The SGLT2 inhibitor empagliflozin for the treatment of type 2 diabetes mellitus: A bench to bedside review

INTRODUCTION: The treatment of type 2 diabetes mellitus (T2DM) continues to pose challenges for clinicians and patients. The dramatic rise in T2DM prevalence, which has paralleled the rise in obesity, has strained the healthcare system and prompted the search for therapies that not only effectively treat hyperglycemia, but are also weight neutral or promote weight loss. In most clinical situations after diagnosis, patients are advised to adopt lifestyle changes and metformin is initiated to help control blood glucose levels. However, metformin may not be tolerated, or may not be sufficient for those with higher glucose levels at diagnosis. Even among those who have initial success with metformin, the majority eventually require one or more additional agents to achieve their treatment goals. Because T2DM is a progressive disease, the requirement for combination treatment escalates over time, driving the need for therapies with complementary mechanisms of action. METHODS AND RESULTS: Online public resources were searched using “empagliflozin”, identifying 32 articles in PubMed, and 12 abstracts presented at the 2013 American Diabetes Association meeting. Peer-reviewed articles and abstracts describing preclinical studies and clinical trials were retrieved, and relevant publications included in this review. Trials registered on clinicaltrials.gov were searched for ongoing empagliflozin studies. CONCLUSION: The sodium–glucose co-transporter 2 (SGLT2) inhibitors are of great interest since they provide a novel, insulin-independent mechanism of action. The SGLT2 inhibitor empagliflozin has demonstrated promising pharmacodynamic and pharmacokinetic properties. In clinical trials, empagliflozin has demonstrated a good efficacy and safety profile in a broad range of patients with T2DM, and appears to be an attractive adjunct therapeutic option for the treatment of T2DM. Ongoing trials, including patients with T2DM and comorbidities such as hypertension, are expected to provide important additional data, which will further define the role of empagliflozin in a growing movement toward individualized approaches to diabetes care. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13300-014-0063-1) contains supplementary material, which is available to authorized users

Optimal use of β-blockers in high-risk hypertension: A guide to dosing equivalence

Hypertension is the number one diagnosis made by primary care physicians, placing them in a unique position to prescribe the antihypertensive agent best suited to the individual patient. In individuals with diabetes mellitus, blood pressure (BP) levels >130/80 mmHg confer an even higher risk for cardiovascular and renal disease, and these patients will benefit from aggressive antihypertensive treatment using a combination of agents. β-blockers are playing an increasingly important role in the management of hypertension in high-risk patients. β-blockers are a heterogeneous class of agents, and this review presents the differences between β-blockers and provides evidence-based protocols to assist in understanding dose equivalence in the selection of an optimal regimen in patients with complex needs. The clinical benefits provided by β-blockers are only effective if patients adhere to medication treatment long term. β-blockers with proven efficacy, once-daily dosing, and lower side effect profiles may become instrumental in the treatment of hypertensive diabetic and nondiabetic patients

The Effectiveness of the Use of Puppets in Oral Language Development of Culturally Disadvantaged First-Grade Children

The purposes of this study were 1) to ascertain the effectiveness of puppets with instructional media in oral language development of culturally disadvantaged first-grade children, and 2) to derive the implications of this effect for instructors, teachers, and volunteers working in programs for the culturally disadvantaged child

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: The FINE-ONE trial

AIMS: Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. METHODS: FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months\u27 duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-\u3c 5000 mg/g (≥ 22.6-\u3c 565 mg/mmol) and eGFR of ≥ 25-\u3c 90 ml/min/1.73 m RESULTS: The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. CONCLUSIONS: FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT05901831

Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc

The Clinical Usefulness of Measuring Apolipoproteins in Diabetic Patients: A Preliminary Report

A commercial assay for apolipoproteins A-1 and B as well as total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol was applied to 12-hour fasted serum from 24 insulin-dependent and 19 noninsulin-dependent diabetic persons. Women with noninsulin-dependent diabetes mellitus (NIDDM) had the highest levels of total cholesterol and apolipoprotein B. Apolipoprotein B values fell within the normal range in all patients except the NIDDM females, where four of the ten (40%) samples were elevated. When apolipoprotein B was elevated, total cholesterol was also elevated, over 220 mg/dL. Apolipoprotein A-1 values fell within or above the normal range in all subjects, and a considerable discordance was observed between apolipoprotein A-1 elevations and HDL cholesterol elevations. The divergence between HDL cholesterol and apolipoprotein A-1 supports the altered composition of HDL in the diabetic persons studied. Further study should elucidate the clinical usefulness of apolipoprotein measurements in diabetic patients