Glucose-lowering Treatment Research Articles

Glucagon-Like Peptide-1 Receptor Agonists and Pancreatic Cancer Risk in Patients With Type 2 Diabetes

Concerns have been raised that glucagon-like peptide-1 receptor agonists (GLP-1RA) may increase the risk of pancreatic cancer. To investigate the association of GLP-1RA treatment with pancreatic cancer incidence over 9 years of follow-up. In this population-based historical cohort study, adult patients (aged 21 to 89 years) with type 2 diabetes insured by Clalit Healthcare Services, the largest state-mandated health organization in Israel, were followed up from 2009, when GLP-1RA became available in Israel, until pancreatic cancer diagnosis, death, reaching age 90 years, or end of follow-up (December 2017). Data were analyzed from June 2022 to November 2023. Treatment with GLP-1RA was compared with basal insulin. Pancreatic cancer incidence was compared according to weighted cumulative exposures to GLP-1RA and to basal insulin in a Cox model implemented in discrete time, with time origin at 2 years after diabetes diagnosis, adjusting for confounding. In sensitivity analyses, propensity score-matched pair new-user design and prevalent new-user design were used for the comparison. Because of risk for reverse-causation bias, results in the fifth to seventh year after medication were emphasized. During a cumulative follow-up of 3 290 439 person-years of 543 595 adults with a mean (SD) age of 59.9 (12.8) years (277 502 women [51%]) with incident diabetes, 1665 patients received pancreatic cancer diagnoses. In total, 33 377 patients (6.1%) used GLP-1RA and 106 849 (19.7%) used basal insulin. The estimated hazard ratio (HR) for pancreatic cancer associated with incremental use of 1 defined daily dose per day of GLP-1RA compared with basal insulin in the fifth to seventh year previously (all other characteristics, including age, sex, ethnic background, sociodemographic status, baseline body mass index, smoking history, history of pancreatitis, other glucose-lowering medications treatment history, and length of diabetes, being equal) was 0.50 (95% CI, 0.15-1.71). The new-user and prevalent new-user designs showed HRs from the fifth year onwards following initiation of GLP-1RA vs basal insulin of 0.52 (95 % CI, 0.19-1.41) and 0.75 (95 % CI, 0.37-1.53), respectively. In this historical cohort study of adults with type 2 diabetes, no support for an increased pancreatic cancer incidence over 7 years following start of GLP-1RA treatment was found. However, monitoring for pancreatic cancer risk beyond 7 years following initiation of therapy is still required. ClinicalTrials.gov Identifier: NCT02072902.

Body Fat Depletion: the Yin Paradigm for Treating Type 2 Diabetes.

To highlight that body fat depletion (the Yin paradigm) with glucose-lowering treatments (the Yang paradigm) are associated with metabolic benefits for patients with type 2 diabetes mellitus (T2DM). The sodium-glucose cotransporter-2 inhibitor-mediated sodium/glucose deprivation can directly improve glycemic control and kidney outcome in patients with T2DM. The glucose deprivation might also promote systemic fatty acid β-oxidation to deplete ectopic/visceral fat and thereby contribute to the prevention of cardiovascular diseases. As with metabolic surgery, bioengineered incretin-based medications with potent anorexigenic and insulinotropic efficacy can significantly reduce blood glucose as well as body weight (especially in the ectopic/visceral fat depots). The latter effects could be a key contributor to their cardiovascular-renal protective effects. In addition to a healthy diet, the newer glucose-lowering medications, with body fat reduction effects, should be prioritized when treating patients with T2DM, especially for those with established cardiovascular/renal risks or diseases.

Lung dendritic-cell metabolism underlies susceptibility to viral infection in diabetes

People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.

MR Assessed Changes of Renal Sinus Fat in Response to Glucose Regulation in West European and South Asian Patients With Type 2 Diabetes.

Ethnic differences in the progression and outcome of diabetic kidney disease (DKD) remain to be elucidated. MRI-quantified renal sinus fat volume could be a potential biomarker to help investigate the changes of DKD risk in response to glucose regulation. To evaluate whether the effect of glucose-lowering treatment on renal sinus fat volume differed in West Europeans (WE) compared to South Asians (SA), and whether ethnic-related difference exists regarding the effect of liraglutide on renal sinus fat. Retrospective. Ninety-three patients with type 2 diabetes mellitus, including 47 WE (27 males) aged 59.3 ± 6.5 years, and 46 SA (19 males) aged 54.4 ± 9.8 years. 3.0 T dual-echo fast gradient-echo pulse sequence using two-point Dixon technique with a phase-correction algorithm. Changes of renal sinus fat volume were measured by a radiologist (LL) with 4-years' experience, and were compared between the two ethnic groups, together with glycemic level, metabolic risk factors and renal function. The effects of liraglutide were assessed. Normality of the data was visually evaluated by histograms and Q-Q plots. Within-group and between-group differences were analyzed using paired t-tests and analysis of covariance. Associations were analyzed by person's correlation and multiple linear regression models. Renal sinus fat decreased in SA patients (Δ% = -7.6% ± 14.8%), but increased in WE patients (Δ% = 5.0% ± 13.1%), with a significant difference between the two ethnic groups. In the WE group, the increase of sinus fat volume was significant in the placebo subgroup (Δ% = 6.8% ± 12.5%), in contrast to the nonsignificant increase in the liraglutide subgroup (Δ% = 3.0% ± 13.8%, P = 0.444). Renal sinus fat accumulation responds differently to glucose regulation, showing a reduction in SA patients in contrast to a persistent accumulation in WE patients. A trend of less accumulation of sinus fat in WE patients receiving liraglutide has been observed. 4 TECHNICAL EFFICACY: Stage 4.

Durability of Effectiveness Between Users of Once-Weekly Semaglutide and Dipeptidyl Peptidase4 Inhibitors (DPP-4i) in US Adults with Type2 Diabetes.

Long-term effectiveness and durability of glucose-lowering medications are important considerations in managing type2 diabetes (T2D). This study aimed to compare durability of treatment efficacy of once-weekly (OW) semaglutide for T2D with that of the dipeptidyl peptidase4 inhibitor (DPP-4i) class. This observational cohort study used 2017-2022 data from the Optum® Clinformatics® Data Mart to compare long-term clinical outcomes associated with semaglutide or DPP-4i in US adults with T2D. The primary outcomes were HbA1c at 2-year follow-up, change in HbA1c from baseline, and the odds of achieving HbA1c targets. BMI at 2-year follow-up, change in BMI from baseline, odds of reducing BMI category, and the need for treatment augmentation were exploratory outcomes. Bivariate and multivariate analyses were conducted using inverse probability of treatment weighting (IPTW) weighted descriptive statistics. Weighted HbA1c and BMI cohorts included 865 and 642 semaglutide users and 779 and 537 DPP-4i users, respectively. In the weighted HbA1c cohort, semaglutide and DPP-4i users had an average age of 60years and similar baseline characteristics including HbA1c level and comorbidity status. Two-year follow-up HbA1c with semaglutide was 0.56% lower than with DPP-4i; reduction in HbA1c from baseline was 0.61% greater. Odds of achieving HbA1c level < 7% were 2.16 times greater after covariate adjustment (all, p < 0.001). Semaglutide was associated with 1.03kg/m2 greater reduction in BMI and 2.27 times greater odds of reducing BMI category vs DPP-4i (p < 0.001). Semaglutide users were less likely to add new glucose-lowering treatment (hazard ratio [HR] 0.57; p < 0.001) or initiate insulin (HR 0.49; p < 0.001) vs DPP-4i users. Compared with DPP-4i, semaglutide was associated with lower follow-up HbA1c and BMI, greater reduction in HbA1c and BMI from baseline, and reduced likelihood of requiring treatment augmentation or insulin initiation to manage T2D in US adults, suggesting better durability of semaglutide vs DPP-4i. INFOGRAPHIC.

Age disparities in glucose-lowering treatment for Danish people with type 2 diabetes: a cross-sectional study between 2019 and 2020

The pharmacotherapeutic guidelines for type 2 diabetes have changed considerably during the past decades. SGLT2 inhibitors and GLP-1 receptor agonists have emerged as first-line agents by preventing cardiovascular events within a few years of treatment. In contrast, sulphonylureas and insulin have been deprioritised due to less beneficial effects and the risk of hypoglycaemia-particularly in older people who are frail. We hypothesised that medications with a high risk of hypoglycaemia were used more often in older people compared with younger people. In a nationwide cohort of people with type 2 diabetes in Denmark from 2019 to 2020, we described the use of specific glucose-lowering medications in relation to age and glycated haemoglobin A1C (HbA1c) by descriptive statistics and regression models adjusted for sex, socioeconomic factors, renal function, and several comorbidities. Among 290 890 people with type 2 diabetes, glucose-lowering medication usage peaked at age 70 years. Increasing age was associated with relatively less use of metformin, GLP-1 receptor agonists, and SGLT2 inhibitors and more use of basal insulin, DDP-4 inhibitors, and sulphonylureas. When comparing 80-year-olds with 60-year-olds at similar HbA1c levels of 6·5% (48 mmol/mol), 80-year-olds used 8% (95% CI 7-10%) fewer glucose-lowering medications, were 55% less likely to receive GLP-1 receptor agonists or SGLT2 inhibitors (relative ratio 0·45, 95% CI 0·42-0·48), and 65% more likely to receive sulphonylureas (1·65, 1·54-1·76). Among 23 032 individuals aged 80 years or older with HbA1c levels of less than 6·5% (<48 mmol/mol), 2291 (10%) used sulphonylureas or insulin. In Danish people with type 2 diabetes, the likelihood of using glucose-lowering medications with a high risk of hypoglycaemia (eg, sulphonylureas and basal insulin) increased with age, whereas the likelihood of using GLP-1 receptor agonists and SGLT2 inhibitors decreased. Some people aged 80 years or older with an HbA1c level of less than 6·5% (48 mmol/mol) were potentially overtreated with sulphonylureas or insulin. These findings emphasise the importance of frequently re-evaluating glucose-lowering treatments. None. For the Danish translation of the abstract see Supplementary Materials section.

Real-life use of novel glucose lowering agents after acute myocardial infarction and stable coronary artery disease in patients with diabetes - experience from national use in the SWEDEHEART-registry

Abstract Background Recently Sodium Glucose Lowering Transport 2 receptor inhibitors (SGLT2i) and Glucagon Like Peptide Receptor Agonists (GLP-1 RA) have demonstrated preventive effects in patients with established diabetes and evidence of cardiovascular disease, and is recommended in guidelines regardless of glucose control. Less is known about the real uptake of these therapies and the demographic of patients prescribed these drugs. Purpose To explore trends and real-life use of novel glucose lowering agents in patients with diabetes and coronary artery disease (CAD) and these patients’ prognosis in a national perspective. Methods All patients with diabetes and CAD admitted for coronary angiography in 2010-2021 reported in the Swedish angiography and angioplasty registry (SCAAR) were included. Information on glucose lowering agents dispended within 6 months to the coronary angiography was collected from the Prescribed Drug Registry and grouped into classes. Information on comorbidities and death until December 2021 was collected from the National Patient Registry. Mortality was assessed by Cox proportional survival analysis with novel cardioprotective glucose lowering agents as a reference. Results Of 38 671 patients, mean age was 68.6 years (SD 10.6) and 67.3% (n=26 017) were men. Figure 1 depicts trends in use of glucose lowering classes 2010-2021; use of novel glucose lowering agents increased rapidly from the year 2016 with a continuously high rise (proportion 7% to 47%). This was mainly driven by the use of SGLT2i (from 4% to 38%) and less of GLP-1 RA (4% to 15%). In parallel with this, use of insulin and absence of glucose lowering treatment decreased slightly and use of sulfonylurea decreased dramatically while use of metformin slightly increased. Patients who received the new agents (SGLT2; n=3191 and GLP-1 RA; n=1570), compared to patients on other glucose lowering agents than SGLT2i or GLP-1 RA (n=25 967), were younger (mean age 66 [SD 10] vs. 68 years [SD 10]), more often men (72.8%; n=3465 vs. 67.1%; n=17 427) and with less frequent heart failure (5.0%; n=239 vs. 6.8%; n=1770) and previous myocardial infarction (7.7%; n=367 vs. 10.5%; n=2736). Cumulative event rate is depicted in Figure 2. All-cause death within 1 year occurred in 1.7% (n=79) of patients with SGLT2i and/or GLP-1 RA compared to 4.5% (n=1114) in patients without new cardioprotective agents whose adjusted associated risk for all-cause death was higher, HR 1.22 (95% CI 1.09-1.37). Conclusion The fast uptake of novel cardioprotective glucose lowering agents in patients with diabetes in Sweden is encouraging. However, there is a signal that those agents are more often prescribed to a population with lower cardiovascular risk with an associated better outcome and less often to those at high risk for new events. This may be one explanation for the lower mortality rate seen. An increased awareness is needed to use effective cardioprotective treatment also in a high-risk population.Figure 1.Use of glucose lowering agentsFigure 2.Death by glucose lowering drugs

Abstract 11760: Prevalence of Atherosclerosis, Heart Failure, and Chronic Kidney Disease Among Patients With Type 2 Diabetes and Management With Diabetes Pharmacotherapy

Introduction: Individuals with type 2 diabetes (T2D) are at increased risk for cardiovascular disease (CVD), the leading cause of mortality in these patients, and chronic kidney disease (CKD). Recent clinical guidelines recommend the use of diabetes pharmacotherapy with cardiovascular or renal benefits in patients with T2D and CVD or CKD. Aims: The aims of this study were to 1) assess the prevalence of established CVD, including atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), and CKD, and 2) determine the proportion of patients prescribed CVD/CKD-protective diabetes pharmacotherapy (SGLT-2i and GLP1-RA) among individuals with T2D receiving primary care in the US. Data: Data for this retrospective, cross-sectional study were obtained from Optum Labs Data Warehouse, which contains de-identified administrative claims and electronic health record data representing a diversity of age, race, and ethnicity across the US. Eligible individuals were aged ≥18 years, had established T2D and were required to have ≥1 outpatient visit with a primary care provider in 2019. Results: This study included 843,119 individuals with T2D receiving care in 2019. Among these patients, the prevalence of CVD was 44.1%, with 41.5% having evidence of ASCVD and 14.4% having evidence of HF, and the prevalence of CKD was 34.6%. The prevalence of these comorbidities increased with age. For individuals who had T2D and ASCVD, HF, or CKD, 14.0%, 11.7% and 15.1%, respectively, were prescribed SGLT-2i or GLP1-RA, relative to 16.8% of patients with T2D without these comorbidities. Additionally, compared with younger patients, comorbid patients older than 65 years were prescribed these therapies at much lower rates. Conclusions: Among patients with T2D and established CVD, 9 of 10 patients had ASCVD: a 3-fold higher prevalence than HF. Less than 17% of individuals with T2D were prescribed a guideline-recommended glucose-lowering treatment with cardiovascular and renal benefits. The data from this study suggest that patients with T2D and CVD/CKD were prescribed less SGLT-2i or GLP1-RA compared to patients with T2D without these comorbidities. This trend was concerning among older patients, who had both higher rates of these comorbidities and lower prescribing trends.

The role of hyperglycemia in the outcome of intracerebral hemorrhage: A causative analysis

BackgroundHyperglycemia in the acute phase of intracerebral hemorrhage (ICH) has been associated with poor functional outcomes, however all interventions to lower glucose have yielded neutral or negative results. We attempt an explanation of the causal role of hyperglycemia in ΙCH outcome using generalized structural equation modeling. Materials and methodsConsecutive primary ICH patients admitted to an academic hospital between 2007 and 2018 were identified. Patients with missing baseline or follow up CT scans and without 90 day follow up status were excluded. We constructed a causal model accounting for pre-defined markers of ICH severity to evaluate the association between mean 72 h glucose and 90 day functional outcome measured by modified Rankin Scale, dichotomized as favorable ≤2 or unfavorable >2. ResultsPrimary analyses included 410 patients (70.4 ± 13.8years, 43 % female). Mean 72 h glucose was 137.5 ± 33.4mg/dl and 102 (25 %) patients were diabetic. On univariable analysis, higher glucose levels were negatively correlated with favorable outcome (p < 0.0001). However in the structural equation model, this relationship was significantly attenuated (p = 0.06) after accounting for the causal effect of diabetes (p < 0.0001), hematoma volume (p < 0.0001), intraventricular extension (p = 0.01) and Glasgow coma scale (p = 0.001) on glucose levels. On secondary analyses stratifying by diagnosis of diabetes, higher glucose levels were negatively correlated with favorable outcome in patients without diabetes (p = 0.04), but not in patients with diabetes (p = 0.35). ConclusionsHyperglycemia may be a downstream effect of other markers of ICH severity, particularly among patients without diabetes, suggesting a possible explanation for the limited evidence of glucose lowering interventions in outcome.

Hypoglycemia and Cardiovascular Disease: Exploring the Connections.

It has long been known that administering insulin or insulin secretagogues to treat diabetes has the unfavorable side effect of hypoglycemia. Because hypoglycemia can disrupt normal brain function, it can have a profound impact on people's lives. Studies have shown a connection between hypoglycemia and a higher risk of death and cardiovascular disease. Through experimental studies, numerous potential reasons for the start of cardiovascular events have been discovered. In addition, studies on people have demonstrated that hypoglycemia can result in ventricular arrhythmias. According to recent studies, a number of factors may affect the relationship between hypoglycemia, cardiovascular events, and mortality. Confounding factors may explain the apparent correlation, at least in part. People with comorbidities may experience more hypoglycemia, increasing their risk of mortality. Those who have type 1 or type 2 diabetes, however, seem to be more susceptible to the negative effects of hypoglycemia on the cardiovascular system. When choosing appropriate glucose-lowering treatments and setting glycemic objectives with patients, clinicians should be aware of this risk.

Glycemic control, HbA1c variability, and major cardiovascular adverse outcomes in type 2 diabetes patients with elevated cardiovascular risk: insights from the ACCORD study

BackgroundAlthough recent guidelines advocate for HbA1c target individualization, a comprehensive criterion for patient categorization remains absent. This study aimed to categorize HbA1c variability levels and explore the relationship between glycemic control, cardiovascular outcomes, and mortality across different degrees of variability.MethodsAction to Control Cardiovascular Risk in Diabetes study data were used. HbA1c variability was measured using the HbA1c variability score (HVS) and standard deviation (SD). K-means and K-medians clustering were used to combine the HVS and SD.ResultsK-means clustering was the most stable algorithm with the lowest clustering similarities. In the low variability group, intensive glucose-lowering treatment significantly reduced the risk of adverse cardiovascular outcomes (HR: 0·78 [95% CI: 0·63, 0·97]) without increasing mortality risk (HR: 1·07 [0.81, 1·42]); the risk of adverse cardiovascular events (HR: 1·33 [1·14, 1·56]) and all-cause mortality (HR: 1·23 [1·01,1·51]) increased with increasing mean HbA1c. In the high variability group, treatment increased the risk of cardiovascular events (HR: 2.00 [1·54, 2·60]) and mortality (HR: 2·20 [1·66, 2·92]); a higher mean HbA1c (7·86%, [7·66%, 8·06%]) had the lowest mortality risk, when the mean HbA1c was < 7·86%, a higher mean HbA1c was associated with a lower mortality risk (HR: 0·63 [0·42, 0·95]). In the medium variability group, a mean HbA1c around 7·5% was associated with the lowest risk.ConclusionsHbA1c variability can guide glycemic control targets for patients with type 2 diabetes. For patients with low variability, the lower the HbA1c, the lower the risk. For those with medium variability, controlling HbA1c at 7·5% provides the maximum benefit. For patients with high variability, a mean HbA1c of around 7·8% presents the lowest risk of all-cause mortality, a lower HbA1c did not provide cardiovascular benefits but instead increased the mortality risk. Further studies, especially those with patients that reflect the general population with type 2 diabetes undergoing the latest therapeutic approaches, are essential to validate the conclusions of this study.

Comprehensive Evaluation of the Clinical Efficacy of an Anti-Diabetic Polyherbal Formulation

Background: There are several clinical studies examining the health advantages of several single medicinal herbs utilized in traditional blood glucose-lowering treatments. But very few or no studies on herbal formulations were made as Polyherbal for the same goal. As a result, it is now necessary to confirm that patients with hyperglycemia can benefit from such Polyherbal medicines as Dolabi. Methods: This prospective open-label, herbal coded test drug-controlled, randomized trial was conducted at the Munshiganj and Dhaka area in Bangladesh. We enrolled 108 male and 104 female patients of 30-70 years with primary and moderate hyperglycemia. They were recruited from the OPD of an Unani &amp; Ayurvedic hospital in Munshiganj and different Unani clinics in Dhaka, Bangladesh after fulfilling the inclusion criteria. Patients were randomly assigned to receive metformin hydrochloride 500 mg two times daily and 2 tablets of Dolabi two times daily by using a random numbers table with the help of an assistant. Blood samples, height, weight, blood pressure, and personal data were recorded—laboratory results were obtained at the study baseline, after 1.5 months and after 3 months of intervention. Results: In the case of the test drug, results showed a significant decrease in blood glucose level between the baseline and after 3 months, in males, it was from 9.83±1.17 to 7.72±1.06 mg/dL for fasting glucose, from 16.60±2.35 to 8.23±1.17 mg/dL for 2 hours PP glucose, from 9.33±1.17 to 7.45±2.03 percent for HbA1c and for Insulin it reduces from 183.10±27.59 to 168.10±29.59 pmol/ L. The control drug metformin hydrochloride also showed a significant decrease in blood glucose level between baseline and after 3 months, in the case of males it was from 9.99±2.52 to 6.97±1.76 mg/dL for fasting glucose, from 17.43±5.05 to 7.89±2.42 mg/dL for 2 hours PP glucose, from 10.43±2.36 to 6.87±1.18 percent for HbA1c and for Insulin it reduces from 198.75±30.61 to 183.75±30.61p mol/L. In the case of females the test drug showed a significant reduction in fasting glucose, 2 hours PP glucose, HbA1c and Insulin between the baseline and after 3 months, it was from 10.02±1.11 to 7.78±0.93 mg/dL, from 16.88±2.21 to 8.16±1.11 mg/dL, from 9.84±1.04 to 7.45±1.03 percent and from 199.47±30.90 to 173.47±30.90 mg/dL respectively. In the case of females, the control drug showed a significant reduction in fasting glucose, 2 hours PP glucose, HbA1c and Insulin between baseline and after 3 months, it was from 10.18±1.92 to 6.71±1.59 mg/dL, from 18.70±3.88 to 7.60±3.74 mg/dL, from 10.58±1.08 to 6.98±1.08 percent and from 200.00±31.83 to 188.00±31.83 mg/dL respectively. Conclusions: We can infer the following from the present study’s findings: The polyherbal formulation Dolabi is able to reduce the blood glucose level. It can be an effective drug for primary hyperglycemic patients.

Disturbed hippocampal histidine metabolism contributes to cognitive impairment induced by recurrent nonsevere hypoglycemia in diabetes

Hypoglycemia is a common adverse reaction to glucose-lowering treatment. Diabetes mellitus (DM) combined with recurrent nonsevere hypoglycemia (RH) can accelerate cognitive decline. Currently, the metabolic pattern changes in cognition-related brain regions caused by this combined effect of DM and RH (DR) remain unclear. In this study, we first characterized the metabolic profiles of the hippocampus in mice exposed to DR using non-targeted metabolomic platforms. Our results showed that DR induced a unique metabolic pattern in the hippocampus, and several significant differences in metabolite levels belonging to the histidine metabolism pathway were discovered. Based on these findings, in the follow-up experiment, we found that histidine treatment could attenuate the cognitive impairment and rescue the neuronal and synaptic damage induced by DR in the hippocampus, which are closely related to ameliorated mitochondrial injury. These findings provide new insights into the metabolic mechanisms of the hippocampus in the progression of DR, and l-histidine supplementation may be a potential metabolic therapy in the future.

Empagliflozin Normalizes Fasting Hyperglycemia and Improves Postprandial Glucose Tolerance in Totally Pancreatectomized Patients: A Randomized, Double-Blind, Placebo-Controlled Crossover Study.

Insulin remains the only glucose-lowering treatment modality recommended for totally pancreatectomized patients. We investigated the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin on fasting and postprandial glucose concentrations in pancreatectomized patients and matched healthy control participants. In a randomized, double-blind, placebo-controlled crossover study, 10 pancreatectomized patients and 10 matched control participants underwent two 3-h liquid mixed meal tests preceded by two doses of 25 mg empagliflozin (administered the night before and in the morning of the meal test) or placebo, respectively. Basal insulin was administered as usual, but bolus insulin was omitted before the meal test during experimental days. Compared with placebo, empagliflozin lowered fasting plasma glucose (5.0 ± 0.4 vs. 7.9 ± 0.9 mmol/L [mean ± SEM], P = 0.007) and postprandial plasma glucose excursions as assessed by baseline-subtracted area under the curve (1,080 [733; 1,231] vs. 1,169 [1,036; 1,417] pmol/L × min [median (25th and 75th percentiles)], P = 0.014) in the pancreatectomized patients. In the control participants, empagliflozin lowered fasting plasma glucose compared with placebo (5.1 ± 0.1 vs. 5.5 ± 0.1 mmol/L, P = 0.008) without affecting postprandial glucose excursions significantly. The pancreatomy group exhibited greater postprandial glucagon excursions compared with the control group on both experimental days (P ≤ 0.015); no within-group differences between days were observed. Empagliflozin administered the day before and immediately before a standardized liquid mixed meal test normalized fasting hyperglycemia and improved postprandial glucose tolerance in pancreatectomized patients.

Design and rationale of the myocardial infarction and new treatment with metformin study (MIMET) - Study protocol for a registry-based randomised clinical trial

AimsTo investigate if addition of metformin to standard care (life-style advice) reduces the occurrence of cardiovascular events and death after myocardial infarction (MI) in patients with newly detected prediabetes. MethodsThe Myocardial Infarction and new treatment with Metformin study (MIMET) is a large multicentre registry-based randomised clinical trial (R-RCT) within the SWEDEHEART registry platform expected to include 5160 patients with MI and newly detected prediabetes (identified with fasting blood glucose, HbA1c or 2-h glucose on oral glucose tolerance test) at ∼20 study sites in Sweden. Patients 18–80 years, without known diabetes and naïve to glucose lowering therapy, will be randomised 1:1 to open-label metformin therapy plus standard care or standard care alone. OutcomesPatients will be followed for 2 years for the primary outcome new cardiovascular event (first of death, non-fatal MI, hospitalisation for heart failure or non-fatal stroke). Secondary endpoints include individual components of the primary endpoint, diabetes diagnosis, initiation of any glucose lowering therapy, cancer, and treatment safety. Events will be collected from national healthcare registries. ConclusionsThe MIMET study will investigate if metformin is superior to standard care after myocardial infarction in preventing cardiovascular events in patients with prediabetes (Clinicaltrials.gov identifier: NCT05182970; EudraCT No: 2019-001487-30).

Glucose-lowering treatment pathways of individuals with chronic kidney disease and type 2 diabetes according to the Kidney Disease: Improving Global Outcomes 2012 risk classification.

To describe treatment pathways for key glucose-lowering therapies in individuals with chronic kidney disease (CKD) and type 2 diabetes (T2D) using retrospective data from DISCOVER CKD (NCT04034992). Data were extracted from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data (2008-2020) and the US integrated Limited Claims and Electronic Health Records Database (LCED; 2012-2019). Eligible individuals were aged ≥18 years with CKD, identified by two consecutive estimated glomerular filtration rate (eGFR) measures (15-<75 mL/min/1.73 m2 ; 90-730 days apart; index date was the second measurement) and T2D. Chronological treatment pathways for glucose-lowering therapies prescribed on or after CKD index to end of follow-up were computed. Median time and proportion of overall follow-up time on treatment were described for each therapy by database and by eGFR and urinary albumin-to-creatinine ratio (UACR) categories. Of 36,951 and 4339 eligible individuals in the CPRD and LCED, respectively, median baseline eGFR was 67.8 and 64.9 mL/min/1.73 m2 ; 64.2 and 63.9% received metformin prior to index; and median (interquartile range) time on metformin during follow-up was 917 (390-1671) and 454 (192-850) days (accounting for ~75% of follow-up time in both databases). The frequency of combination treatment increased over time. There were trends towards decreased metformin prescriptions with decreasing eGFR and increasing UACR within each eGFR category. Individuals with CKD and T2D had many combinations of therapies and substantial follow-up time on therapy. These results highlight opportunities for improved CKD management.

Effect of semaglutide on major adverse cardiovascular events by baseline kidney parameters in participants with type 2 diabetes and at high risk of cardiovascular disease: SUSTAIN 6 and PIONEER 6 post hoc pooled analysis

BackgroundSemaglutide is a glucose-lowering treatment for type 2 diabetes (T2D) with demonstrated cardiovascular benefits; semaglutide may also have kidney-protective effects. This post hoc analysis investigated the association between major adverse cardiovascular events (MACE) and baseline kidney parameters and whether the effect of semaglutide on MACE risk was impacted by baseline kidney parameters in people with T2D at high cardiovascular risk.MethodsParticipants from the SUSTAIN 6 and PIONEER 6 trials, receiving semaglutide or placebo, were categorised according to baseline kidney function (estimated glomerular filtration rate [eGFR] < 45 and ≥ 45–<60 versus ≥ 60 mL/min/1.73 m2) or damage (urine albumin:creatinine ratio [UACR] ≥ 30–≤300 and > 300 versus < 30 mg/g). Relative risk of first MACE by baseline kidney parameters was evaluated using a Cox proportional hazards model. The same model, adjusted with inverse probability weighting, and a quadratic spline regression were applied to evaluate the effect of semaglutide on risk and event rate of first MACE across subgroups. The semaglutide effects on glycated haemoglobin (HbA1c), body weight (BW) and serious adverse events (SAEs) across subgroups were also evaluated.ResultsIndependently of treatment, participants with reduced kidney function (eGFR ≥ 45–<60 and < 45 mL/min/1.73 m2: hazard ratio [95% confidence interval]; 1.36 [1.04;1.76] and 1.52 [1.15;1.99]) and increased albuminuria (UACR ≥ 30–≤300 and > 300 mg/g: 1.53 [1.14;2.04] and 2.52 [1.84;3.42]) had an increased MACE risk versus those without. Semaglutide consistently reduced MACE risk versus placebo across all eGFR and UACR subgroups (interaction p value [pINT] > 0.05). Semaglutide reduced HbA1c regardless of baseline eGFR and UACR (pINT>0.05); reductions in BW were affected by baseline eGFR (pINT<0.001) but not UACR (pINT>0.05). More participants in the lower eGFR or higher UACR subgroups experienced SAEs versus participants in reference groups; the number of SAEs was similar between semaglutide and placebo arms in each subgroup.ConclusionsMACE risk was greater for participants with kidney impairment or damage than for those without. Semaglutide consistently reduced MACE risk across eGFR and UACR subgroups, indicating that semaglutide provides cardiovascular benefits in people with T2D and at high cardiovascular risk across a broad spectrum of kidney function and damage.Trial registrationsNCT01720446; NCT02692716.

Empagliflozin improves insulin sensitivity in patients with recent acute coronary syndrome and newly detected dysglycaemia

BackgroundEmpagliflozin reduces the risk of cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM) and high cardiovascular risk via mechanisms which have not been fully explained. The mechanisms of such benefit have not been fully understood, and whether empagliflozin can be safely administered as first-line treatment in patients with CVD at the initial stages of glycaemic perturbations remains to be established. We investigated the effects of empagliflozin on insulin resistance, insulin sensitivity and β-cell function indexes in patients with a recent acute coronary event and newly detected dysglycaemia, i.e., impaired glucose tolerance (IGT) or T2DM.MethodsForty-two patients (mean age 67.5 years, 19% females) with a recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected dysglycaemia were randomized to either empagliflozin 25 mg daily (n = 20) or placebo (n = 22). Patients were investigated with stress-perfusion cardiac magnetic resonance imaging before randomization, 7 months after the start of study drug and 3 months following its cessation. Indexes of insulin resistance, sensitivity and β-cell function were calculated based on glucose and insulin values from 2-hour oral glucose tolerance tests (OGTT) and fasting C-peptide. The differences in glucose, insulin, C-peptide, mannose levels and indexes between the two groups were computed by repeated measures ANOVA including an interaction term between the treatment allocation and the time of visit.ResultsAfter 7 months, empagliflozin significantly decreased glucose and insulin values during the OGTT, whereas C-peptide, mannose and HbA1c did not differ. Empagliflozin significantly improved insulin sensitivity indexes but did not impact insulin resistance and β-cell function. After cessation of the drug, all indexes returned to initial levels. Insulin sensitivity indexes were inversely correlated with left ventricular mass at baseline.ConclusionsEmpagliflozin improved insulin sensitivity indexes in patients with a recent coronary event and drug naïve dysglycaemia. These findings support the safe use of empagliflozin as first-line glucose-lowering treatment in patients at very high cardiovascular risk with newly diagnosed dysglycaemia.Trial registration numberEudraCT number 2015-004571-73.

Risk of first-time major cardiovascular event among individuals with newly diagnosed type 2 diabetes: data from Danish registers

Aims/hypothesisWe aimed to examine whether individuals with initial omission of glucose-lowering drug treatment (GLDT), including those achieving initial remission of type 2 diabetes, may experience a higher risk of major adverse cardiovascular events (MACE) compared with well-controlled individuals on GLDT after a new type 2 diabetes diagnosis in real-world clinical practice. Furthermore, we examined whether a higher risk could be related to lower initiation of statins and renin–angiotensin system inhibitors (RASi).MethodsIn this cohort study, we used Danish registers to identify individuals with a first measured HbA1c between 48 and 57 mmol/mol (6.5–7.4%) from 2014 to 2020. Six months later, we divided participants into four groups according to GLDT and achieved HbA1c (<48 vs ≥48 mmol/mol [6.5%]): well-controlled and poorly controlled on GLDT; remission and persistent type 2 diabetes not on GLDT. We reported how much the standardised 5 year risk of MACE could be reduced for each group if initiation of statins and RASi was the same as in the well-controlled group on GLDT.ResultsWe included 14,221 individuals. Compared with well-controlled participants on GLDT, the 5 year standardised risk of MACE was higher in the three other exposure groups: by 3.3% (95% CI 1.6, 5.1) in the persistent type 2 diabetes group not on GLDT; 2.0% (95% CI 0.4, 3.7) in the remission group not on GLDT; and 3.5% (95% CI 1.3, 5.7) in the poorly controlled group on GLDT. Fewer individuals not on GLDT initiated statins and RASi compared with individuals on GLDT. If initiation of statins and RASi had been the same as in the well-controlled group on GLDT, participants not on GLDT could have reduced their risk of MACE by 2.1% (95% CI 1.2, 2.9) in the persistent type 2 diabetes group and by 1.1% (95% CI 0.4, 1.9) in the remission group.Conclusions/interpretationCompared with well-controlled individuals on GLDT, individuals not on initial GLDT had a higher 5 year risk of MACE, even among those achieving remission of type 2 diabetes. This may be related to lower use of statins and RASi.Graphical

Cost-Effectiveness of Glucose-Lowering Therapies as Add-on to Standard Care for People With Type 2 Diabetes in Malaysia

ObjectivesThis study aims to evaluate the cost-effectiveness of various glucose-lowering therapies as add-on to standard care for people with type 2 diabetes (T2D) in Malaysia. MethodsA state-transition microsimulation model was developed to compare the clinical and economic outcomes of 4 treatments: standard care, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT2is), and glucagon-like peptide-1 receptor agonists. Cost-effectiveness was assessed from a healthcare provider’s perspective over a lifetime horizon with 3% discount rate in a hypothetical cohort of people with T2D. Data input were informed from literature and local data when available. Outcome measures include costs, quality-adjusted life-years, incremental cost-effectiveness ratios, and net monetary benefits. Univariate and probabilistic sensitivity analyses were performed to assess uncertainties. ResultsOver a lifetime horizon, the costs to treat a person with T2D ranged from RM 12 494 to RM 41 250, whereas the QALYs gains ranged from 6.155 to 6.731, depending on the treatment. Based upon a willingness-to-pay threshold of RM 29 080 per QALY, we identified SGLT2i as the most cost-effective glucose-lowering treatment, as add-on to standard care over patient’s lifetime, with the net monetary benefit of RM 176 173 and incremental cost-effectiveness ratios of RM 12 279 per QALY gained. The intervention also added 0.577 QALYs and 0.809 LYs compared with standard care. Cost-effectiveness acceptability curve showed that SGLT2i had the highest probability of being cost-effective in Malaysia across varying willingness-to-pay threshold. The results were robust to various sensitivity analyses. ConclusionsSGLT2i was found to be the most cost-effective intervention to mitigate diabetes-related complications.