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Objective To assess whether an electronic health record (EHR)-based diabetes intensification tool can improve the rate of A1C goal attainment among patients with type 2 diabetes and an A1C ≥8%. Methods An EHR-based tool was developed and sequentially implemented in a large, integrated health system using a four-phase, stepped-wedge design (single pilot site [phase 1] and then three practice site clusters [phases 2–4]; 3 months/phase), with full implementation during phase 4. A1C outcomes, tool usage, and treatment intensification metrics were compared retrospectively at implementation (IMP) sites versus nonimplementation (non-IMP) sites with sites matched on patient population characteristics using overlap propensity score weighting. Results Overall, tool utilization was low among patient encounters at IMP sites (1,122 of 11,549 [9.7%]). During phases 1–3, the proportions of patients achieving the A1C goal ( Conclusion Utilization of a diabetes intensification tool was low and did not influence rates of A1C goal attainment or time to treatment intensification. The low level of tool adoption is itself an important finding highlighting the problem of therapeutic inertia in clinical practice. Testing additional strategies to better incorporate, increase acceptance of, and improve proficiency with EHR-based intensification tools is warranted.

To conduct an adjusted indirect treatment comparison (aITC) of the efficacy of tirzepatide 5/10/15 mg versus semaglutide 2 mg in patients with type 2 diabetes.The primary analysis was a Bucher aITC of the change from baseline at week 40 in HbA1c (%) and body weight (kg). Aggregate data from the SURPASS-2 study that met the HbA1c inclusion criterion of the SUSTAIN FORTE study and from SUSTAIN FORTE metformin-only treated patients were used for primary analysis.The SURPASS-2 refined population comprised 238/245/240 and 240 participants for tirzepatide 5/10/15 mg and semaglutide 1 mg, respectively. The SUSTAIN FORTE metformin-only population comprised 222 and 227 participants for semaglutide 1 and 2 mg, respectively. In this aITC, tirzepatide 10 and 15 mg significantly reduced HbA1c versus semaglutide 2 mg with an estimated treatment difference (ETD) of -0.36% (95% confidence interval [CI] -0.63, -0.09) and -0.4% (95% CI -0.67, -0.13), respectively. Tirzepatide 10 and 15 mg significantly reduced body weight versus semaglutide 2 mg with an ETD of -3.15 kg (95% CI -4.84, -1.46) and -5.15 kg (95% CI -6.85, -3.45), respectively. There were no significant differences between tirzepatide 5 mg and semaglutide 2 mg on change from baseline in HbA1c and body weight.In this aITC, HbA1c and weight reductions were significantly greater for tirzepatide 10 and 15 mg versus semaglutide 2 mg and were similar for tirzepatide 5 mg versus semaglutide 2 mg. These findings provide comparative effectiveness insights in the absence of a head-to-head clinical trial.

AimsContemporary patterns of care of patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D) and the adoption of finerenone are not known. The FINE-REAL study (NCT05348733) is a prospective observational study in patients with CKD and T2D to provide insights into the use of the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone in clinical practice.MethodsFINE-REAL is an international, prospective, multicenter, single-arm study enrolling approximately 5500 adults with CKD and T2D in an estimated 200 sites across 22 countries. The study is anticipated to be ongoing until 2027.ResultsThe primary objective is to describe treatment patterns in patients with CKD and T2D treated with finerenone in routine clinical practice. Secondary objectives include assessment of safety with finerenone. Other endpoints include characterization of healthcare resource utilization and occurrence of newly diagnosed diabetic retinopathy or its progression from baseline in patients with existing disease. A biobank is being organized for future explorative analyses with inclusion of participants from the United States.ConclusionsFINE-REAL is the first prospective observational study with a nonsteroidal MRA in a population with CKD and T2D and is expected to provide meaningful insights into the treatment of CKD associated with T2D. FINE-REAL will inform decision-making with respect to initiation of finerenone in patients with CKD and T2D.

BACKGROUND When type 2 diabetes is suboptimally controlled with basal insulin, prandial insulin injections are commonly added (i.e., a basal-bolus insulin regimen), which can increase treatment burden and hypoglycemia risk. The once-daily injectable iGlarLixi is an alternative treatment. METHODS This retrospective analysis of the U.S. Optum Clinformatics database compared outcomes in adults (≥18 years of age) with type 2 diabetes who previously received basal insulin and were newly initiated on iGlarLixi or basal-bolus insulin therapy. Cohorts were propensity score–matched in a 1:1 ratio on baseline characteristics, and imbalances were adjusted in multivariate analyses. Subgroup analyses were performed for people ≥65 years of age and those with a baseline A1C ≥9%. The primary end point was persistence with therapy at 12 months in the overall population. Secondary end points were treatment adherence, health care resource utilization (HCRU), costs, any hypoglycemia, and A1C change at 12 months. RESULTS Cohorts each comprised 1,070 participants. Treatment persistence at 12 months was statistically significantly higher for iGlarLixi versus basal-bolus insulin therapy (43.7 vs. 22.3%, hazard ratio 0.51, 95% CI 0.46–0.57, adjusted P CONCLUSION In this observational study, initiation of once-daily iGlarLixi versus basal-bolus insulin was associated with higher persistence, lower hypoglycemia, and similar A1C reduction without increasing HCRU or costs regardless of age or A1C. iGlarLixi could be an alternative to basal-bolus insulin, particularly for older adults with type 2 diabetes who require treatment simplification with lower hypoglycemia risk.

To evaluate progression patterns and associated economic outcomes, using estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) based on the Kidney Disease: Improving Global Outcomes (KDIGO) risk categories, among patients with type 2 diabetes (T2D) and chronic kidney disease (CKD).Patients with T2D and moderate- or high-risk CKD were selected from the Optum electronic health records database (January 2007-December 2019). Progression patterns and post-progression economic outcomes were assessed.Adults with T2D and CKD in clinical settings.Baseline KDIGO risk categories.Progression to a more severe KDIGO risk category; healthcare resource utilization and medical costs.Progression probability was estimated using cumulative incidence. Healthcare resource utilization and costs were compared across progression groups.Of 269,187 patients (mean age 65.6 years) with T2D and CKD of moderate or high baseline risk, 18.9% progressed to the very high-risk category within 5 years. Among moderate-risk patients, 17.8% of CKD stage G1-A2, 44.0% of stage G2-A2, and 61.3% of stage G3a-A1 patients progressed to a higher KDIGO risk category. Among high-risk patients, 63.9% of stage G3b-A1/G3a-A2 and 56.0% of stage G2-A3 patients progressed to very high risk. Within the same eGFR stage, a higher UACR stage was associated with 4- to 7-times higher risk of progressing to very high risk and faster eGFR decline. Nonprogressors had lower annual medical costs ($16,924) than patients who progressed from moderate risk to high risk ($22,117,Infrequent lab testing might have caused lags in identifying progression; medical costs were calculated using unit costs.Patients with T2D and CKD of moderate or high risk per KDIGO risk categories had high probabilities of progression, incurring a substantial economic burden. The results highlight the value of UACR in CKD management.

Aims Little is known about the impact of weight loss on developing comorbidities in patients with obesity in real-world settings. Understanding health benefits and associated comorbidities with weight loss are critical to addressing the global obesity health epidemic. This study aimed to determine health outcomes associated with weight loss in individuals with obesity, and to better understand the relationship between disease burden (i.e., prior comorbidities, healthcare utilization) and weight loss in individuals with obesity. Electronic health records (EHRs) represent an important resource to investigate these impacts. Materials and methods We conducted a case-control study using deidentified EHR-derived information from 204,921 patients seen at the Cleveland Clinic between 2000-2018. Patients were ≥20 years of age with BMI ≥30 kg/m2 and ≥7 weight measurements, over ≥3 years. Thirty outcomes were investigated, including chronic and acute diseases, as well as psychological and metabolic disorders. Weight change was investigated three, five, and ten years prior to an event. Results Weight loss was associated with reduced incidence of many outcomes (e.g., type 2 diabetes, non-alcoholic steatohepatitis/non-alcoholic fatty liver disease, obstructive sleep apnea, hypertension) (P 10% was associated with increased incidence of certain outcomes including stroke and substance abuse. However, many outcomes that increased with weight loss were attenuated by disease burden adjustments. Conclusions This study provides the most comprehensive real-world evaluation of health impacts of weight change to date. After comorbidity burden and healthcare utilization adjustments, weight loss was associated with an overall reduction in risk of many adverse outcomes. This article is protected by copyright. All rights reserved.

Reports indicate that coronavirus disease 2019 (COVID-19) may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA). We compared pre– and post–COVID-19 HbA1c and T2D risk in a large real-world clinical cohort of 8,755 COVID-19(+) patients and 11,998 COVID-19(−) matched control subjects. We investigated whether DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N = 701) or T2D (N = 21,830), or by race and sex. We observed a statistically significant, albeit clinically insignificant, HbA1c increase post–COVID-19 (all patients ΔHbA1c = 0.06%; with T2D ΔHbA1c = 0.1%) and no increase among COVID-19(−) patients. COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared with COVID-19(−) patients and 28% more likely for the same HbA1c change as COVID-19(−) patients, indicating that COVID-19–attributed T2D risk may be due to increased recognition during COVID-19 management. DKA in COVID-19(+) patients with T1D was not increased. COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (hazard ratio 2.46 [95% CI 1.48–6.09], P = 0.004) compared with White patients, suggesting a need for further clinical awareness and investigation.

Aim: Premixed insulin (premix) , conventionally administered twice daily, is often used in the US to treat T2D that is suboptimally controlled with BI, particularly for people with consistent eating patterns who require affordable treatment. This analysis evaluated use of once daily iGlarLixi vs. premix on T2D outcomes. Method: This retrospective analysis of the US Optum Clinformatics database compared outcomes in adults (≥18 y) with T2D who previously received BI and newly initiated iGlarLixi or premix. Persistence (primary endpoint) , adherence, healthcare resource utilization (HRU) , costs, any hypoglycemia, and HbA1c change were assessed at 12 months. Results: After propensity score matching, cohorts (n=834 each) were well balanced with respect to age, HbA1c, use of oral agents, BI, and HRU. The primary endpoint was met with persistence being statistically significantly higher for iGlarLixi vs. premix at 12 months. Adherence and HbA1c reduction were similar between groups, whereas hypoglycemia rates, HRU, and costs were numerically lower for iGlarLixi (Table) . Conclusion: In this observational study, once daily iGlarLixi was an effective post-BI treatment with higher treatment persistence than premixed insulin, with similar adherence and HbA1c reduction, and numerically lower hypoglycemia rates, HRU, and costs. Disclosure R.Lajara: None. C.Heller: Consultant; Sanofi, Employee; Aetion. K.M.Pantalone: Consultant; AstraZeneca, Bayer AG, Corcept Therapeutics, Diasome, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi, Research Support; Bayer AG, Merck & Co., Inc., Novo Nordisk, Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk. E.Lew: Employee; Sanofi. X.Li: Employee; Eisai Co., Ltd., Sanofi. T.A.Dex: Employee; Sanofi, Stock/Shareholder; Pfizer Inc., Teva Pharmaceutical Industries Ltd., Viatris Inc. R.Kilpatrick: Speaker's Bureau; Abbott Diabetes, Amgen Inc., Novo Nordisk, Sanofi. Funding Sanofi

Aim: When T2D is suboptimally controlled with BI, 1-3 daily injections of prandial insulin are commonly added (BB regimen) . Once daily iGlarLixi is an alternative treatment. This analysis evaluated the use of iGlarLixi vs. BB on T2D outcomes. Methods: This retrospective analysis of the US Optum Clinformatics database compared outcomes in adults (≥18 y) with T2D who previously received BI and newly initiated iGlarLixi or BB between Jan 1, 2017, and Jun 30, 2020. Persistence (primary endpoint) , adherence, healthcare resource utilization (HRU) , costs, any hypoglycemia, and HbA1c change were assessed at 12 months. Results: Propensity score matching generated cohorts (n=1070 each) that were well balanced with similar mean ± SD age (iGlarLixi: 63.9 ± 11.0 y; BB: 64.5 ± 11.3 y) , HbA1c (iGlarLixi: 9.2 ± 1.7%; BB: 9.2 ± 1.8%) , oral agent use, BI use, and HRU. The primary endpoint was met with treatment persistence being statistically significantly higher for iGlarLixi vs. BB at 12 months. Adherence was numerically higher for iGlarLixi, and hypoglycemia rates, HRU and costs, numerically lower. HbA1c reduction was similar between groups (Table) . Conclusions: In this observational study, initiation of once daily iGlarLixi vs. BB insulin was associated with higher persistence and similar HbA1c reduction without increasing HRU or costs. Disclosure K.M. Pantalone: Consultant; AstraZeneca, Bayer AG, Corcept Therapeutics, Diasome, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. Research Support; Bayer AG, Merck & Co., Inc., Novo Nordisk. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk. C. Heller: Consultant; Sanofi. Employee; Aetion. R. Lajara: None. E. Lew: Employee; Sanofi. X. Li: Employee; Eisai Co., Ltd., Sanofi. T.A. Dex: Employee; Sanofi. Stock/Shareholder; Pfizer Inc., Teva Pharmaceutical Industries Ltd., Viatris Inc. R. Kilpatrick: Speaker's Bureau; Abbott Diabetes, Amgen Inc., Novo Nordisk, Sanofi. Funding Sanofi

Tirzepatide (TZP) is a novel dual GIP/GLP-1 receptor agonist in development for treatment of type 2 diabetes (T2D) . TZP 5 mg, mg, and 15 mg demonstrated superiority versus semaglutide 1 mg (SEMA) and titrated insulin degludec (iDeg) in HbA1c change from baseline and proportion of patients reaching HbA1c Disclosure K.M. Pantalone: Consultant; AstraZeneca, Bayer AG, Corcept Therapeutics, Diasome, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. Research Support; Bayer AG, Merck & Co., Inc., Novo Nordisk. Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk. A. Viljoen: Advisory Panel; Eli Lilly and Company, Mundipharma. Consultant; Amgen Inc., Daiichi Sankyo. Research Support; Eli Lilly and Company, Novo Nordisk. Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Novartis AG, Novo Nordisk A/S, Sanofi. R.J. Galindo: Advisory Panel; Sanofi, WW International, Inc. Research Support; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk. X. Cui: Employee; Eli Lilly and Company. R. Huh: None. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Patel: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company

Objective To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes. Methods This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses. Results In the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m2, weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant. Conclusion Both TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes.

Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES: Upon completion of this educational activity, participants should be able to: Identify risk factors and learn when to suspect MODY-monogenic diabetes. Obtain appropriate diagnostic testing and evaluation prior to treatment. Determine appropriate monitoring and treatment for microvascular and macrovascular comorbidities. Recognize the recommended approach to treatment and monitoring that was performed in a patient with MODY-monogenic diabetes. TARGET AUDIENCE: This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.

Despite treatment advances leading to improved outcomes over the past 2 decades, cardiovascular (CV) disease (CVD) remains the leading cause of morbidity and mortality in people with diabetes. People with type 2 diabetes (T2D) have a 2‐ to 4‐fold increased risk of CVD and CV death. Individuals with T2D have not seen the same improvements in CV morbidity and mortality as those without T2D. Given this, it is important to understand the CV impact of drugs used to treat T2D. In patients with T2D, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have shown a reduction in HbA1c and body weight regardless of their differences in chemical structure and pharmacokinetic variables. Glycaemic efficacy, accompanied by the potential for weight reduction and a low risk of hypoglycaemia, has moved GLP‐1 RAs to the first treatment of choice following metformin monotherapy in the latest American Diabetes Association treatment guidelines. Additionally, all GLP‐1 RAs have shown CV safety and several have proven CV benefit. GLP‐1 RAs have been evaluated in cardiovascular outcomes trials (CVOTs) of varying sizes, designs and patient populations with differing reported effects on CV outcomes. The purpose of this article is to review the completed GLP‐1 RA CVOTs with special attention to how their design, size, patient populations and conduct may influence the interpretation of results.

OBJECTIVE To assess patient characteristics and treatment factors associated with uncontrolled type 2 diabetes (T2D) and the probability of hemoglobin A1c (A1C) goal attainment. RESEARCH DESIGN AND METHODS This was a retrospective cohort study using the electronic health record at Cleveland Clinic. Patients with uncontrolled T2D (A1C >9%) were identified on the index date of 31 December 2016 (n = 6,973) and grouped by attainment (n = 1,653 [23.7%]) or nonattainment (n = 5,320 [76.3%]) of A1C RESULTS For the entire population, median age at index date was 57.7 years (53.3% male), and the majority were white (67.2%). Median A1C was 10.2%. Obesity (50.6%), cardiovascular disease (46.9%), and psychiatric disease (61.1%) were the most common comorbidities. Metformin (62.7%) and sulfonylureas (38.7%) were the most common antidiabetes medications. Only 1,653 (23.7%) patients achieved an A1C CONCLUSIONS A minority of patients with an A1C >9% achieved an A1C

OBJECTIVE To determine if natural language processing (NLP) improves detection of nonsevere hypoglycemia (NSH) in patients with type 2 diabetes and no NSH documentation by diagnosis codes and to measure if NLP detection improves the prediction of future severe hypoglycemia (SH). RESEARCH DESIGN AND METHODS From 2005 to 2017, we identified NSH events by diagnosis codes and NLP. We then built an SH prediction model. RESULTS There were 204,517 patients with type 2 diabetes and no diagnosis codes for NSH. Evidence of NSH was found in 7,035 (3.4%) of patients using NLP. We reviewed 1,200 of the NLP-detected NSH notes and confirmed 93% to have NSH. The SH prediction model (C-statistic 0.806) showed increased risk with NSH (hazard ratio 4.44; P < 0.001). However, the model with NLP did not improve SH prediction compared with diagnosis code–only NSH. CONCLUSIONS Detection of NSH improved with NLP in patients with type 2 diabetes without improving SH prediction.

Summary Objective In shared medical appointments (SMAs), multiple patients with a similar clinical diagnosis are seen by a multidisciplinary team for interactive group sessions. Very few studies have specifically studied SMAs and weight loss in patients with obesity. This study compared weight loss outcomes and anti‐obesity medication (AOM) access between patients with obesity managed through (SMAs) versus individual appointments. Methods Retrospective study of adults seen for obesity between September 2014 and February 2017 at Cleveland Clinic Institute of Endocrinology and Metabolism. Percent weight loss from baseline was compared between two propensity score‐matched populations: patients who attended ≥1 SMA and patients managed with individual medical appointments. Results From all eligible patients identified (n=310 SMA, n=1,993 non‐SMA), 301 matched pairs were evaluated for weight loss. The SMA group (n=301) lost a mean of 4.2%, 5.2% and 3.8% of baseline weight over 6, 12 and 24 months; the non‐SMA group (n=301) lost significantly less weight (1.5%, 1.8% and 1.6%, respectively) (paired t‐test, P

Type 2 diabetes (T2D) has a strong association with atrial fibrillation (AF) which increases risk of thromboembolic events, heart failure, and frequent hospitalizations. Metformin is the first-line medication for T2D with proposed anti-inflammatory, pro-metabolic, and cardio-protective benefits. Our objective was to investigate if initial therapy with metformin is associated with reduced incidence of AF in comparison to other non-insulin anti-hyperglycemic agents in patients with newly diagnosed T2D.This retrospective cohort analysis included adults with a new diagnosis of T2D who were started on monotherapy (except insulin) between 2007 and 2017, without prior anti-hyperglycemic agent use, history of arrhythmias, or estimated GFR (eGFR) ≤ 30 ml/min. A multivariate analysis was performed using a fine-gray regression competing risk analysis to control for confounding variables after which pooled hazard ratios and 95 % confidence intervals were reported. Patients were followed until the end of study date, development of AF, addition of more anti-hyperglycemic agents, or death, whichever occurred first.Among 4584 metformin initiators compared to 1080 non-metformin monotherapy initiators, 10-year cumulative incidence of AF in metformin group was 5.2 % as compared to 8.1 % with other agents which was not statistically significant. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92, 95 % CI 0.69 to 1.21; P = 0.55). Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1.29, 95 % CI: 1.21 to 1.37; P ≤ 0.001; HR: 2.73, 95 % CI: 1.62 to 4.61; P ≤ 0.001, respectively).Initiation of metformin as a first line monotherapy for T2D, when compared to other non-insulin monotherapies, was not associated with decreased risk of developing AF in this retrospective observational study.

Aims To evaluate HbA1c and body weight changes when semaglutide 0.5 mg or 1.0 mg once weekly (QW) is switched to dulaglutide 3.0 mg or 4.5 mg QW via exposure-response modelling. Materials and methods HbA1c and body weight time-course models were developed and validated with data from SUSTAIN 1 to 10 trials for semaglutide and AWARD-11 trial for dulaglutide. Simulations were conducted for HbA1c and body weight over 52 weeks. In the initial 26 weeks, semaglutide was initiated at 0.25 mg and titrated to 0.5 or 1.0 mg QW via 4-weekly stepwise titration, followed by 26 weeks of dulaglutide initiated at 0.75 or 1.5 mg QW and escalated to 3.0 or 4.5 mg QW via 4-weekly stepwise titration. Results At 26 weeks, model-predicted mean changes from baseline in HbA1c and weight for semaglutide 0.5 mg were up to -1.55% and -3.44 kg, respectively. After switching to dulaglutide 3.0 mg, further reductions were 0.19% and 1.40 kg, respectively, at 52 weeks. Predicted mean HbA1c and weight changes for semaglutide 1.0 mg at 26 weeks were -1.84% and -4.96 kg, respectively; after switching to dulaglutide 4.5 mg, HbA1c was maintained with additional weight reduction of up to 0.57 kg at 52 weeks. Glycemic control was preserved switching from semaglutide 1.0 mg to dulaglutide 3.0 mg. Conclusions Switching from semaglutide 0.5 mg to dulaglutide 3.0 or 4.5 mg with dose escalation potentially yields additional HbA1c and weight reductions; switching from semaglutide 1.0 mg to dulaglutide 4.5 mg may enhance weight loss. This article is protected by copyright. All rights reserved.

Dulaglutide 3.0 and 4.5 mg subcutaneous (SC) once weekly (QW) doses are approved for glycemic control in patients with type 2 diabetes (T2D). Using pharmacokinetic/pharmacodynamic models built from and validated with published data from SUSTAIN 1 to 10 trials for SC semaglutide and patient-level data from AWARD-11 for dulaglutide, simulations were used to predict the glycated hemoglobin (A1c) and bodyweight effects of switching from semaglutide 0.5 mg or 1.0 mg QW to 3.0 mg or 4.5 mg dulaglutide. Simulations of 100 trials with 100 virtual patients with T2D per scenario were generated by a sampling with replacement method from the AWARD-11 study dataset, which compared 3.0 and 4.5 mg dulaglutide doses to 1.5 mg as an add-on to metformin in 1842 patients with T2D with a mean baseline age of 57 years, weight of 96 kg and A1c of 8.6%. In the simulations, semaglutide was initiated at 0.25 mg for 4 weeks per approved label, and 52-week time-course predictions were conducted for changes from baseline (CFB) in mean A1c and body weight for semaglutide 0.5 mg QW or 1.0 mg QW for 26 weeks, followed by a switch to dulaglutide 0.75 mg QW or 1.5 mg QW and dose-escalated every 4 weeks to 3.0 mg QW or 4.5 mg QW, for the remaining 26 weeks. At 26 weeks, model-predicted CFB mean A1c and weight for 0.5 mg semaglutide were -1.5 % and -3.4 kg, and at 52 weeks, after switching to 3.0 mg dulaglutide dosed with escalation for 26 weeks, these were -1.7 % and -4.8 kg, respectively. Model-predicted mean A1c and weight CFB for 1.0 mg semaglutide after 26 weeks were -1.8 % and -4.9 kg, and at 52 weeks, after switching to 4.5 mg dulaglutide with dose escalation, these values were -1.8 % and -5.4 kg, respectively. In conclusion, switching from semaglutide 0.5 mg QW to dulaglutide 3.0 mg QW and from 1 mg semaglutide QW to dulaglutide 4.5 mg QW predicted additional and comparable CFB A1c, respectively, but with greater weight loss for both modeled scenarios. Disclosure L. Tham: Employee; Self; Eli Lilly and Company. K. M. Pantalone: Consultant; Self; AstraZeneca, Bayer Inc., Corcept Therapeutics, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Research Support; Self; Bayer Inc., Merck & Co., Inc., Novo Nordisk, Speaker’s Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk. K. M. Dungan: Advisory Panel; Self; Eli Lilly and Company, Tolerion, Inc., Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Elsevier, Novo Nordisk, Other Relationship; Self; UpToDate, Research Support; Self; Abbott, Sanofi-Aventis, Viacyte, Inc. K. M. Munir: None. C. Tang: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Novartis AG. M. Konig: Employee; Self; Eli Lilly and Company. A. Kwan: Employee; Self; Eli Lilly and Company, Employee; Spouse/Partner; Eli Lilly and Company, Stock/Shareholder; Self; Eli Lilly and Company, Stock/Shareholder; Spouse/Partner; Eli Lilly and Company.

Obesity is a major risk factor for the development of severe coronavirus disease 2019 (COVID‐19) infection and mortality. However, it is not known whether patients with obesity are at a greater risk of developing postacute sequelae of COVID‐19 (PASC). In a median follow‐up time of 8 months and counting from 30 days following a positive viral test of 2839 patients who did not require intensive care unit admission and survived the acute phase of COVID‐19, 1230 (43%) patients required medical diagnostic tests, 1255 (44%) patients underwent hospital admission, and 29 (1%) patients died. Compared with patients with a normal body mass index (BMI), the risk of hospital admission was 28% and 30% higher in patients with moderate and severe obesity, respectively. The need for diagnostic tests to assess different medical problems, compared with patients with normal BMI, was 25% and 39% higher in patients with moderate and severe obesity, respectively. The findings of this study suggest that moderate and severe obesity (BMI ≥ 35 kg/m2) are associated with a greater risk of PASC.

Objective Among patients with type 2 diabetes (T2D), the prevalence of hidden hypercortisolism (HidHyCo, formally called subclinical hypercortisolism or mild autonomous cortisol secretion) was estimated to be 2.2-12.1%. The aim of this study was to investigate whether the available literature helps to identify the characteristics of T2D patients more frequently associated with HidHyCo. Methods A meta-analysis was performed using studies that assessed both the prevalence of HidHyCo in patients with T2D and the characteristics of these patients with and without HidHyCo. The DerSimonian and Laird (DSL) and the Hartung, Knapp, Sidik and Jonkman (HKSJ) methods were utilized. Results Among the 18 available studies, 6 studies provided the necessary data. The association between HidHyCo and advanced T2D (based on the patients’ description given in each study in presence of micro/ microvascular complications, or insulin treatment plus hypertension, or hypertension treated with ≥2 drugs), hypertension, insulin treatment and dyslipidemia was reported in 5 (2184 patients), 6 (2283 patients), 3 (1440 patients), and 3 (987 patients) studies, respectively. HidHyCo was associated with advanced T2D as assessed with both DSL (odds ratio, OR, 3.47, 95% Confidence Interval, 95%CI, 2.12-5.67) and HKSJ method (OR 3.60, 95%CI 2.03-6.41) and with the prevalence of hypertension or of insulin treatment as assessed by the DSL approach (OR 1.92, 95%CI 1.05-3.50 and OR 2.29, 95%CI 1.07-4.91, respectively), but not as assessed with HKSJ method. Conclusions Patients with advanced T2D have a higher prevalence of HidHyCo. These data inform about the selection of T2D patients for HidHyCo screening.

Hypothyroidism is a well-known cause of pericardial effusion (with an incidence of 3%–37%) and can cause cardiac tamponade in severe cases. In this review, we present the current knowledge on the epidemiology of hypothyroid-induced pericardial diseases, the mechanism through which low thyroid hormone levels affect the pericardium, the associated clinical manifestations, diagnostic tests and management options. Hypothyroidism causes pericardial effusion through increased permeability of the epicardial vessels and decreased lymphatic drainage of albumin, resulting in accumulation of fluid in the pericardial space. Interestingly, autoimmunity does not seem to play a major role in the pathophysiology, and a majority of effusions are asymptomatic due to slow fluid accumulation. The diagnosis is generally made when the pericardial disease is associated with an elevated thyroid-stimulating hormone level, and other secondary causes are excluded. Management consists of thyroid replacement therapy, along with pericardial drainage in case of tamponade.In conclusion, hypothyroidism-induced pericardial diseases are underdiagnosed. Initiating treatment early in the disease process and preventing complications relies on early diagnosis through systematic screening per guidelines.

AIM To assess the effect of dulaglutide on the relative contribution of basal hyperglycaemia (BHG) and postprandial hyperglycaemia (PPHG) to overall hyperglycaemia across HbA1c categories in patients with type 2 diabetes. METHODS Data from five phase 3 studies (N = 673) were pooled to assess the change in relative contributions of BHG and PPHG to overall hyperglycaemia across different HbA1c categories after 6 months of treatment intensification with dulaglutide 1.5 mg as monotherapy or with 1 or 2 oral medication(s) in patients with type 2 diabetes. BHG and PPHG were calculated using the area under the curve (AUC) of 7-point self-monitored plasma glucose concentration profiles. As a secondary objective, relative contribution of BHG and PPHG for dulaglutide versus liraglutide, exenatide BID and insulin glargine was assessed by individual studies at 6 months. RESULTS In pooled data, after 6 months of treatment intensification with dulaglutide 1.5 mg, there was a significant reduction from baseline in overall hyperglycaemia (AUCoverall ) [(mean ± SE) -466.31 ± 18.32 mg*h/dL (P < 0.001)], BHG (AUCbasal ) [(mean ± SE) -371.46 ± 16.36 mg*h/dL (P < 0.001)] and PPHG (AUCpostprandial ) [(mean ± SE) -94.84 ± 7.97 mg*h/dL (P < 0.001)]. At baseline, relative contributions of BHG increased and PPHG decreased with increasing HbA1c levels. This pattern was maintained at 6 months, even as overall glycaemia improved with decreasing HbA1c values. CONCLUSIONS In patients with type 2 diabetes, dulaglutide reduces HbA1c by lowering both basal and postprandial hyperglycaemia across various HbA1c levels.

The risk of adverse cardiovascular events and mortality associated with testosterone replacement therapy is controversial. The purpose of this report was to evaluate the effect of testosterone replacement therapy (TRT) in men with secondary hypogonadism on the risk of myocardial infarction (MI), stroke (CVA) or all-cause mortality.A retrospective cohort study was conducted using the Cleveland Clinic's electronic health record. Men ≥40 years of age, with at least two testosterone levels 220 ng/dL, with one level obtained between 7 am and 10 am, were identified. Men with primary hypogonadism, secondary hypogonadism related to overt hypothalamic pituitary pathology, human immunodeficiency virus infection, metastatic cancer, and select contraindications to TRT, were excluded. Men exposed to TRT were matched to controls that were not exposed. A survival analysis was performed on the composite outcome of MI, CVA, or all-cause mortality.One hundred sixty-five patients exposed to TRT (treatment group) were matched with 210 not exposed to TRT (comparison group). The prevalence of established cardiovascular disease (CVD) was 20.0% in the treatment group vs. 17.1% in the comparison group (In hypogonadal men with a modest prevalence of established CVD, TRT was not observed to confer a protective or adverse effect on the risk of MI, CVA or all-cause mortality.Le risque d’événements cardiovasculaires indésirables et de mortalité associé au traitement de substitution de la testostérone est controversé. Le but du présent article est d’évaluer chez les hommes qui présentent un hypogonadisme secondaire l’effet du traitement de substitution de la testostérone (TST) sur le risque d’infarctus du myocarde (IM), d’accident cérébrovasculaire (ACV) ou de mortalité toutes causes confondues.Une étude de cohorte rétrospective a été menée en utilisant les dossiers de santé électroniques de la Clinique Cleveland. Ont été identifiés les hommes âgés de plus de 40 ans qui avaient au moins deux dosages de testostérone inférieurs à 220ng/dl, dont l’un obtenu le matin entre 7 et 10 heures. Ont été exclus les hommes qui présentaient un hypogonadisme primaire, un hypogonadisme secondaire lié à une pathologie hypothalamo-hypophysaire évidente, une infection par le virus de l’immunodéficience humaine, un cancer métastatique, et ceux qui présentaient des contrindications déterminées au TST. Les hommes exposés au TST ont été appariés à des témoins non exposés au TST. Une analyse de survie a été réalisée sur le paramètre composite incluant l’IM, l’AVC et la mortalité toutes causes confondues.165 patients exposés au TST (groupe traité) ont été appariés à 210 hommes non exposés au TST (groupe de référence). La prévalence de maladie cardiovasculaire (MCV) établie était de 20.0% dans le groupe traité versus 17.1% dans le groupe de référence (P=0.478). La médiane (écart interquartile (EI)) de l’âge et de l’indice de masse corporelle (IMC) était respectivement de 55 (49, 62) ans et de 35.6 (32.1, 40.1) kg/m2 dans le groupe traité, et respectivement de 55 (49, 61.7) ans et 36.3 (32.1, 40.8) kg/m2 dans le groupe de référence. Il y eut 12 événements indésirables (7.3%) dans le groupe traité, et 16 (7.6%) dans le groupe de référence. La médiane du temps (en années) des événements composites était de 2.1 (EI 0.9, 4.6) et de 1.8 (EI 0.6, 3.4) respectivement pour les groupes traité et de référence. Aucune différence n’a été observée en ce qui concerne le risque cardiovasculaire entre le groupe traité et le groupe de référence, rapport de risque (RR) 0.81 (Intervalle de Confiance à 95% [IC]: 0.38-1.71;Chez les hommes qui présentent un hypogonadisme et une faible prévalence de maladie cardiovasculaire (MCV) établie, le TST n’apparait pas conférer un effet protecteur ou défavorable sur le risque de d’infarctus du myocarde (IM), d’accident cérébrovasculaire (ACV) ou de mortalité toutes causes confondues.Traitement de substitution de la testostérone, Hypogonadisme masculin, Risque cardiovasculaire, Mortalité.

AIMS To assess the effects of 'clinical' and 'intensification inertia' by evaluating the impact of different intensification interventions on the probability of HbA1c goal attainment using real-world data. METHODS Electronic health records (Cleveland Clinic, 2005-2016) were used to identify 7389 people with Type 2 diabetes mellitus and HbA1c ≥53 mmol/mol (≥7.0%), despite a stable regimen of two oral antihyperglycaemic drugs for ≥6 months. The participants were stratified by index HbA1c and analysed over a 6-month period for pharmacological intensification, and then for 12 additional months for HbA1c goal attainment (

The COVID-19 pandemic has rapidly changed the landscape of medical care and the healthcare system needs to quickly adapt in order to continue providing optimal medical care to hospitalized patients in an efficient, effective, and safe manner. Endocrinology diseases are commonly present in patients with COVID-19 and often are major risk factors for development of severe disease. The use of electronic consultation and telemedicine have already been well-established in the outpatient setting but yet not commonly implemented in the inpatient arena. This type of remote medical care has the potential to provide a reliable delivery of endocrine care while protecting providers and patients from spreading infection. This short review intends to provide the initial steps for the development of an inpatient telemedicine endocrine service to patients with endocrine diseases. Telehealth will become part of our daily practices and has a potential to provide a safe and efficient method of consultative service.

OBJECTIVE Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. RESEARCH DESIGN AND METHODS ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. RESULTS We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; P = 2.01 × 10−3) and microvascular outcomes (HR 0.86; P = 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P = 4.34 × 10−7). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P = 4.02 × 10−6), but not reduced risk of microvascular outcomes (P < 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P < 0.05). CONCLUSIONS We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.

The coronavirus disease 2019 (COVID-19) pandemic may have delayed care for chronic disease (1). We sought to examine factors associated with total and virtual health care use for primary care visits for patients with type 2 diabetes (T2D) during the pandemic. Using our electronic medical record, we identified patients in the Cleveland Clinic Health System with a diagnosis of T2D with a prepandemic primary care visit between 1 August 2019 and 14 March 2020 (period 0), with follow-up data collected during two pandemic periods: period 1, from 15 March 2020 to 30 June 2020, when in-person visits were rapidly converted to virtual (telephone or video); and period 2, from 1 July 2020 to 15 November 2020, when in-person visits resumed. We obtained demographic characteristics including age, sex, race, insurance type, median income estimated by zip code based on the American Community Survey 2014–2018 5-year estimates (2), and baseline glycosylated hemoglobin (HbA1c). Patient characteristics were summarized with appropriate descriptive statistics. We assessed factors associated with completing any follow-up visits using logistic regression and then assessed factors associated with completing virtual visits using a mixed-effects logistic regression model with a random intercept at the patient level. All statistical analyses were performed in R (cran.r-project.org), and statistical significance was established at two-sided P values

Background: PTHrP-secreting pancreatic neuroendocrine tumors (PNET) are a recognized cause of malignancy associated hypercalcemia. Herein, we report a case of severe hypercalcemia due to an extreme elevation of PTHrP from a PNET, where after treatment of the hypercalcemia, symptomatic hypocalcemia occurred. Clinical Case: A 59 year-old-woman with a recurrent PNET with liver metastases undergoing an evaluation for multi-visceral transplant presented with acute confusion, nausea and vomiting. Diagnostic testing identified an extreme elevation of total calcium (Ca) [>20.1 mg/dL (8.5 - 10.2)] from two different samples [serum albumin 4.1 g/dL (3.9 - 4.9)]. The total Ca level one month earlier was 8.3 mg/dL with a serum albumin of 3.1 g/dL. Total Ca measurements were performed with the Ca Gen.2 assay on a cobas c702 chemistry analyzer (Roche Diagnostics). Results greater than the analytical measurement range (0.8 – 20.1 mg/dL) were diluted with saline and confirmed (22.6 mg/dL). A Radiometer ABL 800 Flex blood gas analyzer was used to determine the ionized Ca concentration [2.94 mmol/L (1.08 - 1.30)]. Upon presentation the serum creatinine (Cr) was 2.07 mg/dL (0.58 - 0.96); eGFR utilizing the MDRD equation 24 mL/min/1.73m2; baseline serum Cr 0.78 mg/dL. Her serum 25-OH vitamin D was 31 ng/mL (31.0 - 80.0), PTH 12 pg/mL (15 - 65), phosphate 4.3 mg/dL (2.7 - 4.8) and 1, 25-OH vitamin D 39.1 (15.0 - 60.0). PTHrP measurements were performed by ARUP Laboratories via liquid chromatography tandem mass spectrometry (LC-MS/MS) and resulted in a reported value of >2500 pmol/L (0.0 - 3.4). Her symptoms resolved and the corrected Ca gradually decreased to 8 mg/dL after treatment with IV fluids, calcitonin 200 units sc every 12 hours for 48 hours, 60 mg IV pamidronate, and five sessions of hemodialysis. Within thirteen days of receiving pamidronate, her corrected Ca slowly increased to 12mg/dL; thus, she received a single dose of 120 mg sc denosumab. Nine days later, the patient developed symptomatic hypocalcemia (7.3 mg/dL) manifested by paresthesia in the hands and feet and perioral numbness. She then received multiple doses of oral and intravenous Ca along with 50,000 units of oral ergocalciferol twice weekly. The corrected Ca normalized (8.1 mg/dL) and symptoms resolved. The patient was discharged with plans for future treatment of her underlying malignancy. Conclusion: This is the first report of a PNET producing an extreme elevation of PTHrP of higher than 2500 pmol/L, resulting in a concordant extreme elevation of total calcium within a month of documented normocalcemia. Treatment of hypercalcemia with denosumab may result in the development of hypocalcemia requiring treatment.

Guidelines recommend individualized treatment for patients with type 2 diabetes (T2D), avoidance of clinical inertia, and specific therapeutic choices for patients at risk for cardiovascular disease, congestive heart failure, or chronic kidney disease. However, a gap exists in translating these guidelines into practice. We created an electronic medical record (EMR) tool to improve evidence-based treatment intensification for T2D and studied its implementation in endocrinology and primary care (PC). The tool included a best practice alert (BPA) informing providers at an office visit of an A1C ≥ 8% and prompted providers, within the tool, to make therapeutic choices based upon five priority care goals- cardiovascular risk reduction, A1c lowering, low hypoglycemia risk, cost, or weight loss. After a 3-month pilot at one site, the tool was implemented using a stepped-wedge approach from March-November 2019 to all PC (N=52) and endocrinology (N=17) sites in our health system with 1903 eligible patient visits by November 2019. Within endocrinology, provider tool usage ranged from 94% of visits at the pilot site to 34% after full rollout; in PC, usage ranged from 52% during the pilot to just above 5%. Usage varied by practice site (range Uptake of a point of care EMR tool to promote treatment intensification for T2D in endocrinology and PC demonstrated variation at the specialty, practice site, and provider levels. Our findings also suggest that, given time pressures, provider focused point of care EMR-based interventions to improve T2D care may need to be supplemented with tools asynchronous to the office visit and should address patient factors in adherence. Further analyses will focus on tool effects on A1c control. Disclosure A.D. Misra-Hebert: Research Support; Self; Agency for Healthcare Research and Quality, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. K.M. Pantalone: Consultant; Self; Bayer Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. S. Rajpathak: Employee; Self; Menarini Group. T. Weiss: Employee; Self; Merck & Co., Inc. M. Hamaty: Research Support; Self; Merck & Co., Inc. R.S. Zimmerman: Research Support; Self; Bayer U.S., Merck & Co., Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; LifeScan, Inc., Merck & Co., Inc. Stock/Shareholder; Self; Baxter, Bristol-Myers Squibb, Pfizer Inc., Procter & Gamble Company.

Background: Atrial fibrillation (AF) is the most frequent cardiac arrhythmia and is associated with an increased risk of thromboembolic events, heart failure, and frequent hospitalizations. Type 2 diabetes mellitus (T2DM) has one of the strongest associations with AF with an overall 35% increased risk. Metformin is the first-line medication for T2DM and it has been proposed to have anti-inflammatory, pro-metabolic and cardioprotective benefits, but its effect on AF is not well studied. Our objective was to investigate whether the initial metformin monotherapy was associated with reduced AF rates compared to other non-insulin agents. Methods: This retrospective cohort analysis involved adults with newly diagnosed T2DM between 2007 and 2017, without any history of arrhythmias or contraindications to metformin use including GFR less than 30 ml/min who initiated a single antidiabetes therapy (except insulin). A multivariate analysis was performed to control for other variables that may have impacted the association between initial therapy with metformin and the outcomes of interest. Results: Out of 42384 cases with newly diagnosed diabetes, 5664 patients met the inclusion criteria. The majority of patients initiated monotherapy with metformin (81%), followed by sulfonylureas (13%) and thiazolidinediones (4%). The 10-year cumulative incidence of AF in the metformin group was 5.2% vs. 8.1% with others. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92 95% CI 0.69 to 1.21; P = 0.55). Increased age and the presence of CHF were associated with significantly higher risk of AF (HR: 1.29, 95% CI: 1.21 to 1.37; P Conclusion: In this observational study following patients with newly diagnosed T2DM, first-line therapy with metformin, when compared to other non-insulin antidiabetes therapies, was not found to be associated with a decreased risk of developing AF. Disclosure Z. Tekin: None. A. Milinovich: Research Support; Self; Novartis AG, Novo Nordisk Inc. X. Ji: Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. J. Bauman: None. M. Kattan: Consultant; Self; GlaxoSmithKline plc. Research Support; Self; Boehringer Ingelheim (Canada) Ltd., Novo Nordisk Inc. K.M. Pantalone: Consultant; Self; Bayer Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker’s Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. R.S. Zimmerman: Research Support; Self; Bayer U.S., Merck & Co., Inc., Novo Nordisk A/S. Speaker’s Bureau; Self; LifeScan, Inc., Merck & Co., Inc. Stock/Shareholder; Self; Baxter, Bristol-Myers Squibb, Pfizer Inc., Procter & Gamble Company. M.K. Chung: None. S. Kashyap: Other Relationship; Self; GI Dynamics Inc.

Testosterone is an anabolic hormone that is responsible for the development of male sex organs. It also increases muscle mass and fortifies bone density. In addition to being responsible for primary sexual characteristics at birth and puberty (development and changes of sexual organs such as uterus, vagina, penis, and testes), testosterone is also involved in maintaining secondary sexual characteristics. Patients with low testosterone who are symptomatic should be treated with testosterone replacement therapy (TRT) once the diagnosis has been confirmed. The goal of treatment is to improve the symptoms including the physical, sexual, and cognitive health with the aim being to keep the testosterone in the mid-normal limit of the reference range. Male hypogonadism has been increasingly diagnosed and treated in elderly males since the last decade. A proportionate increase in the prescription of testosterone has been seen as well. The relationship of testosterone levels with cardiovascular (CV) outcomes is challenging and has shown conflicting results. Moreover, in patients with established CV disease, those with high CV risk factors including diabetes, or those with significant risk factors for atherosclerotic CV disease (ASCVD), the benefits of TRT should be weighed against the risks of replacement. Risks and benefits of TRT should be discussed with every patient prior to starting or restarting the procedure.

Monogenic Diabetes (MODY) results from mutations or changes in a single gene, and currently account for about 1 to 4% of all cases of diabetes (1). Our group has previously published on the successful use of glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in three consecutive generations of a family with an HNF1A mutation (MODY-3) (2). Although GLP-1 RA therapy has been studied in patients with HNF1A mutations (MODY-3) (3), it has not been studied in patients with HNF4A mutations (MODY-1). In this father-son cohort, we demonstrate successful use of GLP-1 RA therapy in two patients with c.790:1 bp deletion of G; codon:264 mutations of HNF4A. The son first presented with neonatal hypoglycemia, then later developed diabetes and presented to our clinic at age 20, when genetic testing was performed and confirmatory for an HNF4A mutation. He was prescribed glimepiride and titrated to 4 mg twice daily, and two years later, his hemoglobin A1c (HbA1c) rose to 8.7%. He was switched to semaglutide 0.25 mg once weekly and was titrated to a maximum dose of 1 mg weekly over 8 weeks. The patient reports improvement in his post-prandial blood glucose values at this time, but HbA1c has not yet been repeated. The father had been diagnosed with monogenic diabetes in his early 20s and had been on sulfonylurea therapy until age 40, at which time he was transitioned to a regimen of long- and short-acting insulin therapy. Thereafter, he presented to our clinic in July, 2018 with a HbA1c of 9.6% and was transitioned to long-acting insulin once daily and liraglutide 0.6 mg once daily which was subsequently titrated to 1.8 mg once daily over 3 weeks. The patient tolerated this well and has been off short acting insulin since December 2018, with notable improvement in his HbA1c to 5.9% and marked improvement in his post-prandial glycemic control. To our knowledge this is the first report demonstrating the benefits of GLP-1 RA therapy in patients with the HNF4A mutations (MODY-1). Based on this report, it appears that GLP-1 RA therapy could be an effective therapy in patients with MODY-1. 1). Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. The Journal of Clinical Endocrinology and Metabolism. 2013;98(10):4055–4062. 2). Maricor Docena, Charles Faiman, Christine Stanley, and Kevin Pantalone (2014) Mody-3: Novel HNF1A Mutation and the Utility of Glucagon-Like Peptide (GLP)-1 Receptor Agonist Therapy. Endocrine Practice: February 2014, Vol. 20, No. 2, pp. 107–111. 3). Ostoft SH, Bagger JI, Hansen T, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7):1797–17805.

Purpose Type 2 diabetes–related polyneuropathy (DPN) is associated with increased vascular events and mortality, but determinants and outcomes of pain in DPN are poorly understood. We sought to examine the effect of neuropathic pain on vascular events and mortality in patients without DPN, DPN with pain (DPN + P), and DPN without pain (DPN-P). Methods A retrospective cohort study was conducted within a large health system of adult patients with type 2 diabetes from January 1, 2009 through December 31, 2016. Using an electronic algorithm, patients were classified as no DPN, DPN + P, or DPN-P. Primary outcomes included number of vascular events and time to mortality. Independent associations with DPN + P were evaluated using multivariable negative binomial and Cox proportional hazards regression models, adjusting for demographics, socioeconomic characteristics, and comorbidities. Results Of 43 945 patients with type 2 diabetes (age 64.6 ± 14.0 years; 52.1% female), 13 910 (31.7%) had DPN: 9104 DPN + P (65.4%) vs 4806 DPN-P (34.6%). Vascular events occurred in 4538 (15.1%) of no DPN patients, 2401 (26.4%) DPN + P, and 1006 (20.9%) DPN-P. After adjustment, DPN + P remained a significant predictor of number of vascular events (incidence rate ratio [IRR] = 1.55, 95% CI, 1.29-1.85), whereas no DPN was protective (IRR = 0.70, 95% CI, 0.60-0.82), as compared to DPN-P. Compared to DPN-P, DPN + P was also a significant predictor of mortality (hazard ratio = 1.42, 95% CI, 1.25-1.61). Conclusions Our study found a significant association between pain in DPN and an increased risk of vascular events and mortality. This observation warrants longitudinal study of the risk factors and natural history of pain in DPN.

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 ABSTRACT This 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

Aims To assess efficacy and safety of dulaglutide 1.5 mg combined with insulin, categorized by subgroups of baseline glycated haemoglobin (HbA1c; ≤9% and >9% [≤74.9 and >74.9 mmol/mol]), age (9% [>74.9 mmol/mol]; 70% aged 9% (>74.9 mmol/mol) (range − 1.3% to −2.5% [−14.2 to −27.3 mmol/mol]). The incidence rates of documented symptomatic and severe hypoglycaemia were similar in all subgroups in both trials. The most common adverse events observed in each trial were gastrointestinal in nature. Conclusion Dulaglutide 1.5 mg combined with basal or prandial insulin is efficacious for patients with T2D irrespective of age, duration of diabetes or baseline HbA1c.

BACKGROUND The aim of the present study was to assess the longitudinal accumulation of diabetes-related complications and the effect of glycemic control on the Diabetes Complications Severity Index (DCSI) score in people with newly diagnosed type 2 diabetes (T2D). METHODS A retrospective cohort study was conducted using electronic health records from a large integrated healthcare system. People with newly diagnosed T2D were identified between 2005 and 2016 and stratified by initial HbA1c category (

Aims To assess the potential impact of glucagon-like peptide-1 receptor agonist (GLP-1RA) exposure on cardiovascular disease (CVD) and mortality outcomes in patients with type 2 diabetes (T2D), using a large retrospective cohort. Research Design and Methods Patients who had T2D between 2005 and 2014 (N = 105 862) were identified from the electronic health record system at Cleveland Clinic using a validated electronic phenotype. A time-dependent, Cox, multiple regression analysis was used to assess the association between GLP-1RA exposure and risk of acute myocardial infarction (AMI), stroke/cerebrovascular accident (CVA), and overall mortality, as well as the composite of all three outcomes. The findings were further evaluated by assessing the effect of GLP-1RAs on the same variables in patients with and without prior CVD. The model adjusted for differences in demographic information, hypertension, laboratory/vital signs, history of outcomes, and T2D medications. Results There were significantly lower rates of AMI (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.65 to 0.99; P = .045), CVA (HR 0.82, 95% CI 0.74 to 0.91, P

Background/Aim Episodes of non-severe hypoglycemia can be captured through diagnoses documented in the electronic medical record. We aimed to create a clinically useful prediction model for a severe hypoglycemia event, requiring an emergency department visit or hospitalization, in patients with Type 2 diabetes with a history of non-severe hypoglycemia. Methods Using electronic medical record data from 50,439 patients with Type 2 diabetes in one health system, number of severe hypoglycemia events and associated patient characteristics from 2006 to 2015 were previously defined. Using the landmarking method, a dynamic prediction model was built using the subset of 1876 patients who had a documented non-severe hypoglycemia diagnosis code, using logistic regression to obtain landmark-specific odds of severe hypoglycemia in this group. For model performance, the bootstrap procedure was employed for internal validation and area under the curve (AUC) and index of prediction accuracy (IPA) were calculated. Results Glycosylated hemoglobin (HbA1c) less than 7% (53 mmol/mol) was associated with increased odds ratio (OR) of severe hypoglycemia at 3 months (OR 1.92 95% Confidence Interval (CI) 1.19–3.10 at HbA1c 5% (31 mmol/mol) and OR 1.21, CI 1.03–1.41 at HbA1c 6%(42 mmol/mol).) History of non-severe hypoglycemia within the past 3 months increased odds for severe hypoglycemia (OR 2.58 95% CI 1.80–3.70) as did Black race, insulin use with the past 3 months, and comorbidities. Metformin and sulfonlylurea use in the past 3 months, increasing age and body mass index had lower odds of a future severe hypoglycemia event. For the prediction model for 3 month risk of severe hypoglycemia, the AUC was 0.890 (CI 0.843–0.907) and the IPA was 10.8% (CI 4.4% - 12.4%). Conclusion In patients with a documented diagnosis of non-severe hypoglycemia, a dynamic prediction model identifies patients with Type 2 diabetes with 3-month increased risk of severe hypoglycemia, allowing for preventive efforts, such as medication changes, at the point of care.

Objective: The effectiveness of anti-obesity medications (AOMs) outside of clinical trials is unclear. The objective of this study was to compare the short-term effectiveness of AOMs in real-world practice. Methods: This retrospective study included adults aged ≥18 years, with body mass index ≥30 kg/m2 or ≥27 kg/m2 with at least one obesity-related comorbidity who were prescribed phentermine hydrochloride, phenterminetopiramate, bupropion-naltrexone, or lorcaserin for 12 consecutive weeks between 2006 and 2016 at a large tertiary healthcare system. Propensity score-matched cohorts were created for each pair of AOMs. The primary outcomes were percent and absolute weight loss from baseline after 12 weeks. A prediction model was constructed to estimate weight loss with different AOMs based on demographic and clinical data. Results: Of the 3,411 patients included in this study, patients lost an average of 3.45% of body weight from baseline. All AOMs were associated with a significant weight loss from baseline (P

An electronic health record (EHR)-based tool was developed for EPIC My Practice at Cleveland Clinic to aid treatment decisions and combat therapeutic inertia in patients with type 2 diabetes (T2D) and suboptimal glycemic control (A1C ≥8%). The tool consists of three separate components activated during an office visit: a best practice alert (BPA) if a patient had an A1C ≥ 8% within the past 6 months, a Smartform (patient summary and order entry form), and a Smartset for T2D medications to achieve patient-centered treatment goals, supplies, laboratory, and consult orders. The provider may acknowledge the BPA and pursue therapy intensification or defer. The tool was piloted for 3 months (primary care providers (PCP) n=12, endocrinology providers n=5). BPA acknowledgement and utilization practices were recorded by specialty. The CollaboRATE survey (3 items, scale 0-9) was used to assess patient perceptions of shared decision-making afforded by the tool. The BPA appeared for 420/1,766 T2D patients at an office-based encounter with a PCP or endocrinology provider. While the BPA was acknowledged at most endocrinology visits (95%) and approximately 50% of primary care visits, use of all three components of the tool only occurred in ∼10% of eligible encounters. The CollaboRATE survey was administered to a subset of 83 patients exposed to the tool. Most chose the highest rating for questions assessing if efforts were made to: 1. help them better understand their health issue (87%), 2. listen to what matters most to them about their health issue (93%) and 3. integrate what matters to them into next steps (92%). Use of an EHR-based tool to aid treatment decisions is variable by specialty, though appears to lead to a high perception of shared decision-making for T2D patients. Additional provider education and improved incorporation of the tool into PCP work-flow may help to address therapeutic inertia in routine clinical practice. Disclosure K.M. Pantalone: Consultant; Self; Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker's Bureau; Self; AstraZeneca, Merck & Co., Inc., Novo Nordisk Inc. A.D. Misra-Hebert: Research Support; Self; Agency for Healthcare Research and Quality, Merck & Co., Inc., Novo Nordisk Inc. S. Rajpathak: None. T. Weiss: Employee; Self; Merck & Co., Inc. M. Hamaty: Consultant; Self; Applied Clinical Intelligence, LLC. R.S. Zimmerman: Consultant; Self; Novo Nordisk Inc. Research Support; Self; Merck & Co., Inc., Novo Nordisk Inc. Speaker's Bureau; Self; Johnson & Johnson Diabetes Institute, Merck & Co., Inc.

We would like to thank Larroumet et al. (1) for their interest in our article (2) and for sharing their institution’s significant experience (3). Certainly, admission to a specialized ward can durably improve the HbA1c control in patients with uncontrolled type 2 diabetes (T2D). Investigating this concept was not part of our initial intention and research focus; rather, our focus was to develop a prediction model regarding …

OBJECTIVE “Clinical inertia” has been used to describe the delay in the intensification of type 2 diabetes treatment among patients with poor glycemic control. Previous studies may have exaggerated the prevalence of clinical inertia by failing to adequately monitor drug dose changes and nonmedication interventions. This project evaluated the intensification of diabetes therapy and hemoglobin A1c (A1C) goal attainment among patients with newly diagnosed type 2 diabetes when metformin monotherapy failed. RESEARCH DESIGN AND METHODS The electronic health record at Cleveland Clinic was used to identify patients with newly diagnosed type 2 diabetes between 2005 and 2013 who failed to reach the A1C goal after 3 months of metformin monotherapy. A time-dependent survival analysis was used to compare the time until A1C goal attainment in patients who received early intensification of therapy (within 6 months of metformin failure) or late intensification. The analysis was performed for A1C goals of 7% (n = 1,168), 7.5% (n = 679), and 8% (n = 429). RESULTS Treatment was intensified early in 62%, 69%, and 72% of patients when poor glycemic control was defined as an A1C >7%, >7.5%, and >8%, respectively. The probability of undergoing an early intensification was greater the higher the A1C category. Time until A1C goal attainment was shorter among patients who received early intensification regardless of the A1C goal (all P < 0.05). CONCLUSIONS A substantial number of patients with newly diagnosed type 2 diabetes fail to undergo intensification of therapy within 6 months of metformin monotherapy failure. Early intervention in patients when metformin monotherapy failed resulted in more rapid attainment of A1C goals.

Neonatal diabetes mellitus (NDM), defined as persistent hyperglycemia occurring in the first months of life, is a rare cause of hyperglycemia and is often misdiagnosed as type 1 diabetes mellitus (T1DM). Numerous reports have shown that the successful transition from insulin to sulfonylurea agents can be achieved in up to 90% of patients with NDM. However, most of the reports pertain to infants; the literature is limited regarding treatment of adults with NDM. We present our experience with a patient with permanent NDM, initially misdiagnosed as T1DM, who subsequently was successfully transitioned to oral sulfonylurea therapy after 37 years of insulin dependence.

Aim To assess the relationship between weight change and glycated haemoglobin (HbA1c) change in dulaglutide-treated patients by analysing data from six head-to-head phase III AWARD clinical trials. Methods At 26 weeks, the relationship between weight and HbA1c was analysed in each trial rather than by pooling data because of differences in design and background therapy. The effect of baseline characteristics was also evaluated with regard to weight and HbA1c response. Results Across the studies, 87–97% and 83–95% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, had reductions in HbA1c levels, while 57–88% and 43–84% of patients treated with dulaglutide 1.5 and 0.75 mg, respectively, experienced weight loss. The majority (55–83%) of patients receiving dulaglutide 1.5 mg experienced weight loss and HbA1c reductions, while 41–79% of patients in the dulaglutide 0.75 mg arm lost weight and had reductions in HbA1c level. A weak and inconsistent correlation was observed between the changes in weight and HbA1c (range from −0.223 to 0.267) in patients treated with dulaglutide. The baseline characteristics of gender, age, duration of diabetes, HbA1c, body weight and BMI were not related to different combinations of weight and HbA1c responses. Conclusions Dulaglutide is an effective treatment option across the type 2 diabetes treatment spectrum. Dulaglutide showed dose-dependent effects on both weight loss and HbA1c reduction. These effects had a weak correlation and appeared to be independent.