A Guide to Follow-on Biologics and Biosimilars with a Focus on Insulin

Objective: Many healthcare providers in the U.S. are not familiar with follow-on biologics and biosimilars nor with their critical distinctions from standard generics. Our aim is to provide a detailed review of both, with a focus on insulins in the U.S. regulatory system.Methods: Literature has been reviewed to provide information on various aspects of biosimilars and a follow-on biologic of insulin. This will include structure, efficacy, cost, switching, and legal issues.Results: Biologic products are large, complex molecules derived from living sources. Follow-on biologics are copies of the original innovator biologics. It is not possible to copy their structure exactly, leading to possible differences in efficacy and safety. Thus, regulations involving biologics are complex. Follow-on biologics are regulated under two Federal laws until March 23, 2020: the Public Health Service Act (PHS Act) and the Federal Food, Drug, and Cosmetic Act. Biosimilars are follow-on biologics which have been approved via the PHS Act. They consist of those which are “highly similar” to the reference drug and those which are “expected” to produce the same clinical result as the reference drug (interchangeable biosimilars). Interchangeable biosimilars have been determined by the U.S. Food and Drug Administration to be substitutable by the pharmacist “without the intervention” of the prescriber. From the patient perspective, switching to a follow-on biologic may necessitate a change in delivery device, which may create issues for patient adherence and dosing.Conclusion: Although they present several challenges in terms of regulation and acceptance, follow-on biologics have the potential to significantly reduce costs for patients requiring insulin therapy.Abbreviations:BLA = biologics license applicationEU = European UnionFDA = Food and Drug AdministrationFD&C = Food, Drug, and CosmeticHCPCS = Healthcare Common Procedure Coding SystemINN = internatinal nonproprietary nameNDA = new drug applicationPHS = Public Health Service     

Potential Place of SGLT2 Inhibitors in Treatment Paradigms for type 2 Diabetes Mellitus

Objective: Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms.Methods: The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin.Results: Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time.Conclusion: The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.Abbreviations: AE = adverse event A1C = glycated hemoglobin CI = confidence interval CKD = chronic kidney disease DKA = diabetic ketoacidosis DPP-4 = dipeptidyl peptidase 4 eGFR = estimated glomerular filtration rate FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide 1 HDL-C = high-density lipoprotein cholesterol HR = hazard ratio LADA = late-onset autoimmune diabetes of adulthood LDL-C = low-density lipoprotein cholesterol MACE = major adverse cardiovascular events SGLT1 = sodium glucose cotransporter 1 SGLT2 = sodium glucose cotransporter 2 T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus UACR = urine albumin to creatinine ratio     

American Association of Clinical Endocrinologists and American College of Endocrinology – Clinical Practice Guidelines for Developing A Diabetes Mellitus Comprehensive Care Plan – 2015 — Executive Summary

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 Cardiovascular Risk in Diabetes ACE = angiotensin-converting enzyme ADA = American Diabetes Association AER = albumin excretion rate ApoB = apolipoprotein B ARB = angiotensin II receptor blocker ASCVD = atherosclerotic cardiovascular disease BEL = best evidence level BMI = body mass index CDC = Centers for Disease Control and Prevention CDE = certified diabetes educator CGM = continuous glucose monitoring CKD = chronic kidney disease CPAP = continuous positive airway pressure CPG = clinical practice guideline CSI = continuous subcutaneous insulin infusion CVD = cardiovascular disease DPP-4 = dipeptidyl peptidase 4 DSME = diabetes self-management education DSPN = distal symmetric polyneuropathy EL = evidence level ESRD = end-stage renal disease FDA = U.S. Food and Drug Administration FPG = fasting plasma glucose GDM = gestational diabetes mellitus GFR = glomerular filtration rate GLP-1 = glucagon-like peptide 1 HBV = hepatitis B virus HDL-C = high-density lipoprotein cholesterol HR = hazard ratio ICU = intensive care unit IFG = impaired fasting glucose IGT = impaired glucose tolerance ISF = insulin sensitivity factor LDL-C = low-density lipoprotein cholesterol LDL-P = low-density lipoprotein particles MDI = multiple daily injections MNT = medical nutrition therapy NPH = neutral protamine Hagedorn OGTT = oral glucose tolerance test OSA = obstructive sleep apnea PG = plasma glucose POC = point-of-care PPG = postprandial glucose PTH = parathyroid hormone Q = clinical question R = recommendation RAAS = reninangiotensin-aldosterone system RCT = randomized controlled trial SFN = small-fiber neuropathy SGLT2 = sodium glucose cotransporter 2 SMBG = self-monitoring of blood glucose T1D = type 1 diabetes T2D = type 2 diabetes TZD = thiazolidinedione     

American Association of Clinical Endocrinologists and American College of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis

Abbreviations:AACE = American Association of Clinical EndocrinologistsACE = American College of EndocrinologyDKA = diabetic ketoacidosisEMA = European Medicines AgencyFDA = U.S. Food and Drug AdministrationSGLT-2 = sodium glucosecotransporter 2T1D = type 1 diabetesT2D = type 2 diabetes     

Integrated Insulin Pump and Continuous Glucose Monitoring Technology in Diabetes Care Today: A Perspective of Real-Life Experience With the Minimed™ 670G Hybrid Closed-Loop System

Objective: Intensive glucose management with insulin pump and continuous glucose monitoring therapy in insulin-treated patients with diabetes poses many challenges in all aspects of daily life. Automated insulin delivery (AID) is the ultimate goal of insulin replacement therapy to reduce the burden of managing this condition. Many systems are being tested in the clinical research setting, and one hybrid closed-loop (HCL) system has received Food and Drug Administration (FDA) approval for use in type 1 diabetes patients above the age of 14 years.Methods: Literature review and clinical practice experience from the Diabetes and Technology Program at an academic medical center.Results: This review outlines recent advances in AID systems, focusing on the FDA-approved MiniMed™ 670G HCL system and the real-life experience 1-year post-release in an academic medical center with over 60 patients on this system. The unique challenges of adapting to this new system outside the clinical trial setting are highlighted, and a training protocol designed specifically for the onboarding of first-time users is described.Conclusion: HCL insulin therapy offers several advantages, at the same time posing unique challenges to the user. Systematic training of patients with diabetes transitioning to this system is essential for retention and success of use.Abbreviations: AID = automated insulin delivery; CGM = continuous glucose monitoring; FDA = Food and Drug Administration; HbA1c = glycated hemoglobin; HCL = hybrid closed-loop; ICR = insulin to carbohydrate ratio; SAP = sensor augmented pump; T1DM = type 1 diabetes     

Historical and Current Perspective in the Use of Thyroid Extracts for the Treatment of Hypothyroidism

Objective: To describe the history, refinements, implementation, physiology, and clinical outcomes achieved over the past several centuries of thyroid hormone replacement strategies.Methods: A Medline search was initiated using the following search terms: bioidentical thyroid hormone, thyroid hormone extract, combination thyroxine (T4) and tri-iodothyronine (T3) therapy, homeopathic thyroid hormone therapy, and thyroid hormone replacement. Pertinent articles of interest were identified by title (and where available abstract) for further review. Additional references were identified during a review of the identified literature.Results: A rich history of physician intervention in thyroid dysfunction was identified dating back more than 2 millennia. Although not precisely documented, thyroid ingestion from animal sources had been used for centuries but was finally scientifically described and documented in Europe over 130 years ago. Since the reports by Bettencourt and Murray, there has been a continuous documentation of outcomes, refinement of hormone preparation production, and updating of recommendations for the most effective and safe use of these hormones for relieving the symptoms of hypothyroidism. As the thyroid extract preparations contain both levothyroxine (LT4) and liothyronine (LT3), current guidelines do not endorse their use as controlled studies do not clearly document enhanced objective outcomes compared with LT4 monotherapy. Among current issues cited, the optimum ratio of LT4 to LT3 has yet to be determined, and the U.S. Food and Drug Administration (FDA) does not appear to be monitoring the thyroid hormone ratios or content in extract preparations on the market. Taken together, these limitations are important detriments to the use of thyroid extract products.Conclusion: The evolution of thyroid hormone therapies has been significant over the extended period of time they have been in use to treat hypothyroidism. Although numerous websites continue to advocate the use of thyroid hormone extracts as a superior therapy for hypothyroidism, none of the most recent guidelines of major endocrine societies recommend thyroid extract use for hypothyroidism.Abbreviations: AACE = American Association of Clinical Endocrinologists ATA = American Thyroid Association BMR = basal metabolic rate FDA = Food and Drug Administration FT4 = free thyroxine 131-I = radioactive iodine 131 LT3 = liothyronine LT4= levothyroxine NDA = new drug application PBI = proteinbound iodine T3 = triiodothyronine T4 = thyroxine TSH = thyroid-stimulating hormone TT3 = total triiodothyronine USP = U.S. Pharmacopeia     

Intravenous Contrast In Patients With Diabetes On Metformin: New Common Sense Guidelines

Abbreviations:ACR = American College of RadiologyAKI = acute kidney injuryCT = computed tomographyCr = creatinineDM = diabetes mellituseGFR = estimated glomerular filtration rateFDA = Food and Drug AdministrationFDG = fluorodeoxyglucoseIV = intravenous     

Anti-Obesity Pharmacotherapy and the Potential for Preventing Progression from Prediabetes to Type 2 Diabetes

Objective: Type 2 diabetes and its associated complications place heavy burdens on affected individuals, their caregivers, and society. The prevalence of type 2 diabetes is increasing worldwide. Attempts to combat this problem have been extended to the treatment of obesity and prevention of progression from prediabetes to type 2 diabetes. As such, weight loss is an important component of type 2 diabetes prevention. However, successful strategies for achieving sustained weight loss have remained elusive. Although lifestyle modification remains a cornerstone of this approach, it has become clear that changes to lifestyle alone will not suffice for many patients. A pragmatic approach includes consideration of pharmacotherapeutic options.Methods: This review discusses the different pharmacotherapeutic options for the treatment of obesity and prediabetes.Results: Approved anti-obesity therapies and antihyperglycemic agents associated with weight loss may prove effective earlier in the treatment paradigm, and other promising agents that are in clinical development for chronic weight management show promise for both weight reduction and a reduction in the risk of type 2 diabetes in high-risk individuals.Conclusion: Long-term evaluation of safety and efficacy is required for many of these agents before we can begin to optimize their use in clinical practice, but treatment choices for obese or prediabetic patients are increasing.Abbreviations: AACE = American Association of Clinical Endocrinologists ADA = American Diabetes Association AE = adverse event AMA = American Medical Association BMI = body mass index CI = confidence interval CR = controlled release DPP = Diabetes Prevention Program IFG = impaired fasting glucose IGT = impaired glucose tolerance FDA = Food and Drug Administration FPG = fasting plasma glucose GLP-1 = glucagon-like peptide-1 GLP-1 RA = glucagon-like peptide-1 receptor agonist HbA_1c= glycosylated hemoglobin ITT-LOCF = intention-totreat with last observation carried forward LS = least squares NB = naltrexone/bupropion OR = odds ratio PHEN = phentermine PYE = patient years of exposure PYY = peptide YY SGLT-2 = sodium glucose cotransporter 2 TPM = topiramate TZD = thiazolidinedione     

American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity

Objective: Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs).Methods: Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors.Results: There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A], 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,788 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 351 (19.6%) based on reviews and opinions (EL 4).Conclusion: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision-making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety.Abbreviations:A1C = hemoglobin A1cAACE = American Association of Clinical EndocrinologistsACE = American College of EndocrinologyAMA = American Medical AssociationBEL = best evidence levelBMI = body mass indexCCO = Consensus Conference on ObesityCPG = clinical practice guidelineCSS = cross-sectional studyCVD = cardiovascular diseaseEL = evidence levelFDA = Food and Drug AdministrationGERD = gastroesophageal reflux diseaseHDL-c = high-density lipoprotein cholesterolIFG = impaired fasting glucoseIGT = impaired glucose toleranceLDL-c = low-density lipoprotein cholesterolMNRCT = meta-analysis of non-randomized prospective or case-controlled trialsNE = no evidencePCOS = polycystic ovary syndromeRCT = randomized controlled trialSS = surveillance studyU.S = United States     

Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Quality of DXA Scans and Reports

Objective: High-quality dual-energy X-ray absorptiometry (DXA) scans are necessary for accurate diagnosis of osteoporosis and monitoring of therapy; however, DXA scan reports may contain errors that cause confusion about diagnosis and treatment. This American Association of Clinical Endocrinologists/American College of Endocrinology consensus statement was generated to draw attention to many common technical problems affecting DXA report conclusions and provide guidance on how to address them to ensure that patients receive appropriate osteoporosis care.Methods: The DXA Writing Committee developed a consensus based on discussion and evaluation of available literature related to osteoporosis and osteodensitometry.Results: Technical errors may include errors in scan acquisition and/or analysis, leading to incorrect diagnosis and reporting of change over time. Although the International Society for Clinical Densitometry advocates training for technologists and medical interpreters to help eliminate these problems, many lack skill in this technology. Suspicion that reports are wrong arises when clinical history is not compatible with scan interpretation (e.g., dramatic increase/decrease in a short period of time; declines in previously stable bone density after years of treatment), when different scanners are used, or when inconsistent anatomic sites are used for monitoring the response to therapy. Understanding the concept of least significant change will minimize erroneous conclusions about changes in bone density.Conclusion: Clinicians must develop the skills to differentiate technical problems, which confound reports, from real biological changes. We recommend that clinicians review actual scan images and data, instead of relying solely on the impression of the report, to pinpoint errors and accurately interpret DXA scan images.Abbreviations: AACE = American Association of Clinical Endocrinologists; BMC = bone mineral content; BMD = bone mineral density; DXA = dual-energy X-ray absorptiometry; ISCD = International Society for Clinical Densitometry; LSC = least significant change; TBS = trabecular bone score; WHO = World Health Organization     

American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Growth Hormone Deficiency in Adults and Patients Transitioning from Pediatric to Adult Care

Objective: The development of these guidelines is sponsored 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 (CPG).Methods: Recommendations are based on diligent reviews of clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.Results: The Executive Summary of this 2019 updated guideline contains 58 numbered recommendations: 12 are Grade A (21%), 19 are Grade B (33%), 21 are Grade C (36%), and 6 are Grade D (10%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 357 citations of which 51 (14%) are evidence level (EL) 1 (strong), 168 (47%) are EL 2 (intermediate), 61 (17%) are EL 3 (weak), and 77 (22%) are EL 4 (no clinical evidence).Conclusion: This CPG is a practical tool that practicing endocrinologists and regulatory bodies can refer to regarding the identification, diagnosis, and treatment of adults and patients transitioning from pediatric to adult-care services with growth hormone deficiency (GHD). It provides guidelines on assessment, screening, diagnostic testing, and treatment recommendations for a range of individuals with various causes of adult GHD. The recommendations emphasize the importance of considering testing patients with a reasonable level of clinical suspicion of GHD using appropriate growth hormone (GH) cut-points for various GH–stimulation tests to accurately diagnose adult GHD, and to exercise caution interpreting serum GH and insulin-like growth factor-1 (IGF-1) levels, as various GH and IGF-1 assays are used to support treatment decisions. The intention to treat often requires sound clinical judgment and careful assessment of the benefits and risks specific to each individual patient. Unapproved uses of GH, long-term safety, and the current status of long-acting GH preparations are also discussed in this document.LAY ABSTRACTThis updated guideline provides evidence-based recommendations regarding the identification, screening, assessment, diagnosis, and treatment for a range of individuals with various causes of adult growth-hormone deficiency (GHD) and patients with childhood-onset GHD transitioning to adult care. The update summarizes the most current knowledge about the accuracy of available GH–stimulation tests, safety of recombinant human GH (rhGH) replacement, unapproved uses of rhGH related to sports and aging, and new developments such as long-acting GH preparations that use a variety of technologies to prolong GH action. Recommendations offer a framework for physicians to manage patients with GHD effectively during transition to adult care and adulthood. Establishing a correct diagnosis is essential before consideration of replacement therapy with rhGH. Since the diagnosis of GHD in adults can be challenging, GH–stimulation tests are recommended based on individual patient circumstances and use of appropriate GH cut-points. Available GH–stimulation tests are discussed regarding variability, accuracy, reproducibility, safety, and contraindications, among other factors. The regimen for starting and maintaining rhGH treatment now uses individualized dose adjustments, which has improved effectiveness and reduced reported side effects, dependent on age, gender, body mass index, and various other individual characteristics. With careful dosing of rhGH replacement, many features of adult GHD are reversible and side effects of therapy can be minimized. Scientific studies have consistently shown rhGH therapy to be beneficial for adults with GHD, including improvements in body composition and quality of life, and have demonstrated the safety of short- and long-term rhGH replacement.Abbreviations: AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AHSG = alpha-2-HS-glycoprotein; AO-GHD = adult-onset growth hormone deficiency; ARG = arginine; BEL = best evidence level; BMD = bone mineral density; BMI = body mass index; CI = confidence interval; CO-GHD = childhood-onset growth hormone deficiency; CPG = clinical practice guideline; CRP = C-reactive protein; DM = diabetes mellitus; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = Food and Drug Administration; FD-GST = fixed-dose glucagon stimulation test; GeNeSIS = Genetics and Neuroendocrinology of Short Stature International Study; GH = growth hormone; GHD = growth hormone deficiency; GHRH = growth hormone–releasing hormone; GST = glucagon stimulation test; HDL = high-density lipoprotein; HypoCCS = Hypopituitary Control and Complications Study; IGF-1 = insulin-like growth factor-1; IGFBP = insulin-like growth factor–binding protein; IGHD = isolated growth hormone deficiency; ITT = insulin tolerance test; KIMS = Kabi International Metabolic Surveillance; LAGH = long-acting growth hormone; LDL = low-density lipoprotein; LIF = leukemia inhibitory factor; MPHD = multiple pituitary hormone deficiencies; MRI = magnetic resonance imaging; P-III-NP = procollagen type-III amino-terminal pro-peptide; PHD = pituitary hormone deficiencies; QoL = quality of life; rhGH = recombinant human growth hormone; ROC = receiver operating characteristic; RR = relative risk; SAH = subarachnoid hemorrhage; SDS = standard deviation score; SIR = standardized incidence ratio; SN = secondary neoplasms; T3 = triiodothyronine; TBI = traumatic brain injury; VDBP = vitamin D-binding protein; WADA = World Anti-Doping Agency; WB-GST = weight-based glucagon stimulation test     

Clinical Practice Patterns for Postoperative Water Balance After Pituitary Surgery

Objective: Abnormalities of water and sodium balance, including diabetes insipidus and the syndrome of inappropriate antidiuretic hormone (SIADH), are common complications of transsphenoidal surgery. Postoperative practice patterns vary among clinicians, and no consensus guidelines exist to direct their monitoring and management. We aimed to identify and compare practice patterns regarding the evaluation and management to these postoperative complications.Methods: A questionnaire was utilized to capture demographic data and practice habits in the postoperative setting. Respondents were members of the Pituitary Society, an international organization comprised of clinicians and researchers dedicated to the study of pituitary disease.Results: Eighty-six respondents completed at least part of the survey. The geographic distribution of respondents was roughly even between American and non-American practitioners. The majority of respondents practiced at academic institutions (67.4%), worked in multidisciplinary teams (88.4%), and possessed significantly greater than 10 years of clinical experience (71%). Compared to non-American practitioners, American practitioners described a shorter length of stay postoperatively (P<.001) and prescribed more restrictive volume recommendations for postoperative SIADH (P = .0035). Early career clinicians (less than 10 years in practice) checked first postoperative sodium level earlier than later career clinicians (P = .010).Conclusion: Water and sodium dysregulation are common following transsphenoidal surgery, but their management is not well-standardized in clinical practice. We created a questionnaire to define and compare practice patterns. Most respondents practice in academic settings in multidisciplinary teams. The length of clinical experience did not significantly impact practice habits. Practice location influenced length of stay postoperatively and fluid restriction in SIADH.Abbreviations: AVP = arginine vasopressin; DI = diabetes insipidus; LOS = length of stay; SIADH = syndrome of inappropriate antidiuretic hormone     

Use of Metformin in Clinical Endocrinology

Abbreviations:CKD = chronic kidney diseaseDM = diabetes mellituseGFR = estimated glomerular filtration rateFDA = Food & Drug Administration     

Continuous Glucose Monitoring: A Consensus Conference of the American Association of Clinical Endocrinologists and American College of Endocrinology

Objective/Methods: Barriers to continuous glucose monitoring (CGM) use continue to hamper adoption of this valuable technology for the management of diabetes. The American Association of Clinical Endocrinologists and the American College of Endocrinology convened a public consensus conference February 20, 2016, to review available CGM data and propose strategies for expanding CGM access.Results: Conference participants agreed that evidence supports the benefits of CGM in type 1 diabetes and that these benefits are likely to apply whenever intensive insulin therapy is used, regardless of diabetes type. CGM is likely to reduce healthcare resource utilization for acute and chronic complications, although real-world analyses are needed to confirm potential cost savings and quality of life improvements. Ongoing technological advances have improved CGM accuracy and usability, but more innovations in human factors, data delivery, reporting, and interpretation are needed to foster expanded use. The development of a standardized data report using similar metrics across all devices would facilitate clinician and patient understanding and utilization of CGM. Expanded CGM coverage by government and private payers is an urgent need.Conclusion: CGM improves glycemic control, reduces hypoglycemia, and may reduce overall costs of diabetes management. Expanding CGM coverage and utilization is likely to improve the health outcomes of people with diabetes.Abbreviations:A1C = glycated hemoglobinAACE = American Association of Clinical EndocrinologistsACE = American College of EndocrinologyASPIRE = Automation to Simulate Pancreatic Insulin ResponseCGM = continuous glucose monitoringHRQOL = health-related quality of lifeICER = incremental cost-effectiveness ratioJDRF = Juvenile Diabetes Research FoundationMARD = mean absolute relative differenceMDI = multiple daily injectionsQALY = quality-adjusted life yearsRCT = randomized, controlled trialSAP = sensor-augmented pumpSMBG = self-monitoring of blood glucoseSTAR = Sensor-Augmented Pump Therapy for A1C ReductionT1D = type 1 diabetesT2D = type 2 diabetes     

Biosimilars and New Insulin Versions

Objective: To provide clinicians with an overview of similar biologic products including biosimilars and new insulin versions available in the U.S. and of key issues associated with such products, including differences in manufacturing and regulatory approaches and their impact on clinical use.Methods: We reviewed the relevant clinical and regulatory literature.Results: Patent protections for many biologics including several insulin preparations have or will expire shortly. This opens the door for new insulin versions to enter the U.S. and global marketplace. The development, manufacturing, and approval process for similar biologic products is more complex than for generic versions of small molecules. Most similar biologic products in the U.S. will be submitted for approval under section 351(k), a newly created biosimilar regulatory pathway. However, some biologics, including new insulin versions, will be submitted via the existing 505(b) regulatory pathway. These regulatory pathways have implications for how such products may be labeled, how they may be dispensed, and how patients may perceive them. The immunogenicity of biologics can affect safety and efficacy and can be altered through subtle changes in manufacturing. With the arrival of new insulin versions, health care providers will need to understand the implications of interchangeability, therapeutic equivalence, substitution, switching, and new delivery devices.Conclusion: An understanding of the above topics will be important as physicians, payers, and patients choose between similar versions of a reference listed biologic product.Abbreviations:BLA = biologics license applicationBPCIA = Biologics Price Competition and Innovation ActEU = European UnionFDA = Food and Drug AdministrationINN = international nonproprietary nameNDA = new drug applicationPD = pharmacodynamicPK = pharmacokineticPRCA = pure red cell aplasia     

American Association Of Clinical Endocrinologists And American College Of Endocrinology Guidelines For Management Of Dyslipidemia And Prevention Of Cardiovascular Disease - Executive Summary

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: Each Recommendation is based on a diligent review of the clinical evidence with transparent incorporation of subjective factors.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 202 (29.1 %) are evidence level (EL) 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 237 (34.1%) are EL 4 (no clinical evidence).Conclusion: This CPG is a practical tool that endocrinologists, other healthcare professionals, regulatory bodies and health-related organizations can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of patients with various lipid disorders. These recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously recommended and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to patients with diabetes, familial hypercholesterolemia, women, and pediatric patients with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions.AbbreviationsA1C = hemoglobin A1CACE = American College of EndocrinologyACS = acute coronary syndromeAHA = American Heart AssociationASCVD = atherosclerotic cardiovascular diseaseATP = Adult Treatment Panelapo = apolipoproteinBEL = best evidence levelCKD = chronic kidney diseaseCPG = clinical practice guidelinesCVA = cerebrovascular accidentEL = evidence levelFH = familial hypercholesterolemiaHDL-C = high-density lipoprotein cholesterolHeFH = heterozygous familial hypercholesterolemiaHIV = human immunodeficiency virusHoFH = homozygous familial hypercholesterolemiahsCRP = high-sensitivity C-reactive proteinLDL-C = low-density lipoprotein cholesterolLp-PLA₂ = lipoprotein-associated phospholipase A₂MESA = Multi-Ethnic Study of AtherosclerosisMetS = metabolic syndromeMI = myocardial infarctionNCEP = National Cholesterol Education ProgramPCOS = polycystic ovary syndromePCSK9 = proprotein convertase subtilisin/kexin type 9T1DM = type 1 diabetes mellitusT2DM = type 2 diabetes mellitusTG = triglyceridesVLDL-C = very low-density lipoprotein cholesterol