Use Of Glucagon-like Peptide-1 Receptor Agonists Research Articles

Use of GLP-1 Receptor Agonists in the Treatment of Obesity in Women with PCOS

Use of GLP-1 Receptor Agonists in the Treatment of Obesity in Women with PCOS

Effects of Glucagon-Like Peptide1 Receptor Agonists on Atrial Fibrillation Recurrence After Catheter Ablation: A Systematic Review and Meta-analysis.

Despite the technological advancements in catheter ablation strategies, the recurrence of atrial fibrillation (AF) post-ablation remains a concern that requires further investigation. Glucagon-like peptide1 (GLP-1) receptor agonists have shown a significant effect on weight reduction, which in turn is associated with freedom from AF recurrence in both patients who are obese and not obese undergoing ablation. Therefore, we aimed to summarize the available evidence on the efficacy of GLP-1 receptor agonists in maintaining sinus rhythm post-ablation. Medline, Cochrane Library, and Scopus were searched until June 9, 2024. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled using DerSimonian-Laird random effects meta-analysis. Three propensity score-matched studies (n = 6031 participants) were analyzed. Over a 12-months follow-up, the use of GLP-1 receptor agonists was associated with a significant reduction in AF recurrence compared to controls, hazard ratio (HR) = 0.549, 95% confidence interval (CI) = [0.315, 0.956], P = 0.034; I2 = 57%. No significant heterogeneity was observed (Qstatistic = 4.6, heterogeneity P = 0.1). The use of GLP-1 receptor agonists is associated with a lower risk of AF recurrence in patients receiving AF ablation therapy. Further large-scale randomized trials are necessary to explore the efficacy of GLP-1 receptor agonists in maintaining ablation outcomes over the long term.

GLP-1RA vs DPP-4i Use and Rates of Hyperkalemia and RAS Blockade Discontinuation in Type 2 Diabetes

Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk. To compare rates of hyperkalemia and RASi persistence among new users of GLP-1RAs vs dipeptidyl peptidase-4 inhibitors (DPP-4is). This cohort study included all adults with T2D in the region of Stockholm, Sweden, who initiated GLP-1RA or DPP-4i treatment between January 1, 2008, and December 31, 2021. Analyses were conducted between October 1, 2023, and April 29, 2024. GLP-1RAs or DPP-4is. The primary study outcome was time to any hyperkalemia (potassium level >5.0 mEq/L) and moderate to severe (potassium level >5.5 mEq/L) hyperkalemia. Time to discontinuation of RASi use among individuals using RASis at baseline was assessed. Inverse probability of treatment weights served to balance more than 70 identified confounders. Marginal structure models were used to estimate per-protocol hazard ratios (HRs). A total of 33 280 individuals (13 633 using GLP-1RAs and 19 647 using DPP-4is; mean [SD] age, 63.7 [12.6] years; 19 853 [59.7%] male) were included. The median (IQR) time receiving treatment was 3.9 (1.0-10.9) months. Compared with DPP-4i use, GLP-1RA use was associated with a lower rate of any hyperkalemia (HR, 0.61; 95% CI, 0.50-0.76) and moderate to severe (HR, 0.52; 95% CI, 0.28-0.84) hyperkalemia. Of 21 751 participants who were using RASis, 1381 discontinued this therapy. The use of GLP-1RAs vs DPP-4is was associated with a lower rate of RASi discontinuation (HR, 0.89; 95% CI, 0.82-0.97). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function. In this study of patients with T2D managed in routine clinical care, the use of GLP-1RAs was associated with lower rates of hyperkalemia and sustained RASi use compared with DPP-4i use. These findings suggest that GLP-1RA treatment may enable wider use of guideline-recommended medications and contribute to clinical outcomes in this population.

Trends in utilization patterns of newer glucose-lowering drugs in US adults with type 2 diabetes and a history of coronary heart disease or heart failure: 2005–2019

BackgroundThe 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). ObjectiveThis 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. MethodWe used 2005–2019 data from the Medical Expenditure Panel Survey (MEPS). Individuals with self-reported diabetes and CVD history were identified. ResultsThere 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. ConclusionThe 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. SummaryWe 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.

Disparities in Use of Novel Diabetes Medications by Insurance: A Nationally Representative Cohort Study.

Minority racial and ethnic populations have the highest prevalence of type 2 diabetes mellitus but lower use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra), novel medications that reduce morbidity and mortality. Observed disparities may be due to differences in insurance coverage, which have variable cost-sharing, prior authorization, and formulary restrictions that influence medication access. To assess whether racial/ethnic differences in SGLT2i and GLP1ra use differ by payer. Cross-sectional analysis of 2018 and 2019 Medical Expenditure Panel Survey data. Adults ≥ 18years old with diabetes. We defined insurance as private, Medicare, or Medicaid using ≥ 7months of coverage in the calendar year. We defined race/ethnicity as White (non-Hispanic) vs non-White (including Hispanic). The primary outcome was use of ≥ 1 SGLT2i or GLP1ra medication. We used multivariable logistic regression to assess the interaction between payer and race/ethnicity adjusted for cardiovascular, socioeconomic, and healthcare access factors. We included 4997 adults, representing 24.8 million US adults annually with diabetes (mean age 63.6years, 48.8%female, 38.8%non-White; 33.5% private insurance, 56.8% Medicare, 9.8% Medicaid). In our fully adjusted model, White individuals with private insurance had significantly more medication use versus non-White individuals (16.1% vs 8.3%, p < 0.001), which was similar for Medicare beneficiaries but more attenuated (14.7% vs 11.0%, p = 0.04). Medication rates were similar among Medicaid beneficiaries (10.0% vs 9.0%, p = 0.74). Racial/ethnic disparities in novel diabetes medications were the largest among those with private insurance. There was no disparity among Medicaid enrollees, but overall prescription rates were the lowest. Given that disparities vary considerably by payer, differences in insurance coverage may account for the observed disparities in SGLT2i and GLP1ra use. Future studies are needed to assess racial/ethnic differences in novel diabetes use by insurance formulary restrictions and out-of-pocket cost-sharing.

Glucagon-like peptide-1 receptor agonist therapy effects on glycemic control and weight in a primary care clinic population.

Glucagon-like peptide-1 receptor agonist (GLP-1a) medications have been shown in randomized controlled trials (RCTs) to have consistent and impressive effectiveness in lowering hemoglobin A1c (HbA1c) and weight, but limited data exist on the efficacy of GLP-1a medications in clinical practice. We studied the association between GLP-1a therapy and changes in weight and HbA1c in a real-world patient population. In this retrospective cohort study of patients seen in a primary care clinic between 2012 and 2021, we examined the change in weight and HbA1c over 12 months in a cohort of patients with at least one prescription for a GLP-1a. Within this cohort, treatment was defined as having ≥2 GLP-1a prescriptions at a therapeutic dosage separated by ≥10 months. The cohort included 693 patients of whom 393 (57%) were treated with GLP-1a therapy. The treatment group had a mean change in body mass index (BMI) of -0.83 kg/m2 (±2.88) compared to -0.70 kg/m2 (±2.99) in the without GLP-1a group (p = 0.57). Treated patients had a mean change in HbA1c of -1.00% (±2.07) compared to -0.83% (±1.92) in the without GLP-1a group (p = 0.27). For treated and without GLP-1a patients, respectively, the proportion of patients with a decrease in BMI was 65 versus 64% (p = 0.86), and the proportion with a decrease in HbA1c was 73 versus 69% (p = 0.28). In clinical practice, GLP-1a therapy was associated with more modest reductions in weight and HbA1c than shown in prior RCTs. As GLP-1a use continues to expand throughout primary care, the real-world impact of this pharmacotherapy will require further evaluation.

Utilization of Glucagon-Like Peptide-1 Receptor Agonist and Dipeptidyl Peptidase-4 Inhibitors at the Veterans Health Administration.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are incretin-based therapies commonly used in the management of type 2 diabetes. Public interest in GLP-1RA soared after discovering their ability to lower body weight in patients without diabetes. Objective: To examine recent trends in usage of GLP-1RA and DPP-4i in the Veterans Health Administration (VHA). Methods: We extracted GLP-1RA and DPP-4i use from the national VHA Corporate Data Workhouse (CDW) between fiscal years (FYs) 2011 to 2021, which encompass medication class, name, dosage, date of filled prescription, and patients' characteristics. Results: A total of 3 037 006 prescriptions for DPP-4i and 2 183 294 prescriptions for GLP-1RA were filled during FY 2011 to 2021. More patients were prescribed DPP-4i (273 002 subjects) compared with GLP-1RA (157 209 subjects) from FY 2011 to 2021. Overall, 10.7% used DPP-4i for 90 days or less in comparison to 9.1% in GLP-1RA (P < 0.001). The proportion of patients prescribed DPP-4i who were 75 years of age or older was relatively stable over the years 2011 to 2021 (mean proportion = 19%). However, the proportion of patients who were 75 years of age or older prescribed GLP-1RA increased from 4.2% in 2011 to 16.9% in 2021. Conclusions: Incretin-based therapies have become a well-established class of drugs within the VHA. Even though DPP-4i usage in older adults has remained stable over the past 10 years, prescriptions for GLP-1RA in older adults have increased multifold over the last few years, which might be attributed to recent trial evidence showing benefit in cardiovascular outcomes and weight reduction.

SGLT2 Inhibitors, but Not GLP-1 Receptor Agonists, Reduce Incidence of Gout in People Living With Type 2 Diabetes Across the Therapeutic Spectrum

PurposeThis study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data. MethodsWe conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation. FindingsPrior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], P < 0.0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74–0.92], P < 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], P < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], P < 0.0001). ImplicationsIn this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population.

Medication adherence to sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists: A meta-analysis.

To perform a meta-analysis comparing real-world medication adherence to sodium-glucose cotransporter-2 inhibitors (SGLT2is) versus glucagon-like peptide-1 receptor agonists (GLP-1RAs). A systematic search of Medline and Embase was conducted through October 2023. To meet inclusion criteria, articles had to be published in full text form and directly compare medication adherence to SGLT2is versus GLP-1RAs in adults. Only studies evaluating real-world data and utilizing the proportion of days covered (PDC) to measure adherence were included. Non-adherence, defined as the proportion of patients with a PDC <80%, was the primary outcome. A subgroup analysis evaluating results among studies conducted in the United States was performed. We identified eight studies evaluating 205 103 patients for inclusion. The most common country from which the data was derived was the United States (n = 5 studies). Upon meta-analysis, we observed no difference in non-adherence (i.e. PDC <80%) to SGLT2is versus GLP-1RAs (relative risk = 0.86; 95% confidence interval = 0.72-1.02). In the analysis, including only US studies, SGLT2i use was associated with a 23% lower risk of non-adherence compared with GLP-1RA use (relative risk = 0.77; 95% confidence interval = 0.72-0.82). In this meta-analysis of eight studies that included approximately 200 000 patients, there was no difference in adherence to SGLT2is versus GLP-1RAs. However, SGLT2i use was associated with higher adherence when the analysis was limited to US studies.

Dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists do not worsen diabetic macular edema

AimsThere are limited studies on dipeptidyl-peptidase 4 inhibitor (DPP-4i), sodium glucose cotransporter 2 inhibitor (SGLT2-i), and glucagon-like peptide 1 (GLP-1) receptor agonist use and occurrence of diabetic macular edema (DME). The objective of this study was to determine the association between DPP-4i, SGLT2-i, and GLP-1 receptor agonist use and occurrence of DME. MethodsProportional hazard models were used to evaluate the change in hazard of developing DME associated with DPP-4i, SGLT2-i, or GLP-1 receptor agonist use. Models accounted for age at DR diagnosis, DR severity (proliferative vs non-proliferative stage), time-weighted average of HbA1c level, sex, and self-reported race/ethnicity. A p-value ≤ 0.05 was considered statistically significant. ResultsThe hazard ratio of developing DME after diagnosis of DR was 1.2 (CI = 0.75 to 1.99; p = 0.43) for DPP-4i use, 0.93 (CI = 0.54 to 1.61; p = 0.81) for GLP-1 receptor agonist use, 0.82 (CI = 0.20 to 3.34; p = 0.78) for SGLT2-i use, 1.1 (CI = 0.75 to 1.59; p = 0.66) for any one medication use, 1.1 (CI = 0.62 to 2.09; p = 0.68) and for any two or more medications use. ConclusionsWe did not find an association between DPP-4i, SGLT2-i, or GLP-1 receptor agonist use and increased hazard of development of DME among patients with DR.

Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials

SGLT2 inhibitors and GLP-1 receptor agonists both improve cardiovascular and kidney outcomes in patients with type 2 diabetes. We sought to evaluate whether the benefits of SGLT2 inhibitors are consistent in patients receiving and not receiving GLP-1 receptor agonists. We conducted a collaborative meta-analysis of trials included in the SGLT2 Inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium, restricted to participants with diabetes. Treatment effects from individual trials were obtained from Cox regression models and pooled using inverse variance weighted meta-analysis. The two main cardiovascular outcomes assessed included major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death), and hospitalisation for heart failure or cardiovascular death. The main kidney outcomes assessed were chronic kidney disease progression (≥40% decline in estimated glomerular filtration rate [eGFR], kidney failure [eGFR <15 mL/min/1·73 m2, chronic dialysis, or kidney transplantation], or death due to kidney failure), and the rate of change in eGFR over time. Safety outcomes were also assessed. Across 12 randomised, double-blind, placebo-controlled trials, 3065 (4·2%) of 73 238 participants with diabetes were using GLP-1 receptor agonists at baseline. SGLT2 inhibitors reduced the risk of major adverse cardiovascular events in participants both receiving and not receiving GLP-1 receptor agonists (hazard ratio [HR] 0·81, 95% CI 0·63-1·03 vs 0·90, 0·86-0·94; p-heterogeneity=0·31). Effects on hospitalisation for heart failure or cardiovascular death (0·76, 0·57-1·01 vs 0·78, 0·74-0·82; p-heterogeneity=0·90) and chronic kidney disease progression (0·65, 0·46-0·94 vs 0·67, 0·62-0·72; p-heterogeneity=0·81) were also consistent regardless of GLP-1 receptor agonist use, as was the effect on the chronic rate of change in eGFR over time (heterogeneity=0·92). Fewer serious adverse events occurred with SGLT2 inhibitors compared with placebo, irrespective of GLP-1 receptor agonist use (relative risk 0·87, 95% CI 0·79-0·96 vs 0·91, 0·89-0·93; p-heterogeneity=0·41). The effects of SGLT2 inhibitors on cardiovascular and kidney outcomes are consistent regardless of the background use of GLP-1 receptor agonists. These findings suggest independent effects of these evidence-based therapies and support clinical practice guidelines recommending the use of these agents in combination to improve cardiovascular and kidney metabolic outcomes. National Health and Medical Research Council of Australia and the Ramaciotti Foundation.

Incretin-based therapy and the risk of diabetic foot ulcers and related events.

To investigate the effect of dipeptidyl peptidase-4 inhibitors (DPP4-Is) and glucagon-like peptide-1 receptor agonists (GLP1-RAs) on diabetic foot ulcer (DFU) and DFU-related outcomes (lower limb amputation [LLA], DFU-related hospitalization and mortality). We performed a cohort study with data from the Clinical Practice Research Datalink Aurum database with linkage to hospital data. We included people with type 2 diabetes starting treatment with metformin. Then we propensity score matched new users of DPP4-Is and sulphonylureas (N = 98 770), and new users of GLP1-RAs and insulin (N = 25 422). Cox proportional hazards models estimated the hazard ratios (HRs) for the outcomes. We observed a lower risk of DFU with both DPP4-I use versus sulphonylurea use (HR 0.88, 95% confidence interval [CI]: 0.79-0.97) and GLP1-RA use versus insulin use (HR 0.44, 95% CI: 0.32-0.60) for short-term exposure (≤ 400 days) and HR 0.74 (95% CI: 0.60-0.92) for long-term exposure (>400 days). Furthermore, the risks of hospitalization and mortality were lower with both DPP4-I use and GLP1-RA use. The risk of LLA was lower with GLP1-RA use. The results remained consistent across several sensitivity analyses. Incretin-based therapy was associated with a lower risk of DFU and DFU-related outcomes. This suggests benefits for the use of this treatment in people at risk of DFU.

Cardio-Renal-Metabolic Outcomes Associated With the Use of GLP-1 Receptor Agonists After Heart Transplantation.

The use of glucagon-like-peptide 1 receptor agonists (GLP1-RA) has dramatically increased over the past 5 years for diabetes mellitus type 2(T2DM) and obesity. These comorbidities are prevalent in adult heart transplant (HT) recipients. However, there are limited data evaluating the efficacy of this drug class in this population. The aim of the current study was to describe cardiometabolic changes in HT recipients prescribed GLP1-RA at a large-volume transplant center. We retrospectively reviewed all adult HT recipients who received GLP1-RA after HT for a minimum of 1-month. Cardiometabolic parameters including body mass index (BMI), lipid panel, hemoglobin A1C, estimated glomerular filtration rate (eGFR), and NT-proBNP were compared prior to initiation of the drug and at most recent follow-up. We also evaluated for significant dose adjustments to immunosuppression after drug initiation and adverse effects leading to drug discontinuation. Seventy-four patients were included (28% female, 53% White, 20% Hispanic) and followed for a median of 383 days [IQR 209, 613] on a GLP1-RA. The majority of patients (n = 56, 76%) were prescribed semaglutide. The most common indication for prescription was T2DM alone (n = 33, 45%), followed by combined T2DM and obesity (n = 26, 35%). At most recent follow-up, mean BMI decreased from 33.3 to 31.5 kg/m2 (p < 0.0001), HbA1C from 7.3% to 6.7% (p = 0.005), LDL from 78.6 to 70.3 mg/dL (p = 0.018) and basal insulin daily dose from 32.6 to 24.8 units (p = 0.0002). HT recipients prescribed GLP1-RA therapy showed improved glycemic control, weight loss, and cholesterol levels during the study follow-up period. GLP1-RA were well tolerated and were rarely associated with changes in immunosuppression dosing.

Use of glucagon-like peptide-1 receptor agonists for type 2 diabetes mellitus and outcomes of inflammatory bowel disease.

Glucagon-like peptide-1 receptor agonists (GLP-1RA) show anti-inflammatory properties. To evaluate their clinical impact on inflammatory bowel disease (IBD) outcomes. Retrospective cohort study utilising the TriNetX database comparing IBD-specific outcomes in patients with ulcerative colitis (UC) or Crohn's disease (CD) and type 2 diabetes mellitus (T2DM) on GLP-1RA compared to oral hypoglycaemic agents. The primary outcome was hospitalisation requiring intravenous steroids and IBD-related surgery within 3 years. We performed 1:1 propensity score matching (PSM) for demographics, co-morbid conditions, BMI, laboratory values, HbA1c, and IBD medications including steroids. We identified 1130 patients in the UC GLP-1RA cohort (mean age: 58.9 ± 11.6 years, 56.3% female, 70.2% White, 57.2% with obesity) and 1140 patients in the CD GLP-1RA cohort (mean age: 56.7 ± 11.5, 61.9% female, 73.6% White, 56.2% with obesity). After PSM, there was no difference in the risk of intravenous steroid use (aHR: 1.21, 95% CI: 0.92-1.59) but a lower risk of colectomy (aHR: 0.37, 95% CI: 0.14-0.97) between the UC GLP-1RA and control cohort. There was no difference in the risk of intravenous steroid use (aHR: 1.04, 95% CI: 0.80-1.34) but a lower risk of surgery (aHR: 0.55, 95% CI: 0.36-0.84) between the CD GLP-1RA and CD control cohort. There was no difference in the risk of oral steroid use or advanced therapy initiation in the UC and CD GLP-1RA than control cohorts. We found an association between lower risk of IBD-related surgery and GLP-1RA use for T2DM in patients with UC or CD.

SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: population based cohort study

ObjectivesTo evaluate the comparative effectiveness of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in preventing hyperkalemia in people with type 2 diabetes in...

Potential kidney protective effects of glucagon-like peptide-1 receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained increasing attention for their potential benefits in people with type 2 diabetes (T2DM) with chronic kidney disease (CKD). This class of medication has demonstrated promising results in reducing albuminuria, preserving estimated glomerular filtration rate (eGFR), and mitigating cardiovascular (CV) risk, making them potential therapeutic options for individuals with CKD. The kidney protective effects of GLP-1RAs extend beyond glycaemic control, and are thought to be attributed to their anti-inflammatory, antioxidant, and natriuretic properties. Despite these promising findings, the use of GLP-RAs has yet to be definitively shown to slow progression to chronic kidney failure, or reduce CV and kidney related death in people with T2DM and CKD. The Research Study to See How Semaglutide (a once weekly subcutaneous administered GLP-1RA) Works Compared to Placebo in People with Type 2 Diabetes and Chronic Kidney Disease (FLOW trial) was recently stopped because of efficacy. The primary end point for the FLOW trial consists of a composite endpoint of (i) onset of chronic kidney failure; (ii) death from kidney failure; (iii) cardiovascular death; and (iv) onset of a persistent ≥50% reduction in eGFR from baseline. It has also been reported by the sponsors of the trial that the primary end point of the trial was reduced by 24% with both CKD and CV outcomes contributing to risk reduction. In anticipation of the results of the FLOW trial being published, we review the current evidence surrounding kidney outcomes and proposed kidney protective pathways associated with GLP-1RA use.

A review of the latest real-world evidence studies in diabetic kidney disease: What have we learned about clinical practice and the clinical effectiveness of interventions?

Diabetic nephropathy, also known as diabetic kidney disease (DKD), remains a challenge in clinical practice as this is the major cause of kidney failure worldwide. Clinical trials do not answer all the questions raised in clinical practice and real-world evidence provides complementary insights from randomized controlled trials. Real-life longitudinal data highlight the need for improved screening and management of diabetic nephropathy in primary care. Adherence to the recommended guidelines for comprehensive care appears to be suboptimal in clinical practice in patients with DKD. Barriers to the initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with DKD persist in clinical practice, in particular for the elderly. Attainment of blood pressure targets often remains an issue. Initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in routine clinical practice is associated with a reduced risk of albuminuria progression and a possible beneficial effect on kidney function. Real-world evidence confirms a beneficial effect of SGLT2 inhibitors on the decline of glomerular filtration, even in the absence of albuminuria, with a lower risk of acute kidney injury events compared to GLP-1RA use. In addition, SGLT2 inhibitors confer a lower risk of hyperkalaemia after initiation compared with dipeptidyl peptidase-4 inhibitors in patients with DKD. Data from a large population indicate that diuretic treatment increases the risk of a significant decline in glomerular filtration rate in the first few weeks of treatment after SGLT2 inhibitor initiation. The perspective for a global approach targeting multifaceted criteria for diabetic individuals with DKD is emerging based on real-world evidence but there is still a long way to go to achieve this goal.

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study

Diabetic osteopathy is a frequent complication in patients with type 2 diabetes mellitus (T2DM). The association between T2DM and increased fracture risk has led to study the impact of new antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetic drugs which have many pleiotropic properties. The relationship between GLP-1RAs and bone is very complex: while in vitro and animal studies have demonstrated a protective effect on bone, human studies are scarce. We led a 12 months longitudinal study evaluating bone changes in 65 patients withT2DM for whom a therapy with GLP-1RAs had been planned. Fifty-four T2DM patients completed the 12-month study period; of them, 30 had been treated with weekly dulaglutide and 24 with weekly semaglutide. One-year therapy with GLP-1RAs resulted in a significant reduction in weight and BMI. Bone mineral density (BMD), bone metabolism, trabecular bone score (TBS), adiponectin, and myostatin were evaluated before and after 12 months of GLP-1RAs therapy. After 12 months of therapy bone turnover markers and adiponectin showed a significant increase, while myostatin values showed a modest but significant reduction. BMD-LS by DXA presented a significant reduction while the reduction in BMD-LS by REMS was not significant and TBS values showed a marginal increase. Both DXA and REMS techniques showed a modest but significant reduction in femoral BMD. In conclusion, the use of GLP-1RAs for 12 months preserves bone quality and reactivates bone turnover. Further studies are needed to confirm whether GLP-1RAs could represent a useful therapeutic option for patients with T2DM and osteoporosis.

Comparative effectiveness of sodium-glucose cotransporter-2 inhibitors for new-onset gastric cancer and gastric diseases in patients with type 2 diabetes mellitus: a population-based cohort study

ObjectiveTo compare the risks of gastric cancer and other gastric diseases in patients with type-2 diabetes mellitus (T2DM) exposed to sodium-glucose cotransporter 2 inhibitors (SGLT2I), dipeptidyl peptidase-4 inhibitors (DPP4I) or glucagon-like peptide-1 receptor agonists (GLP1a).DesignThis was a population-based cohort study of prospectively collected data on patients with T2DM prescribed SGLT2I, DPP4I or GLP1a between January 1st 2015 and December 31st 2020 from Hong Kong. The outcomes were new-onset gastric cancer, peptic ulcer (PU), acute gastritis, non-acute gastritis, and gastroesophageal reflux disease (GERD). Propensity score matching (1:1) using the nearest neighbour search was performed, and multivariable Cox regression was applied. A three-arm comparison between SGLT2I, DPP4I and GLP1a was conducted using propensity scores with inverse probability of treatment weighting.ResultsA total of 62,858 patients (median age: 62.2 years old [SD: 12.8]; 55.93% males; SGLT2I: n = 23,442; DPP4I: n = 39,416) were included. In the matched cohort, the incidence of gastric cancer was lower in SGLT2I (Incidence rate per 1000 person-year, IR: 0.32; 95% confidence interval, CI 0.23–0.43) than in DPP4I (IR per 1000 person-year: 1.22; CI 1.03–1.42) users. Multivariable Cox regression found that SGLT2I use was associated with lower risks of gastric cancer (HR 0.30; 95% CI 0.19–0.48), PU, acute gastritis, non-acute gastritis, and GERD (p < 0.05) compared to DPP4I use. In the three-arm analysis, GLP1a use was associated with higher risks of gastric cancer and GERD compared to SGLT2I use.ConclusionsThe use of SGLT2I was associated with lower risks of new-onset gastric cancer, PU, acute gastritis, non-acute gastritis, and GERD after matching and adjustments compared to DPP4I use. SGLT2I use was associated with lower risks of GERD and gastric cancer compared to GLP1a use.Graphical abstract

Effect of lixisenatide on liquid gastric emptying in type 2 diabetes – Implications for the use of GLP-1 receptor agonists before procedures

Gastric emptying of a glucose drink was measured in people with type 2 diabetes given lixisenatide (20 μg/day or placebo) for 8 weeks. Intragastric retention at 240 min (2 (0−11)% vs 48 (3–97)%; P < 0.0001) was much greater with lixisenatide than placebo. Accordingly, lixisenatide may delay liquid gastric emptying markedly.