Therapies for type 2 diabetes: lowering HbA1c and associated cardiovascular risk factors

<p>Abstract</p> <p>Objectives</p> <p>To summarize data supporting the effects of antidiabetes agents on glucose control and cardiovascular risk factors in patients with type 2 diabetes.</p> <p>Methods</p> <p>Studies reporting on the effects of antidiabetes agents on glycemic control, body weight, lipid levels, and blood pressure parameters are reviewed and summarized for the purpose of selecting optimal therapeutic regimens for patients with type 2 diabetes.</p> <p>Results</p> <p>National guidelines recommend the aggressive management of cardiovascular risk factors in patients with type 2 diabetes, including weight loss and achieving lipid and blood pressure treatment goals. All antidiabetes pharmacotherapies lower glucose; however, effects on cardiovascular risk factors vary greatly among agents. While thiazolidinediones, sulfonylureas, and insulin are associated with weight gain, dipeptidyl peptidase-4 inhibitors are considered weight neutral and metformin can be weight neutral or associated with a small weight loss. Glucagon-like peptide-1 receptor agonists and amylinomimetics (e.g. pramlintide) result in weight loss. Additionally, metformin, thiazolidinediones, insulin, and glucagon-like peptide-1 receptor agonists have demonstrated beneficial effects on lipid and blood pressure parameters.</p> <p>Conclusion</p> <p>Management of the cardiovascular risk factors experienced by patients with type 2 diabetes requires a multidisciplinary approach with implementation of treatment strategies to achieve not only glycemic goals but to improve and/or correct the underlying cardiovascular risk factors.</p

Structure based inhibitor design targeting glycogen phosphorylase b. Virtual screening, synthesis, biochemical and biological assessment of novel N-acyl-β-d-glucopyranosylamines

Glycogen phosphorylase (GP) is a validated target for the development of new type 2 diabetes treatments. Exploiting the Zinc docking database, we report the in silico screening of 1888 β- D-glucopyranose-NH-CO-R putative GP inhibitors differing only in their R groups. CombiGlide and GOLD docking programs with different scoring functions were employed with the best performing methods combined in a “consensus scoring” approach to ranking of ligand binding affinities for the active site. Six selected candidates from the screening were then synthesized and their inhibitory potency was assessed both in vitro and ex vivo. Their inhibition constants’ values, in vitro, ranged from 5 to 377 µM while two of them were effective at causing inactivation of GP in rat hepatocytes at low µM concentrations. The crystal structures of GP in complex with the inhibitors were defined and provided the structural basis for their inhibitory potency and data for further structure based design of more potent inhibitors

RE-MIND2: comparative effectiveness of tafasitamab plus lenalidomide versus polatuzumab vedotin/bendamustine/rituximab (pola-BR), CAR-T therapies, and lenalidomide/rituximab (R2) based on real-world data in patients with relapsed/refractory diffuse large B-cell lymphoma

Abstract: RE-MIND2 (NCT04697160) compared patient outcomes from the L-MIND (NCT02399085) trial of tafasitamab+lenalidomide with those of patients treated with other therapies for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are autologous stem cell transplant ineligible. We present outcomes data for three pre-specified treatments not assessed in the primary analysis. Data were retrospectively collected from sites in North America, Europe, and the Asia Pacific region. Patients were aged ≥18 years with histologically confirmed DLBCL and received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients enrolled in the observational and L-MIND cohorts were matched using propensity score-based 1:1 nearest-neighbor matching, balanced for six covariates. Tafasitamab+lenalidomide was compared with polatuzumab vedotin+bendamustine+rituximab (pola-BR), rituximab+lenalidomide (R2), and CD19-chimeric antigen receptor T-cell (CAR-T) therapies. The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and progression-free survival. From 200 sites, 3,454 patients were enrolled in the observational cohort. Strictly matched patient pairs consisted of tafasitamab+lenalidomide versus pola-BR (n = 24 pairs), versus R2 (n = 33 pairs), and versus CAR-T therapies (n = 37 pairs). A significant OS benefit was observed with tafasitamab+lenalidomide versus pola-BR (HR: 0.441; p = 0.034) and R2 (HR: 0.435; p = 0.012). Comparable OS was observed in tafasitamab+lenalidomide and CAR-T cohorts (HR: 0.953, p = 0.892). Tafasitamab+lenalidomide appeared to improve survival outcomes versus pola-BR and R2, and comparable outcomes were observed versus CAR-T. Although based on limited patient numbers, these data may help to contextualize emerging therapies for R/R DLBCL. Clinical trial registration: NCT04697160 (January 6, 2021

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

BACKGROUND: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. OBJECTIVE: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). METHODS: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. RESULTS: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. CONCLUSION: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF

Improved Efficacy of Tafasitamab plus Lenalidomide versus Systemic Therapies for Relapsed/Refractory DLBCL: RE-MIND2, an Observational Retrospective Matched Cohort Study

PURPOSE: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. RESULTS: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R-GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P &lt; 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). CONCLUSIONS: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908

Smallholder farmers' adaptation to climate change and determinants of their adaptation decisions in the Central Rift Valley of Ethiopia

Background: The agricultural sector remains the main source of livelihoods for rural communities in Ethiopia, but faces the challenge of changing climate. This study investigated how smallholder farmers perceive climate change, what adaptation strategies they practice, and factors that influence their adaptation decisions. Both primary and secondary data were used for the study, and a multinomial logit model was employed to identify the factors that shape smallholder farmers’ adaptation strategies. Results: The results show that 90% of farmers have already perceived climate variability, and 85% made attempts to adapt using practices like crop diversification, planting date adjustment, soil and water conservation and management, increasing the intensity of input use, integrating crop with livestock, and tree planting. The econometric model indicated that education, family size, gender, age, livestock ownership, farming experience, frequency of contact with extension agents, farm size, access to market, access to climate information and income were the key factors determining farmers’ choice of adaptation practice. Conclusion: In the Central Rift Valley of Ethiopia, climate change is a pressing problem, which is beyond the capacity of smallholders to respond to autonomously. Farmers’ capacity to choose effective adaptation options is influenced by household demography, as well as positively by farm size, income, access to markets, access to climate information and extension, and livestock production. This implies the need to support the indigenous adaptation strategies of the smallholder farmers with a wide range of institutional, policy, and technology support; some of it targeted on smaller, poorer or female-headed households. Moreover, creating opportunities for non-farm income sources is important as this helps farmers to engage in those activities that are less sensitive to climate change. Furthermore, providing climate change information, extension services, and creating access to markets are crucial

RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a real-world lenalidomide monotherapy cohort in relapsed or refractory diffuse large B-cell lymphoma

Purpose: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse largeB-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MINDto delineate the contribution of tafasitamab to the efficacy of the combination. Patients and Methods: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates.The primary endpointwas investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). Results: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P &lt; 0.0001]. HigherCR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. Conclusions: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL

Climate change and agricultural adaptation in Sri Lanka: a review

Climate change is inevitable and will continue into the next century. Since the agricultural sector in Sri Lanka is one of the most vulnerable to climate change, a thorough understanding of climate transition is critical for formulating effective adaptation strategies. This paper provides an overview of the status of climate change and adaptation in the agricultural sector in Sri Lanka. The review clearly indicates that climate change is taking place in Sri Lanka in terms of rainfall variability and an increase in climate extremes and warming. A number of planned and reactive adaptation responses stemming from policy and farm-level decisions are reported. These adaptation efforts were fragmented and lacked a coherent connection to the national development policies and strategies. Research efforts are needed to develop and identify adaptation approaches and practices that are feasible for smallholder farmers, particularly in the dry zone where paddy and other food crops are predominately cultivated. To achieve the envisaged growth in the agricultural sector, rigorous efforts are necessary to mainstream climate change adaptation into national development policies and ensure that they are implemented at national, regional and local levels

Recent Progress in the Use of Glucagon and Glucagon Receptor Antagonists in the Treatment of Diabetes Mellitus

Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques