Type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) frequently coexist, posing a significant challenge due to increased risks of cardiovascular disease and mortality. Glucagon-like peptide-1 receptor agonists, such as semaglutide, have demonstrated potential for enhancing glucose control and reducing cardiovascular and renal risks.

Randomized controlled trials (RCTs) were taken to compare semaglutide with placebo or standard care in adults with T2DM and CKD. Key outcomes assessed included cardiovascular mortality, major adverse cardiovascular events (MACE), kidney-related adverse events, all-cause mortality, and hospitalization rates.

Three RCTs involving 10 013 patients were included. Semaglutide demonstrated a 29% reduction in cardiovascular mortality (risk ratio [RR]: 0.71; 95% confidence interval [CI]: 0.52-0.97; P = 0.03; I 2 = 59%) and a 20% reduction in MACE (RR: 0.80; 95% CI: 0.71-0.91; P = 0.0007; I 2 = 0%). A significant 20% decrease in kidney-related adverse events was observed (RR: 0.80; 95% CI: 0.71-0.89; P < 0.0001; I 2 = 0%), and semaglutide also reduced the need for cardiovascular medications (RR: 0.86; 95% CI: 0.81-0.91; P < 0.00001; I 2 = 13%).

Semaglutide shows promise as a therapeutic option for T2DM patients with CKD, significantly improving cardiovascular and renal outcomes. Its integration into treatment regimens for high-risk patients may enhance clinical outcomes and reduce treatment complexity. However, more extensive and longer-term studies are needed to confirm these findings.

Health disparities affecting minority populations and resulting in poorer outcomes for disadvantaged groups have been documented in the literature. Sodium/glucose-cotransporter 2 (SGLT2i) inhibitors and GLP-1 receptor agonists (GLP-1RA) markedly decrease mortality from kidney and cardiovascular events. However, little is known about the factors and disparities that lead to differences in SGLT2i and GLP-1RA initiation across different ethnic groups.

This scoping review queried databases using key terms related to disparities in the initiation of SGLT2i and GLP-1RA among high-risk populations. Relevant data from eligible studies were extracted, organized, and analyzed thematically to identify key trends and patterns in the literature.

Nineteen studies were included in this review. Key risk factors influencing uptake included age, provider type, race, sex, education, comorbidities, insurance, and income, with minority patients consistently showing lower rates of initiation due to systemic barriers and socioeconomic disparities. Patients who were younger, male, had higher education or income levels, and received care from specialists were more likely to use these therapies.

The adoption of SGLT2i and GLP-1RA remains suboptimal despite their proven kidney and cardiovascular benefits. Targeted efforts to reduce socioeconomic and racial inequities based on the factors identified should be encouraged.

Diabetes mellitus (DM) is a persistent condition characterized by high levels of glucose in the blood due to irregularities in the secretion of insulin, its action, or both. The disease was believed to be incurable until insulin was extracted, refined, and produced for sale. In DM, insulin delivery devices and insulin analogs have improved glycemic management even further. Sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones are examples of newer-generation medications having high efficacy in decreasing hyperglycemia as a result of scientific and technological advancements. Incretin mimetics, dual glucose-dependent insulinotropic polypeptide, GLP-1 agonists, PPARs, dipeptidyl peptidase-4 inhibitors, anti-CD3 mAbs, glucokinase activators, and glimins as targets have all performed well in recent clinical studies. Considerable focus was placed on free FA receptor 1 agonist, protein tyrosine phosphatase-1B inhibitors, and Sparc-related modular calcium-binding protein 1 which are still being studied. Theranostics, stem cell therapy, gene therapy, siRNA, and nanotechnology are some of the new therapeutic techniques. Traditional Chinese medicinal plants will also be discussed. This study seeks to present a comprehensive analysis of the latest research advancements, the emerging trends in medication therapy, and the utilization of delivery systems in treating DM. The objective is to provide valuable insights into the application of different pharmaceuticals in the field of diabetes mellitus treatment. Also, the therapeutic approach for diabetic patients infected with COVID-19 will be highlighted. Recent clinical and experimental studies evidence the Egyptian experience. Finally, as per the knowledge of the state of the art, our conclusion and future perspective will be declared.

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is approved for the treatment of type 2 diabetes, heart failure, and chronic kidney disease. DAPA-HF and DELIVER trial results demonstrate that the cardiovascular protective effect of dapagliflozin extends to non-diabetic patients. Hence, the mechanism-of-action may extend beyond glucose-lowering and is not completely elucidated. We have previously shown that dapagliflozin reduces cardiac hypertrophy, inflammation, fibrosis, and apoptosis and increases ejection fraction in BTBR mice with type 2 diabetes.

We conducted a follow-up RNA-sequencing study on the heart tissue of these animals and performed differential expression and Ingenuity Pathway analysis. Selected markers were confirmed by RT-PCR and Western blot.

SGLT2 had negligible expression in heart tissue. Dapagliflozin improved cardiac metabolism by decreasing glycolysis and pyruvate utilization enzymes, induced antioxidant enzymes, and decreased expression of hypoxia markers. Expression of inflammation, apoptosis, and hypertrophy pathways was decreased. These observations corresponded to the effects of dapagliflozin in the clinical trials.

A panel of primary care and diabetes specialists conducted focused literature searches on the current role of glycaemic control in the management of type 2 diabetes and revisited the evolution of evidence supporting the importance of early and intensive blood glucose control as a central strategy to reduce the risk of adverse long-term outcomes. The optimal approach to type 2 diabetes management has evolved over time as the evidence base has expanded from data from trials that established the role of optimising glycaemic control to recent data from cardiovascular outcomes trials (CVOTs) demonstrating organ-protective effects of newer glucose-lowering drugs (GLDs). The results from these CVOTs were derived mainly from people with type 2 diabetes and prior cardiovascular and kidney disease or multiple risk factors. In more recent years, earlier diagnosis in high-risk individuals has contributed to the large proportion of people with type 2 diabetes who do not have complications. In these individuals, a legacy effect of early and optimal control of blood glucose and cardiometabolic risk factors has been proven to reduce cardiovascular and kidney disease events and all-cause mortality. As there is a lack of RCTs investigating the potential synergistic effects of intensive glucose control and organ-protective effects of newer GLDs, this article re-evaluates the evolution of the scientific evidence and highlights the importance of integrating glycaemic control as a pivotal early therapeutic goal in most people with type 2 diabetes, while targeting existing cardiovascular and kidney disease. We also emphasise the importance of implementing multifactorial management using a multidisciplinary approach to facilitate regular review, patient empowerment and the possibility of tailoring interventions to account for the heterogeneity of type 2 diabetes.

Two prerequisites must be met for the precision treatment approach to be beneficial for treated individuals. First, there must be treatment heterogeneity; second, in case of treatment heterogeneity, clinical predictors to identify people who would benefit from one treatment more than from others must be available. There is an established meta-regression approach to assess these two prerequisites that relies on measuring the variability of a clinical outcome after treatment in placebo-controlled randomised trials. We recently applied this approach to the treatment of type 2 diabetes for the clinical outcomes of glycaemic control and body weight and repeat it for the clinical outcome of all-cause mortality.

We performed a meta-regression analysis using digitalized individual participant information on time to death from 10 large cardiovascular outcome trials (7563 deaths from 99,746 participants) on DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors with respect to the variability of all-cause mortality and its potential predictors after treatment.

The adjusted difference in log(SD) values of time to death between the verum and placebo arms was -0.036 (95%-CI: -0.059; -0.013), showing larger variability of time to death in the placebo arms. No clinical predictors were found to explain treatment heterogeneity.

This analysis suggests that the potential of the precision treatment approach in type 2 diabetes is low, at least with regard to improvement of all-cause mortality in population with high cardiovascular risk. This extends our previous findings for the clinical outcomes of glycaemic control and body weight.

For aromatase inhibitor treatment (AIT) in breast cancer, there is an unresolved concern about ischaemic cardiotoxicity. We investigated the association between AIT and ischaemic cardiotoxicity in a prospective cohort of female patients with early breast cancer who received contemporary treatment in Denmark.

In this prospective cohort study in Denmark, we identified postmenopausal patients of any age diagnosed with breast cancer as recorded in the nationwide Danish Breast Cancer Cooperative Group (DBCG) clinical database between Jan 1, 2009, and Dec 31, 2020, and linked them to other nationwide registries. Exclusion criteria included having a history of other primary cancer, less than 2 years of residency in Denmark, and no inclusion in a treatment protocol according to the DBCG database, including for metastatic or locally advanced breast cancer. Information on demography, hospital diagnoses, filled prescriptions, laboratory testing, and socioeconomic status were recorded. We stratified the patient cohort according to history (yes vs no) of selected cardiovascular disease defined as ischaemic heart disease, ischaemic stroke, and heart failure, and defined the primary outcome as two-point major adverse cardiovascular events (MACE; acute myocardial infarction or ischaemic stroke). We estimated cause-specific hazard ratios (HRs) according to allocation to AIT versus not in an intention-to-treat analysis using a Cox proportional hazards regression model with age as the underlying time scale, adjusting for demographic characteristics, tumour characteristics, and other anti-cancer treatments.

43 440 postmenopausal patients diagnosed with breast cancer were identified, of whom 32 635 were followed up and included in analyses. Of 29 118 postmenopausal patients with no history of selected cardiovascular disease, we observed 510 two-point MACEs among 22 135 patients allocated to AIT (incidence rate 4·3/1000 person-years of follow-up) and 170 two-point MACEs among 6983 patients not allocated to AIT (4·1/1000 person-years). The adjusted HR was 0·91 (95% CI 0·73-1·14) for patients allocated to AIT versus patients not allocated to AIT. Among 3517 patients with a history of selected cardiovascular disease, we observed 158 two-point MACEs among 2661 patients allocated to AIT (incidence rate 12·4/1000 person-years) and 50 two-point MACEs (12·1/1000 person-years) among 856 patients not allocated to AIT (adjusted HR 0·81 [95% CI 0·58-1·15]).

Our findings do not support a clinically relevant ischaemic cardiotoxic potential of AIT in patients with early breast cancer and do not support avoiding AIT prescription in patients with early breast cancer.

Bispebjerg and Frederiksberg Hospital, Kræftens Bekæmpelse, Fonden til Lægevidenskabens Fremme, Aase og Ejnar Danielsens Fond, Helsefonden, and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis' Legat.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a promising class of medications for type 2 diabetes (T2D) management. While their glucose-lowering effects are well-established, their long-term impact on cardiovascular outcomes remains a subject of ongoing research and debate. This systematic review aims to assess the long-term cardiovascular effects of GLP-1 RAs in adults with T2D compared to placebo, standard care, or other glucose-lowering medications. We systematically searched PubMed, Embase, and the Cochrane Library for randomized controlled trials (RCTs) and observational studies published from database inception to April 2024. Two independent reviewers screened the studies and extracted the data. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. Secondary outcomes included individual components of MACE, hospitalization for heart failure, and all-cause mortality. We included 15 studies (eight RCTs and seven observational studies) involving over 180,000 participants. GLP-1 RAs were associated with a significant reduction in MACE compared to placebo or standard care (risk ratio: 0.88, 95% CI: 0.82-0.94, p<0.001). GLP-1 RAs also demonstrated superior cardiovascular protection compared to DPP-4 inhibitors and sulfonylureas. The benefits were particularly pronounced in reducing the risk of stroke and MI. Notably, some studies found larger cardiovascular benefits in frail patients. The effects on heart failure outcomes were mixed, with potential attenuated benefits in patients with baseline heart failure. GLP-1 RAs also showed promising effects on renal outcomes and metabolic parameters. The quality of evidence ranged from moderate to high across outcomes. This systematic review provides strong evidence that GLP-1 RAs offer significant cardiovascular benefits in adults with T2D, particularly in reducing MACE, stroke, and MI. The findings support current guidelines recommending GLP-1 RAs as preferred agents in patients with established cardiovascular disease or high cardiovascular risk. However, the variability in effects across different patient subgroups underscores the need for personalized treatment approaches. Future research should focus on head-to-head comparisons between different GLP-1 RAs, long-term follow-up studies, and investigation of combination therapies to further optimize the use of these agents in clinical practice.

The newer glucose-lowering drugs (GLDs), including Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), have demonstrated superior cardio- and renal protective benefits compared to older GLDs in individuals with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD).

This study examined the trends of the newer GLDs use in people with T2D who had a history of coronary heart disease or heart failure in the United States.

We used 2005-2019 data from the Medical Expenditure Panel Survey (MEPS). Individuals with self-reported diabetes and CVD history were identified.

There was a steady increase in the use of GLP-1RA only from 2008 (3 %) to 2019 (21 %) and SGLT2i only from 2014 (5 %) to 2019 (12 %). Individuals with dual use of both newer GLD classes increased from 0.62 % in 2015 to 6 % in 2019. The overall uptake of these two newer drugs in 2019 was less than 40 %. In other words, 60 % of individuals who can substantially benefit from these newer treatments did not use the treatments.

The use of GLP-1RA and SGLT2i among individuals with T2D and a history of CVD was low and varied by insurance type. Policy-level interventions are needed to improve the use of these newer treatments further.

We examined how newer glucose-lowering drugs are used among individuals with type 2 diabetes and at high risk for coronary heart disease or heart failure in the US. We found that 60 % of individuals who can substantially benefit from these newer treatments did not use the treatments due to the variation of insurance type.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects 1 in 3-4 adult individuals and can progress to metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. Insulin resistance plays a central role in MASLD/MASH pathophysiology with higher rates of MASLD (2 in 3) and MASH with fibrosis (1 in 5) in adults with obesity and diabetes. This review summarizes the role of glucagon-like peptide-1 receptor agonists in treating MASLD/MASH. Although not approved by the Food and Drug Administration for the treatment of MASLD, this class of medication is available to treat obesity and type 2 diabetes and has been shown to reverse steatohepatitis, reduce cardiovascular risk, and is safe to use across the spectrum of MASLD with or without fibrosis.

To demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups.

PubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years).

For SGLT-2is, five CVOTs (46,969 patients, 45-50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85-0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73-0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79-0.93]) with no difference in subgroups <65 or ≥65 years. For GLP-1RAs, nine CVOTs (n = 64,236, 34-75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83-0.95]), stroke (RR; 0.86 [CI, 0.76-0.97]) and ACM (RR; 0.90 [CI, 0.83-0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years. Four CVOTs (n = 33,063; 35-58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups.

The overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were initially developed for their glucose-lowering effects and have shown a modest glycaemic benefit in people with type 2 diabetes mellitus (T2DM). In the past decade, a series of large, robust clinical trials of these therapies have demonstrated striking beneficial effects for various care goals, transforming the chronic disease therapeutic landscape. Cardiovascular safety studies in people with T2DM demonstrated that SGLT2 inhibitors reduce cardiovascular death and hospitalization for heart failure. Subsequent trials in participants with heart failure with reduced or preserved left ventricular ejection fraction demonstrated that SGLT2 inhibitors have beneficial effects on heart failure outcomes. In dedicated kidney outcome studies, SGLT2 inhibitors reduced the incidence of kidney failure among participants with or without diabetes. Post hoc analyses have suggested a range of other benefits of these drugs in conditions as diverse as metabolic dysfunction-associated steatotic liver disease, kidney stone prevention and anaemia. SGLT2 inhibitors have a generally favourable adverse effect profile, although patient selection and medication counselling remain important. Concerted efforts are needed to better integrate these agents into routine care and support long-term medication adherence to close the gap between clinical trial outcomes and those achieved in the real world.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining importance due to their effects on cardiovascular parameters. This review discusses the findings of dedicated cardiovascular outcome trials of GLP-1RAs and summarizes their utility to help clinicians understand their role in cardiovascular disease.

Patients with diabetes mellitus are at an increased risk of cardiovascular disease. Cardiovascular outcome trials have shown GLP-1RAs decrease the primary composite outcome of the first occurrence of major adverse cardiovascular events (MACE) in patients with diabetes. Additionally, select GLP-1RAs have also shown improved cardiovascular outcomes in patients without diabetes who are either overweight (BMI ≥ 27), or obese (BMI ≥ 30). There have also been encouraging results in patients with heart failure with preserved ejection fraction. There is increasing evidence showing GLP-1RAs are beneficial across the cardiometabolic spectrum of disease. Implementation of these therapeutics into clinical practice is important to improve cardiovascular risk.

The research on sodium-glucose cotransporter 2 (SGLT2) inhibitors has been increasing rapidly in the last decade, as well as indications for their use. This study aimed to analyze the methodological characteristics of clinical trials on SGLT2 inhibitors registered on ClinicalTrials.gov.

We conducted a cross-sectional study of trials on SGLT2 inhibitors registered on ClinicalTrials.gov up to November 11, 2022. We included clinical trials that tested SGLT2 inhibitors for any clinical condition, as a single or combined SGLT2 therapy, compared to any other medication or placebo and mapped their characteristics.

We identified 1102 eligible trials on 14 different SGLT2 inhibitors. The first trial registration was in 2005. There were 993 (90%) interventional and 109 (10%) observational trials. Most trials were in Phase 1 (29%), Phase 3 (23%), or Phase 4 (24%). Interventional trials were mostly randomized (85%); almost half of them did not use masking (44%). Trials on empagliflozin, dapagliflozin, and canagliflozin accounted for 75% of all trials. More than 60% of trials included patients with diabetes mellitus, 13% included only healthy subjects, and 12% included patients with heart diseases. Overall, these trials included more than 9.5 million participants (~ 312,000 of which in interventional studies). Almost 65% of all clinical trials were industry-funded. Most trials were completed (60%) and 35% of those reported results. For trials that are obligated to report results by the Food and Drugs Administration (FDA), 88% of them did so. Trials fully or partially funded by industry more frequently published results compared to non-industry funded trials (46.1% vs. 11.2%; p < 0.001).

The number of registered trials on SGLT2 inhibitors is increasing progressively along with expanding indications for its use, shifting from diabetes mellitus to cardiovascular and renal diseases. Public reporting of trial results improved with time but remains suboptimal.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are two incretins that bind to their respective receptors and activate the downstream signaling in various tissues and organs. Both GIP and GLP-1 play roles in regulating food intake by stimulating neurons in the brain's satiety center. They also stimulate insulin secretion in pancreatic β-cells, but their effects on glucagon production in pancreatic α-cells differ, with GIP having a glucagonotropic effect during hypoglycemia and GLP-1 exhibiting glucagonostatic effect during hyperglycemia. Additionally, GIP directly stimulates lipogenesis, while GLP-1 indirectly promotes lipolysis, collectively maintaining healthy adipocytes, reducing ectopic fat distribution, and increasing the production and secretion of adiponectin from adipocytes. Together, these two incretins contribute to metabolic homeostasis, preventing both hyperglycemia and hypoglycemia, mitigating dyslipidemia, and reducing the risk of cardiovascular diseases in individuals with type 2 diabetes and obesity. Several GLP-1 and dual GIP/GLP-1 receptor agonists have been developed to harness these pharmacological effects in the treatment of type 2 diabetes, with some demonstrating robust effectiveness in weight management and prevention of cardiovascular diseases. Elucidating the underlying cellular and molecular mechanisms could potentially usher in the development of new generations of incretin mimetics with enhanced efficacy and fewer adverse effects. The treatment guidelines are evolving based on clinical trial outcomes, shaping the management of metabolic and cardiovascular diseases.

Inflammation plays a pathophysiological role in atherosclerosis and its clinical consequences. In addition to glycemic control, glucagon-like peptide-1 receptor agonists (GLP-1RAs) are of wide concern for cardioprotective effects. The structure, half-life, homology, and clinical efficacy of GLP-1RAs exhibit remarkable disparity. Several studies have compared the disparities in anti-inflammatory effects between daily and weekly GLP-1RAs. This study aimed to compare the similarities and differences between liraglutide and dulaglutide in terms of inhibiting atherosclerotic inflammation and improving co-cultured endothelial cell function. The expression of inflammation markers was examined by immunofluorescence, Western blotting, and real-time PCR. The tube-forming ability of endothelial cells was tested on Matrigel. The results verify that 10/50/100 nmol/L liraglutide and 100 nmol/L dulaglutide markedly suppressed the expression of inflammatory factors in LPS-induced atherosclerosis after 24 and 72 hours, respectively. Moreover, they promoted the polarization of M1 macrophages toward the M2 phenotype and improved the function of co-cultured endothelial cells. Both liraglutide and dulaglutide ameliorate atherosclerosis development. The difference between the two resided in the extended intervention duration required to observe the effect of dulaglutide, and liraglutide demonstrated a superior dose-dependent manner. We provide a potential strategy to understand the dynamics of drug action and possible timing administration.

Providing physical health and mental health training promotion is necessary for a sustainable change in attitude and lifestyle of diabetic patients. The present study was conducted with the aim of comparing the effect of physical health training and psychological training of the theory of reasoned action (TRA) model on the life quality of patients with type 2 diabetes.

This experimental study was conducted in 2022 with two intervention groups and one control group consisting of 129 patients with type 2 diabetes who were referred to Imam Khomeini Hospital in Tehran. Over the course of one month, each individual in intervention group 1 received 15 text messages focusing on physical health, while intervention group 2 received 15 psychological text messages related to the TRA. The control group did not receive any text messages during this period. The data collection tool used was the "Audit of Diabetes-Dependent Quality of Life (ADDQoL)" questionnaire, which was completed by the participants before and after the intervention. The data were analyzed using SPSS version 16 software at a statistical significance level of 0.05.

In the intervention-1 group, the average life quality score was 8.51 units (P < 0.001), while in the intervention-2 group, it was 19.25 units (P < 0.001) higher than the control group. The psychological training group had a 17.62 units (P < 0.05) lower average fasting blood sugar (FBS) and a 10.74 units (P < 0.001) higher average quality of life compared to the physical training group.

The results of this study showed that the effectiveness of psychological training of the TRA model in improving life quality and reducing FBS in patients with diabetes is greater than physical health training. It is suggested that policy makers and health managers base future plans on physical health promotion training along with TRA model mental health training for the development of education in patients with diabetes. Specialists and healthcare workers can also act to improve personal health characteristics, especially those related to reducing FBS and increasing the quality of life of patients with diabetes, by using training through mobile phone text messages, particularly with psychological content TRA based.

In the last three decades, much effort has been invested in measuring and improving the quality of diabetes care. We assessed the association between adherence to diabetes quality indicators and all-cause mortality in the primary care setting.

A nationwide, population-based, historical cohort study of all people aged 45-80 with pharmacologically-treated diabetes in 2005 (n = 222,235). Data on annual performance of quality indicators (including indicators for metabolic risk factor management and glycemic control) and vital status were retrieved from electronic medical records of the four Israeli health maintenance organizations. Cox proportional hazards and time-dependent models were used to estimate hazard ratios (HRs) for mortality by degree of adherence to quality indicators.

During 2,000,052 person-years of follow-up, 35.8% of participants died. An inverse dose-response association between the degree of adherence and mortality was shown for most of the quality indicators. Participants who were not tested for proteinuria or did not visit an ophthalmologist during the first-5-years of follow-up had HRs of 2.60 (95%CI:2.49-2.69) and 2.09 (95%CI:2.01-2.16), respectively, compared with those who were fully adherent. In time-dependent analyses, not measuring LDL-cholesterol, blood pressure, HbA1c, or HbA1c>9% were similarly associated with mortality (HRs ≈1.5). The association of uncontrolled blood pressure with mortality was modified by age, with increased mortality shown for those with controlled blood pressure at older ages (≥65 years).

Longitudinal adherence to diabetes quality indicators is associated with reduced all-cause mortality. Primary care professionals need to be supported by health care systems to perform quality indicators.

A precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA).

We designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: liraglutide [n=389] and albiglutide [n=1682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability and longer-term risk of new-onset microvascular complications, macrovascular complications and adverse kidney events.

Model development identified marked heterogeneity in glycaemic response, with 4787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>0.3%) with SGLT2i over GLP1-RA and 5551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with women markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 liraglutide (GLP1-RA): 4.4 mmol/mol (95% credible interval [95% CrI] 2.2, 6.3) (0.4% [95% CrI 0.2, 0.6]) greater response in women than men. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications.

Precision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries.

The objective of this study was to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes.

Using the United Kingdom Clinical Practice Research Datalink (2007-2019), we assembled two new-user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP-1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP-1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively.

Compared with sulfonylureas, GLP-1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person-years, respectively; HR 0.96, 95% CI 0.53-1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person-years, respectively; HR 1.03, 95% CI 0.80-1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses.

In this population-based cohort study, GLP-1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas.

Vascular large conductance Ca2+-activated K+ (BK) channel, composed of the α-subunit (BK-α) and the β1-subunit (BK-β1), is a key determinant of coronary vasorelaxation and its function is impaired in diabetic vessels. However, our knowledge of diabetic BK channel dysregulation is incomplete. The Sorbs2 (Sorbin homology [SoHo] and Src homology 3 [SH3] domains-containing protein 2), is ubiquitously expressed in arteries, but its role in vascular pathophysiology is unknown.

The role of Sorbs2 in regulating vascular BK channel activity was determined using patch-clamp recordings, molecular biological techniques, and in silico analysis.

Sorbs2 is not only a cytoskeletal protein but also an RNA-binding protein that binds to BK channel proteins and BK-α mRNA, regulating BK channel expression and function in coronary smooth muscle cells. Molecular biological studies reveal that the SH3 domain of Sorbs2 is necessary for Sorbs2 interaction with BK-α subunits, while both the SH3 and SoHo domains of Sorbs2 interact with BK-β1 subunits. Deletion of the SH3 or SoHo domains abolishes the Sorbs2 effect on the BK-α/BK-β1 channel current density. Additionally, Sorbs2 is a target gene of the Nrf2 (nuclear factor erythroid-2-related factor 2), which binds to the promoter of Sorbs2 and regulates Sorbs2 expression in coronary smooth muscle cells. In vivo studies demonstrate that Sorbs2 knockout mice at 4 months of age display a significant decrease in BK channel expression and function, accompanied by impaired BK channel Ca2+-sensitivity and BK channel-mediated vasodilation in coronary arteries, without altering their body weights and blood glucose levels. Importantly, Sorbs2 expression is significantly downregulated in the coronary arteries of db/db type 2 diabetic mice.

Sorbs2, a downstream target of Nrf2, plays an important role in regulating BK channel expression and function in vascular smooth muscle cells. Vascular Sorbs2 is downregulated in diabetes. Genetic knockout of Sorbs2 manifests coronary BK channelopathy and vasculopathy observed in diabetic mice, independent of obesity and glucotoxicity.

Absolute treatment benefits-expressed as numbers needed to treat-of the glucose lowering and cardiovascular drugs, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transporter 2 (SGLT2) inhibitors on renal outcomes remain uncertain. With the present meta-analysis of digitalized individual patient data, we aimed to display and compare numbers needed to treat of both drugs on a composite renal outcome.

From Kaplan-Meier plots of major cardiovascular outcome trials of GLP-1 receptor agonists and SGLT2 inhibitors vs. placebo, we digitalized individual patient time-to-event information on composite renal outcomes with WebPlotDigitizer 4.2; numbers needed to treat from individual cardiovascular outcome trials were estimated using parametric Weibull regression models and compared to original data. Random-effects meta-analysis generated meta-numbers needed to treat with 95% confidence intervals (CI).

Twelve cardiovascular outcome trials (three for GLP-1 receptor agonists, nine for SGLT2 inhibitors) comprising 90,865 participants were included. Eight trials were conducted in primary type 2 diabetes populations, two in a primary heart failure and two in a primary chronic kidney disease population. Mean estimated glomerular filtration rate at baseline ranged between 37.3 and 85.3 ml/min/1.73 m2. Meta-analyses estimated meta-numbers needed to treat of 85 (95% CI 60; 145) for GLP-1 receptor agonists and 104 (95% CI 81; 147) for SGLT2 inhibitors for the composite renal outcome at the overall median follow-up time of 36 months.

The present meta-analysis of digitalized individual patient data revealed moderate and similar absolute treatment benefits of GLP-1 receptor agonists and SGLT2 inhibitors compared to placebo for a composite renal outcome.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition characterized by the presence of low levels of a monoclonal protein in the serum and a low percentage of clonal plasma cells in the bone marrow. MGUS may progress to multiple myeloma or other plasma cell disorders at a rate of 1% annually. However, MGUS may also have adverse effects on the cardiovascular system independent of its malignant potential. Emerging data have shown that MGUS is associated with cardiovascular disease. The mechanisms underlying this association are not fully understood but may involve genetic abnormalities, vascular calcification, cryoglobulinemia, cold agglutinin disease, autoantibodies and the direct or indirect effects of the monoclonal protein on the vascular endothelium. Herein, we review current evidence in this field and we suggest that patients with MGUS may benefit from regular cardiovascular risk assessment to prevent severe cardiovascular complications, in parallel with close hematological follow-up to monitor potential disease progression.

To compare the cardiovascular and renal outcomes of GLP-1 RA versus DPP4i and basal insulin in the management of T2DM.

Data from 22 studies involving over 200,000 participants were pooled using the inverse variance method and random-effects meta-analysis. The review was reported in accordance with PRISMA.

Compared with DPP4i, treatment with GLP-1 RA was associated with a greater benefit on composite cardiovascular outcomes (HR:0.77, 95% CI:0.69-0.87), myocardial infarction (HR:0.82, 95% CI:0.69-0.97), stroke (HR:0.83, 95% CI: 0.74-0.93), cardiovascular mortality (HR:0.76, 95% CI:0.68-0.85) and all-cause mortality (HR:0.65, 95% CI:0.48-0.90). There was no difference in effect on heart failure (HR:0.97, 95% CI:0.82-1.15). Compared with basal insulin, GLP-1 RA was associated with better effects on composite cardiovascular outcomes (HR:0.62, 95% CI:0.48-0.79), heart failure (HR:0.57, 95% CI:0.35-0.92), myocardial infarction (HR:0.70, 95% CI:0.58-0.85), stroke (HR:0.50, 95% CI:0.40-0.63) and all-cause mortality (HR:0.31, 95% CI:0.20-0.48). Evidence from a small number of studies suggests that GLP-1 RA had better effects on composite and individual renal outcomes, such as eGFR, compared with either DPP4i and basal insulin.

Available evidence suggests that treating T2DM with GLP-1 RA can yield better benefits on composite and specific cardiorenal outcomes than with DPP4i and basal insulin.

CRD42022335504.

Type 2 diabetes is a chronic and progressive cardiometabolic disorder that affects more than 10% of adults worldwide and is a major cause of morbidity, mortality, disability, and high costs. Over the past decade, the pattern of management of diabetes has shifted from a predominantly glucose centric approach, focused on lowering levels of haemoglobin A1c (HbA1c), to a directed complications centric approach, aimed at preventing short term and long term complications of diabetes, and a pathogenesis centric approach, which looks at the underlying metabolic dysfunction of excess adiposity that both causes and complicates the management of diabetes. In this review, we discuss the latest advances in patient centred care for type 2 diabetes, focusing on drug and non-drug approaches to reducing the risks of complications of diabetes in adults. We also discuss the effects of social determinants of health on the management of diabetes, particularly as they affect the treatment of hyperglycaemia in type 2 diabetes.

Randomised clinical trials showed that compared with placebo, SGLT2 inhibitors and GLP-1 receptor agonists reduced risk of adverse cardiovascular events. The evidence base for the older antihyperglycaemic drug classes (DPP-4 inhibitors and sulfonylureas) is generally less well developed. Because most randomised trials evaluated one antihyperglycaemic medication versus placebo, a head-to-head comparative effectiveness analysis of the newer drug classes (SGLT2 inhibitors vs GLP-1 receptor agonists) or newer (SGLT2 inhibitors or GLP-1 receptor agonists) versus older (DPP-4 inhibitors or sulfonylureas) drug classes on risk of major adverse cardiovascular events (MACE) is not available. In this study, we aimed to evaluate the comparative effectiveness of incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas on risk of MACE.

We first specified the protocol of a four-arm randomised pragmatic clinical trial and then emulated it using the health-care databases of the US Department of Veterans Affairs. We built a cohort of metformin users with incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas between Oct 1, 2016 and Sept 30, 2021, and followed up until Dec 31, 2022. We used the overlap weighting approach to balance the treatment groups using a battery of predefined variables and a set of algorithmically selected variables from high-dimensional data domains. Both intention-to-treat and per-protocol analyses (the latter estimated the effect of maintained use of the antihyperglycaemic throughout follow-up) were conducted to estimate risk of MACE-defined as a composite endpoint of stroke, myocardial infarction, and all-cause mortality.

The final cohort consisted of 283 998 new users of SGLT2 inhibitors (n=46 516), GLP-1 receptor agonists (n=26 038), DPP-4 inhibitors (n=55 310), or sulfonylureas (n=156 134). In intention-to-treat analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with lower risk of MACE (hazard ratio [HR] 0·77 [95% CI 0·74-0.80], 0·78 [0·74-0·81), and 0·90 [0·86-0.93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·86 [0·82-0·89] and 0·86 [0·82-0·90], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 0·99 (0·94-1·04). In per-protocol analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP1 receptor agonists, and DPP-4 inhibitors were associated with reduced risk of MACE (HR 0·77 [95% CI 0·73-0·82], 0·77 [0·72-0·82], and 0·88 [0·83-0·93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·88 [0·83-0·93] and 0·88 [0·82-0·93], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 1·01 (0·94-1·07).

Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with reduced risk of MACE compared with DPP-4 inhibitors or sulfonylureas. DPP-4 inhibitors were associated with reduced risk of MACE compared with sulfonylureas. There was no statistically significant difference in risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists. The results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy.

US Department of Veterans Affairs and the American Society of Nephrology.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have recently been recommended as preferred agents for management of hyperglycemia in type 2 diabetes, primarily based on their ability to reduce a composite of major cardiovascular adverse events (3-point major adverse cardiovascular events [MACE]), predominantly by reducing cardiovascular death. However, reduction of the individual components, myocardial infarction (MI), or stroke (fatal and nonfatal) events have not been well explored.

In this meta-analysis, we included data available from cardiovascular outcome trials only, which were event-driven, randomized, and placebo-controlled. Pooled efficacy outcomes included Mantel Haenszel (MH) risk ratio using fixed model (with 95% CI) for fatal and nonfatal MI, stroke, and total MI and stroke.

Data from 4 eligible trials included 42,568 subjects. Total MACE, MI, and stroke were reported in 4176, 2157, and 1288 subjects, respectively. SGLT2is did not significantly reduce either MI or stroke individually or in totality. The MH risk ratio (95% CI) for fatal and nonfatal MI and stroke with different SGLT2is was found to be 0.93 (95% CI, 0.85-1.01) and 1.00 (95% CI, 0.89-1.11), respectively. For total atherosclerotic cardiovascular disease (ASCVD) events, MH risk ratio (95% CI) was 0.95 (95% CI, 0.89-1.02). For all nonfatal ASCVD (combined nonfatal MI and nonfatal stroke), MH risk ratio (95% CI) was 0.94 (95% CI, 0.88-1.02).

SGLT2is reduce MACE without any discernable significant reduction of the incidence of MI or stroke (fatal and nonfatal), probably implicating mechanisms unrelated to anti-atherogenic effects.

Atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF) are two major complications of type 2 diabetes (T2DM). Cardiovascular protection is a key objective, yet not fully reached in clinical practice.

Both glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have proven their efficacy in reducing major cardiovascular events in high-risk patients with T2DM and SGLT2is in reducing hospitalization for HF in placebo-controlled randomized trials. However, real-life studies worldwide revealed that only a minority of patients with T2DM receive either a GLP-1RA or an SGLT2i and surprisingly even less patients with established ASCVD or HF are treated with these cardioprotective antihyperglycemic agents.

Bridging the gap between evidence-based cardiovascular protection with GLP-1RAs and SGLT2is and their underuse in daily clinical practice in patients with T2DM at high risk is crucial from a public health viewpoint. However, the task appears hazardous and the goal not attained considering the current failure. Education of specialists/primary care physicians and patients is critical. Multifaceted and coordinated interventions involving all actors (physicians, patients and broadly health-care system) must be implemented to stimulate the adoption of these cardioprotective antihyperglycemic medications as part of routine cardiovascular care among patients with T2DM.

The past decade of population research for diabetes has seen a dramatic proliferation of the use of real-world data (RWD) and real-world evidence (RWE) generation from non-research settings, including both health and non-health sources, to influence decisions related to optimal diabetes care. A common attribute of these new data is that they were not collected for research purposes yet have the potential to enrich the information around the characteristics of individuals, risk factors, interventions, and health effects. This has expanded the role of subdisciplines like comparative effectiveness research and precision medicine, new quasi-experimental study designs, new research platforms like distributed data networks, and new analytic approaches for clinical prediction of prognosis or treatment response. The result of these developments is a greater potential to progress diabetes treatment and prevention through the increasing range of populations, interventions, outcomes, and settings that can be efficiently examined. However, this proliferation also carries an increased threat of bias and misleading findings. The level of evidence that may be derived from RWD is ultimately a function of the data quality and the rigorous application of study design and analysis. This report reviews the current landscape and applications of RWD in clinical effectiveness and population health research for diabetes and summarizes opportunities and best practices in the conduct, reporting, and dissemination of RWD to optimize its value and limit its drawbacks.

Despite newer guideline-recommended antidiabetic agents demonstrating a reduction of disease burden and improved health outcomes, high drug cost and restrictive insurance coverage limit public access. To address this issue, many manufacturers offer free medication through manufacturer patient assistance programs.

This study aimed to determine the impact of pharmacist intervention using manufacturer patient assistance programs in individuals who are uninsured or enrolled in Medicare Part D prescription drug plan and to evaluate the impact of pharmacist utilization in meeting diabetic quality measures set forth by accountable care organizations (ACOs).

This single-center, retrospective cohort study evaluated 171 participants enrolled into a manufacturer patient assistance program owing to pharmacist intervention compared with 171 participants receiving usual care. The primary outcome was the change in glycosylated hemoglobin (A1c) between groups. Secondary outcomes included the impact of pharmacist management on change in weight, change in blood pressure, and the number of participants meeting ACO quality measures.

The average change in A1c in the intervention group was -2.5% compared with an average A1c reduction of -1.3% in the control group (95% CI -2.11 to -1.67, P < 0.001). The average change in weight of the intervention group was -4.01 kg, whereas the control group had an average weight reduction of -1.4 kg from baseline (95% CI -3.95 to -1.61, P < 0.05). The body mass index (BMI) of the intervention group was a value of 1.4 kg/m2 lower whereas the BMI of the control group was 0.6 kg/m2 lower than at baseline (95% CI -1.38 to -0.61, P < 0.05).

Participants who were enrolled in a manufacturer patient assistance program by a pharmacist and were followed for diabetes care management experienced greater A1c lowering and weight loss than participants receiving usual care.

Background. Older and sicker adults with type 2 diabetes (T2D) were underrepresented in randomized trials of glucagon-like peptide 1 receptor-agonist (GLP1RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2I), and thus, health benefits are uncertain in this population. Objective. To assess the impact of age, health status, and life expectancy in older adults with T2D on health benefits of GLP1RA and SGLT2I. Design. We used the United Kingdom Prospective Diabetes Study (UKPDS) model to simulate lifetime health outcomes. We calibrated the UKPDS model to improve mortality prediction in older adults using a common geriatric prognostic index. Participants. National Health and Nutrition Examination Survey 2013-2018 participants 65 y and older with T2D, eligible for GLP1RA or SGLT2I according to American Diabetes Association guidelines. Interventions. GLP1RA or SGLT2I use versus no additional medication. Main Measures. Lifetime complications and weighted life-years (LYs) and quality-adjusted life-years (QALYs) across overall treatment arms and life expectancies. Key Results. The overall older adult population was predicted to experience significant health benefits from GLP1RA (+0.29 LY [95% confidence interval: 0.27, 0.31], +0.15 QALYs [0.14, 0.16]) and SGLT2I (+0.26 LY [0.24, 0.28], +0.13 QALYs [0.12, 0.14]) as compared with no added medication. However, expected benefits declined in subgroups with shorter life expectancies. Participants with <4 y of life expectancy had minimal gains of <0.05 LY and <0.03 QALYs from added medication. Accounting for injection-related disutility, GLP1RA use reduced QALYs (-0.03 QALYs [-0.04, -0.02]). Conclusions. While GLP1RA and SGLT2I have substantial health benefits for many older adults with type 2 diabetes, benefits are not clinically significant in patients with <4 y of life expectancy. Life expectancy and patient preferences are important considerations when prescribing newer diabetes medications.

On average, older adults benefit significantly from SGLT2I and GLP1RA use. However, the benefits of these drugs are not clinically significant among older patients with life expectancy less than 4 y.There is potential harm in injectable GLP1RA use in the oldest categories of adults with type 2 diabetes.Heterogeneity in life expectancy and patient preferences for injectable versus oral medications are important to consider when prescribing newer diabetes medications.

Cardiorenal syndrome (CRS) is a pathology where the heart and kidney are involved, and the deterioration of one of them leads to the malfunction of the other. Diabetes mellitus (DM) carries a higher risk of HF and a worse prognosis. Furthermore, almost half of people with DM will have chronic kidney disease (CKD), which means that DM is the main cause of kidney failure. The triad of cardiorenal syndrome and diabetes is known to be associated with increased risk of hospitalization and mortality. Cardiorenal units, with a multidisciplinary team (cardiologist, nephrologist, nursing), multiple tools for diagnosis, as well as new treatments that help to better control cardio-renal-metabolic patients, offer holistic management of patients with CRS. In recent years, the appearance of drugs such as sodium-glucose cotransporter type 2 inhibitors, have shown cardiovascular benefits, initially in patients with type 2 DM and later in CKD and heart failure with and without DM2, offering a new therapeutic opportunity, especially for cardiorenal patients. In addition, glucagon-like peptide-1 receptor agonists have shown CV benefits in patients with DM and CV disease in addition to a reduced risk of CKD progression.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to improve cardiovascular and renal outcomes in patients with established cardiovascular disease, chronic kidney disease (CKD), and heart failure (HF) with reduced or preserved ejection fraction. Clinical benefit has been substantiated in patients with and without type 2 diabetes (T2D). Consequently, SGLT2is have an increasingly important role in HF and CKD management that extends beyond T2D treatment. Their pleiotropic pharmacological effects underlying their cardiovascular and renal benefits are not completely understood but include significant effects beyond blood glucose reduction. SGLT2is inhibit the reabsorption of glucose and sodium in the proximal tubule which, in addition to lowering blood glucose, activates tubuloglomerular feedback, leading to reduced glomerular hydrostatic pressure and the mitigation of glomerular filtration rate loss. SGLT2is have diuretic and natriuretic effects, leading to decreased blood pressure, preload, and left ventricular (LV) filling pressure, and improvements in other surrogates of afterload. In HF, SGLT2is mitigate the risks of hyperkalemia and ventricular arrhythmia and improve LV dysfunction. SGLT2is also reduce sympathetic tone and uric acid levels, increase hemoglobin levels, and are postulated to have anti-inflammatory properties. This narrative review discusses the multifactorial and interrelated pharmacological mechanisms underlying the cardiovascular and renal benefits of SGLT2is.

We aimed to compare the severity of liver disease, metabolic profile and cardiovascular disease (CVD) risk of chronic hepatitis B (CHB) patients with and without hepatic steatosis and patients with non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD and CHB were prospectively enrolled from 10 Asian centres. Fibroscan was performed for all patients and hepatic steatosis was defined based on controlled attenuation parameter >248 dB/m. CVD risk was assessed using the Framingham risk score. The data for 1080 patients were analysed (67% NAFLD, 33% CHB). A high proportion (59%) of CHB patients had hepatic steatosis. There was a significant stepwise increase in alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, controlled attenuation parameter and liver stiffness measurement, from CHB patients without hepatic steatosis to CHB patients with hepatic steatosis to NAFLD patients (p < 0.001 for all comparisons). There was a significant stepwise increase in the proportion of patients with metabolic syndrome and in CVD risk, with very high or extreme CVD risk seen in 20%, 48% and 61%, across the groups (p < 0.001 between CHB patients with and without hepatic steatosis and p < 0.05 between CHB patients with hepatic steatosis and NAFLD patients). In conclusion, there was a high proportion of CHB patients with hepatic steatosis, which should be diagnosed, as they may have more severe liver disease, so that this and their metabolic risk factors can be assessed and managed accordingly for a better long-term outcome.

Despite the availability of new treatment classes, glycaemic control in patients with diabetes remains suboptimal globally. The latter is associated with high risk of premature mortality related to diabetes and its microvascular and macrovascular complications. Practice guidelines typically focus on glycated haemoglobin < 7.0% as a therapeutic goal in type 2 diabetes (T2D). Reducing glycated haemoglobin has been proven to reduce the risk of these complications while early attainment of glycaemic goal can have a legacy effect in later life. Both glucocentric and cardiorenal-centric treatment strategies have complementary effects in reducing the trajectory of cardiorenal diseases. In real-word settings, implementation of practice guidelines developed in the USA and Europe may not be applicable to regions such as Asia, where differences in epidemiology, patient phenotypes, cultures, resource availability, and treatment affordability are important considerations. In the present review, we discuss the need to use a pragmatic, albeit evidence-based approach, to combine glucocentric and cardiorenal risk reduction strategies to improve the outcomes in patients with T2D, with particular relevance to Asia Pacific.

Basal insulin glargine has a neutral effect on cardiovascular risk in type 2 diabetes (T2DM). In practice, basal insulin is often paired with a glucagon-like peptide-1 receptor agonist (GLP1-RA) or meal insulin; however, the cardiovascular implications of these combinations have not been fully elucidated. In this context, we sought to evaluate the vascular function effects of adding the GLP1-RA exenatide or meal insulin lispro to basal glargine therapy in early T2DM.

In this 20-week trial, adults with T2DM of < 7-years duration were randomized to 8-weeks treatment with (i) insulin glargine (Glar), (ii) glargine + thrice-daily lispro (Glar/Lispro), or (iii) glargine + twice-daily exenatide (Glar/Exenatide), followed by 12-weeks washout. At baseline, 8-weeks, and washout, fasting endothelial function was assessed with reactive hyperemia index (RHI) measurement by peripheral arterial tonometry.

At baseline, there were no differences in blood pressure (BP), heart rate (HR) or RHI between participants randomized to Glar (n = 24), Glar/Lispro (n = 24), and Glar/Exenatide (n = 25). At 8-weeks, Glar/Exenatide decreased systolic BP (mean - 8.1 mmHg [95%CI - 13.9 to - 2.4], p = 0.008) and diastolic BP (mean - 5.1 mmHg [- 9.0 to - 1.3], p = 0.012) compared to baseline, with no significant changes in HR or RHI. Notably, baseline-adjusted RHI (mean ± SE) did not differ between the groups at 8-weeks (Glar 2.07 ± 0.10; Glar/Lispro 2.00 ± 0.10; Glar/Exenatide 1.81 ± 0.10; p = 0.19), nor did baseline-adjusted BP or HR. There were no differences between the groups in baseline-adjusted RHI, BP or HR after 12-weeks washout.

Adding either exenatide or lispro to basal insulin therapy does not appear to affect fasting endothelial function in early T2DM.

ClinicalTrials.Gov NCT02194595.

Wearable devices, such as smartwatches and activity trackers, are commonly used by patients in their everyday lives to manage their health and well-being. These devices collect and analyze long-term continuous data on measures of behavioral or physiologic function, which may provide clinicians with a more comprehensive view of a patients' health compared with the traditional sporadic measures captured by office visits and hospitalizations. Wearable devices have a wide range of potential clinical applications ranging from arrhythmia screening of high-risk individuals to remote management of chronic conditions such as heart failure or peripheral artery disease. As the use of wearable devices continues to grow, we must adopt a multifaceted approach with collaboration among all key stakeholders to effectively and safely integrate these technologies into routine clinical practice. In this Review, we summarize the features of wearable devices and associated machine learning techniques. We describe key research studies that illustrate the role of wearable devices in the screening and management of cardiovascular conditions and identify directions for future research. Last, we highlight the challenges that are currently hindering the widespread use of wearable devices in cardiovascular medicine and provide short- and long-term solutions to promote increased use of wearable devices in clinical care.

This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) is intended to provide clinicians an overview of type 2 diabetes mellitus (T2DM), an obesity-related cardiometabolic risk factor.

The scientific support for this CPS is based upon published citations and clinical perspectives of OMA authors.

Topics include T2DM and obesity as cardiometabolic risk factors, definitions of obesity and adiposopathy, and mechanisms for how obesity causes insulin resistance and beta cell dysfunction. Adipose tissue is an active immune and endocrine organ, whose adiposopathic obesity-mediated dysfunction contributes to metabolic abnormalities often encountered in clinical practice, including hyperglycemia (e.g., pre-diabetes mellitus and T2DM). The determination as to whether adiposopathy ultimately leads to clinical metabolic disease depends on crosstalk interactions and biometabolic responses of non-adipose tissue organs such as liver, muscle, pancreas, kidney, and brain.

This review is intended to assist clinicians in the care of patients with the disease of obesity and T2DM. This CPS provides a simplified overview of how obesity may cause insulin resistance, pre-diabetes, and T2DM. It also provides an algorithmic approach towards treatment of a patient with obesity and T2DM, with "treat obesity first" as a priority. Finally, treatment of obesity and T2DM might best focus upon therapies that not only improve the weight of patients, but also improve the health outcomes of patients (e.g., cardiovascular disease and cancer).

To analyze whether prescription use of GLP-1RA and SGLT2i in individuals with type 2 diabetes with cardiovascular disease (CVD) has increased after the ADA/EASD consensus guidelines (2018) in a German Real-World setting and which clinical characteristics are associated with prescription use of these drugs.

The Disease Analyzer database (IQVIA) comprises a representative panel of 1,373 general practitioners, diabetologists, and cardiologists throughout Germany (01/2015-12/2020: 12.6 million patients). Newly diagnosed type 2 diabetes (n=45,531) was identified by ICD-10 codes (E11). Matching (1:1) on practice specialty, sex, age, and year of diabetes diagnosis was performed for CVD. Logistic regression models were fitted to obtain adjusted odds ratios (OR) for characteristics associated with prescription use (median follow-up: 1.9 years).

Overall, 35% of patients (n=16,006) were treated with glucose-lowering drugs during the first year after type 2 diabetes diagnosis (HbA1c≥7.0%: 80%). GLP-1RA (2.4%) and SGLT2i (8.5%) were rarely prescribed. After the consensus, use of GLP-1RA and SGLT2i increased, however, almost independently of pre-existing CVD (12/2019-11/2020 vs. 12/2017-11/2018: yes, no): GLP-1RA: from 5.7 to 9.2%, 5.2 to 7.6%; SGLT2i: from 13.9 to 20.4%, 12.1 to 16.6%. Among cardiovascular risk factors, the largest OR for GLP-1RA was for obesity (4.5; 95%CI: 3.2-6.3). CVD was moderately related with SGLT2i (1.45; 1.32-1.60) and GLP-1RA (1.35; 1.08-1.69) prescriptions. A weak association was observed between SGLT2i and heart failure (1.18; 95%CI: 1.05-1.32).

National prescription use of GLP-1RA and SGLT2i did not come close to the recommendation in subjects with CVD issued by the 2018 ADA/EASD consensus.

Patients with type 2 diabetes mellitus (T2DM) can have multiple comorbidities and premature mortality due to atherosclerotic cardiovascular disease, hospitalization with heart failure and/or chronic kidney disease. Traditional drugs that lower glucose, such as metformin, or that treat high blood pressure and blood levels of lipids, such as renin-angiotensin-system inhibitors and statins, have organ-protective effects in patients with T2DM. Amongst patients with T2DM treated with these traditional drugs, randomized clinical trials have confirmed the additional cardiorenal benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA) and nonsteroidal mineralocorticoid receptor antagonists. The cardiorenal benefits of SGLT2i extended to patients with heart failure and/or chronic kidney disease without T2DM, whereas incretin-based therapy (such as GLP1RA) reduced cardiovascular events in patients with obesity and T2DM. However, considerable care gaps exist owing to insufficient detection, therapeutic inertia and poor adherence to these life-saving medications. In this Review, we discuss the complex interconnections of cardiorenal-metabolic diseases and strategies to implement evidence-based practice. Furthermore, we consider the need to conduct clinical trials combined with registers in specific patient segments to evaluate existing and emerging therapies to address unmet needs in T2DM.