Bridging the gap between GLP1-receptor agonists and cardiovascular outcomes: evidence for the role of tirzepatide.

Tirzepatide is a new drug targeting glucagon-like peptide 1(GLP1) and gastric inhibitory polypeptide (GIP) receptors. This drug has demonstrated great potential in improving the clinical outcomes of patients with type 2 diabetes. It can lead to weight loss, better glycemic control, and reduced cardiometabolic risk factors. GLP1 receptor agonists have been proven effective antidiabetic medications with possible cardiovascular benefits. Even though they have been proven to reduce the risk of major adverse cardiovascular events, their effectiveness in treating heart failure is unknown. Unlike traditional GLP1 receptor agonists, tirzepatide is more selective for the GIP receptor, resulting in a more balanced activation of these receptors. This review article discusses the possible mechanisms tirzepatide may use to improve cardiovascular health. That includes the anti-inflammatory effect, the ability to reduce cell death and promote autophagy, and also its indirect effects through blood pressure, obesity, and glucose/lipid metabolism. Additionally, tirzepatide may benefit atherosclerosis and lower the risk of major adverse cardiac events. Currently, clinical trials are underway to evaluate the safety and efficacy of tirzepatide in patients with heart failure. Overall, tirzepatide's dual agonism of GLP1 and GIP receptors appears to provide encouraging cardiovascular benefits beyond glycemic control, offering a potential new therapeutic option for treating cardiovascular diseases and heart failure.

Effectiveness and safety of once-weekly semaglutide: findings from the SEMACOL-REAL retrospective multicentric observational study in Colombia.

Introduction: Diabetes stands as one of the leading causes of death worldwide. Glucagon-like peptide-1 receptor agonists rank among the most effective medications for lowering blood glucose and body weight, as well as reducing cardiovascular risk in individuals with diabetes. Observational studies complement experimental evidence in new settings, different populations, and real-world healthcare practices. Methods: A multicentric observational study of adults with type 2 diabetes treated with once-weekly subcutaneous semaglutide in four health centers in Colombia was conducted. The protocol for the present study was not pre-registered. Results: Data from 186 patients were included. Most patients were women (57%) with a mean age of 62.8 ± 12.1 years. One year of once-weekly semaglutide usage was associated with a mean reduction in HbA1C of -1.47% (95% CI -1.76, -1.17), weight loss of -4.23 kg (95% CI -5.34, -3.12), and albumin/creatinine ratio of -18.6 mg/g (95% CI -60.2, -5.9). Approximately half the treated patients achieved a level of HbA1c ≤7% by the end of follow-up. Adverse events were rare and consistent with clinical trial safety profiles. Conclusion: In Colombia, administering semaglutide subcutaneously once a week over a 1-year period led to an average weight loss of 4.2 kg and a decrease of 1.4% in HbA1c.

Epidemiology of potential drug- drug interactions in hospitalized patients with type 2 diabetes mellitus in China: a retrospective study.

Background: Combination therapy was associated with an increased risk of drug- drug interactions (DDIs) in patients with type 2 diabetes mellitus (T2DM). The present study aimed to investigate the epidemiology of potential DDIs (pDDIs), including potential chemical drug-drug interactions (pCDIs) and potential herb-drug interactions (pHDIs), and classify the influencing factors of pDDIs in these patients. Methods: A retrospective study of the epidemiology of pDDIs among T2DM hospitalized patients older than 18 years and treated with at least two drugs during hospitalization was conducted over a 12-month period in 2019. PDDIs were identified with C (monitor therapy), D (consider therapy modification), and X (avoid combination) risk ratings. Binary logistic regression was used to analyze the risk factors of pDDIs. Results: A total of 6796 pDDIs were identified from 737 T2DM hospitalized patients during hospitalization, with 0.87% classified as X risk rating, 13.39% as D risk rating. Additionally, 1753 pDDIs were identified after discharge, with 0.11% as X and 25.73% as D risk rating. The drug-drug association networks showed that the majority of pCDIs were associated with cardiovascular system drugs. Chlorphenamine-potassium chloride and danshen-warfarin were the most prevalent interacting pairs of pCDIs and pHDIs with X rating during hospitalization. Multivariate analysis indicated that the likelihood of developing over 4 pDDIs was significantly higher among T2DM patients who had received over 8 medications. The presence of pDDIs after discharge was strongly associated with the complications of T2DM and the number of discharge medications. Conclusions: T2DM patients were frequently exposed to pDDIs, including pCDIs and pHDIs, both during hospitalization and after discharge. Multi-drug combination was the primary risk factor for pDDIs. Strategies such as enhancing the monitoring and warning for pDDIs, increasing clinical pharmacological experience, as well as developing universally applicable clinical guidelines for pDDIs may be beneficial in reducing the incidence of potentially harmful drug-combinations.

Retinopathy risk factors in patients with type 2 diabetes on liraglutide.

Liraglutide, a glucagon-like peptide 1 receptor agonist, effectively treats type 2 diabetes(T2D) by lowering glucose levels, suppressing glucagon release, and promoting insulin secretion. Liraglutide has been shown to reduce body weight and glycated hemoglobin (HbA1c) levels and improve cardiovascular outcomes. However, evidence regarding the association between liraglutide and diabetic retinopathy in the Middle East is insufficient. Therefore, this study aimed to investigate the characteristics and risk factors of diabetic retinopathy in patients with T2D treated with liraglutide in Saudi Arabia. This retrospective cohort study was conducted on patients (≥14 years) with T2D treated with liraglutide between 2015 and 2021, who had a documented retinopathy assessment at baseline before liraglutide initiation and during follow-up, at King Abdulaziz Medical City (KAMC), Riyadh. Data collection included demographic information, retinopathy status, body mass index (BMI), and HbA1c level at baseline and follow-up after liraglutide use. The study included 181 patients with a mean age of 58.2 (9.8) years. Of these, 72.9% were females. At baseline, the median weight (interquartile range) was 88 (77-100) kg, diabetes duration was 19 (13-23.5) years, and HbA1c level was 9% (8-10%). Total of 69.6% were on insulin, 22.7% were on oral hypoglycemic agents, and 7.7% were on no other medications in addition to liraglutide. After a median of 2 years follow-up, both HbA1c level and weight decreased significantly (P < .001). Seventy-one of the 87 patients (81.6%) without retinopathy at baseline continued to show no retinopathy. Among patients with retinopathy at baseline, 25.5% showed improvement and 44.7% showed no change. In the multivariate binary mixed effect analysis, factors significantly associated with retinopathy were: use of insulin (odds ratio [OR]:2.68; 95% confidence interval [CI]: 1.18-6.09, P = .019), older age (OR:1.03; 95% CI: 1.00-1.06; P = .022), higher HbA1c level (OR:1.17; 95% CI: 1.02-1.34; P = .024), Hypertension (OR:2.56; 95% CI: 1.13-5.76; P=<.0001) and longer diabetes duration (OR:1.04; 95% CI: 1.00-1.08; P = .024). In conclusion, liraglutide use caused significant reductions in the HbA1c level and weight of patients with T2D. Most patients showed no change in retinopathy status after liraglutide use.

Glucagon-Like Peptide-1 Receptor Agonists and Major Adverse Cardiovascular Events in Patients With and Without Diabetes: A Meta-Analysis of Randomized-Controlled Trials.

INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown encouraging results regarding cardiovascular outcomes mainly in patients with diabetes. In the present study, we compared the efficacy of GLP-1 RAs in cardiovascular events between patients with and without diabetes. METHODS: After finding eligible studies assessing the impact of GLP-1 RAs on cardiovascular events in patients with and without diabetes using a systematic search, we performed a meta-analysis on randomized-controlled trials (RCTs) comparing cardiovascular outcomes between patients taking GLP-1 RAs and placebo stratified by the presence or absence of diabetes. Relative risk (RR) and its 95% confidence interval (CI) were set as the reporting effect size using the random-effects model. RESULTS: A total of 24 RCTs (50 033 with GLP-1 RAs and 44 514 with placebo) were included. Patients on GLP-1 RAs had lower risk of major adverse cardiovascular events (MACE) (RR 0.87, 95% CI 0.82-0.93), cardiovascular death (RR 0.88, 95% CI 0.82-0.94), myocardial infarction (MI) (RR 0.87, 95% CI 0.77-0.97), stroke (RR 0.86, 95% CI 0.80-0.92), and hospitalization for heart failure (RR 0.90, 95% CI 0.83-0.98). Both subgroups were shown to be effective in terms of MACE and mortality. Nondiabetic patients had decreased risk of hospitalization for heart failure and MI, whereas the diabetic subgroup had marginally nonsignificant efficacy. CONCLUSION: The findings of this meta-analysis indicated that patients who are overweight/obese but do not have diabetes have a comparable reduction in the risk of adverse cardiovascular events as those with diabetes. These results need to be confirmed further by large-scale randomized trials in the future.

Preadmission metformin use increased the incidence of hyperlactatemia at admission and 30-day in-hospital mortality among T2D patients with heart disease at high risk of hypoxia.

BACKGROUND: Surprisingly, despite the high prevalence of metformin use in type 2 diabetes (T2D) patients with heart disease, limited safety data is available regarding metformin use in patients with acute and critical heart disease. METHODS: In this single-center retrospective study, patients admitted to the cardiology department for heart failure (HF) or acute coronary syndrome (ACS) between December 2013 and December 2021 and who underwent arterial blood gas analysis at admission with an estimated glomerular clearance rate of ≥45 ml/min/1.73 m2 were identified. The incidences of hyperlactatemia, acidosis, and 30-day in-hospital mortality were compared between preadmission metformin users and nonusers. RESULTS: Of 526 admissions, 193/193 metformin users/nonusers were selected in a propensity score-matched model. Metformin users had greater lactate levels (2.55 ± 2.07 mmol/l vs. 2.00 ± 1.80 mmol/l P < 0.01), a greater incidence of hyperlactatemia [odds ratio (OR) = 2.55; 95% confidence interval (CI), 1.63-3.98; P < 0.01] and acidosis (OR = 1.78; 95% CI, 1.00-3.16; P < 0.05) at admission and a greater incidence of in-hospital mortality (OR = 3.83; 95% CI, 1.05-13.94; P < 0.05), especially those with HF/acute myocardial infarction, elderly age, or without preadmission insulin use. CONCLUSIONS: Our results suggest that, compared to metformin nonusers, preadmission use of metformin may be associated with a greater incidence of hyperlactatemia and acidosis at admission and greater 30-day in-hospital mortality among T2D patients with HF or ACS at high risk of hypoxia, particularly those without preadmission insulin use. The safety of metformin in this population needs to be confirmed in prospective controlled trials.

ProtecT-2-D trial protocol: cardiovascular protection in patients with type 2 diabetes and established heart and/or vascular disease at a cardio-metabolic clinic-a randomized controlled trial.

BACKGROUND: Cardiovascular disease remains the primary cause of morbidity and mortality despite advancements in the treatment of patients with type 2 diabetes. Effective diabetes management extends beyond blood glucose control and includes cardiovascular prevention and treatment. However, the conventional healthcare model often emphasizes single-disease-specific management, leading to fragmented care. We aim to establish an affordable Cardio-Metabolic Clinic (CMC) that can provide comprehensive assessment and specialized care with a focus on cardiovascular protection. METHODS: The ProtecT-2-D study is a prospective, randomized control trial at the Cardiovascular Research Unit, Odense University Hospital Svendborg, Denmark. In this study, 1500 participants with type 2 diabetes and cardiovascular disease will be randomly assigned in a 2:1 ratio to receive either the intervention: treatment in the CMC, or the control: standard of care. The Cardio-Metabolic Clinic applies a decision-making algorithm coded with the latest guidelines to evaluate lifestyle factors and manage medical treatment. Health examinations are conducted at baseline and after three years, and clinical events will be assessed through registry and journal audits after five and ten years. The primary outcome is the time to the first occurrence of a composite of cardiovascular deaths, non-fatal acute myocardial infarctions, non-fatal stroke, or hospitalization due to heart failure at a time frame of five years. DISCUSSION: The Cardio-Metabolic Clinic represents a pioneering approach to diabetes management that aims to improve patient outcomes by reducing the cardiovascular disease burden. This study could transform diabetes care and offer a multidisciplinary, cost-effective, and specialized treatment. We need to establish the efficacy and feasibility of a CMC to integrate comparable clinics into broader healthcare systems, and potentially enhance cardiovascular health in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT06203860.

Optimizing metformin therapy in practice: Tailoring therapy in specific patient groups to improve tolerability, efficacy and outcomes.

Metformin is the first-line medication for type 2 diabetes. It is effective and safe, provided some caution is taken in specific populations. In patients with chronic kidney disease, metformin may provide long-term benefits, and it is a first-line therapy for diabetes, but the estimated glomerular filtration rate (eGFR) must be assessed regularly, to minimize the risk for metformin accumulation. When eGFR is 30-60 mL/min/1.73m2, the dose should be reconsidered, and sick-days education provided. Metformin should be discontinued when eGFR falls below 30 mL/min/1.73m2. Metformin accumulation may increase the risk for lactic acidosis if concomitant risk factors for hyperlactataemia (liver or respiratory insufficiency, sepsis, acute heart failure) are present; in these conditions, metformin is contraindicated, even although the available evidence is reassuring. Patients on metformin often complain of gastrointestinal side effects (mainly diarrhoea and nausea) during therapy initiation, but they may sometimes occur after years of stable therapy. These usually resolve if the dose is carefully titrated, or by switching to the extended-release formulation. Patients with obesity may benefit from the significant, although modest, metformin-associated weight loss and appetite reduction. During pregnancy, metformin is associated with a reduction of pregnancy complications, especially in obese women, but some concern remains, because metformin crosses the placenta, and it is associated with a significantly lower mean birth weight than insulin. In the elderly, gastrointestinal tolerability and renal function must be reassessed more often. Vitamin B-12 should be screened regularly in long-time metformin users because metformin may induce clinical vitamin B-12 deficiency.

Efficacy and safety of semaglutide 2.4 mg by race and ethnicity: A post hoc analysis of three randomized controlled trials.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of semaglutide 2.4 mg, a glucagon-like peptide-1 receptor agonist, by race and ethnicity, across three phase 3 trials. METHODS: The Semaglutide Treatment Effect in People with Obesity (STEP) clinical trials evaluated the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg. Here, STEP 1 and 3 data were pooled for analysis; STEP 2 data were examined separately. All analyses were conducted using data from racial and ethnic subgroups. The primary outcome was the estimated treatment difference in percent body weight change for semaglutide 2.4 mg versus placebo. RESULTS: Participants reported race as White (STEP 1 and 3, 75.3%; STEP 2, 59.4%), Black (8.8%; 8.9%), Asian (10.6%; 27.3%), or other racial group (5.3%; 4.4%); and ethnicity as Hispanic or Latino (13.9%; 11.9%) or not Hispanic or Latino (83.9%; 88.1%). There were no significant interactions between treatment effect and race (STEP 1 and 3: p ≥ 0.07; STEP 2: p ≥ 0.15) or ethnicity (p ≥ 0.40; p ≥ 0.85). The safety of semaglutide 2.4 mg was consistent across subgroups. CONCLUSIONS: The treatment effect of semaglutide was statistically significant versus placebo and clinically relevant across all racial and ethnic subgroups in STEP 1 and 3 and STEP 2. All subgroups across both samples demonstrated good tolerability.