Perioperative Management of Glucagon-like Peptide-1 Receptor Agonists and Sodium-Glucose Co-transporter 2 Inhibitors

New Glucose-Lowering Agents for Diabetic Kidney Disease.

New Medications for the Treatment of Diabetes

Diabetes is a global emergency involving >463 million people as of 2019 and a projection for growth to nearly 700 million by 2045. The vast majority of people (>95%) with diabetes have type 2 diabetes. Despite what is known about effective lifestyle and pharmacologic interventions, the number of people living with diabetes will expand dramatically for the foreseeable future. As a consequence, the number with diabetes complications, including diabetic kidney disease, will also multiply. Diabetic kidney disease occurs in about 40% of those with type 2 diabetes, and it is the most common cause of CKD and kidney failure worldwide. However, death largely due to cardiovascular diseases outcompetes diabetic kidney disease progression by >2:1, and only 10% reach kidney failure. The standard of care for treatment of diabetic kidney disease is use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker—a strategy that has been in place for over two decades. Yet, residual risk of kidney disease progression remained high, and prevalence of diabetic kidney disease and kidney failure attributable to diabetes only escalated over the same time period. The arrival of sodium-glucose cotransporter 2 (SGLT2) inhibitors as kidney-protective agents for diabetic kidney disease prevention and treatment is a welcome advance (1). However, even with application of canagliflozin on top of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, many patients with diabetic kidney disease still have considerable residual risk for kidney disease progression or death. Therefore, great unmet need remains for a broad selection of agents to prevent or treat diabetic kidney disease. The glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), a class of newer glucose-lowering agents, represent another potential avenue for diabetic kidney disease therapeutics. Similar to SGLT2 inhibitors, the initial observations for kidney protection came from postmarket-approval cardiovascular disease safety trials of GLP-1 RA that had kidney disease end points as secondary or exploratory outcomes. The Trial to Evaluate Cardiovascular and Other Long-Term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (n=3297) and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER; n=9340) trial tested semaglutide and liraglutide, respectively, versus placebo in participants with type 2 diabetes at high cardiovascular risk. Both trials demonstrated reductions in new or worsening “nephropathy” (albuminuria, doubling of serum creatinine, kidney failure, or kidney disease death), which was mainly driven by a decrease in macroalbuminuria (2,3). Notably, in the LEADER trial, liraglutide reduced risk of atherosclerotic cardiovascular disease in participants with eGFR<60 ml/min per 1.73 m2, with a significant between-group interaction indicating even greater benefit in those with low eGFR (4). In the largest cardiovascular disease trial to date, the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (n=9901) trial, testing dulaglutide versus placebo, similar results for kidney disease outcomes were reproduced along with a new exploratory finding of risk reductions for 40% or 50% eGFR decline (5). The Study Comparing Dulaglutide with Insulin Glargine on Glycemic Control in Participants with Type 2 Diabetes (T2D) and Moderate or Severe CKD (n=577) trial tested dulaglutide versus an active comparator for glycemic control (insulin glargine) in patients with type 2 diabetes and moderate to severe CKD (mean eGFR =38 ml/min per m2, 29% had microalbuminuria, and 46% had macroalbuminuria) (6). Following 52 weeks of treatment, both dulaglutide treatment groups experienced significantly less eGFR decline compared with those in the insulin glargine group. This benefit was greatest in participants with macroalbuminuria. In this group, mean eGFR decline was −5.5 ml/min per 1.73 m2 in the insulin glargine group compared with −0.7 and −0.5 ml/min per 1.73 m2 in the lower- and higher-dose dulaglutide groups, respectively. A prespecified exploratory analysis demonstrated that, in the higher-dose dulaglutide group, a composite end point of kidney failure or >40% eGFR decline was decreased by half compared with the insulin glargine group (5.2% versus 10.8%; P=0.04). In time to event analysis, the hazard ratio for this composite end point in macroalbuminuric participants was 0.25; 95% confidence interval, 0.10 to 0.86 (P=0.006) among those receiving higher-dose dulaglutide versus those receiving insulin glargine. Although the mechanism of action of GLP-1 RA leading to kidney protection has not been fully elucidated, both indirect and direct pathways may be involved as reviewed elsewhere (7). For indirect pathways, GLP-1 RA reduces hyperglycemia, weight, and BP, all of which may decrease risk of diabetic kidney disease. Beyond affecting such traditional risk factors for diabetic kidney disease progression, activation of GLP-1 augments proximal tubular natriuresis via blocking the sodium-hydrogen exchanger-3, which could theoretically promote tubuloglomerular feedback, afferent constriction, and reduced glomerular hypertension. Studies in patients with and without diabetes have, however, shown that, although natriuresis does occur, kidney function does not change (7). Outside of solute handling, GLP-1 activation also inhibits a variety of injurious pathways within the kidney, including oxidative stress (NADPH oxidase inhibition), inflammation (reduced expression of cytokines and chemokines), and fibrosis (reduced expression of TGF-β1 and collagen IV) (7). Despite their emerging salutary effects, the use of GLP-1 RA is generally low in patients with diabetic kidney disease and low kidney function—a situation perhaps in part related to uncertainty about safety or use of these agents in moderate to severe CKD. Accordingly, in their manuscript in this issue of CJASN, Mann et al. (8) report the result of a post hoc analysis assessing the safety of liraglutide in patients with and without CKD in the LEADER trial (2). In this cohort, 2158 patients had CKD defined as eGFR<60 ml/min per 1.73 m2, and 220 participants had an eGFR<30 ml/min per 1.73 m2. In the overall cohort, 966 patients had macroalbuminuria, and 2456 had microalbuminuria. Mean eGFR at baseline was 45.7±10.9 ml/min per 1.73 m2 in patients with CKD and 90.8±21.6 ml/min per 1.73 m2 in those without CKD. Participants with CKD had more serious adverse events versus patients without CKD, but there was no imbalance between liraglutide- versus placebo-treated patients. Fewer liraglutide- versus placebo-treated participants experienced a serious adverse event leading to treatment discontinuation. Although numerically more patients with CKD had nausea leading to discontinuation and acute gallstone disease in the liraglutide group versus the placebo group, these differences were not statistically significant. For other gastrointestinal adverse events, nausea, vomiting, and diarrhea leading to permanent discontinuation were, as expected, numerically more common with liraglutide versus placebo (not significantly different), but they occurred at similar rates in patients with CKD versus patients without CKD. From a metabolic perspective, severe hypoglycemia risk was 27% lower in patients with CKD randomized to liraglutide versus placebo, and a similar trend was present in participants without CKD. For AKI, the risk was higher in participants with CKD versus participants without CKD, but there were no differences observed across liraglutide- versus placebo-treated participants. In summary, no new safety concerns were identified in the CKD cohort, and liraglutide was associated with less hypoglycemia, an important cause of morbidity and mortality in patients with diabetes. Several major themes have, therefore, emerged from recent GLP1-RA trials. First, these agents exert clinically significant glycemic and weight-lowering effects in patients with and without CKD. Importantly, glycemic lowering is similar compared with insulin therapy with reduced risk of hypoglycemia (6,9). Second, GLP1-RA agents are (in cardiovascular safety trials and in a dedicated study of patients with CKD) associated with clinically relevant reductions in albuminuria and lower risk of eGFR decline (6,9). Third, as shown in the analysis by Mann et al. (8), GLP1-RA therapy with liraglutide was safe and well tolerated by patients with CKD compared with patients without CKD. In patients with CKD, as kidney function declines toward 30 ml/min per 1.73 m2, patients tend to be switched from oral agents to insulin, which promotes volume expansion, weight gain, higher BP, and an increased risk of hypoglycemia. The analysis by Mann et al. (8) is clinically important because it offers additional evidence around both efficacy and safety with liraglutide—a drug in a class that avoids many deleterious effects associated with insulin. Accordingly, as with other newer glucose-lowering therapies that have major cardiovascular- and/or kidney-protective effects, such as SGLT2 inhibitors, nephrologists need to become familiar with GLP-1 RA, which has been shown to reduce cardiovascular risk. Regardless of the mechanism, it is becoming increasingly clear that GLP-1 RA should be used preferentially in appropriate patient groups, including those with atherosclerotic cardiovascular disease and patients with diabetic kidney disease who do not tolerate SGLT2 inhibition (10). In clinical practice, uptitration of GLP-1 RA agents should occur approximately every 4 weeks to reduce gastrointestinal side effects. In addition, in patients taking other agents that can induce hypoglycemia, such as insulin or sulfonylureas with appropriate glycemic control (hemoglobin A1c about <7%), these background therapies may be downtitrated. Ultimately, the completion of dedicated diabetic kidney disease trials with GLP-1 RAs is required to fully understand the role of these agents in kidney protection. Fortunately, the Research Study to See How Semaglutide Works Compared with Placebo in People with Type 2 Diabetes and CKD with Semaglutide (NCT00696657) is recruiting patients across a range of eGFR and albuminuria—including patients with and without SGLT2 inhibition as background therapy. Until the results of these studies are complete, the analysis by Mann et al. (8) offers clinicians reassurance that GLP-1 RA can be used safely in patients with diabetic kidney disease. Disclosures Dr. Cherney has received honoraria from Abbvie, AstraZeneca, Bayer, BMS, Boehringer Ingelheim-Lilly, Janssen, Merck, Mitsubishi-Tanabe, Novo-Nordisk, Prometic, and Sanofi and has received operational funding for clinical trials from AstraZeneca, Boehringer Ingelheim-Lilly, Janssen, Merck, Novo-Nordisk, and Sanofi. Dr. Tuttle has received consulting fees, speaking honorarium, or both from Astra Zeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Janssen, Lilly, and Novo Nordisk.

The purpose of this review is to inform healthcare professionals that the combination of several risk factors (RF) has a serious effect on the progression of atherosclerosis, the development of cardiovascular (CV) diseases and death in people with type 2 diabetes (T2DM). Each of the factors, as a rule, enhances the effect of the other, and if the patient has several of them, then combining them with diabetes is deadly for him. Only an integrated approach to the treatment and effects on RF can improve the prognosis for patients with type 2 diabetes. It is shown that in the treatment of modern classes of hypoglycemic drugs, complex metabolic control is important. Prevention of CV disease is, therefore, a goal of treatment of T2DM as important as glycemic control. The use of drugs with proven cardiovascular benefits is recommended as part of of glucose-lowering therapy. The data of international studies of preparations of a sodium–glucose co-transporter 2 (SGLT2) inhibitor and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) various links in the pathogenesis of complications of diabetes mellitus (DM) reduce the risk of CV events. Based on the original trial results healthcare professionals should the use of antidiabetic drugs that have been proven to reduce cardiovascular events and mortality.

ObjectiveTo determine whether the combined use of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors is associated with a decreased risk of major adverse cardiovascular events and serious...

Aims/hypothesisOur aim was to assess treatment discontinuation, reinitiation and switching between drugs within the same drug class for glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors in individuals with type 2 diabetes.MethodsWe used data from nationwide registers in Sweden to perform separate analyses for all patients with type 2 diabetes who filled a first prescription of a GLP-1 receptor agonist or an SGLT2 inhibitor between 2017 and 2021. Patients were considered to be on treatment for the period during which prescriptions were refilled before the estimated end date of the most recent prescription, including a 90-day grace period, i.e. the time allowed between and after prescriptions before treatment is considered as discontinued. We used the Aalen–Johansen estimator to estimate cumulative incidences of discontinuation and reinitiation, and Fine–Gray sub-distribution hazard models to assess the association of clinical variables with the risk of discontinuation.ResultsAmong 73,895 new users of GLP-1 receptor agonists, the cumulative incidence of treatment discontinuation was 23.6% at 1 year and 38.5% at 3 years. Among patients who discontinued, the cumulative incidence of treatment reinitiation was 41.1% at 1 year and 57.4% at 3 years after discontinuation. Among 113,207 new users of SGLT2 inhibitors, the cumulative incidence of treatment discontinuation was 27.9% at 1 year and 45.9% at 3 years, with a cumulative incidence of reinitiation of 40.4% at 1 year and 55.7% at 3 years after discontinuation. When varying the grace period between 60 days and 365 days, treatment discontinuation rates at 3 years ranged from 23.3% to 43.6% among GLP-1 receptor agonist users and from 28.8% to 50.6% among SGLT2 inhibitor users. The proportion of patients who had ongoing treatment, regardless of previous discontinuation episodes, ranged between approximately 70% and 80% for both drugs during a 1–5 year period after treatment initiation across analyses using various grace periods. In terms of switching, 22.9% of the GLP-1 receptor agonist users and 2.1% of the SGLT2 inhibitor users switched between drugs within the same drug class. Patient characteristics associated with treatment discontinuation were similar for GLP-1 receptor agonists and SGLT2 inhibitors, although the association between higher BMI and a lower likelihood of treatment discontinuation was stronger for GLP-1 receptor agonists.Conclusions/interpretationApproximately half of type 2 diabetes patients who had started using GLP-1 receptor agonists or SGLT2 inhibitors had discontinued treatment within 5 years of follow-up. However, more than half of those who discontinued treatment subsequently reinitiated treatment, such that the proportion with ongoing treatment was approximately 70–80% for both drugs during a 1–5 year period after treatment initiation. This suggests that the proportion of patients with long-term use of the medications is larger than indicated by analyses focusing on treatment discontinuation. Patient characteristics associated with treatment discontinuation were similar for GLP-1 receptor agonists and SGLT2 inhibitors.Graphical

&lt;p dir="ltr"&gt;&lt;b&gt;KEY POINTS&lt;/b&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;· The influence of social determinants of health (SDOH) on sodium–glucose cotransporter 2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist prescribing for people with type 2 diabetes and chronic kidney disease (CKD) is not well known.&lt;/p&gt;&lt;p dir="ltr"&gt;· This study found that younger age and higher A1C were associated with increased likelihood of initiation of SGLT2 inhibitors and GLP-1 receptor agonists. SDOH factors were not associated with initiation of these drugs. A CKD population health management intervention did not affect these associations.&lt;/p&gt;&lt;p dir="ltr"&gt;· These findings suggest targets for new interventions to increase incident use of SGLT2 inhibitors and GLP-1 receptor agonists among individuals with type 2 diabetes and CKD.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Objective.&lt;/b&gt;&lt;b&gt; &lt;/b&gt;Negative social determinants of health (SDOH) are associated with greater kidney disease incidence and progression, partly because of suboptimal management. We studied the association of demographic, clinical, and individual- and contextual-level SDOH factors with sodium–glucose cotransporter 2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist initiation in patients with type 2 diabetes and whether these associations were modified by the Kidney Coordinated HeAlth Management Partnership (K-CHAMP) population health management (PHM) program.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Research Design and Methods.&lt;/b&gt; Using data from the K-CHAMP trial, which cluster-randomized 101 primary care offices to a control arm or the PHM intervention (including nephology electronic consultation, chronic kidney disease education, and pharmacist medication review), we explored associations between SGLT2 inhibitor and GLP-1 receptor agonist initiation with a priori patient factors using adjusted Poisson regression. Enrolled patients with type 2 diabetes who were not prescribed an SGLT2 inhibitor or a GLP-1 receptor agonist at baseline were included. Effect modification by K-CHAMP was assessed using interaction terms.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Results. &lt;/b&gt;The cohort had 891 patients (402 receiving the PHM intervention and 489 in the control group). Fifty-five percent of participants were female and 89% were White; the cohort had had a mean age of 73 ± 9 years, mean BMI of 33 ± 7 kg/m&lt;sup&gt;2&lt;/sup&gt;, mean A1C of 7.3 ± 1.5%, and mean estimated glomerular filtration rate of 37.4 ± 8.3 mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt;; and 24% were rural living. Over a median follow-up of 17.7 months (interquartile range [IQR] 12.4–23.8 months), 238 (26.7%) initiated an SGLT2 inhibitor or GLP-1 receptor agonist. In adjusted analysis, age (incidence rate ratio [IRR] 0.92, 95% CI 0.85–0.99) and A1C (IRR 1.15, 95% CI 1.07–1.24) were significantly associated with SGLT2 inhibitor or GLP-1 receptor agonist initiation. The K-CHAMP PHM intervention did not significantly modify association of any factors.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Conclusion. &lt;/b&gt;Younger age and higher A1C were associated with increased likelihood of initiating&lt;b&gt; &lt;/b&gt;an SGLT2 inhibitor or GLP-1 receptor agonist. Other demographic, clinical, and SDOH factors were not significantly associated with medication initiation. The K-CHAMP PHM intervention did not moderate the association of patient-level or SDOH factors with initiation of an SGLT2 inhibitor or GLP-1 receptor agonist.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;

&lt;p dir="ltr"&gt;&lt;b&gt;KEY POINTS&lt;/b&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;· The influence of social determinants of health (SDOH) on sodium–glucose cotransporter 2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist prescribing for people with type 2 diabetes and chronic kidney disease (CKD) is not well known.&lt;/p&gt;&lt;p dir="ltr"&gt;· This study found that younger age and higher A1C were associated with increased likelihood of initiation of SGLT2 inhibitors and GLP-1 receptor agonists. SDOH factors were not associated with initiation of these drugs. A CKD population health management intervention did not affect these associations.&lt;/p&gt;&lt;p dir="ltr"&gt;· These findings suggest targets for new interventions to increase incident use of SGLT2 inhibitors and GLP-1 receptor agonists among individuals with type 2 diabetes and CKD.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Objective.&lt;/b&gt;&lt;b&gt; &lt;/b&gt;Negative social determinants of health (SDOH) are associated with greater kidney disease incidence and progression, partly because of suboptimal management. We studied the association of demographic, clinical, and individual- and contextual-level SDOH factors with sodium–glucose cotransporter 2 (SGLT2) inhibitor and glucagon-like peptide 1 (GLP-1) receptor agonist initiation in patients with type 2 diabetes and whether these associations were modified by the Kidney Coordinated HeAlth Management Partnership (K-CHAMP) population health management (PHM) program.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Research Design and Methods.&lt;/b&gt; Using data from the K-CHAMP trial, which cluster-randomized 101 primary care offices to a control arm or the PHM intervention (including nephology electronic consultation, chronic kidney disease education, and pharmacist medication review), we explored associations between SGLT2 inhibitor and GLP-1 receptor agonist initiation with a priori patient factors using adjusted Poisson regression. Enrolled patients with type 2 diabetes who were not prescribed an SGLT2 inhibitor or a GLP-1 receptor agonist at baseline were included. Effect modification by K-CHAMP was assessed using interaction terms.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Results. &lt;/b&gt;The cohort had 891 patients (402 receiving the PHM intervention and 489 in the control group). Fifty-five percent of participants were female and 89% were White; the cohort had had a mean age of 73 ± 9 years, mean BMI of 33 ± 7 kg/m&lt;sup&gt;2&lt;/sup&gt;, mean A1C of 7.3 ± 1.5%, and mean estimated glomerular filtration rate of 37.4 ± 8.3 mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt;; and 24% were rural living. Over a median follow-up of 17.7 months (interquartile range [IQR] 12.4–23.8 months), 238 (26.7%) initiated an SGLT2 inhibitor or GLP-1 receptor agonist. In adjusted analysis, age (incidence rate ratio [IRR] 0.92, 95% CI 0.85–0.99) and A1C (IRR 1.15, 95% CI 1.07–1.24) were significantly associated with SGLT2 inhibitor or GLP-1 receptor agonist initiation. The K-CHAMP PHM intervention did not significantly modify association of any factors.&lt;/p&gt;&lt;p dir="ltr"&gt;&lt;b&gt;Conclusion. &lt;/b&gt;Younger age and higher A1C were associated with increased likelihood of initiating&lt;b&gt; &lt;/b&gt;an SGLT2 inhibitor or GLP-1 receptor agonist. Other demographic, clinical, and SDOH factors were not significantly associated with medication initiation. The K-CHAMP PHM intervention did not moderate the association of patient-level or SDOH factors with initiation of an SGLT2 inhibitor or GLP-1 receptor agonist.&lt;/p&gt;&lt;p&gt;&lt;br&gt;&lt;/p&gt;

Objective: The aim of this study was to evaluate the efficacy and safety of combination therapy with sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in the treatment of type 2 diabetes mellitus (T2DM). Methods: We searched clinical trials indexed in PubMed, Embase, CENTRAL, Web of Science, and Scopus from inception through December 3, 2018. A meta-analysis was conducted of trials involving patients receiving SGLT2 inhibitors and GLP-1 agonists using Stata 12.0 software. Results: A total of 9 clinical trials, including 5 randomized controlled trials (RCTs), that enrolled 1369 participants were identified for meta-analysis. Compared with the control/placebo group, the combination therapy group had significantly reduced fasting plasma glucose level by 0.78 mmol/L (95% confidence interval [CI]: -1.36, -0.2), 2-h postprandial glucose level by 0.47mmol/L (95% CI: -0.69, -0.24), glycosylated hemoglobin (HbA1c) by 0.73% (95% CI: -1.45, 0); body weight that was lower by 0.39 kg (95% CI: -0.59, -0.18) (4 non-randomized controlled trials indicated a larger reduction in body weight of 3.53 kg), and systolic blood pressure (SBP) that was lower by 0.26 mmHg (95% CI: -0.40, -0.11). The total incidence of adverse events (AEs) and genital and urinary infections in the therapy group did not significantly differ from those in the control group, with relative risks (RRs) of 1.06 (95% CI: 0.96, 1.17) and 1.19 (95% CI: 0.69, 2.07), respectively. An increased incidence of hypoglycemia was seen in the combination therapy group (RR=2.49; 95% CI: 1.40, 4.45). Conclusions: SGLT2 inhibitor and GLP-1 agonist combination treatment improved glycemic control, reduced body weight, and decreased SBP without an increase in total AEs or genital and urinary infections in patients with T2DM. However, the risk of hypoglycemia should be carefully monitored in future clinical trials. Disclosure M. Guo: None. J. Gu: None. J. Li: None. Y. Xu: None. Funding National Natural Science Foundation of China (81800741)

Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used for the treatment of type 2 diabetes, yet their downstream consequences in routine clinical practice remain incompletely characterized. We compared downstream treatment burden following initiation of GLP-1 receptor agonists versus SGLT2 inhibitors among adults with type 2 diabetes. We conducted a retrospective, propensity score-matched cohort study using a multi-centre electronic health record network. Adults with type 2 diabetes who newly initiated a GLP-1 receptor agonist or an SGLT2 inhibitor between 1 January 2017 and 1 June 2025 were included. After 1:1 matching, approximately 164 000 patients were retained in each treatment group. Outcome-specific baseline-free cohorts with uniform washout periods were constructed, yielding sample sizes of approximately 124 000-164 000 per outcome. Primary outcomes were initiation of seven downstream medication classes. Secondary outcomes included gastrointestinal and nutritional diagnoses and health-care utilization. Across all seven medication classes, downstream pharmacotherapy initiation occurred more frequently among GLP-1 initiators. The largest differences were observed for symptom-driven medications, including antidepressant, an absolute risk difference of 3.38% (95% CI -3.61 to -3.15) and a hazard ratio (HR) of 0.78 (95% CI 0.76-0.80), antiemetic, sedatives/hypnotics. Proton pump inhibitors, laxatives, histamine-2 receptor antagonists and antidiarrheal were also more frequently initiated, though differences were modest. Differences in secondary diagnoses were smaller. Gastroesophageal reflux disease and esophagitis were more common after GLP-1 initiation, whereas peptic ulcer disease and endoscopic procedures occurred more frequently among SGLT2 initiators. Nutrient deficiency and unspecified anaemia were more frequent following GLP-1 therapy. Overall health-care utilization was similar, except for inpatient acute care, which was more frequent among SGLT2 initiators. Initiation of GLP-1 receptor agonists is associated with a downstream pharmacologic cascade characterized by increased use of symptom-driven medication without corresponding increases in health-care utilization. Medication initiation may provide a more sensitive measure of treatment burden than diagnostic codes or utilization metrics in routine diabetes care. To our knowledge, this study represents the largest multicentre real-world evaluation of downstream pharmacologic cascades following initiation of GLP-1 receptor agonists and SGLT2 inhibitors.

Background: To test the hypothesis that patients treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide 1 receptor agonists (GLP1RA) was associated with lower risk of cardiovascular endpoints vs dipeptidyl peptidase 4 inhibitors (DPP4). Methods: A retrospective cohort combined Veterans Administration, Medicare, and National Death Index databases. Patients using metformin, sulfonylurea or insulin alone or in combination were followed until a new fill of one of the following classes: SGLT2; GLP1RA; or DPP4. The index date and start of follow-up was the new prescription fill date. The composite outcome was major adverse cardiovascular event (MACE) or heart failure (HF) hospitalization: acute myocardial infarction (AMI), stroke, acute HF or cardiovascular (CV) death. Cox Proportional Hazards models compared MACE and HF for the comparison groups of interest, separately, in propensity score (PS) weighted cohorts adjusted for clinical covariates, laboratory data, ejection fraction (EF), smoking, and selected medications. Results: After PS weighting the cohorts included 46018 GLP1RA vs 45814 DPP4 and 36646 SGLT2 vs 36261 DPP4 participants. Median age was 69 years and diabetes duration of 9.0 (5.2, 13.4) years for GLP1RA vs DPP4 and 9.3 (5.7, 13.8) years for SGLT2 vs DPP4 users. Most new agents were added as third drug to either metformin + sulfonylurea or metformin + insulin regimen. GLP1RA was associated with lower hazard of MACE/HF vs DPP4 (0.73 [0.68, 0.78]) (panel A) yielding an adjusted risk difference (aRD) of 10.5 events [8.5, 12.4]); results were consistent for all outcome components. SGLT2 was associated with a lower hazard of MACE and HF (0.76 [0.69, 0.85]) (panel B) (aRD 8.1 [5.2, 10.7]); primarily due to reduction in CV death (0.71 [0.56, 0.90]) and HF hospitalization with reduced EF (0.40 [0.26, 0.62]). Conclusions: Use of GLP1RA or SGLT2 for diabetes treatment was associated with reduced risk of MACE and HF hospitalization vs DPP4.

There is substantial interest in how GLP-1RA (glucagon-like peptide-1 receptor agonists) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated. We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.

To review whether sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists decrease the risk of depression, suicidal ideation and cognitive impairment in later life. The results of studies using information derived from large registries and administrative health datasets suggest that GLP-1 receptor agonists (RAs) increase the risk of suicidality, although findings have been inconsistent. One nested-case control study reported that SGLT2i decreases the risk of depression among adults with diabetes, and findings from a small trial of the SGLT2i empagliflozin provided supportive evidence. Several observational studies reported that SGLT2i and GLP-1 RAs decrease dementia risk, with a target trial finding greater cognitive benefit associated with the use of GLP-1 RAs compared with other medicines commonly used to manage diabetes. Recent results from large observational studies suggest that SGLT2i and GLP-1 RA may decrease the risk of cognitive impairment in later life. The effects of these medicines on mood have not been as well explored, but there are concerns about the potential increased risk of suicidality among GLP-1 RA users. Prescription bias could explain some of these associations, so that robust trial evidence is now needed to confirm or dismiss the reported findings.

Background:Recent evidence has raised concerns about potential pro-oncogenic effects associated with glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter 2 (SGLT2) inhibitors, particularly regarding gastrointestinal malignancies. Colorectal tumors, the third most diagnosed cancer globally, already show increased incidence in patients with metabolic disorders who typically require these medications. For example, obese subjects had a significantly higher risk of colorectal tumors than healthy subjects. However, existing evidence on this association remains inconsistent. This network meta-analysis (NMA) evaluated the comparative incidence of colorectal tumors associated with specific GLP-1 receptor agonists and SGLT2 inhibitors.Materials and Methods:We conducted a confirmatory NMA focused specifically on colorectal tumor incidence as an adverse effect, following Cochrane methodological recommendations. We performed a frequentist-based NMA of randomized controlled trials (RCTs) evaluating GLP-1 receptor agonists or SGLT2 inhibitors. Our primary outcome was colorectal tumor incidence, with safety profiles assessed by dropout rates as a secondary outcome.Results:This NMA encompassing 68 RCTs with 207 200 participants found that only semaglutide was associated with increased incidence of colorectal tumors compared to controls. A dose-stratified analysis revealed that high-dose injectable semaglutide (2.4 mg/week) was the only regimen associated with increased incidence. Furthermore, when focusing on RCTs of obese subjects, the increased colorectal tumor rate related to semaglutide still existed. Neither other GLP-1 receptor agonists nor any SGLT2 inhibitors demonstrated significant associations with colorectal tumor development.Conclusion:Our study provides the first comprehensive NMA addressing the incidence of colorectal tumors related to individual GLP-1 receptor agonists and SGLT2 inhibitors, suggesting a dose–dependent relationship to semaglutide, particularly in its high-dose injectable form (2.4 mg/week). These findings represent a potential risk signal that requires further validation, given the already elevated baseline colorectal tumor risk in the target population, especially in subjects with obesity. Future research should focus on long-term follow-up studies to better characterize the mechanisms and clinical implications of this semaglutide-specific risk signal.What this adds to the existing literature:This network meta-analysis, based on 68 randomized controlled trials, suggested that only semaglutide, especially in highdose injectable form (2.4 mg/week), was associated with increased incidence of colorectal tumors compared to controls, especially in obese patients. Neither other GLP-1 receptor agonists nor any SGLT2 inhibitors demonstrated significant associations with colorectal tumor development.Learning points:Our study provides evidence regarding the increased incidence of colorectal tumors related to semaglutide in a dose dependent way (2.4 mg/week).

Time to Follow the Evidence: Glycemic Control and Cardiovascular Benefits of New Diabetes Medications