used as the criterion for hypoglycemia.

Aim: To compare the efficacy and safety of ultra-long-acting insulin degludec (IDeg) tositagliptin (Sita), a DPP-4 inhibitor, in a 26-week, open-label trial.