Approximately 34.2 million people in the United States have diabetes.1 Diabetes puts individuals at risk for cardiovascular (CV) disease, including hypertension, hyperlipidemia, myocardial infarction (MI), stroke, and heart failure (HF), as well as an increased risk for all-cause mortality.2,3
Treatment of type 2 diabetes (T2DM) is aimed at not only glycemic control, but also management of complications, such as prevention of CV disease or worsening kidney function.4,5 Past research had demonstrated that intensive glycemic control improved microvascular outcomes (e.g., peripheral neuropathy, retinopathy, nephropathy) but evidence supporting risk reduction of macrovascular outcomes (e.g., CV disease) was lacking.6,7 However, over the past few years, evidence has emerged from new drugs, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RA) for reducing CV risk and slowing the progression of kidney disease.4,5 In fact, in the 2021 Standards of Medical Care from the American Diabetes Association (ADA), it is recommended that in patients with indicators of high-risk or established atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), or HF, a GLP-1 RA or SGLT2 inhibitor should be considered as part of their care plan.4 The recommendation breaks down further to first recommend a SGLT2 inhibitor in patients with HF, especially those with a left ventricular ejection fraction of <45%, or in those with diabetic kidney disease (DKD) and albuminuria.4 A GLP-1 RA should be added on in patients with DKD, if additional glucose lowering is indicated or if a SGLT2 inhibitor is not tolerated. For patients with established ASCVD or indicators of high risk for ASCVD (e.g., age >55 years with coronary, carotid, or lower-extremity artery stenosis of >50% of left ventricular hypertrophy), a GLP-1 RA or SGLT2 inhibitor with proven CV benefit should be initiated.4
To fully understand these recommendations, this review will highlight the evidence supporting these recommendations, as well as guidelines and consensus statements available for guiding drug selection and appropriateness in this population.
Evidence supporting SGLT2 inhibitors

           The SGLT2 inhibitors canagliflozin (Invokana®), empagliflozin (Jardiance®), dapagliflozin (Farxiga®), and ertugliflozin (SteglatroTM) employ a novel mechanism of action to achieve their glucose lowering effect.4 They increase glucosuria by blocking renal reabsorption of glucose from urine through inhibition of sodium glucose co-transporters in the proximal tubule where approximately 90% of urine glucose reabsorption occurs.8-9 Their ability to reduce blood glucose is most evident during episodes of hyperglycemia and less so as blood glucose normalizes.6 The antihyperglycemic mechanism of SGLT2 inhibitors depends on renal function; therefore, patients with reduced estimated glomerular filtration rate (eGFR) may have a smaller reduction in glucose plasma levels with these agents.6 The mechanism by which SGLT2 inhibitors promote glucosuria also increases natriuresis and diuresis, which may explain their ability to lower blood pressure.6 In fact, SGLT2 inhibitors have demonstrated CV benefits in patients with T2DM and established ASCVD with or without DKD.4,5,10-13 The mechanisms by which SGLT2 inhibitors achieve CV benefits are not well known. However, several studies have examined their possible effects on, and mechanisms of vasodilation, ventricular loading, myocardium remodeling, and regulation of pro- and anti-inflammatory markers, and more studies are ongoing.14-17

In order to understand how the SGLT2 inhibitor CV benefit discussion began; it is best to look at the CV Outcomes Trials (CVOTs) for the SGLT2 inhibitors that brought this information to light. The CVOTs are summarized in Table 1, including EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), CANVAS (Canagliflozin Cardiovascular Assessment Study), DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58), and DAPA-HF (Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction).10-13 Notably, fewer patients in DECLARE-TIMI 58 had established CV disease (41%) compared to EMPA-REG (75%) and CANVAS (65%).10-12 The DAPA-HF trial focused on patients with a history of HF, regardless of baseline diabetes diagnosis, versus HF rates of 10-14% in the previous trials, thus demonstrating the HF benefit of SGLT2 inhibitors with or without diabetes.10-13 In all of these studies, the trial drugs were added to background therapy.
The EMPA-REG and CANVAS trials each showed a reduction in the primary outcome (composite of major adverse cardiovascular events (MACE) defined as CV mortality, nonfatal MI, or nonfatal stroke also known as 3-point MACE), which favored empagliflozin at a rate of 10.5% compared to 12.1% in the placebo arm (HR 0.86, 95% CI 0.74–0.99, noninferiority P <0.001, NNT 62), and favored canagliflozin with a rate of 26.9 versus 31.5 participants per 1,000 patient-years having an event (HR 0.86, 95% CI 0.75–0.97, P <0.001 for noninferiority, P = 0.02 for superiority), respectively.10,11 In addition, the EMPA-REG trial demonstrated a statistically significant reduction in CV death with empagliflozin (12.4 versus 20.2 events per 1,000 patient years with placebo HR 0.62, 95 CI 0.49-0.77, P <0.001) when compared to placebo.10 While, DECLARE-TIMI 58 did not show a statistically significant reduction in 3-point MACE for dapagliflozin, there were lower rates of CV death or hospitalizations from heart failure (HHF) compared to placebo (4.9 vs. 5.8%, HR 0.83, 95 CI 0.73–0.95, P = 0.005), primarily driven by HHF.12 Ultimately, statistically significant reductions in HHF were observed with canagliflozin, empagliflozin, and dapagliflozin when compared to placebo.10-12
The latest SGLT2 inhibitor CVOT, VERTIS-CV (Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes) trial studied the effects of ertugliflozin (n = 5499) versus placebo (n = 2747) in patients with established ASCVD (99.9% of the study population).18 This trial demonstrated non-inferiority for the primary outcome of CV death, nonfatal MI, or nonfatal stroke for ertugliflozin compared to placebo (HR 0.97, 95% CI 0.85-1.11, P <0.001 for noninferiority).18 Time to first HHF was reduced with ertugliflozin compared to placebo (HR 0.70, 95% CI 0.54-0.90, P = 0.006), which was consistent across ertugliflozin doses.18 While the renal outcome of composite of renal death, dialysis/transplant, or doubling of serum creatinine was not statistically significant, it did trend towards benefit (HR 0.81, 95% CI 0.63 to 1.04, P = 0.08) and in sub-group analyses, patients with reduced kidney function, defined as eGFR <60 ml/min/1.73m2, had more pronounced HF benefit from ertugliflozin compared to placebo.18
Further analysis of secondary and exploratory renal outcomes in the previous trials suggested that SGLT2 inhibitor use may lead to a reduction in progression of renal disease for some patients.10-13 The CREDENCE (Canagliflozin and Renal Outcomes in Type 2 Diabetes and Neuropathy) trial randomized 4,401 patients with T2DM and albuminuric CKD to receive canagliflozin 100 mg daily (n = 2202) or placebo (n = 2199), in addition to background therapy.19 Similar to other SGLT2 inhibitor trials, patients were mostly white males with a mean age of 63 and a mean A1c of 8.3%. Patients had a mean eGFR of 56 mL/min/1.73m2 and a median urine albumin-to-creatinine ratio (UACR) of 927 mg/g.19 Canagliflozin showed a 30% reduced risk in the primary composite outcome of end-stage kidney disease, doubling of serum creatinine, or renal or CV death, when compared to placebo (HR 0.70, 95% CI 0.59 to 0.82; P = 0.00001).19 Subgroup analyses suggest that patients with more advanced renal disease (those with eGFR < 60 mL/min/1.73m2 or UACR > 1000 mg/g) may see a greater benefit from the addition of canagliflozin to their diabetes regimen.19 The effect of SGLT2 inhibitors on slowing the progression of CKD was explored further with dapagliflozin in the DAPA-CKD (Dapagliflozin in Patients with Chronic Kidney Disease) trial that enrolled patients with an eGFR > 25 mL/min/1.73m2 but <75 mL/min/1.73m2 with or without diabetes to receive dapagliflozin 10 mg once daily (n = 2152) or placebo (n = 2152).20 The trial was stopped early due to efficacy of the primary outcome of a composite of sustained decline in the eGFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes, which occurred in 9.2% of the dapagliflozin group compared to 12.5% of the placebo group (HR 0.61, 95% CI 0.51 to 0.72; P <0.001, NNT 19).20 When examining the primary outcome in those with diabetes or without diabetes, benefit was seen in both groups (with diabetes: HR 0.64, 95% CI 0.52 to 0.79; without diabetes: HR 0.50, 95% CI 0.35 to 0.72).20 As seen in other SGLT2 inhibitor trials, there was benefit for reduction of HHF or death from CV causes (HR 0.71, 95% CI 0.55 to 0.92, P =0.009).20 The DAPA-CKD trial demonstrated renal and CV protection in patients with or without T2DM, thus demonstrating the ability to use dapagliflozin as add-on to ACE/ARB for kidney protection, regardless of diabetes diagnosis.20
Ultimately, data from these trials suggest a consistent class benefit with respect to reduction in HHF. Major adverse cardiac event reductions have only been statistically significant for canagliflozin and empagliflozin. Dapagliflozin and canagliflozin have proven benefit for slowing progression of chronic kidney disease, with evidence also pointing to benefit with empagliflozin. 10-13,18-20
Despite the benefits demonstrated by this class, use is not without risks. Patients prescribed any SGLT2 inhibitor may be at an increased risk of genital mycotic infections due to increased glycosuria.6 Patients should be informed of the risk and educated on perineal hygiene and how to monitor for infections prior to starting an SGLT2 inhibitor.5,6,21 In 2017, the U.S. Food and Drug Administration (FDA) mandated a Black Box Warning (BBW) for increased risk of amputations associated with canagliflozin based on data from the CANVAS trial. However, in August of 2020 the FDA rescinded the BBW stating that evidence from subsequent safety and efficacy studies showed that while there is an increased risk of amputations with canagliflozin, the risk is much lower than previously reported.22 However, patients should be educated on the importance of maintaining adequate hydration and how to inspect their feet and limbs for sores, ulcers, and infections.21,23 Diabetic ketoacidosis (DKA) is a rare but serious complication of T2DM, that is most often associated with a hyperglycemic state but can occur in an euglycemic state.4,5 While the risk of euglycemic DKA is low in SGLT2 inhibitor use, a patient’s risk for developing euglycemic DKA should be assessed prior to initiation of therapy and patients should be educated to monitor for signs and symptoms of DKA such as; polydipsia, polyuria, nausea, vomiting, weakness, fatigue, confusion, or altered mental status that may resemble alcohol intoxication.4,5,21,24
Evidence supporting GLP-1 receptor agonists

           There are currently six subcutaneous GLP-1 RAs available in the United States, broken into daily injections (i.e., exenatide IR (Byetta®), lixisenatide (Adlyxin®), and liraglutide (Victoza®)) and once weekly injections (i.e., exenatide IR (Bydureon BCise®), dulaglutide (Trulicity®), and semaglutide (Ozempic®), as well as one oral GLP-1 RA, semaglutide (Rybelsus®). Most of GLP-1 RAs have also demonstrated cardiovascular benefits in patients with T2DM and established ASCVD or high risk for ASCVD. GLP-1 RAs work by enhancing endogenous GLP-1 (peptide hormone) function, thereby reducing blood glucose by increasing glucose dependent insulin secretion from beta cells in the pancreas. This in turn decreases glucagon secretion and delays gastric emptying. This process also indirectly affects blood pressure, weight management, and triglycerides, which all are important benefits to reduce cardiovascular events.25

A summary of key trials related to GLP-1 receptor agonists are shown in Table 2, including ELIXA (Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndromes), LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), SUSTAIN-6 (Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes), EXSCEL (Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes), REWIND (Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes), and PIONEER-6 (Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes).26-31 Similar to the SGLT2 inhibitor trials, the populations enrolled within each trial differed slightly, especially in regard to the proportion of the population that had established ASCVD at baseline.
 In terms of composite primary outcomes, ELIXA was the only trial to do a 4-point MACE (composite of death from CV causes, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina), while all the others had a 3-point MACE (composite of death from CV causes, nonfatal MI, or nonfatal stroke). For lixisenatide (ELIXA), the primary outcome of the 4-point MACE was not statistically significant for superiority compared to placebo but did demonstrate non-inferiority (13.4% vs. 13.2%, P <0.001 for noninferiority, P = 0.81 for superiority).26 For liraglutide (LEADER), the primary composite outcome of time to first occurrence of 3-point MACE, occurred in fewer patients when compared to placebo (13% vs. 14.9%, HR 0.87, 95% CI 0.78–0.97, P <0.001 for noninferiority, P = 0.01 for superiority).27 Injectable semaglutide (SUSTAIN-6) demonstrated a statistically significant reduction in the primary outcome of a 3-point MACE compared to placebo (6.6% vs. 8.9%, HR 0.74, 95% CI 0.58-0.95, P <0.001 for noninferiority, P = 0.02 for superiority).28 This finding was largely driven by reduction in stroke.28 Exenatide (EXSCEL) demonstrated a reduction in the primary outcome of 3-point MACE compared to placebo (11.4% vs 12.2%, HR 0.91, 95% CI 0.83-1.00, P <0.001 for noninferiority, P = 0.06 for superiority).29 While the trial failed to show superiority, it did demonstrate non-inferiority.29 Dulaglutide (REWIND) demonstrated a statistically significant reduction in the primary outcome of 3-point MACE compared to placebo (12% vs. 13.4%, HR 0.88, 95% CI 0.79–0.99, P = 0.026 for superiority), driven largely by reduced risk of fatal and nonfatal stroke (2.7 vs. 3.5%, P = 0.017).30 Oral semaglutide (PIONEER-6) demonstrated non-inferiority (but not superiority) to placebo for reduction in the primary outcome of 3-point MACE (3.8% vs 4.8%, HR 0.79, 95% CI 0.57 to 1.11, O <0.001 for noninferiority, P = 0.17 for superiority).31
ELIXA, which evaluated lixisenatide, is the only GLP-1 RA trial to fail to show any CV benefit, while all of the other trials were able to show some extent of CV benefit (Table 2).26-31 Lixisenatide, as well as exenatide, induces more antibody formation than human-based GLP-1 agonists, which may contribute to decreased efficacy. The low extent of drug exposure of lixisenatide and exenatide may have potentially limited statistically significant CV benefit.32
In terms of renal events, no renal outcomes trials have been conducted, although trials are underway. However, a meta-analysis of ELIXA, EXSCEL, LEADER, and SUSTAIN-6 demonstrated a reduction in the composite renal outcome, defined as development of microalbuminuria, doubling in serum creatinine or decline in eGFR >40%, development of end-stage kidney disease, or death due to kidney disease (HR 0.83, 95% CI 0.78 to 0.89).33 Renal benefits were presumed to be largely driven by reductions in proteinuria, as no significant improvements were seen in eGFR. Currently, the ADA recognizes that in the CVOTs, there have been positive renal endpoints, driven by albuminuria, for liraglutide, semaglutide, and dulaglutide.4 To this end, these agents are recommended, after a SGLT2 inhibitor for DKD with albuminuria.4
As with the SGLT2 inhibitors, there are adverse effects to be aware of and/or counsel your patients on. The most common side effects seen in GLP-1 RAs are gastrointestinal side effects, including nausea, vomiting, and diarrhea.4 GLP-1 RAs should be used with caution in patients with a history of pancreatitis who are at an increased risk for reoccurrence (e.g., precipitating factor of pancreatitis still exists such as active gallstones, alcoholism, extremely elevated triglycerides).4 Should pancreatitis develop during therapy, the GLP-1 RA should be discontinued.4

Prescribing guidance regarding SGLT2 inhibitor versus GLP-1 receptor agonist

The decision to initiate a SGLT2 inhibitor or GLP-1 RA for patients with T2DM should be guided by a patient-clinical discussion of the patient’s preferences and a thorough review of the patient's medical history (Figure 1).4,5 SGLT2 inhibitors are once daily oral medications with proven CV and renal benefits for patients with or without ASCVD; however, this must be weighed with the increased risk of genital mycotic infections, increased urination, and possible volume depletion, which may contribute to acute kidney injury.4,5 These agents are also preferred in patients with a history of HF.4,5 On the other hand, GLP-1 RAs are daily or weekly injectable medications that have demonstrated reductions in MACE and suggested delayed progression of microalbuminuria, but they may cause increased nausea at initiation and up-titration of doses.4,5 To overcome the injection barrier with GLP-1 receptor agonists, the oral version of semaglutide (Rybelsus®) may be preferred; however, there are many administration pearls to be aware, such as the need to take on an empty stomach with no food (30 minutes before a meal) with less than 4 ounces, which may limit its utility.34 Despite the potential for nausea, significant weight loss benefits may make GLP-1 RAs appealing for overweight or obese patients.4,5 Both SGLT2 inhibitors and GLP-1 RAs have a low risk of hypoglycemia when used alone or in conjunction with metformin or other oral antihyperglycemic agents, although use with insulin secretagogues may increase the risk of hypoglycemia and require dose adjustments.4,5
The cardiovascular and renal benefits of SGLT2 inhibitors and GLP-1 RAs are independent of a patient’s A1c or their use of other antihyperglycemic agents.4,5 For example, the DAPA-HF study, in which the majority of patients did not have T2DM, found similar reductions in both CV death and worsening HF among participants with our without T2DM.13 Similarly, the DAPA-CKD trial found similar renal benefits for those with our without diabetes.20 Based on the independent benefit for CV and renal risk reduction, in patients with indicators of high-risk or established ASCVD, CKD, or HF, the ADA recommends considering a SGLT2 inhibitor or GLP-1 RA independently of baseline A1c, individualized A1c target, or metformin use, as most patients in the trials were on background metformin therapy. However, metformin and comprehensive lifestyle modification (diet and exercise) remain first line therapy in the treatment of patients with T2DM.4
The 2021 ADA Standards of Medical Care also recommends concomitant use of SGLT2 inhibitor and GLP-1 RA, with demonstrated CV benefit, to improve glycemic control for patients with T2DM with ASCVD, at high risk for ASCVD, CKD, or HF who have not achieved their target A1c with metformin plus an SGLT2 inhibitor or a GLP-1 RA.4 While either agent alone has shown significant reductions in CV and/or renal benefits, there have been no trials to date studying the combined CV risk reduction in patients taking both an SGLT2 inhibitors and a GLP-1 RA. However, trials have demonstrated that add-on therapy of a SGLT2 inhibitor and/or GLP-1 RA to a regimen that already has one or the other demonstrated additional glycemic control, weight loss, and systolic blood pressure improvements, thus it may be presumed that dual SGLT2 inhibitor and GLP-1 RA therapy would provide a greater extent of CV and/or renal risk reduction than either agent alone.35 However, further trials are warranted to determine the extent of this presumed additional benefit.

Overwhelmingly, the evidence has demonstrated that SGLT2 inhibitors and GLP-1 receptor agonists offer both cardiovascular and renal benefits for patients with T2DM. Incorporating these therapies into patient’s care plans will offer not only glycemic benefit but will help reduce co-morbidities, such as CV disease or nephropathy. Selection of which class and specific agent to utilize should take into consideration patient-specific factors, as well as medication formulary/drug coverage within each class.


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