Combination Therapy With Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Older Patients With Type 2 Diabetes: A Real-World Evidence Study

Objectives: Scientific literature about the combination of glucagon-like peptide-1 receptor agonists (GLP1ra) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in older patients is scarce. We sought to assess the real-world efficacy and safety of SGLT2 inhibitors and GLP-1ra combination therapy in older patients (>65 years of age). Methods: This was an observational, prospective, multicenter study based on clinical practice. Patients were stratified according to tertiles of baseline glycated hemoglobin (A1C) levels and to treatment schedule. Results: We included 113 patients (65.5% men, mean age 70.4±8.8 years). The body mass index was 36.5 (±6.6) kg/m2. The baseline A1C level was 8.0% (±1.2%). At the 6-month follow up, we found a significant reduction in A1C levels (–1.1%; p<0.0001), body mass index (–2.1 kg/m2; p<0.00003) and systolic blood pressure (–13 mmHg; p<0.000005). Patients who had the highest baseline A1C levels (≥8.4%) showed greater improvement in A1C levels (p<0.0001), weight (p<0.0001) and quality-of-life scores (p<0.0001). The greatest reduction in A1C levels and weight was seen in patients who started both drugs simultaneously (p<0.0001). The second greatest reduction was seen when GLP-1ra was added to previous treatment with an SGLT2i (p<0.0001). Also of note was a decrease in systolic blood pressure in patients for whom an SGLT2i was added to previous GLP-1ra treatment (p<0.0001). Of the patients, 34.3% achieved the combined endpoint of A1C levels <7% and weight loss ≥5% without hypoglycemia. Conclusions: This study’s findings provide evidence of clinically meaningful reductions in A1C level, body weight and systolic blood pressure in older patients with type 2 diabetes who are taking combined regimens. The dropout and hypoglycemia rates were minimal, and treatment was tolerated well

Early biomarkers of diabetic kidney disease. A focus on albuminuria and a new combination of antidiabetic agents

Aims: We aimed to determine the efficacy and safety of sodium-glucose cotransporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists to prevent worsening urinary albumin-to-creatinine ratio as an early biomarker of diabetes kidney disease. Methods: A total of 178 patients with type 2 diabetes and obesity received combination treatment with SGLT2i added to GLP1ra (n = 76), GLP1ra added to SGLT2i (n = 50) or GLP1ra plus SGLT2i from start (n = 52), according to investigators´ best clinical judgement. Major outcomes assessed at 26 weeks were changes in urine albumintocreatinine-ratio (UACR), estimated glomerular filtration rate (eGFR), glycated haemoglobin, body weight and systolic blood pressure. Results: All patients (58.6% men, mean age 61.9 ± 10.0 years) completed the study. Baseline HbA1c, weight and eGFR levels were 8.2 ± 0.9%, 109.9 ± 19 kg and 83.3 ± 19.6 mL/min/m2 , respectively. At 26 weeks, we found significant reductions in HbA1c (1.16%), weight (5.17 kg) and systolic blood pressure (8.13 mmHg). The reduction in UACR was 15.14 mg/g (95% CI 8.50-22.4) (-24.6 ± 64.7%), which was greatest in the group of patients with SGLT2i added on to GLP1ra therapy (116.7 mg/g; 95% CI: 54-296.5 mg/g; P < .001. Patients with urinary albumin-to-creatinine ratio ≥30 mg/g, showed a higher declines (63.18 mg/g [95% CI 44.5-104.99]) (-56 ± 65.9%). The greatest reduction in urinary albumin-to-creatinine ratio was obtained when SGLT2i was added to GLP1ra (116.7 mg/g). The eGFR did not significantly change along the study period. Conclusion: Our results show the beneficial effect of GLP1ra and SGLT2i combination therapy on early biomarkers of diabetes kidney disease such as albuminuria and in other significant outcomes for diabetes control

Adipose Tissue Gene Expression of Factors Related to Lipid Processing in Obesity

BACKGROUND: Adipose tissue lipid storage and processing capacity can be a key factor for obesity-related metabolic disorders such as insulin resistance and diabetes. Lipid uptake is the first step to adipose tissue lipid storage. The aim of this study was to analyze the gene expression of factors involved in lipid uptake and processing in subcutaneous (SAT) and visceral (VAT) adipose tissue according to body mass index (BMI) and the degree of insulin resistance (IR). METHODS AND PRINCIPAL FINDINGS: VLDL receptor (VLDLR), lipoprotein lipase (LPL), acylation stimulating protein (ASP), LDL receptor-related protein 1 (LRP1) and fatty acid binding protein 4 (FABP4) gene expression was measured in VAT and SAT from 28 morbidly obese patients with Type 2 Diabetes Mellitus (T2DM) or high IR, 10 morbidly obese patients with low IR, 10 obese patients with low IR and 12 lean healthy controls. LPL, FABP4, LRP1 and ASP expression in VAT was higher in lean controls. In SAT, LPL and FABP4 expression were also higher in lean controls. BMI, plasma insulin levels and HOMA-IR correlated negatively with LPL expression in both VAT and SAT as well as with FABP4 expression in VAT. FABP4 gene expression in SAT correlated inversely with BMI and HOMA-IR. However, multiple regression analysis showed that BMI was the main variable contributing to LPL and FABP4 gene expression in both VAT and SAT. CONCLUSIONS: Morbidly obese patients have a lower gene expression of factors related with lipid uptake and processing in comparison with healthy lean persons

Development and evaluation of a machine learning-based in-hospital COVID-19 disease outcome predictor (CODOP): A multicontinental retrospective study

New SARS-CoV-2 variants, breakthrough infections, waning immunity, and sub-optimal vaccination rates account for surges of hospitalizations and deaths. There is an urgent need for clinically valuable and generalizable triage tools assisting the allocation of hospital resources, particularly in resource-limited countries. We developed and validate CODOP, a machine learning-based tool for predicting the clinical outcome of hospitalized COVID-19 patients. CODOP was trained, tested and validated with six cohorts encompassing 29223 COVID-19 patients from more than 150 hospitals in Spain, the USA and Latin America during 2020-22. CODOP uses 12 clinical parameters commonly measured at hospital admission for reaching high discriminative ability up to 9 days before clinical resolution (AUROC: 0.90-0.96), it is well calibrated, and it enables an effective dynamic risk stratification during hospitalization. Furthermore, CODOP maintains its predictive ability independently of the virus variant and the vaccination status. To reckon with the fluctuating pressure levels in hospitals during the pandemic, we offer two online CODOP calculators, suited for undertriage or overtriage scenarios, validated with a cohort of patients from 42 hospitals in three Latin American countries (78-100% sensitivity and 89-97% specificity). The performance of CODOP in heterogeneous and geographically disperse patient cohorts and the easiness of use strongly suggest its clinical utility, particularly in resource-limited countries

Elevated circulating levels of succinate in human obesity are linked to specific gut microbiota

Gut microbiota-related metabolites are potential clinical biomarkers for cardiovascular disease (CVD). Circulating succinate, a metabolite produced by both microbiota and the host, is increased in hypertension, ischemic heart disease, and type 2 diabetes. We aimed to analyze systemic levels of succinate in obesity, a major risk factor for CVD, and its relationship with gut microbiome. We explored the association of circulating succinate with specific metagenomic signatures in cross-sectional and prospective cohorts of Caucasian Spanish subjects. Obesity was associated with elevated levels of circulating succinate concomitant with impaired glucose metabolism. This increase was associated with specific changes in gut microbiota related to succinate metabolism: a higher relative abundance of succinate-producing Prevotellaceae (P) and Veillonellaceae (V), and a lower relative abundance of succinate-consuming Odoribacteraceae (O) and Clostridaceae (C) in obese individuals, with the (P + V/O + C) ratio being a main determinant of plasma succinate. Weight loss intervention decreased (P + V/O + C) ratio coincident with the reduction in circulating succinate. In the spontaneous evolution after good dietary advice, alterations in circulating succinate levels were linked to specific metagenomic signatures associated with carbohydrate metabolism and energy production with independence of body weight change. Our data support the importance of microbe-microbe interactions for the metabolite signature of gut microbiome and uncover succinate as a potential microbiota-derived metabolite related to CVD risk

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Alterations of specific biomarkers of metabolic pathways in vascular tree from patients with Type 2 diabetes

AbstractThe aims of this study were to check whether different biomarkers of inflammatory, apoptotic, immunological or lipid pathways had altered their expression in the occluded popliteal artery (OPA) compared with the internal mammary artery (IMA) and femoral vein (FV) and to examine whether glycemic control influenced the expression of these genes. The study included 20 patients with advanced atherosclerosis and type 2 diabetes mellitus, 15 of whom had peripheral arterial occlusive disease (PAOD), from whom samples of OPA and FV were collected. PAOD patients were classified based on their HbA1c as well (HbA1c ≤ 6.5) or poorly (HbA1c > 6.5) controlled patients. Controls for arteries without atherosclerosis comprised 5 IMA from patients with ischemic cardiomyopathy (ICM). mRNA, protein expression and histological studies were analyzed in IMA, OPA and FV. After analyzing 46 genes, OPA showed higher expression levels than IMA or FV for genes involved in thrombosis (F3), apoptosis (MMP2, MMP9, TIMP1 and TIM3), lipid metabolism (LRP1 and NDUFA), immune response (TLR2) and monocytes adhesion (CD83). Remarkably, MMP-9 expression was lower in OPA from well-controlled patients. In FV from diabetic patients with HbA1c ≤6.5, gene expression levels of BCL2, CDKN1A, COX2, NDUFA and SREBP2 were higher than in FV from those with HbA1c >6.5.The atherosclerotic process in OPA from diabetic patients was associated with high expression levels of inflammatory, lipid metabolism and apoptotic biomarkers. The degree of glycemic control was associated with gene expression markers of apoptosis, lipid metabolism and antioxidants in FV. However, the effect of glycemic control on pro-atherosclerotic gene expression was very low in arteries with established atherosclerosis.This study was undertaken with finance from FIS “Centros de Investigación En Red” (CIBER, CB06/03/0018) and REDINSCOR RD06/0003/0015 from Instituto de Salud Carlos III, Madrid, Spain.Peer Reviewe

Expert Panel Guidance and Narrative Review of Treatment Simplification of Complex Insulin Regimens to Improve Outcomes in Type 2 Diabetes.

Given the progressive nature of type 2 diabetes (T2D), most individuals with the disease will ultimately undergo treatment intensification. This usually involves the stepwise addition of a new glucose-lowering agent or switching to a more complex insulin regimen. However, complex treatment regimens can result in an increased risk of hypoglycaemia and high treatment burden, which may impact negatively on both therapeutic adherence and overall quality of life. Individuals with good glycaemic control may also be overtreated with unnecessarily complex regimens. Treatment simplification aims to reduce individual treatment burden, without compromising therapeutic effectiveness or safety. Despite data showing that simplifying therapy can achieve good glycaemic control without negatively impacting on treatment efficacy or safety, it is not always implemented in clinical practice. Current clinical guidelines focus on treatment intensification, rather than simplification. Where simplification is recommended, clear guidance is lacking and mostly focused on treatment of the elderly. An expert, multidisciplinary panel evaluated the current treatment landscape with respect to guidance, published evidence, recommendations and approaches regarding simplification of complex insulin regimens. This article outlines the benefits of treatment simplification and provides practical recommendations on simplifying complex insulin treatment strategies in people with T2D using illustrative cases