Making a case for the combined use of SGLT2 inhibitors and GLP1 receptor agonists for cardiorenal protection

ABSTRACT

Sodium glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) were initially approved to improve glycemic control in the treatment of type 2 diabetes. Clinical trials have also demonstrated beneficial effects with regards to cardiovascular and renal parameters. Beyond improving glycemic control, these therapies promote weight loss and lower blood pressure when used individually, and in an additive manner when used together. Accordingly, taking advantage of complementary mechanisms of action with the combined use of these two classes of agents to further improve cardiorenal outcomes is conceptually appealing, but has yet to be explored in detail in clinical trials. In this review, we discuss proposed mechanisms for renal protection, clinical benefits, and adverse events associated with the individual and combined use of SGLT2 inhibitors and GLP-1RA. The management of type 2 diabetes has significantly changed over the last few years, moving away from solely glycemic control towards the concurrent management of associated comorbidities in a patient population at significant risk of cardiovascular disease and progression of chronic kidney disease. It is from this perspective that we seek to outline the rationale for the sequential and/or combined use of SGLT2 inhibitors and GLP-1RA in patients with type 2 diabetes.

Keywords:
Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Diabetic Nephropathies; Cardiovascular Diseases; Heart Failure

RESUMO

Inibidores do cotransporter-2 de glicose sódica (SGLT2) e agonistas do receptor peptídeo-1 do tipo glucagon (GLP-1RA) foram inicialmente aprovados para melhorar o controle glicêmico no tratamento da diabetes tipo 2. Os ensaios clínicos também demonstraram efeitos benéficos em relação aos parâmetros cardiovasculares e renais. Além de melhorar o controle glicêmico, essas terapias promovem perda de peso e redução da pressão arterial quando usadas individualmente, e de forma aditiva quando usadas em conjunto. Consequentemente, tirar proveito de mecanismos de ação complementares com o uso combinado dessas duas classes de agentes para melhorar ainda mais os resultados cardiorrenais é conceitualmente atraente, mas ainda precisa ser explorado em detalhes em ensaios clínicos. Nesta revisão, discutimos os mecanismos propostos para proteção renal, benefícios clínicos e eventos adversos associados ao uso individual e combinado de inibidores de SGLT2 e GLP-1RA. O tratamento do diabetes tipo 2 mudou significativamente nos últimos anos, passando do controle exclusivamente glicêmico para o tratamento simultâneo de comorbidades associadas em uma população de pacientes com risco significativo de doença cardiovascular e progressão da doença renal crônica. É nessa perspectiva que procuramos delinear a justificativa para o uso sequencial e/ou combinado de inibidores de SGLT2 e GLP-1RA em pacientes com diabetes tipo 2.

Palavras-chave:
Inibidores do Transportador 2 de Sódio-Glicose; Diabetes Mellitus Tipo 2; Receptor do Peptídeo Semelhante ao Glucagon 1; Nefropatias Diabéticas; Doenças Cardiovasculares; Insuficiência Cardíaca

INTRODUCTION

Based on the results of recent cardiovascular outcome trials (CVOT) using newer glucose lowering therapies, diabetes clinical practice guidelines have had a renewed focus on cardiorenal protection in patients at significant risk for cardiovascular (CV) and kidney disease. In contrast to other anti-hyperglycemic agents, sodium-glucose contransport-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) have individually demonstrated CV and kidney benefits, as described below. Moreover, combined use of these medication classes in patients with T2D is appealing due to possible mechanistic and clinical synergies. In this article, we review the mechanisms and clinical benefits of SGLT2 inhibitors and GLP-1RA and outline the rationale for their sequential or combined use in people with type 2 diabetes (T2D).

PROPOSED MECHANISMS FOR RENAL PROTECTION

SGLT2 INHIBITORS

It is important to have a general overview of the main hypotheses that have been put forward to explain cardiorenal protection with SGLT2 inhibitors. Detailed reviews of mechanisms linked with cardiorenal protection have been published elsewhere.^1-3 Indirect mechanisms - those not directly attributable to intrinsic renal pathways - that may be protective include: 1) Improved glycemic control with improved insulin sensitivity; 2) Body weight loss; and 3) Blood pressure (BP) lowering possibly via decreases in arterial stiffness and modulation of neurohormonal pathways^4-7. There are also several proposed direct renal effects including^2,3,8: 1) Reduced intraglomerular pressure by activating tubuloglomerular feedback (TGF) on the basis of acute proximal tubular natriuresis^9-12 leading to afferent arteriolar vasoconstriction, particularly in the setting of renal hyperfiltration^13-19; 2) Suppression of pro-inflammatory and pro-fibrotic factors in the kidney, possibly via reducing hyperglycemia and by suppressing the renin-angiotensin-aldosterone system (RAAS)^20-24 and also by reducing intraglomerular pressure; and 3) Reducing renal ischemia via multiple pathways, thereby reducing kidney injury^25,26. While it is not known which of these hypotheses is most closely related to kidney protection, the largest body of experimental and human trial evidence exists for changes in glomerular hypertension, which could also explain the rapid anti-proteinuric effect achieved with these agents and the rapid, clinically relevant, reversible “dip” in eGFR seen with these agents^27,28.

GLP-1 RECEPTOR AGONISTS

GLP-1RA may similarly have “indirect” and “direct” effects contributing to their kidney protection. For indirect mechanisms, GLP-1RA therapies have a variety of effects on metabolism that may be cardiorenal protective, including reduced postprandial glucose levels by stimulating insulin secretion, reducing glucagon release and hepatic gluconeogenesis, and slowing gastric emptying²⁹. GLP-1RA additionally act at the central nervous system level, increasing satiety leading to weight loss^30-32. GLP-1RA may also lower blood pressure through effects on the endothelium, and increase heart rate (HR) through stimulation of the sinoatrial node and the sympathetic nervous system (SNS)^33,34. These agents also appear to have anti-atherosclerotic effects through several mechanisms including anti-inflammatory effects at the level of the vessel wall and reduced endothelial dysfunction^29,35, which could also protect the kidney. Proposed direct renal beneficial effects include: 1) natriuresis contributing to BP reduction; 2) albuminuria reduction, possibly mediated by suppression of inflammatory-related pathways; and 3) reduction in renal inflammation and oxidative stress related mechanisms^36-38. Pathways leading to GLP-1RA induced natriuresis are unclear, with inhibition of the sodium hydrogen exchanger-3 (NHE3) antiporter in the proximal tubule being one possibility^39-41. Despite this proximal natriuresis, unlike with SGLT2 inhibition, blockade of sodium reabsorption at this level of the nephron with GLP-1RA does not lead to a characteristic and reversible dip in eGFR with these therapies. Even though glomerular hemodynamics remain unaffected with GLP-1RA, these therapies are linked with a rapid reduction in albuminuria, possibly on the basis of direct anti-inflammatory GLP-1 pathways that may not be dependent on natriuresis^39,42.

IMPACT OF SGLT2 INHIBITORS AND GLP-1RA ON GLYCEMIC CONTROL, BLOOD PRESSURE, AND WEIGHT

GLP-1RAs and SGLT2 inhibitors have beneficial clinical effects on glycemic control, blood pressure, and weight loss, when used alone or together. In terms of glycemic effects, GLP-1RAs reduce mean HbA1c by 0.55-1.2% versus placebo in patients with T2D, with exaggerated effects seen with longer-acting agents⁴³. The glucose-lowering effects of SGLT2 inhibitors are achieved via glucosuria, and are comparatively modest, reducing HbA1c by 0.5-0.7% in patients with normal kidney function, and lesser effects are seen in patients with CKD stage 3 or 4^2,44. Both agents also have systemic hemodynamic effects. GLP-1RA lower systolic and diastolic BP to varying degrees, with estimates of 1.2- 4.6 mmHg systolic / 0 - 1.1 mmHg diastolic^45,46. One study using 24-hour ambulatory blood pressure monitoring over 5 weeks reported a more robust systolic BP lowering effect of 5 mmHg with liraglutide, with a neutral effect on diastolic BP⁴⁷. The effects on BP are independent of glucose control and weight loss³³. BP lowering with GLP-1RA is associated with increases in HR by 2-3 beats/minute in large clinical trials and up to 6-10 beats/minute in 24-hour monitoring studies^34,45. SGLT2 inhibitors have a mean BP lowering effect of 3.8 mmHg systolic/1.4 mmHg diastolic compared to placebo, an effect which appears to be largely independent of the baseline BP and HbA1c lowering, and preserved in patients with CKD^2,4,7. SGLT2 inhibitors do not affect heart rate^6,48. Finally, both agents promote weight loss. GLP-1RA induce weight loss ranging from 0.2-7.2 kg, with approximately 50% of patients achieving a weight loss of ≥5% on therapy⁴⁹. SGLT2 inhibitors lead to a modest weight loss of 2-3 kg, including both fluid and adipose tissue loss. The magnitude of SGLT2 inhibitor-induced weight loss is largely preserved in patients with CKD^4,44.

Based on their distinct mechanisms of action and clinical effects, GLP-1RAs and SGLT2 inhibitors may have complementary renal and systemic effects, leading to interest in the potential for their combined use. There is, however, limited data on the combined use of GLP-1RAs plus SGLT2 inhibition on improving glycemic control, blood pressure, and weight. In the 28-week, phase three randomized control trial (RCT) DURATION-8, dual therapy with an SGLT2 inhibitor (dapagliflozin) and a GLP-1RA (once-weekly exenatide) was shown to reduce HbA1c by 0.4% more than either agent alone, in patients with a starting HbA1c of between 8-12%⁵⁰, illustrating that the glycemic response to dual therapy is less than additive⁵⁰. At the conclusion of DURATION-8, systolic BP was reduced by 1.3 mmHg for patients on single-agent exenatide, 1.8 mmHg for those on single-agent dapagliflozin, and 4.2 mmHg with combined therapy, supporting an additive BP lowering effect of combined therapy⁵⁰. DURATION-8 demonstrated an additive effect of dual therapy in inducing weight loss, with an additional 1.87 kg and 1.20 kg of weight loss versus single-agent exenatide and dapagliflozin, respectively⁵⁰.

Further data comes from AWARD-10, a 24-week, phase three RCT of placebo versus add-on therapy with the GLP-1RA dulaglutide in patients on baseline SGLT2 inhibition⁵¹, and SUSTAIN-9, a 30-week trial looking at add-on therapy with the GLP-1RA semaglutide to baseline SGLT2 inhibition⁵². Both trials included patients with baseline HbA1c lower limit of 7% (mean HbA1c of 8%)^51,52. Add-on therapy with dulaglutide 1.5 mg weekly (but not 0.75 mg) to baseline SGLT2 inhibition in AWARD-10 resulted in 0.9 kg additional weight loss compared to placebo, while add-on therapy with semaglutide 1 mg weekly in SUSTAIN-9 resulted in an additional 3.1 kg weight loss versus placebo^51,52. A separate trial examined dual therapy with dapagliflozin and exenatide in 50 patients with obesity but without T2D in a single-center RCT⁵³. At 24 weeks, patients in the active arm achieved 4.1-kg more weight loss than placebo, with 36% (versus 4.2% in placebo) achieving ≥5% body weight loss⁵³.

Despite what is known about HbA1c, weight, and blood pressure effects of combination therapy, less is known about other mechanisms associated with cardiorenal protection in response to combination therapy such as natriuresis and renal hemodynamics. In the following sections, we describe individual cardiorenal benefits of these agents before outlining a proposal for their combined used.

CARDIORENAL BENEFITS OF SGLT2 INHIBITORS AND GLP-1 RECEPTOR AGONISTS FROM RENAL AND CARDIOVASCULAR OUTCOME TRIALS

Among large-scale clinical trials involving SGLT2 inhibitors and GLP-1RA, there exists only one dedicated renal outcome trial that has been published to date. The CREDENCE trial involved patients with T2D, macroalbuminuria, and eGFR 30-90 mL/min/1.73m².⁵⁴ In this trial involving the SGLT2 inhibitor canagliflozin versus placebo, the risk of the primary outcome - doubling of serum creatinine, end-stage kidney disease, renal death, or CV death - was reduced by 30% with canagliflozin. More recently, the DAPA-CKD study (NCT03036150), studying renal outcomes with dapagliflozin in proteinuric CKD patients (≥25 and ≤75 mL/min/1.73m²) with or without diabetes was stopped early due to overwhelming efficacy with dapagliflozin. The EMPA-KIDNEY trial (NCT03594110) is similarly studying the effect of empagliflozin in patients with diabetic chronic kidney disease (DKD) or non-diabetic chronic kidney disease (CKD), and has a lower limit of inclusion, GFR at ≥20 mL/min/1.73m². Until the results of these studies are available, CVOTs and CREDENCE account for the current dataset related to renal protection across a large cohort of patients with a range of baseline kidney and CV disease related to T2D.

SGLT2 INHIBITORS

Prior to CREDENCE, three CVOTs evaluated SGLT2 inhibitors in participant cohorts with varying degrees of CV and renal risk. EMPA-REG OUTCOME included 7020 patients with established atherosclerotic CV disease (ASCVD)⁴⁸, while the CANVAS Program trial included 10,142 with two-thirds having ASCVD⁵⁵. The most recent DECLARE TIMI-58 had 17,160 patients with approximately 40% having ASCVD⁵⁶. In addition, the trial cohorts also had differences in baseline renal health, with the highest mean baseline eGFR in DECLARE TIMI-58.

EMPA-REG OUTCOME first demonstrated significant reductions in primary 3-point MACE endpoint, CV mortality, overall mortality, and hospitalization for heart failure (HHF) in its entire cohort and in subgroups with varying baseline renal function and proteinuria^48,57. In renal endpoint analyses, Wanner et al. reported a 39% risk reduction for the renal composite of albuminuria progression, serum creatinine doubling or end-stage kidney disease (ESKD), or renal death⁵⁸. Importantly, each component - aside from renal death - was reduced and renal benefits were consistent across multiple subgroups including those with CKD at baseline⁵⁸. Beyond effects on “hard” renal endpoints, empagliflozin also resulted in a reversible eGFR “dip” after approximately 4 weeks of therapy. After 4 weeks, eGFR was better preserved compared to placebo, an effect that was greatest in patients with baseline macroalbuminuria, where placebo-treated patients lost ≈20 mL/min/1.73m² over 3.1 years compared to ≈10 mL/min/1.73m² in the empagliflozin-treated arm²⁸. Interestingly, albuminuria reductions in EMPA-REG OUTCOME persisted in participants with baseline albuminuria even after drug washout, suggesting renal structural changes beyond simple hemodynamic effects²⁸. Finally, renal benefits were independent of HbA1c lowering, while hematocrit/hemoglobin - as markers of hemoconcentration with natriuresis - were most closely associated with CV protection^59,60. This supports the hypothesis that protection against diabetes-related complications are independent of metabolic improvements with SGLT2 inhibitors.

Subsequent to the EMPA-REG OUTCOME trial being published, the CANVAS Program reported its results. This trial comprised an intermediate CV risk cohort and also demonstrated significant reductions in MACE, without individual improvements in all-cause or CV mortality^55,61,62. Foreshadowing CREDENCE, canagliflozin significantly reduced the composite of sustained doubling of serum creatinine, ESKD or renal death, reduced annual eGFR decline by 1.2 mL/min/1.73 m²/year, and UACR decreased by 18% in the overall cohort⁶³. Two years later, DECLARE-TIMI 58 was completed, and reported the impact of SGLT2 inhibition with dapagliflozin in the lowest CV risk cohort⁵⁶. Aside from a 27% reduction in the co-primary endpoint of CV death or HHF (largely driven by HHF reduction), dapagliflozin reduced the risk of 40% decline in eGFR to <60 mL/min/1.73m², ESKD or renal death by 47%⁶⁴. Hazard ratios for CV outcomes and mortality were generally similar across baseline levels of eGFR and albuminuria, aside from a lower HR in the impaired eGFR with albuminuria group⁶⁵. These results demonstrate a consistent role for cardiorenal protection with SGLT2 inhibitors in relatively low renal risk population presumably early in their disease course.

The benefit of SGLT2 inhibition on HHF was further shown in the DAPA-HF trial, which importantly included participants with heart failure and reduced ejection fraction (HFrEF) with and without T2D⁶⁶. Dapagliflozin was effective in reducing the risk of the primary outcome - composite of worsening heart failure, cardiovascular death, or urgent care visit for heart failure - in participants with and without T2D. Benefits on the primary composite endpoint were present across major baseline groups of clinical characteristics, including use of background heart failure therapies.⁶⁷ In DAPA-HF, dapagliflozin was well-tolerated, even in elderly trial participants.⁶⁸ In secondary analyses, there was a trend towards reducing the risk of the composite renal outcome (≥50% sustained decline in eGFR/ESKD/renal death - HR 0.71, 95% CI 0.44-1.16), with the caveat that events rates were low. The investigators also reported a significant separation in the eGFR slope curves favoring dapagliflozin, even when stratified by T2D status.

GLP-1 RECEPTOR AGONISTS

To date, seven CVOTs assessing GLP-1RA have been published, combining a total of 56,004 patients. Multiple meta-analyses certainly confirm a benefit in terms of reductions in MACE in patients with established ASCVD, and reductions in the risk of stroke^69-71. The benefits of GLP-1RA in those without established ASCVD and in reducing the risk of HHF is less clear, and individual trials have not yet demonstrated protection against HHF⁷¹.

For kidney protection, benefits have been reported with GLP-1RA, though less substantial compared to those that have been established in the SGLT2 inhibitor literature. In pre-specified secondary renal outcome analyses in LEADER, new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, need for renal replacement therapy (RRT), and death due to renal disease were reduced with a hazard ratio of 0.78 and an NNT of 67 (95% CI 0.67-0.92; P=0.003)^46,72. This was, however, driven by a reduction in new onset persistent macroalbuminuria, though the number of ‘hard’ renal outcomes was low - 120 of 9340 patients required RRT, 184 of 9430 had a doubling of serum creatinine. In a similar population, SUSTAIN-6 compared semaglutide with placebo and demonstrated a reduction in new or worsening nephropathy with a hazard ratio of 0.64 (95% CI 0.46-0.88; P=0.005)⁷³, again an effect based on a lower risk of albuminuria progression. In an exploratory renal outcome analysis of REWIND, dulaglutide reduced the composite outcome of first occurrence of new macroalbuminuria (UACR >33.9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic RRT (HR 0.85, 95% CI 0.77-0.93; p=0.0004) - also driven by a reduction in new onset macroalbuminuria^74,75. Meta-analyses of GLP-1RA agents have confirmed that relative risk reductions in composite renal outcomes are largely driven by reductions in macroalbuminuria^69-71.

Perhaps the most convincing data for kidney protection beyond albuminuria lowering stems from the AWARD-7 trial. This study evaluated dulaglutide against insulin glargine in 577 patients with moderate-to-severe CKD (stages 3-4, with an approximate mean eGFR of 38 mL/min/1.73m²) for the primary outcome of HbA1c reduction at 26 weeks and secondary outcomes of eGFR and UACR⁷⁶. By design, glycemic lowering between the two treatment arms was similar. Despite glycemic equipoise, dulaglutide was associated with a smaller decline in eGFR at one year, particularly in patients with baseline macroalbuminuria, who also achieved the greatest reduction in urinary albumin-to-creatinine ratio with the higher 1.5 mg dulaglutide dose. This important observation emphasizes that, similar to renal benefits achieved with SGLT2 inhibitors, GLP-1RA effects in the kidney are likely glucose-independent.

HOW TO USE THESE AGENTS TOGETHER?

As observed in trials such as DURATION-8, when used together, SGLT2 inhibitors and GLP-1RA confer additional benefits on glycemic control, BP, and weight loss. However, there are currently no completed clinical trials studying impact of combined SGLT2 inhibitor plus GLP-1RA on CV use on renal outcomes. A post-hoc propensity-matched cohort from the EXSCEL trial with the GLP-1RA exenatide demonstrated that the addition of exenatide in patients on a background of SGLT2 inhibition tended to exhibit improvements in MACE and all-cause mortality, and slower rates of renal decline compared to patients not on an SGLT2 inhibitor⁷⁷. In real-world practice, SGLT2 inhibitors and GLP-1RA are likely to be initiated sequentially. In line with multiple clinical practice guidelines, we recommend a patient-centered approach targeting diabetes-related cardiorenal comorbidities and risk factors, while considering the risk of adverse events, patient preference, and cost (Figure 1).

Figure 1
T2D management with SGLT2 inhibitors and GLP-1 RA.

_aCaveat that strong evidence for reduction in hard renal outcomes with GLP1-RA is limited.

In obese patients with T2D without other comorbidities, while both agents promote weight loss, GLP-1RA may be preferred as the first agent, due to greater weight loss at the upper range than SGLT2 inhibitors, particularly with the longer acting liraglutide and semaglutide⁷⁸. Additionally, weight loss with SGLT2 inhibitors may be limited by compensatory adaptations including hyperphagia⁷⁹. Indeed, liraglutide 3 mg daily is approved as a weight loss agent when used as an adjunct to a reduced caloric diet and physical activity. Given the significant heterogeneity in weight loss with GLP-1RA, inadequate responses may prompt the addition of SGLT2 inhibition in light of results of DURATION-8 and AWARD-10.

Among patients with T2D and established ASCVD, both GLP-1RA and SGLT2 inhibitors reduce MACE by similar magnitudes and initiation of either class is indicated. Such patients may subsequently be prime candidates for combination therapy. In patients with T2D and multiple risk factors for ASCVD but without established disease, meta-analyses have not detected a MACE benefit for GLP-1RA or SGLT2 inhibitors.⁶⁹ Other considerations may include the type of background ASCVD. For example, semaglutide and dulaglutide have demonstrated reductions in risk of stroke, and similar effects have been reported in the class as a whole in meta-analyses^70,73,75. Accordingly, it may be reasonable to preferentially initiate patients with T2D and a history of stroke on a GLP-1RA as the first agent prior to using an SGLT2 inhibitor.

In patients with T2D and heart failure, especially HFrEF, SGLT2 inhibition should be prioritized in addition to other guideline-directed therapy, as demonstrated in the DAPA-HF trial⁶⁶. Additionally, multiple meta-analyses have demonstrated reductions in HHF with SGLT2 inhibitors, reductions that have not been demonstrated with GLP-1RA⁶⁹. Moreover, results of the FIGHT study, where patients with HFrEF were randomized to liraglutide vs placebo, suggested a trend towards harm⁸⁰. One possible reason for this observation could be the opposing chronotropic effects of SGLT2 inhibitors and GLP-1RA discussed in the sections above. The chronotropic effects of GLP-1RA may be particularly deleterious in heart failure patients with higher sympathetic activity contributing to morbidity and mortality^34,80. Conversely, SGLT2 inhibitors are not associated with increased HR despite natriuresis/osmotic diuresis and reduced blood pressure and plasma volume, suggestive of reduced SNS activity^6,81. The addition of GLP-1RA to SGLT2 inhibitors in HF patients with T2D might be considered with a concomitant history of ASCVD. It remains to be seen whether SGLT2 inhibitors diminish increases in HR when used in combination with GLP-1RA.

Finally, in T2D patients with DKD, particularly those with high risk of progression, results from CREDENCE and from secondary CVOT analyses strongly support the use of SGLT2 inhibitors. Anticipated results of the DAPA-CKD and from EMPA-Kidney may also make a case for the use of SGLT2 inhibitors in non-diabetic proteinuric CKD. Persistent proteinuria and/or hypertension, despite maximal dose RAAS blockade plus SGLT2 inhibitor use, may prompt consideration of adding a GLP-1RA. Importantly, the benefits of SGLT2 inhibition have largely been demonstrated in study cohorts already taking background treatments that are cardiorenal protective, such as RAAS blockade. RAAS blockade and SGLT2 inhibitors are both associated with significant renal hemodynamic mediated dips in GFR, which may limit their use in patients with renal function at lower limits of clinical trial inclusion criteria (≤30 mL/min in the CREDENCE trial or ≤25 mL/min in the DAPA-CKD trial). The addition of eGFR neutral GLP-1RA to hemodynamically active RAAS inhibition or SGLT2 inhibition may be desirable under such circumstances given their possible direct renal benefits that are independent of acute GFR “dip” effects.

ADVERSE EVENTS

SGLT2 inhibitors are well tolerated, with mycotic genital infections the most common side effect and diabetic ketoacidosis, a rare but potentially serious complication⁸². Reports of acute kidney injury (AKI) have not been substantiated, with all three CVOTs and CREDENCE reporting reductions in AKI⁸³. An increased risk of lower extremity amputation was observed in CANVAS and a few real-world studies, but not in CREDENCE^54,55,84, suggesting that this is no longer a major concern. GLP-1RA have been associated with dose-dependent gastrointestinal effects including nausea, vomiting, and diarrhea in approximately 5-10% of people⁸⁵. Animal studies and observational data on risks of pancreatitis and medullar thyroid cancer have not been supported in CVOTs^86,87. More recent post-hoc analyses have shown that GLP-1RA is safe and well tolerated in patients with kidney disease^88,89.

GLP-1RA have a glucose-dependent mechanism of action and low rates of hypoglycemia⁹⁰. The risk of hypoglycemia is similarly low with SGLT2 inhibition because the effects on urinary glucose excretion are dampened at lower glucose levels². Importantly, there was no increased risk of hypoglycemia seen with dual therapy in DURATION-8, and minimal risk in AWARD-10 and SUSTAIN-9^50-52. Overall, these trials suggest an acceptable safety profile with combined therapy and no specific signal for heightened risk of adverse effects (Figure 2).

Figure 2
Monitoring and side effect considerations.

CONCLUSIONS

The use of SGLT2 inhibitors and GLP1-RA individually has significantly increased over the past several years. With the emergence of clinical trials in non-diabetic patient populations demonstrating benefits of these agents in cardiovascular and renal outcomes, use of these drugs is anticipated to expand into the arsenal of nephrologists, cardiologists, and neurologists. We expect their combined use to similarly increase, particularly in patients with multiple comorbidities. With respect to their individual use, important questions remain unanswered, including whether or not GLP-1RA reduces the risk of end stage kidney disease or doubling of serum creatinine in cohorts with DKD at baseline - a question currently being studied in the ongoing FLOW trial with semaglutide. In addition, it is not known if there is a lower kidney function limit for cardiorenal protection with either class of drug, especially in patients with non-diabetic conditions. Finally, patients with type 1 diabetes and solid organ transplant recipients, particularly kidney transplant recipients, are other populations in which ongoing investigation for use of these agents is warranted. Ultimately, based on data from studies using individual therapies, it is now of the utmost importance to elucidate the role of combination SGLT2 inhibitor-GLP-1RA therapy as a strategy to reduce cardiorenal complications.

ACKNOWLEDGEMENTS

D.Z.I.C. is supported by a Department of Medicine, University of Toronto Merit Award and receives support from the CIHR, Diabetes Canada, and the Heart and Stroke Richard Lewar Centre of Excellence and the Heart and Stroke Foundation of Canada. V.S.S. is funded by the Clinician Scientist Training Program at the University of Toronto.

• DISCLOSURES
  D.Z.I.C. has received consulting fees or speaking honorarium or both from Janssen, Bayer, Boehringer Ingelheim-Eli, Lilly, AstraZeneca, Merck & Co. Inc., Prometic, Sanofi, Novo Nordisk and Esperion and has received operating funds from Janssen, Boehringer Ingelheim-Eli, Lilly, Sanofi, AstraZeneca, and Merck & Co. Inc and Novo Nordisk. VSS, LD, and JB have no disclosures.

REFERENCES

• ¹
  Lytvyn Y, Bjornstad P, Van Raalte DH, Heerspink HL, Cherney DZI. The new biology of diabetic kidney disease-mechanisms and therapeutic implications. Endocr Rev. 2020;41(12):81-9.
• ²
  Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016 Sep;134(10):752-72.
• ³
  Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 2018 Jul;94(1):26-39.
• ⁴
  Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, et al. Pooled analysis of phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018 Jan;93(1):231-44.
• ⁵
  Cherney DZI, Perkins BA. Sodium-glucose cotransporter 2 inhibition in type 1 diabetes: simultaneous glucose lowering and renal protection?. Can J Diabetes. 2014 Oct;38(5):356-63.
• ⁶
  Cherney DZI, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014 Jan;13:28.
• ⁷
  Sternlicht H, Bakris GL. Blood pressure lowering and sodium-glucose co-transporter 2 inhibitors (SGLT2is): more than osmotic diuresis. Curr Hypertens Rep. 2019 Feb;21(2):12.
• ⁸
  Goldenberg RM, Berall M, Chan CTM, Cherney DZI, Loveshin JA, Senior PA, et al. Managing the course of kidney disease in adults with type 2 diabetes: from the old to the new. Can J Diabetes. 2017 Aug;42(3):325-34.
• ⁹
  Bjornstad P, Laffel L, Tamborlane WV, Simons G, Hantel S, Von Eynatten M, et al. Acute effect of empagliflozin on fractional excretion of sodium and eGFR in youth with type 2 diabetes. Diabetes Care. 2018 Aug;41(8):e129-e30.
• ¹⁰
  Jiménez DL, Cherney DZI, Bjornstad P, Castilla-Guerra L, González JPM. Antihyperglycemic agents as novel natriuretic therapies in diabetic kidney disease. Am J Physiol Renal Physiol. 2018 Nov;315(5):F1406-F15.
• ¹¹
  Lovshin JA, Cherney DZ. Sodium transport in diabetes: two sides to the coin. Nat Rev Nephrol. 2018 Dec;15:125-6.
• ¹²
  Rajasekeran H, Lytvyn Y, Cherney DZI. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016 Mar;89(3):524-6.
• ¹³
  Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014 Feb;129(5):587-97.
• ¹⁴
  Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M, Kanda E, et al. Evaluation of glomerular hemodynamic function by empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019 Jul;140(4):303-15.
• ¹⁵
  Rajasekeran H, Lytvyn Y, Bozovic A, Lovshin JA, Diamandis E, Cattran D, et al. Urinary adenosine excretion in type 1 diabetes. Am J Physiol Renal Physiol. 2017 Aug;313(2):F184-F91.
• ¹⁶
  Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015 Jan;24(1):96-103.
• ¹⁷
  Skrtic M, Yang GK, Perkins BA, Soleymanlou N, Lytvyn Y, Von Eynatten M, et al. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia. 2014 Dec;57(12):2599-602.
• ¹⁸
  Van Bommel EJM, Lytvyn Y, Perkins BA, Soleymanlou N, Fagan NM, Koitka-Weber A, et al. Renal hemodynamic effects of sodium-glucose cotransporter 2 inhibitors in hyperfiltering people with type 1 diabetes and people with type 2 diabetes and normal kidney function. Kidney Int. 2020 Apr;97(4):631-5.
• ¹⁹
  Van Bommel EJM, Muskiet MHA, Van Baar MJB, Tonneijck L, Smits MM, Emanuel AL, et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int. 2020 Jan;97(1):202-12.
• ²⁰
  Burns KD, Cherney D. Renal angiotensinogen and sodium-glucose cotransporter-2 inhibition: insights from experimental diabetic kidney disease. Am J Nephrol. 2019;49(4):328-30.
• ²¹
  Cherney D, Perkins BA, Lytvyn Y, Heerspink H, Rodríguez-Ortiz ME, Mischak H. The effect of sodium/glucose cotransporter 2 (SGLT2) inhibition on the urinary proteome. PLoS ONE. 2017;12(10):e0186910.
• ²²
  Cherney DZI, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann JZ, Woerle HJ, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014 Nov;86(5):1057-8.
• ²³
  Dekkers CCJ, Petrykiv S, Laverman GD, Cherney DZ, Gansevoort RT, Heerspink HJL. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers. Diabetes Obes Metab. 2018 Aug;20(8):1988-93.
• ²⁴
  Kopecky C, Lytvyn Y, Domenig O, Antlanger M, Kovarik JJ, Kaltenecker CC, et al. Molecular regulation of the renin-angiotensin system by sodium-glucose cotransporter 2 inhibition in type 1 diabetes mellitus. Diabetologia. 2019 Jan;62(6):1090-3.
• ²⁵
  Van Raalte DH, Cherney DZI. Sodium glucose cotransporter 2 inhibition and renal ischemia: implications for future clinical trials. Kidney Int. 2018 Sep;94(3):459-62.
• ²⁶
  Verma S, McMurray JJV, Cherney DZI. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure. JAMA Cardiol. 2017 Sep;2(9):939-40.
• ²⁷
  Cherney D, Lund SS, Perkins BA, Groop PH, Cooper ME, Kaspers S, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016 Sep;59(9):1860-70.
• ²⁸
  Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, Von Eynatten M, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017 Aug;5(8):610-21.
• ²⁹
  Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016 Jul;24(1):15-30.
• ³⁰
  Verdich C, Flint A, Gutzwiller JP, Hellström PM, Long SJ, Morgan LM, et al. A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans. J Clin Endocrinol Metab. 2001 Sep;86(9):4382-9.
• ³¹
  Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998 Feb;101(3):515-20.
• ³²
  Nogueiras R, Perez-Tilve D, Veyrat-Durebex C, Morgan DA, Varela L, Haynes WG, et al. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity. J Neurosci. 2009 May;29(18):5916-25.
• ³³
  Katout M, Zhu H, Rutsky J, Shah P, Brook RD, Zhong J, et al. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am J Hypertens. 2014 Jan;27(1):130-9.
• ³⁴
  Lorenz M, Lawson F, Owens D, Raccah D, Roy-Duval C, Lehmann A, et al. Differential effects of glucagon-like peptide-1 receptor agonists on heart rate. Cardiovasc Diabetol. 2017;16:6.
• ³⁵
  Lonborg J, Vejlstrup N, Kelbaek H, Botker HE, Kim WY, Mathiasen AB, et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2012 Jun;33(12):1491-9.
• ³⁶
  Park CW, Kim HW, Ko SH, Lim JH, Ryu GR, Chung HW, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice. J Am Soc Nephrol. 2007 Apr;18(4):1227-38.
• ³⁷
  Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia. 2011 Apr;54(4):965-78.
• ³⁸
  Mazidi M, Karimi E, Rezaie P, Ferns GA. Treatment with GLP1 receptor agonists reduce serum CRP concentrations in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J Diabetes Complications. 2017 Jul;31(7):1237-42.
• ³⁹
  Tonneijck L, Muskiet MHA, Smits MM, Van Bommel EJ, Heerspink HJL, Van Raalte DH, et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017 Apr;28(4):1023-39.
• ⁴⁰
  Muskiet MH, Tonneijck L, Smits MM, Kramer MHH, Diamant M, Joles JA, et al. Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men. Diabetes Obes Metab. 2016 Feb;18(2):178-85.
• ⁴¹
  Tonneijck L, Smits MM, Muskiet MHA, Hoekstra T, Kramer MHH, Danser AHJ, et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016 Jul;59(7):1412-21.
• ⁴²
  Pyke C, Heller RS, Kirk RK, Orskov C, Reedtz-Runge S, Kaastrup P, et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014 Apr;155(4):1280-90.
• ⁴³
  Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017 Apr;19(4):524-36.
• ⁴⁴
  Neuen BL, Cherney DZ, Jardine MJ, Perkovic V. Sodium-glucose cotransporter inhibitors in type 2 diabetes: thinking beyond glucose lowering. CMAJ. 2019 Oct;191(41):E1128-E35.
• ⁴⁵
  Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015 Aug;110(1):26-37.
• ⁴⁶
  Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016 Jul;375(4):311-22.
• ⁴⁷
  Liakos A, Lambadiari V, Bargiota A, Kitsios K, Avramidis I, Kotsa K, et al. Effect of liraglutide on ambulatory blood pressure in patients with hypertension and type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2019 Mar;21(3):517-24.
• ⁴⁸
  Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov;373(22):2117-28.
• ⁴⁹
  Babenko AY, Savitskaya DA, Kononova YA, Trofimova AY, Simanenkova AV, Vasilyeva EY, et al. Predictors of effectiveness of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes and obesity. J Diabetes Res. 2019;2019:1365162.
• ⁵⁰
  Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016 Dec;4(12):1004-16.
• ⁵¹
  Ludvik B, Frías JP, Tinahones FJ, Wainstein J, Jiang H, Robertson KE, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018 May;6(5):370-81.
• ⁵²
  Zinman B, Bhosekar V, Busch R, Holst I, Ludvik B, Thielke D, et al. Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2019 May;7(5):356-67.
• ⁵³
  Lundkvist P, Sjöström CD, Amini S, Pereira MJ, Johnsson E, Eriksson JW. Dapagliflozin once-daily and exenatide once-weekly dual therapy: a 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab. 2017 Jan;19(1):49-60.
• ⁵⁴
  Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019 Jun;380(24):2295-306.
• ⁵⁵
  Neal B, Perkovic V, Mahaffey KW, Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug;377(7):644-57.
• ⁵⁶
  Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019 Jan;380(4):347-57.
• ⁵⁷
  Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, et al. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018 Jan;137(2):119-29.
• ⁵⁸
  Wanner C, Inzucchi SE, Lachin JM, Fitchett D, Von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016 Nov;375(18):323-34.
• ⁵⁹
  Cooper ME, Inzucchi SE, Zinman B, Hantel S, Von Eynatten M, Wanner C, et al. Glucose control and the effect of empagliflozin on kidney outcomes in type 2 diabetes: an analysis from the EMPA-REG OUTCOME Trial. Am J Kidney Dis. 2019 Nov;74(5):713-5.
• ⁶⁰
  Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Shumacher M, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018 Feb;41(2):356-63.
• ⁶¹
  Neuen BL, Ohkuma T, Neal B, Matthews DR, Zeeuw D, Mahaffey KW, et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018 Oct;138(15):1537-50.
• ⁶²
  Ohkuma T, Van Gaal L, Shaw W, Mahaffey KW, Zeeuw D, Matthews DR, et al. Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program. Diabetes Obes Metab. 2020 Apr;22(4):530-9.
• ⁶³
  Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018 Sep;6(9):691-704.
• ⁶⁴
  Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 2019 Aug;7(8):606-17.
• ⁶⁵
  Zelniker TA, Raz I, Mosenzon O, Dwyer JP, Heerspink HJL, Cahn CA, et al. Effect of dapagliflozin on cardiovascular outcomes in patients with type 2 diabetes according to baseline renal function and albuminuria status: insights from DECLARE-TIMI 58. Eur Heart J. 2019 Aug;40(Suppl 1):ehz747.0052.
• ⁶⁶
  McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019 Nov;381(21):1995-2008.
• ⁶⁷
  Docherty KF, Jhund PS, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, et al. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J. 2020 Jul;41(25):2379-92.
• ⁶⁸
  Martinez FA, Serenelli M, Nicolau JC, Petrie MC, Chiang CE, Tereshchenko S, et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation. 2020 Jan;141(2):100-11.
• ⁶⁹
  Zelniker TA, Wiviott SD, Raz I, Im KA, Goodrich EL, Furtado RHM, et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019 Apr;139(17):2022-31.
• ⁷⁰
  Kristensen SL, Rorth R, Jhund PS, Docherty KF, Sattar N, Preiss D, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019 Oct;7(10):776-85.
• ⁷¹
  Giugliano D, Maiorino MI, Bellastella G, Longo M, Chiodini P, Esposito K. GLP-1 receptor agonists for prevention of cardiorenal outcomes in type 2 diabetes: an updated meta-analysis including the REWIND and PIO NEER 6 trials. Diabetes Obes Metab. 2019 Nov;21(11):2576-80.
• ⁷²
  Mann JFE, Orsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017 Aug;377(9):839-48.
• ⁷³
  Marso SP, Bain SC, Consoli A, Eliashewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016 Nov;375(19):1834-44.
• ⁷⁴
  Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019 Jul;394(10193):131-8.
• ⁷⁵
  Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019 Jul;394(10193):121-30.
• ⁷⁶
  Tuttle KR, Lakshmanan MC, Rayner B, Busch RS, Zimmermann AG, Woodward DB, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018 Aug;6(8):605-17.
• ⁷⁷
  Clegg LE, Penland RC, Bachina S, Boulton DW, Thuresson M, Heerspink HJL, et al. Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial. Cardiovasc Diabetol. 2019 Oct;18(1):138.
• ⁷⁸
  Brown E, Wilding JPH, Barber TM, Alam U, Cuthbertson DJ. Weight loss variability with SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes mellitus and obesity: mechanistic possibilities. Obes Rev. 2019 Jun;20(6):816-28.
• ⁷⁹
  Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring). 2012 Aug;20(8):1645-52.
• ⁸⁰
  Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016 Aug;316(5):500-8.
• ⁸¹
  Herat LY, Magno AL, Rudnicka C, Hricova J, Carnagarin R, Ward NC, et al. SGLT2 inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl Sci. 2020 Jan;5(2):169-79.
• ⁸²
  Fitchett D. A safety update on sodium glucose co-transporter 2 inhibitors. Diabetes Obes Metab. 2019 Apr;21(Suppl 2):34-42.
• ⁸³
  Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis. PLoS Med. 2019 Dec;16(12):e1002983.
• ⁸⁴
  Chang HY, Singh S, Mansour O, Baksh S, Alexander GC. Association between sodium-glucose cotransporter 2 inhibitors and lower extremity amputation among patients with type 2 diabetes. JAMA Intern Med. 2018 Sep;178(9):1190-8.
• ⁸⁵
  Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs Context. 2015 Jul;4:212283.
• ⁸⁶
  Storgaard H, Cold F, Gluud LL, Vilsboll T, Knop FK. Glucagon-like peptide-1 receptor agonists and risk of acute pancreatitis in patients with type 2 diabetes. Diabetes Obes Metab. 2017 Jun;19(6):906-8.
• ⁸⁷
  Bethel MA, Patel RA, Thompson VP, Merrill P, Reed SD, Li Y, et al. Changes in serum calcitonin concentrations, incidence of medullary thyroid carcinoma, and impact of routine calcitonin concentration monitoring in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL). Diabetes Care. 2019 Jun;42:1075-80.
• ⁸⁸
  Mann JFE, Fonseca VA, Poulter NR, Raz I, Idorn T, Rasmussen S, et al. Safety of liraglutide in type 2 diabetes and chronic kidney disease. Clin J Am Soc Nephrol. 2020 Apr;15(4):465-73.
• ⁸⁹
  Cherney DZ, Tuttle KR. Liraglutide for the treatment of type 2 diabetes and safety in diabetic kidney disease: liraglutide and diabetic kidney disease. Clin J Am Soc Nephrol. 2020 Mar;15:444-6.
• ⁹⁰
  Garber AJ. Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care. 2011 May;34(Suppl 2):S279-84.

Publication Dates

• Publication in this collection
  11 Sept 2020
• Date of issue
  Oct-Dec 2020

History

• Received
  08 May 2020
• Accepted
  24 June 2020