Two-versus one-bag fluid delivery in pediatric and adolescent diabetic ketoacidosis: A systematic review and meta-analysis.

Two rehydration protocols currently exist to treat diabetic ketoacidosis (DKA) in pediatric patients aged <21 years: the traditional "one-bag" system and the more recent "two-bag" system. This study aimed to evaluate the safety and efficacy of the newer two-bag system versus the well-established one-bag system. The CiNAHL, Cochrane Library, Embase, PubMed, Scopus, and Web of Science databases were comprehensively searched from inception to June 2023 by 2 independent reviewers using the Preferred Reporting Items for Systematic Reviews and Meta-analysis framework. Eligible studies were those that reported participants <21 years of age who presented to the emergency room with a clinical diagnosis of DKA. This review was prospectively registered on PROSPERO (CRD42023427551). From the initial screening of 42 studies, 8 unique studies encompassing 583 patients met the eligibility criteria. The analysis yielded no significant intergroup differences in hypoglycemia (odds ratio, 0.61; 95% confidence interval [CI], 0.20-1.87; I2=3%) or mean glucose correction rate (mean difference [MD], 0.04 mg/dL/hr; 95% CI, -13.10 to 13.17; I2=64%). The incidence of cerebral edema was as low (0.17%) across groups, with only one case reported in the one-bag group. Notably, the mean time to DKA resolution (MD, -3.24 h; 95% CI, -5.57 to -0.91; I2=0%) and mean response time for intravenous fluid changes (MD, -32.75 min; 95% CI, -43.21 to -22.29; I2=59%) was lower for the two-bag system. This meta-analysis presents preliminary evidence suggesting that the two-bag system may confer advantages over the one-bag system for selected patients. However, further studies with greater patient stratification based on DKA severity, fluid composition, and protocol are needed to draw definitive conclusions and elucidate the extent of these advantages.

Switching to Tirzepatide 5 mg From Glucagon-Like Peptide-1 Receptor Agonists: Clinical Expectations in the First 12 Weeks of Treatment.

OBJECTIVE: This prospective study aimed to describe the clinical course in terms of glycemic outcomes, body weight, and adverse events during the first 12 weeks following a switch from glucagon-like peptide-1 receptor agonists (GLP-1 RAs) directly to tirzepatide 5 mg. METHODS: Participants were ≥18 years with type 2 diabetes (T2D), glycated hemoglobin (HbA1c) ≥6.5% to ≤9.0%, body mass index ≥25 kg/m2 and were on a stable treatment dose of GLP-1 RAs (liraglutide every day [1.2, 1.8 mg], semaglutide once-weekly [0.5, 1.0, 2.0 mg], or dulaglutide once-weekly [0.75, 1.5, 3.0, and 4.5 mg]) for ≥3 months at baseline. The primary end point was HbA1c change from baseline at week 12. Secondary end points included change from baseline in fasting serum glucose, body weight, and glucose assessed by continuous glucose monitoring. Safety was also assessed. RESULTS: Participants were 58.3 years on average, with baseline HbA1c 7.39%, body mass index 35.18 kg/m2, T2D duration around 12.4 years, and included 55% females. Semaglutide (55%) and dulaglutide (42%) were the most commonly used GLP-1 RAs at baseline with semaglutide 1.0 mg and dulaglutide 1.5 mg being the most common treatment doses. At week 12, mean HbA1c changed from baseline by -0.43%, fasting serum glucose by -7.83 mg/dL, and body weight by -2.15 kg (all P < .01). Glycemic outcomes and body weight improved in participants in all baseline GLP-1 RA subgroups. Twenty participants (13.2%) developed gastrointestinal events. Three (2%) participants discontinued tirzepatide due to adverse events. There were no severe hypoglycemic events or deaths. CONCLUSION: In this prospective study, when people with T2D on stable GLP-1 RA treatment were switched directly to tirzepatide 5 mg, they experienced improved glycemic outcomes and additional weight reduction with an acceptable risk of adverse gastrointestinal events over 12 weeks.

Continuous Glucose Monitoring Profiles and Health Outcomes after Dapagliflozin Plus Saxagliptin vs Insulin Glargine.

CONTEXT: Glycemic variability and hypoglycemia during diabetes treatment may impact therapeutic effectiveness and safety, even when glycated hemoglobin (HbA1c) reduction is comparable between therapies. OBJECTIVE: We employed masked continuous glucose monitoring (CGM) during a randomized trial of dapagliflozin plus saxagliptin (DAPA+SAXA) vs insulin glargine (INS) to compare glucose variability and patient-reported outcomes (PROs). DESIGN: 24-week sub-study of a randomized, open-label, two-arm, parallel-group, phase 3b study. SETTING: Multicenter study (112 centers in 11 countries). PATIENTS: 283 adults with type 2 diabetes (T2D) inadequately controlled with metformin ± sulfonylurea. INTERVENTIONS: DAPA+SAXA vs INS. MAIN OUTCOME MEASURES: Changes in CGM profiles, HbA1c, and PROs. RESULTS: Changes from baseline in HbA1c with DAPA+SAXA were similar to those observed with INS, with mean difference [95% CI] between decreases of -0.12% [-0.37 to 0.12%], P = .33. CGM analytics were more favorable for DAPA+SAXA, including greater percent time in range (> 3.9 and ≤ 10 mmol/L; 34.3 ± 1.9 vs 28.5 ± 1.9%, P = .033), lower percent time with nocturnal hypoglycemia (area under the curve ≤ 3.9 mmol/L; 0.6 ± 0.5 vs 2.7 ± 0.5%, P = .007), and smaller mean amplitude of glycemic excursions (-0.7 ± 0.1 vs -0.3 ± 0.1 mmol/L, P = .017). Improvements in CGM were associated with greater satisfaction, better body weight image, less weight interference, and improved mental and emotional well-being. CONCLUSIONS: DAPA+SAXA and INS were equally effective in reducing HbA1c at 24 weeks, but people with T2D treated with DAPA+SAXA achieved greater time in range, greater reductions in glycemic excursions and variability, less time with hypoglycemia, and improved patient-reported health outcomes.

Physicians' Considerations and Practice Recommendations Regarding the Use of Sodium-Glucose Cotransporter-2 Inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), although initially developed as glucose-lowering drugs, provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status. Integration of SGLT-2is into clinical practice requires practical guidance for physicians about their use. To overcome physicians' clinical inertia for SGLT-2i use, including addressing safety, potentially a barrier to their use, a roundtable discussion with physicians from three specialties (cardiology, endocrinology, and nephrology) was conducted. This review summarizes the physicians' clinical experience and recommendations about SGLT-2i use across different patient populations, taking into consideration the beneficial effects of SGLT-2is and their safety. The key aspects discussed regarding SGLT-2i safety include acute effects on kidney function (estimated glomerular filtration rate acute dip upon SGLT-2i initiation and acute kidney injury), volume depletion, diabetic ketoacidosis, genitourinary infections, hyperkalemia, and hypoglycemia. To mitigate any potential risks related to SGLT-2i safety, physicians can make minor adjustments to an individual patient's treatment plan, while retaining the SGLT-2i cardiorenal benefits for effective disease management. Recognition by physicians that the benefits of SGLT-2i use on clinical outcomes outweigh the risks will result in the integration of SGLT-2is into clinical practice and lead to improved patient care and outcomes.

Herpes Zoster Incidence and Burden in Adults With Type 2 Diabetes in the U.S.: A Retrospective Database Analysis.

OBJECTIVE: Data on the real-world burden of herpes zoster (HZ) in adults with type 2 diabetes (T2D) in the U.S. are limited. We assessed HZ in patients with and without T2D and measured the impact of HZ on health care resource use (HCRU) and costs. RESEARCH DESIGN AND METHODS: This retrospective cohort analysis used U.S. commercial claims data (sourced from claims incurred between 1 January 2012 and 31 July 2018). HZ incidence rates/1,000 person-years (PYs) were calculated in patients with and without T2D. HZ risk was evaluated using Poisson regression to generate adjusted incidence rate ratios (aIRRs). Patients with T2D with HZ were propensity score matched to patients with T2D only and to patients with HZ without T2D. HCRU and costs were compared across cohorts during a 1-year follow-up period. Cox proportional hazards analyses evaluated factors associated with HZ-related complications. RESULTS: Crude HZ incidence rates in patients with and without T2D were 9.8/1,000 PY and 2.6/1,000 PY, respectively. T2D patients were almost twice as likely to be diagnosed with HZ (aIRR 1.84; 95% CI 1.82-1.85). HZ was associated with increased HCRU and health care costs. At 12 months, unadjusted incremental all-cause health care costs for patients with T2D with HZ versus patients with T2D without HZ were $5,216. The unadjusted incremental HZ-related health care costs for patients with T2D with HZ versus patients with HZ without T2D were $2,726. Age was the most important predictor for HZ-related complications. CONCLUSIONS: Given the increased risk of HZ and HCRU and cost burden in patients with T2D, HZ prevention in patients with T2D may be beneficial.

Sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes: Barriers and solutions for improving uptake in routine clinical practice.

Recent advances in type 2 diabetes (T2D) research have highlighted the benefits of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, including cardiovascular and renal protection. However, uptake rates of these drugs remain low in patients with T2D, particularly in subpopulations most likely to benefit from them. This review considers the potential barriers to prescribing SGLT-2 inhibitors in T2D in clinical practice and outlines potential multidisciplinary recommendations to overcome these barriers. Safety concerns and a lack of clarity in and divergence of guidelines around the introduction of SGLT-2 inhibitors into treatment regimens may represent a barrier to uptake from the clinicians' perspective, including a general lack of understanding of the benefits associated with SGLT-2 inhibitors. Patient characteristics, such as socioeconomic status, may influence uptake because of the cost of SGLT-2 inhibitors, especially in the United States, where health insurance coverage could be a concern. SGLT-2 inhibitor prescription rates vary between clinical specialty (endocrinology, primary care, cardiology, and nephrology) and country, with cardiologists the lowest prescribers, and endocrinologists the highest. Primary care practitioners may experience more challenges in following SGLT-2 inhibitor-related guidelines than diabetes specialists as there may be fewer opportunities for education on how this drug class improves cardiovascular and renal outcomes in patients with T2D. Uptake rates appear to vary between countries because of differences in guidelines and health insurance systems. The amendment of SGLT-2 inhibitor-related guidelines for more multidisciplinary use and the implementation of patient and clinician education may encourage uptake of these drugs, potentially improving long-term health outcomes among patients with T2D.

Flash glucose monitoring in type 2 diabetes managed with basal insulin in the USA: a retrospective real-world chart review study and meta-analysis.

INTRODUCTION: Evidence supporting use of continuous glucose monitoring in type 2 diabetes treated with basal insulin is unclear. This real-world study aimed to assess the impact on glycated hemoglobin (HbA1c) of flash glucose monitoring use in adults with type 2 diabetes managed with basal insulin. RESEARCH DESIGN AND METHODS: Medical records were reviewed for adult individuals with type 2 diabetes using basal insulin for ≥1 year with or without additional antihyperglycemic medication, HbA1c 8.0%-12.0% prior to FreeStyle Libre Flash Glucose Monitoring use for ≥90 days and an HbA1c measurement recorded between 90 and 194 days after device use. Exclusion criteria included utilization of bolus insulin. Meta-analysis data are from the current study (USA) and a similar Canadian cohort. RESULTS: Medical record analysis (n=100) from 8 USA study sites showed significant HbA1c decrease of 1.4%±1.3%, from 9.4%±1.0% at baseline to 8.0%±1.2% after device use, p<0.0001 (mean±SD).Meta-analysis of medical records from USA and Canada sites (n=191) showed HbA1c significantly decreased by 1.1%±0.14% (mean±SE), from baseline 9.2%±1.0% to 8.1%±1.1%, p≤0.0001, with moderate to high heterogeneity between sites (Q=43.9, I2=74.9, p<0.0001) explained by differences in baseline HbA1c between sites.The HbA1c improvement in both groups was observed by age group, body mass index, duration of insulin use and sex at birth. CONCLUSIONS: In a real-world retrospective USA study and a meta-analysis of a larger USA and Canada cohort, HbA1c significantly reduced in basal insulin-treated type 2 diabetes, without bolus insulin initiation and following the commencement of flash glucose monitoring technology.

Assessing the impact of medically tailored meals and medical nutrition therapy on type 2 diabetes: Protocol for Project MiNT.

BACKGROUND: Research has shown that among people with type 2 diabetes mellitus, reduction in hemoglobin A1c (HbA1c) prevents long term complications. Medically tailored meals (MTM) and telehealth-delivered medical nutrition therapy (tele-MNT) are promising strategies for patient-centered diabetes care. OBJECTIVES: Project MiNT will determine whether provision of MTM with and without the addition of telehealth-delivered medical nutrition therapy improves HbA1c and is cost effective for patients with type 2 diabetes mellitus. METHODS: Patients with poorly controlled type 2 diabetes mellitus (HbA1c >8%) will be recruited from Jefferson Health. Eligible patients will be randomized to one of three arms: 1) usual care, 2) 12 weeks of home-delivered MTM, or 3) MTM + 12 months of tele-MNT. All participants (n = 600) will complete three follow-up assessments at 3, 6, and 12 months. The primary outcome is change in HbA1c at 6 months. Secondary outcomes include change in HbA1c at 3 and 12 months and cost-effectiveness of the intervention at 6 and 12 months. Conclusion Findings from Project MiNT will inform MTM coverage and financing decisions, how to structure services for scalability and system-wide integration, and the role of these services in reducing health disparities.

Correction to: Safety and Efficacy of Exenatide Once Weekly in Participants with Type 2 Diabetes and Stage 2/3 Chronic Kidney Disease.

In the original article, the Table 1 has published with error.

Efficacy and Safety Over 2 Years of Exenatide Plus Dapagliflozin in the DURATION-8 Study: A Multicenter, Double-Blind, Phase 3, Randomized Controlled Trial.

OBJECTIVE: In patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin produced greater reductions in glycemic parameters (glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-h postprandial glucose [2-h PPG]), weight, and systolic blood pressure (SBP) than exenatide QW or dapagliflozin alone after 28 weeks of treatment in DURATION-8. Following a 24-week extension period, improvements were sustained at 52 weeks. In this study, we investigated efficacy and safety at 104 weeks after randomization. RESEARCH DESIGN AND METHODS: DURATION-8 was a 104-week, multicenter, double-blind, randomized, active-controlled, phase 3 trial. In total, 695 adults (aged ≥18 years) with type 2 diabetes and inadequate glycemic control (HbA1c 8.0-12.0% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1,500 mg/day) were randomly assigned (1:1:1) to receive exenatide 2 mg QW plus once-daily dapagliflozin 10 mg, exenatide QW plus placebo, or dapagliflozin plus placebo. All 104-week evaluations were exploratory. RESULTS: At week 104, 431 (62.0%) patients completed treatment. The adjusted least squares mean change (SE) from baseline to week 104 in HbA1c was greater with exenatide QW plus dapagliflozin (-1.70% [0.11]) versus exenatide QW plus placebo (-1.29% [0.12]; P = 0.007) and dapagliflozin plus placebo (-1.06% [0.12]; P < 0.001). Clinically relevant changes in FPG, 2-h PPG, weight, and SBP were also observed with exenatide QW plus dapagliflozin. There were no unexpected safety findings, and exenatide QW plus dapagliflozin was well tolerated, with no episodes of major hypoglycemia. CONCLUSIONS: In this exploratory analysis, among those individuals who completed the trial without rescue therapy, there was clinically relevant efficacy over 2 years with exenatide QW plus dapagliflozin, with no unexpected safety findings.

Safety and Efficacy of Exenatide Once Weekly in Participants with Type 2 Diabetes and Stage 2/3 Chronic Kidney Disease.

INTRODUCTION: The safety and efficacy of exenatide once weekly (EQW) is overall well established. EQW is primarily renally eliminated. In this study, the efficacy and renal and gastrointestinal tolerability of EQW were summarised in participants with type 2 diabetes and chronic kidney disease stage 3 (CKD3; moderate renal impairment; estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) or CKD stage 2 (CKD2; mild renal impairment; eGFR ≥ 60 to < 90 mL/min/1.73 m2). METHODS: Data on participants with type 2 diabetes and baseline CKD3 or CKD2 from eight phase 3, double-blind or open-label studies with 26- or 28-week controlled treatment periods were pooled. Participants received EQW or a placebo/non-glucagon-like peptide-1 receptor agonist comparator (sitagliptin, metformin, pioglitazone, dapagliflozin and insulin). RESULTS: Participants with baseline CKD3 (N = 182) or CKD2 (N = 772) receiving EQW differed in a number of baseline characteristics, such as age < 65 years, race, mean body mass index and mean type 2 diabetes duration, whereas mean blood pressure and glycated haemoglobin (HbA1c) were similar. Mean reductions in HbA1c, body weight and systolic blood pressure from baseline to week 26/28 in participants receiving EQW were similar between the CKD subgroups. The proportions of participants (CKD3 and CKD2) with any adverse event (AE) were 81% and 72%, respectively, for EQW and 74% and 68%, respectively, for all comparators; those for serious AEs were 2.7% and 3.4%, respectively, for EQW and 6% and 5%, respectively, for all comparators. Gastrointestinal AE rates were higher in the EQW CKD3 subgroup (42.2% of participants) than in the CKD2 (32.8%) subgroup, although rates for nausea and vomiting were similar. There were no dehydration events; one participant in each treatment group had a serious AE of acute kidney injury (EQW with CKD3, n = 1; pioglitazone with CKD2, n = 1). CONCLUSION: Exenatide once weekly was well tolerated and demonstrated similar efficacy in participants with type 2 diabetes with mild and moderate renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00637273, NCT00676338, NCT02229383, NCT02229396, NCT00641056, NCT01652729, NCT00935532, NCT01003184.

Scleromyxedema in a patient with thyroid disease: an atypical case or a case for revised criteria?

Lichen myxedematosus (LM), commonly referred to as papular mucinosis, is a rare papular eruption defined by mucin deposition in the dermis. Scleromyxedema (SM) is a generalized papular and sclerodermoid form of LM. It is a progressive disease of unknown etiology with systemic manifestations that cause serious morbidity and mortality. Current criteria list thyroid dysfunction as an exclusion for the diagnosis of SM. Cases of LM associated with thyroid dysfunction have been defined as atypical. We describe a patient with uncontrolled hypothyroidism due to Hashimoto thyroiditis who subsequently developed a diffuse papular eruption with systemic signs and symptoms attributable to SM. Diagnostic workup, including laboratory studies and histologic specimens from the skin and muscle, were consistent with SM. Furthermore, our patient responded clinically to intravenous immunoglobulin (IVIg) and lenalidomide. We discuss the diagnostic criteria, differential diagnoses, and diagnostic challenges associated with LM in association with thyroid dysfunction. We propose that the presence of thyroid disease should not preclude the diagnosis of SM. Finally, we add to the case reports and series of successful treatments of SM with IVIg and lenalidomide.

Efficacy and safety of dapagliflozin plus saxagliptin versus insulin glargine over 52 weeks as add-on to metformin with or without sulphonylurea in patients with type 2 diabetes: A randomized, parallel-design, open-label, Phase 3 trial.

AIM: Efficacy and safety of dapagliflozin plus saxagliptin (DAPA + SAXA) were compared with insulin glargine (INS) in patients with type 2 diabetes (T2D) in a 52-week extension study. MATERIALS AND METHODS: This international Phase 3 study randomized adults with T2D on metformin with/without sulphonylurea. They received DAPA + SAXA or INS for 24 weeks (short-term) with a 28-week (long-term) extension. Week 52 exploratory endpoints included adjusted mean change from baseline in glycated haemoglobin A1c (HbA1c) and body weight, and a proportion of patients achieving optimal glycaemic response without hypoglycaemia and without requiring rescue medication. RESULTS: Of the 1163 patients enrolled, 643 received treatment; 600 (DAPA + SAXA, 306; INS, 294) entered the long-term phase. At 52 weeks, HbA1c [adjusted least squares (LS) mean; 95% confidence interval (CI)] decreased more with DAPA + SAXA (-1.5% [-1.6%, -1.4%]) than with INS (-1.3% [-1.4%, -1.1%]); the LS mean difference (95% CI) was -0.25% (-0.4%, -0.1%; P = 0.009). Total body weight reduced with DAPA + SAXA [LS mean (95% CI): -1.8 kg (-2.4, -1.3)] and increased with INS [LS mean (95% CI): +2.8 kg (2.2, 3.3)]. More patients on DAPA + SAXA (17.6%) achieved HbA1c <7.0% without hypoglycaemia versus those on INS (9.1%). Rescue medication was required by 77 patients (23.8%) and 97 patients (30.4%) in the DAPA + SAXA and INS groups, respectively. CONCLUSION: DAPA + SAXA treatment was non-inferior to INS in reducing HbA1c and body weight, and in achieving optimal glycaemic control without hypoglycaemia in patients with T2D 52 weeks after initiation.

Exenatide and dapagliflozin combination improves markers of liver steatosis and fibrosis in patients with type 2 diabetes.

AIM: To assess the efficacy of exenatide (EXE) once weekly + dapagliflozin once daily (DAPA) versus each drug alone in reducing biomarkers of fatty liver/steatosis and fibrosis in a post hoc analysis of DURATION-8, a 104-week study in 695 patients with type 2 diabetes uncontrolled by metformin monotherapy. MATERIALS AND METHODS: We evaluated the impact of the study treatments on non-invasive markers of hepatic steatosis (fatty liver index [FLI] and non-alcoholic fatty liver disease [NAFLD] liver fat score), fibrosis (fibrosis-4 index [FIB-4]) and severe fibrosis (NAFLD fibrosis score), along with liver enzymes and insulin resistance, at weeks 28 and 52. All outcomes in this analysis were exploratory, with nominal P values reported. RESULTS: At week 28, biomarkers of fatty liver/steatosis and fibrosis were reduced from baseline in all treatment groups. At week 28, EXE once weekly + DAPA effects for decrease in FLI were stronger than those of EXE once weekly + placebo (PLB; -2.92, 95% confidence interval [CI] -5.11, -0.73; P = 0.0092) or DAPA+PLB (-2.77 [95% CI -4.93, -0.62]; P = 0.0119), and stronger than those of EXE once weekly + PLB at week 52 (-3.23 [95% CI -5.79, -0.68]; P = 0.0134). FIB-4 showed reduction versus baseline only in the EXE once weekly + DAPA group at both week 28 (-0.06 [95% CI -0.11, -0.01]; P = 0.0135) and week 52 (-0.05 [95% CI -0.09, -0.004]; P = 0.0308). CONCLUSIONS: The EXE once weekly + DAPA combination showed stronger effects than EXE once weekly + PLB or DAPA + PLB in ameliorating markers of hepatic steatosis and fibrosis in patients with type 2 diabetes. Prospective trials are needed to validate these findings.

Hormone-substrate changes with exenatide plus dapagliflozin versus each drug alone: The randomized, active-controlled DURATION-8 study.

AIM: To determine the effects of individual and combined therapies on plasma insulin, glucagon, ß-hydroxybutyrate (ß-OH) and associated metabolites. MATERIALS AND METHODS: In DURATION-8, the combination of once-weekly exenatide (EQW) + 10 mg dapagliflozin (Dapa) in patients with type 2 diabetes poorly controlled with metformin-reduced HbA1c levels and body weight (at weeks 28 and 52) was compared with EQW + placebo (Plb) or Dapa + Plb. The study included 678 patients randomized 1:1:1 to EQW + Dapa, EQW + Plb, or Dapa + Plb. Plasma insulin and glucagon were measured at fasting and 2 hours after a mixed meal. Fasting plasma free fatty acids (FFA) and ß-OH concentrations were measured. RESULTS: The fasting insulin-to-glucagon molar ratio (I/Glg) increased with EQW + Plb only; postprandial I/Glg increased in all groups but significantly more with EQW + Plb. ß-OH, FFA, and glycerol concentrations showed a parallel response: larger increments with Dapa + Plb, larger decrements with EQW + Plb, and intermediate changes with EQW + Dapa. ß-OH levels and I/Glg were inversely related to one another. Patients in the top quartile of ß-OH changes from baseline [median (interquartile range): +207 (305) vs. -65 (-154) µmol/L; P < .0001] were more frequently treated with Dapa + Plb, had higher urine glucose-to-creatinine ratios, and lower fasting insulin [52 (51) vs. 68 (53) pmol/L; P = .0013) and I/Glg [1.76 (1.49) vs. 2.23 (1.70) mol/mol; P = .0020]. Haematocrit increased only in the Dapa group. CONCLUSIONS: The EQW + Dapa combination abolished the Dapa-induced rise in ß-OH, reduced the EQW-induced increase in I/Glg, maintained glycosuria, and increased haematocrit in patients with poorly controlled type 2 diabetes. The drug combination may preserve any putative benefits while mitigating the risk of ketoacidosis.

Dapagliflozin Plus Saxagliptin Add-on Therapy Compared With Insulin in Patients With Type 2 Diabetes Poorly Controlled by Metformin With or Without Sulfonylurea Therapy: A Randomized Clinical Trial.

OBJECTIVE: This study evaluated whether an oral combination of a sodium-glucose cotransporter 2 inhibitor and a dipeptidyl peptidase 4 inhibitor achieved glycemic control similar to basal insulin in patients with type 2 diabetes, poorly controlled with metformin, without increasing hypoglycemia or body weight. RESEARCH DESIGN AND METHODS: In a multinational, open-label, randomized, phase 3 trial (ClinicalTrials.gov reg. no. NCT02551874), adults with type 2 diabetes inadequately controlled on metformin, with or without sulfonylurea, were randomized (1:1) to receive dapagliflozin (DAPA) plus saxagliptin (SAXA) or titrated insulin glargine (INS). The primary end point was change in glycated hemoglobin A1c (HbA1c) from baseline to week 24. DAPA + SAXA treatment was tested for noninferiority versus INS. RESULTS: The efficacy data set included 643 patients (mean ± SD HbA1c, 9.1 ± 1.0% [75 ± 11 mmol/mol]). At week 24, DAPA + SAXA treatment versus INS resulted in noninferior reductions in HbA1c (adjusted mean ± SE change, -1.7 ± 0.1% vs. -1.5 ± 0.1% [18.3 ± 0.7 mmol/mol vs. 16.8 ± 0.7 mmol/mol]; P = 0.118), significantly different body weight change (between-group difference, -3.64 kg [95% CI -4.20 to -3.09]; P < 0.001), fewer patients with confirmed hypoglycemia (21.3% vs. 38.4%, P < 0.001), more patients achieving HbA1c <7.0% (53 mmol/mol) without hypoglycemia (20.9% vs. 13.1%, P = 0.008), and a similar proportion of patients achieving HbA1c <7.0% (33.2% vs. 33.5%, P = 0.924). Mean reductions in 24-h glucose measurements from baseline to week 2 were greater with DAPA + SAXA than with INS (P < 0.0001). No patients in the DAPA + SAXA group and three patients (0.9%) in the INS group experienced severe hypoglycemia. CONCLUSIONS: Adding DAPA + SAXA to insulin-naive patients with poorly controlled type 2 diabetes achieved similar glycemic control, a lower risk of hypoglycemia, and a clinically relevant body weight difference compared with basal INS.

Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome.

Schizophrenia (SCZ) and major depressive disorder (MDD) in treatment-naive patients are associated with increased risk for type 2 diabetes (T2D) and metabolic syndrome (MetS). SCZ, MDD, T2D, and MetS are often comorbid and their comorbidity increases cardiovascular risk: Some risk genes are likely co-shared by them. For instance, transcription factor 7-like 2 (TCF7L2) and proteasome 26S subunit, non-ATPase 9 (PSMD9) are two genes independently reported as contributing to T2D and SCZ, and PSMD9 to MDD as well. However, there are scarce data on the shared genetic risk among SCZ, MDD, T2D, and/or MetS. Here, we briefly describe T2D, MetS, SCZ, and MDD and their genetic architecture. Next, we report separately about the comorbidity of SCZ and MDD with T2D and MetS, and their respective genetic overlap. We propose a novel hypothesis that genes of the prolactin (PRL)-pathway may be implicated in the comorbidity of these disorders. The inherited predisposition of patients with SCZ and MDD to psychoneuroendocrine dysfunction may confer increased risk of T2D and MetS. We illustrate a strategy to identify risk variants in each disorder and in their comorbid psychoneuroendocrine and mental-metabolic dysfunctions, advocating for studies of genetically homogeneous and phenotype-rich families. The results will guide future studies of the shared predisposition and molecular genetics of new homogeneous endophenotypes of SCZ, MDD, and metabolic impairment.

PANCYTOPENIA AND LYMPHOID ORGAN HYPERPLASIA IN A PATIENT WITH GRAVES DISEASE: RESPONSE TO ANTITHYROID DRUG THERAPY.

OBJECTIVE: In rare instances, cytopenias manifest as a complication of thyrotoxicosis. Here, we report a case of Graves disease (GD) thyrotoxicosis presenting as pancytopenia that resolved with antithyroid therapy. METHODS: A 35-year-old male presented with fever and chills following an outpatient colonoscopy. Initial blood work revealed pancytopenia. Workup included viral antigen titers, blood cultures, rheumatologic antibodies, inflammatory markers, immunocompetency, nutrient deficiency, metal toxicity, and malignancy. Bone marrow aspirate was analyzed by microscope, flow cytometry, fluorescence in situ hybridization, and genetic analysis. Computed tomography scan of the chest, abdomen, and pelvis was obtained. Thyroid labs included thyroid-stimulating hormone, total triiodothyronine, free thyroxine, thyroid-stimulating immunoglobulin, anti-thyroid peroxidase antibody, and radioiodine uptake scan. RESULTS: All workup above was non-revelatory except as follows. Imaging revealed thymic hyperplasia and splenomegaly. Thyroid labs revealed thyroid-stimulating hormone <0.02 µIU/mL (reference range is 0.30 to 5.00 µIU/mL), free thyroxine of 4.7 ng/dL (reference range is 0.7 to 1.7 ng/dL), total triiodothyronine of 191 pg/mL (reference range is 90 to 180 pg/mL), thyroid-stimulating immunoglobulin of 522% (reference range is <140%). Bone marrow biopsy was consistent with a reactive process suggesting an infectious or autoimmune process. Radioiodine uptake scan confirmed GD. He was discharged on antithyroid medication. Two-month follow-up labs revealed improved cell counts; his absolute neutrophil count was 1.94 × 109 cells/L (reference range is 1.50 to 8.00 × 109 cells/L), hemoglobin was 12.9 g/dL (reference range is 14.0 to 17.0 g/dL), and platelets were 153 × 109 cells/L (reference range is 140 to 400 × 109 cells/L). Definitive treatment was obtained with 12 mCi of 131-iodine. CONCLUSION: Pancytopenia and lymphoid organ hyperplasia (splenomegaly, thymic hyperplasia, and lymphadenopathy) have been previously reported to be associated with thyrotoxicosis secondary to GD, rarely simultaneously, and manifest from both thyrotoxic and immunologic mechanisms. After excluding alternative life-threatening pathologies, in such presentations, GD should be considered and treated if confirmed.

Safety and Efficacy of Exenatide Once Weekly Plus Dapagliflozin Once Daily Versus Exenatide or Dapagliflozin Alone in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy: 52-Week Results of the DURATION-8 Randomized Controlled Trial.

OBJECTIVE: Among patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin combination produced greater reductions in glycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatide QW or dapagliflozin alone (DURATION-8). Here, we investigated the safety and maintenance of efficacy at 52 weeks, after a 24-week extension. RESEARCH DESIGN AND METHODS: This phase 3, multicenter, double-blind study randomized adults with type 2 diabetes (with glycated hemoglobin [HbA1c] 8.0-12.0% [64-108 mmol/mol] and on metformin ≥1,500 mg/day) to exenatide QW (2-mg subcutaneous injection) plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo, or dapagliflozin plus injected placebo. Extension-period P values were nominal. RESULTS: Of 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change -1.75% [-19.1 mmol/mol]) versus exenatide QW (-1.38% [-15.1 mmol/mol]; P = 0.006) or dapagliflozin (-1.23% [-13.4 mmol/mol]; P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (-3.31 kg and -4.5 mmHg) versus exenatide QW (-1.51 kg and -0.7 mmHg; both P < 0.001) but similar to those with dapagliflozin (-2.28 kg and -2.7 mmHg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site-related adverse events. No major hypoglycemia occurred. CONCLUSIONS: Among patients with type 2 diabetes uncontrolled with metformin, exenatide QW plus dapagliflozin provided sustained improvements in glycemia, weight, and SBP over 52 weeks, with no unexpected safety findings.

Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial.

OBJECTIVE: This 24-week, double-blinded, phase 3 clinical trial (DEPICT-2; ClinicalTrials.gov, NCT02460978) evaluated efficacy and safety of dapagliflozin as adjunct therapy to adjustable insulin in patients with inadequately controlled type 1 diabetes (HbA1c 7.5-10.5%). RESEARCH DESIGN AND METHODS: Patients were randomized 1:1:1 to dapagliflozin 5 mg (n = 271), dapagliflozin 10 mg (n = 270), or placebo (n = 272) plus insulin. Insulin dose was adjusted by investigators according to self-monitored glucose readings, local guidance, and individual circumstances. RESULTS: Baseline characteristics were balanced between treatment groups. At week 24, dapagliflozin significantly decreased HbA1c (primary outcome; difference vs. placebo: dapagliflozin 5 mg -0.37% [95% CI -0.49, -0.26], dapagliflozin 10 mg -0.42% [-0.53, -0.30]), total daily insulin dose (-10.78% [-13.73, -7.72] and -11.08% [-14.04, -8.02], respectively), and body weight (-3.21% [-3.96, -2.45] and -3.74% [-4.49, -2.99], respectively) (P < 0.0001 for all). Mean interstitial glucose, amplitude of glucose excursion, and percent of readings within target glycemic range (>70 to ≤180 mg/dL) versus placebo were significantly improved. More patients receiving dapagliflozin achieved a reduction in HbA1c ≥0.5% without severe hypoglycemia compared with placebo. Adverse events were reported for 72.7%, 67.0%, and 63.2% of patients receiving dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. Hypoglycemia, including severe hypoglycemia, was balanced between groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events with dapagliflozin: 2.6%, 2.2%, and 0% for dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. CONCLUSIONS: Dapagliflozin as adjunct therapy to adjustable insulin in patients with type 1 diabetes was well tolerated and improved glycemic control with no increase in hypoglycemia versus placebo but with more DKA events.