SGLT-2 Inhibitors and GLP-1 Receptor Agonists as Combination Therapy in Type 2 Diabetes

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

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Paradigm shift in the management of DM & CVD-preventing the next CV event.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of incretin-based therapies for the management of hyperglycemia and, in some cases, cardiovascular risk in people with type 2 diabetes. These agents act on multiple physiological pathways involved in type 2 diabetes with the effect of increasing insulin secretion and decreasing glucagon to control glucose levels (1,2). They also transiently slow gastric emptying, reduce appetite, and facilitate weight loss and other metabolic improvements (3). Consensus recommendations from the American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) and American Association of Clinical Endocrinologists/American College of Endocrinology advocate that GLP-1 receptor agonists, among other therapies, should be considered as a second-line treatment option in people with type 2 diabetes when glucose levels are not well controlled on metformin (4–6). Additionally, in patients with type 2 diabetes and atherosclerotic cardiovascular disease or chronic kidney disease, a GLP-1 receptor agonist or sodium–glucose cotransporter 2 (SGLT2) inhibitor with proven cardiovascular benefit is recommended as a first-line therapy for the reduction of cardiovascular risk (4–6). GLP-1 receptor agonists may also be used as a first-line treatment in those who cannot use metformin or when reduced renal function precludes metformin use (human-based GLP-1 receptor agonists only) (4–6). In particular, the recommendations favor GLP-1 receptor agonists and SGLT2 inhibitors because they have a low risk of hypoglycemia and promote weight loss (5). Several GLP-1 receptor agonists are available in the United States and worldwide, some of which are analogs of human GLP-1 (dulaglutide, liraglutide, and semaglutide), whereas others are exendin-based (exenatide and lixisenatide) (7–13). The GLP-1 receptor agonist albiglutide was also approved, but has been withdrawn for commercial reasons. Until recently, all GLP-1 receptor agonists were administered by subcutaneous injection, although a once-daily oral formulation …

Why Choose Between SGLT2 Inhibitors and GLP1-RA When You Can Use Both?: The Time to Act Is Now.

Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined. We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease. In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001). In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.

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...

Chapter 14 - Glucagon-like peptide-1 receptor agonists: role in the prevention and treatment of diabetes-related cardiovascular complications

BackgroundGuidelines recommend combination therapy with glucagonlike peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) for cardiorenal risk reduction in people with type 2 diabetes (T2D); however, there is limited real-world evidence on the long-term effects of combination therapy on cardiometabolic and renal outcomes. The objective of this study was to assess cardiovascular (CV), metabolic, and renal effects of combination therapy with newer generation GLP-1RA (including once-weekly GLP-1RAs, once-daily oral semaglutide, and dual GLP-1/glucose-dependent insulinotropic polypeptide [GIP] agonists) and SGLT2i compared with SGLT2i alone.MethodsThis retrospective cohort study included data on US adults with T2D receiving SGLT2i from Komodo’s Healthcare Map from January 1, 2017, to June 30, 2023. The study included 100,455 people in the combination GLP-1RA and SGLT2i group and 339,540 people in the comparison SGLT2i group across 3 cohorts: T2D with atherosclerotic cardiovascular disease (ASCVD), T2D, and T2D with chronic kidney disease (CKD). Entropy balancing was used to balance patient characteristics. Time to first event of ischemic stroke, myocardial infarction (MI), 3-point major adverse cardiovascular event (MACE), and 5-point MACE in T2D with ASCVD cohort were measured. In the T2D cohort, follow-up and change in glycated hemoglobin (HbA1c) and weight, odds of achieving HbA1c < 7% and HbA1c < 8%, and odds of achieving 5%, 10%, and 15% decrease in weight were also measured.ResultsThe combination and comparison groups included 34,690 and 130,220 people, respectively, in the T2D with ASCVD cohort; 8,220 and 22,891 people, respectively, in the T2D cohort; and 8,783 and 35,532 people, respectively, in the T2D with CKD cohort. Compared with SGLT2i alone, combination therapy was significantly associated with 42% lower risk of ischemic stroke, 37% lower risk of MI, 46% lower risk of 3-point MACE, and 45% lower risk of 5-point MACE among people with T2D and ASCVD. Among the individual GLP-1RAs assessed, the largest reductions in CV risk, HbA1c, and weight outcomes were observed with combination therapy with SGLT2i and once weekly semaglutide for T2D.ConclusionsCombination of SGLT2i and GLP-1RA achieved significantly better cardiometabolic outcomes compared with SGLT2i alone; this supports the hypothesis that the cardioprotective benefits of GLP-1RA and SGLT2i may be additive.Graphical abstract

Compared with glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors were associated with a lower risk of kidney failure among individuals with type 2 diabetes. Use of combination SGLT2 inhibitor and glucagon-like peptide-1 receptor agonist was infrequent but associated with lower kidney failure risk in high-risk individuals. Providers should prioritize SGLT2 inhibitors in patients with type 2 diabetes to prevent progression to kidney failure. The relative effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for kidney protection, both individually and in combination, is incompletely understood. We sought to compare associations of GLP-1 receptor agonists, SGLT2 inhibitors, and both medications in combination with incident kidney failure among individuals with type 2 diabetes. We conducted a target trial emulation study with new user, active comparator design using deidentified electronic health records data from Optum Labs Data Warehouse. We included adults with type 2 diabetes who were prescribed a GLP-1 receptor agonist, SGLT2 inhibitor, or both between January 1, 2015, and June 29, 2024. We estimated the association of medication class with incident kidney failure using inverse probability of treatment weighted Cox proportional hazards regression models in both intention-to-treat and as-treated methodologies. There were 504,151 individuals with 2965 kidney failure events during a median 2.35 (interquartile range 1.09-4.32) years of follow-up. Average prescription duration was 0.69 years for GLP-1 receptor agonists, 0.62 years for SGLT2 inhibitors, and 0.44 years for combination therapy. In the intention-to-treat analysis, compared with GLP-1 receptor agonists, the risk of kidney failure was significantly lower with SGLT2 inhibitors (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.73 to 0.91) but no different with combination therapy (HR, 0.72; 95% CI, 0.45 to 1.15). The results were similar in the as-treated model. Among individuals with CKD or heart failure, the risk of kidney failure was significantly lower with combination therapy compared with GLP-1 receptor agonists (HR, 0.54; 95% CI, 0.30 to 0.97). SGLT2 inhibitors were associated with a lower risk of kidney failure compared to GLP-1 receptor agonists. Among high-risk patients with type 2 diabetes and CKD or heart failure, combination therapy may further reduce the risk of kidney failure.

Several cardiovascular outcome trials on sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking. We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed. A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control. SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles. CRD42020206600.

Introduction: Type 2 diabetes affects approximately 462 million people worldwide. The condition is associated with complex pathophysiology that leads to impaired glucose regulation and the development of both macrovascular and microvascular complications. The economic burden is significant, with high treatment costs and lost productivity due to complications and premature mortality. Current guidelines recommend using glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors in combination for patients at high risk for cardiovascular disease or chronic kidney disease. These treatments have been shown in multiple meta-analyses to reduce the risk of major cardiovascular events, mortality, myocardial infarction, renal failure, and severe hyperglycaemia. Purpose: This review examines the impact of combining GLP-1 receptor agonists and SGLT-2 inhibitors in patients with type 2 diabetes, with a particular focus on cardiovascular risk. Materials and methods: The review analyzed PubMed articles published in the past 10 years, including clinical studies that assessed the effects of combination therapy with GLP-1 receptor agonists and SGLT-2 inhibitors in patients with type 2 diabetes. Summary: Research indicates that the combination of GLP-1 receptor agonists and SGLT-2 inhibitors leads to improved glycaemic control, better lipid management, lower blood pressure, and reduced body weight. It also improves vascular and myocardial health markers, while reducing cardiovascular risk. Although this combination therapy benefits kidney health, certain areas remain unchanged. Considering all of this, combination therapy seems to be a promising treatment, offering greater benefits than other antidiabetic therapies.

Efficacy and safety of the combination or monotherapy with GLP-1 receptor agonists and SGLT-2 inhibitors in Type 2 diabetes mellitus: An update systematic review and meta-analysis

Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular and renal risks in type 2 diabetes mellitus (T2DM), but their relative efficacy remains uncertain due to the absence of direct comparative trials. This systematic review and network meta-analysis aimed to evaluate the efficacy and safety of interventions concerning major adverse cardiovascular events (MACE), heart failure, and renal outcomes. A systematic review and network meta-analysis of large-scale, placebo-controlled cardiovascular outcome trials was conducted. PubMed, Embase, and CENTRAL were searched for trials published up to December 2025. The primary outcome was MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). The secondary outcomes included hospitalization for heart failure (HHF), composite renal outcomes, and all-cause mortality. The evaluated safety outcomes included severe hypoglycemia, diabetic ketoacidosis, amputation, fracture, and genital infections. Data were pooled using a frequentist random-effects model. In total, 14 trials involving 117,633 participants were included. Both drug classes reduced the risk of MACE compared with placebo (SGLT2i: hazard ratio (HR) = 0.89, 95% confidence interval (CI) = 0.84-0.94; GLP-1RA: HR = 0.86, 95% CI = 0.80-0.93), with no statistically significant difference observed between the two (HR = 1.03, 95% CI = 0.94-1.13). SGLT2 inhibitors had a greater efficacy than GLP-1 receptor agonists in reducing HHF (HR = 0.75, 95% CI = 0.66-0.85) and composite renal outcomes (HR = 0.76, 95% CI = 0.66-0.87). Similarly, both classes lowered all-cause mortality. SGLT2 inhibitors exhibited an elevated risk of genital infections (relative risk (RR) = 3.49, 95% CI = 2.63-4.55) and diabetic ketoacidosis (RR = 2.36, 95% CI = 1.33-4.17) compared to GLP-1 receptor agonists. SGLT2 inhibitors and GLP-1 receptor agonists are equally effective in preventing MACE. However, SGLT2 inhibitors offer enhanced protection against heart failure and renal disease progression, whereas GLP-1 receptor agonists exhibit a more favorable safety profile for genital infections and ketoacidosis. These findings support a phenotype-specific treatment approach for patients with T2DM.

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.