Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease : Clinical Journal of the American Society of Nephrology

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Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease

Li, Jiahua1,2,3; Albajrami, Oltjon2,4; Zhuo, Min1,3,5,6; Hawley, Chelsea E.6,7; Paik, Julie M.1,2,3,6,7

Author Information

1Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

2Renal Section, Veterans Affairs Boston Healthcare System, Boston, Massachusetts

3Harvard Medical School, Boston, Massachusetts

4Renal Division, Department of Medicine, Boston Medical Center, Boston University, Boston, Massachusetts

5Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts

6Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts

7New England Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts

J.L. and O.A. contributed equally to this work.

Correspondence: Dr. Jiahua Li, Renal Division, Department of Medicine, Brigham and Women’s Hospital, 4 Blackfan Circle 550, Boston, MA 02115. Email: [email protected]

CJASN 15(11):p 1678-1688, November 2020. | DOI: 10.2215/CJN.02690320
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Abstract

Introduction

Diabetic kidney disease and its comorbidities, including atherosclerotic cardiovascular disease, heart failure, diabetes, and obesity, are interconnected conditions that compound the risk of kidney failure and cardiovascular mortality (1), and exponentiate health care costs (2). Clinical trials exploring the cardiovascular and kidney outcomes of sodium glucose cotransporter 2 inhibitor (SGLT2i) (3–8) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) (9–18) have fundamentally shifted the treatment paradigm of diabetes (Tables 1 and 2). To briefly summarize these trials, the studies enriched patients with high cardiovascular and metabolic disease burdens with primary goals for prevention of cardiovascular disease (all cardiovascular outcome trials), kidney disease progression (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation [CREDENCE]), or heart failure hospitalization (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]). The study populations have an average body mass index of 28–33 kg/m2 and a history of longstanding type 2 diabetes, with an average hemoglobin A1c of 7%–9%. Clinical trials of SGLT2i consistently showed (1) a 12%–14% risk reduction in nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death; (2) a 30% risk reduction in heart failure hospitalization; and (3) a 30%–40% risk reduction in CKD progression (19,20). GLP-1 RA clinical trials showed a 12% risk reduction in nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death and a 20%–30% risk reduction of new macroalbuminuria (21).

Table 1. - Summary of baseline characteristics of major SGLT2i trials
Clinical Trial
Cardiovascular Outcome Trial Kidney Outcome Trial Heart Failure Outcome Trial
EMPA-REG CANVAS DECLARE-TIMI 58 CREDENCE DAPA-HF
Drug Empagliflozin Canagliflozin Dapagliflozin Canagliflozin Dapagliflozin
No. of patients 7020 10,142 17,160 4401 4744
Age, yr 63 63 64 63 66
Duration of DM, yr 14 13.5 11 15.5 NR
BMI, kg/m2 31 32 32 31 28
HbA1c, % 8.1 8.2 8.3 8.3 7.4 a
Atherosclerotic cardiovascular disease, % 100 66 41 51 NR
Heart failure, % 10 14 10 15 100
Reduced eGFR, % b 26 20 7 41 40
Mean eGFR, ml/min per 1.73 m2 74 76 85 56 66
UACR<30 mg/g, % 60 70 69 1 NR
UACR 30–300 mg/g, % 29 22 24 11 NR
UACR≥300 mg/g, % 11 8 7 88 NR
Insulin, % 48 50 41 66 25 a
Sulfonylureas, % 43 43 43 29 20 a
ACEi/ARB, % 85 80 81 100 94
Diuretics, % 44 44 41 47 93
SGLT2i, sodium glucose co-transporter 2 inhibitor; EMPA-REG, The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose; CANVAS, The multicenter Canagliflozin Cardiovascular Assessment Study; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DM, diabetes mellitus; NR, not reported; BMI, body mass index; HbA1c, hemoglobin A1c; UACR, urinary albumin-to-creatinine ratio; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
aFor patients with diabetes.
beGFR<60 ml/min per 1.73 m2.

Table 2. - Summary of baseline characteristics of major GLP-1 RA trials
Clinical Trial
Cardiovascular Outcome Trial Diabetic Trial
ELIXA LEADER EXSCEL HARMONY SUSTAIN-6 PIONEER 6 REWIND AWARD-7
Drug Lixisenatide Liraglutide Exenatide Albiglutide Semaglutide Semaglutide a Dulaglutide Dulaglutide
No. of patients 6068 9340 14,752 9463 3297 3183 9901 577
Age, yr 60 64 62 64 65 66 66 65
Duration of DM, yr 9.2 12.8 12.0 14 14.1 14.7 10.5 18
BMI, kg/m2 30 33 32 32 33 32 32 32
HbA1c, % 7.7 8.7 8.0 8.7 8.7 8.2 7.3 8.6
Atherosclerotic cardiovascular disease, % 100 81 73 100 83 85 31 NR
Heart failure, % 22 14 16 20 24 12 8.5 NR
Reduced eGFR, % b 25 25 22 23 29 27 22 96
Mean eGFR, ml/min per 1.73 m2 76 80 76 79 80 74 75 38
UACR<30 mg/g, % 74 64 79 NR NR 67 65 22
UACR 30–300 mg/g, % 19 26 17 NR NR 33 c 27 33
UACR≥300 mg/g, % 7 10 4 NR NR 8 45
Insulin, % 39 45 46 59 58 61 24 100
Sulfonylureas, % 33 51 37 29 43 32 46 NR
ACEi/ARB, % 85 83 80 82 84 NR 81 94
Diuretics, % 33 42 44 42 31 9 46 71
GLP-1 RA, glucagon-like peptide 1 receptor agonist; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; EXSCEL, Exenatide Study of Cardiovascular Event Lowering Trial; HARMONY, Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies, on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; PIONEER 6, A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; AWARD-7, Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe CKD; DM, diabetes mellitus; BMI, body mass index; HbA1c, hemoglobin A1c; NR, not reported; UACR, urinary albumin-to-creatinine ratio; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
aOral form of semaglutide.
beGFR<60 ml/min per 1.73 m2.
cCombination of UACR 30–300 mg/g and UACR≥300 mg/g.

The American Diabetes Association (ADA) 2020 guidelines recommend prescribing an SGLT2i or GLP-1 RA after metformin in patients with established atherosclerotic cardiovascular disease, heart failure, or CKD (22). However, the adoption of prescribing SGLT2i and GLP-1 RA for patients with diabetic kidney disease has been slow. In this review, we discuss a holistic approach to assess the cardiovascular, kidney, and metabolic risks, and propose a stepwise algorithm for prescribing SGLT2i and GLP-1 RA for heart and kidney protection on the basis of risk stratum. In addition, we discuss practical strategies to monitor and mitigate common adverse effects of SGLT2i and GLP-1 RA.

Comprehensive Risk Assessment in Patients with Diabetic Kidney Disease

Atherosclerotic cardiovascular disease, heart failure, diabetes, and obesity contribute to progression of diabetic kidney disease (23–25), and diabetic kidney disease complicates treatment for its comorbidities and compounds the mortality (26). The introduction of SGLT2i and/or GLP-1 RA is a promising strategy to reduce cardiovascular mortality and CKD progression. We outline elements of a comprehensive risk assessment for patients with diabetic kidney disease below, and how each element relates to the preferential prescription of an SGLT2i or GLP-1 RA (Figure 1).

fig1
Figure 1.:
Decision algorithm for prescribing SGLT2i and GLP-1 RA optimizes heart and kidney protection in patients with diabetic kidney disease. This algorithm prioritizes the prescription of SGLT2i and GLP-1 RA for maximal heart and kidney protection on the basis of risk stratum. ASCVD, atherosclerotic cardiovascular disease; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HHF, hospitalization of heart failure; SGLT2i, sodium-glucose-cotransporter 2 inhibitor; TIMI, Thrombolysis in Myocardial Infarction; UACR, urinary albumin-to-creatinine ratio.

Both SGLT2i and GLP-1 RA Prevent Macroalbuminuria and Reduce Albuminuria

Albuminuria and reduced eGFR are independent factors for CKD progression to kidney failure (27). Albuminuria usually precedes the impairment of kidney function and accelerates eGFR decline (28). Worsening albuminuria and reduced eGFR—both independently and together—are associated with higher risk of major cardiovascular events, kidney failure, and all-cause mortality (29). Conversely, a 30% reduction in albuminuria is associated with 1% absolute risk reduction of kidney failure in 10 years (30). Both SGLT2i and GLP-1 RA reduce the risk of progression to macroalbuminuria (urine albumin-to-creatinine ratio [UACR], ≥300 mg/g) by 20%–30% (4,31). For those who have macroalbuminuria, SGLT2i and GLP-1 RA reduce the albuminuria by 30%–40% (14,32).

SGLT2i Reduces Risk for Sustained eGFR Decline or ESKD

Currently, there is no head-to-head study comparing kidney failure protection between SGLT2i and GLP-1 RA. The recommendation is on the basis of the overall strength of the placebo-controlled trials of SGLT2i and GLP-1 RA. Kidney failure risk stratification, including the degree of albuminuria and extent of eGFR decline, should be the first consideration when determining if an SGLT2i or GLP-1 RA is more appropriate for an individual patient (Figure 2).

fig2
Figure 2.:
Recommendations for SGLT2i versus GLP-1 RA on the basis of kidney failure risk stratification.

In patients with low kidney failure risk (preserved eGFR and without albuminuria), SGLT2i and GLP-1 RA similarly reduce the risk of macroalbuminuria. In patients with moderate kidney failure risk (UACR ranges from 30 to 300 mg/g or eGFR ranges from 30 to 60 ml/min per 1.73 m2 without albuminuria), the overall strength of evidence of SGLT2i in preventing kidney failure is more abundant than for GLP-1 RA. All SGLT2i trials showed consistent reduction in sustained eGFR decline or ESKD in the subgroups with eGFR>60 ml/min per 1.73 m2 and low-grade albuminuria (4,5,8), whereas only dulaglutide in the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial reduced kidney failure in a population with preserved eGFR and low-grade albuminuria (13). In patients with high kidney risk (UACR≥300 mg/g) and adequate eGFR (eGFR≥30 ml/min per 1.73 m2), an SGLT2i should be initiated independent of baseline hemoglobin A1c level and may be continued even when eGFR falls below 30 ml/min per 1.73 m2, according to the CREDENCE trial (6). Currently, the benefits and safety of initiating SGLT2i in patients with eGFR<30 ml/min per 1.73 m2 remain unclear. Ongoing clinical trials, including the Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) (testing dapagliflozin; Clinicaltrials.gov identifier NCT03036150) and the Study of Heart and Kidney Protection With Empagliflozin (EMPA-Kidney) (testing empagliflozin; Clinicaltrials.gov identifier NCT03594110), are studying the kidney failure prevention of SGLT2i in patients with eGFRs as low as 20–25 ml/min per 1.73 m2. Moreover, to fill an important evidence gap, EMPA-Kidney and DAPA-CKD trials are testing SGLT2i in kidney failure prevention in nondiabetic CKD and in CKD without albuminuria (EMPA-Kidney only). GLP-1 RA may be considered when SGLT2i is contraindicated (e.g., eGFR<30 ml/min per 1.73 m2) or not tolerated. In the Dulaglutide versus Insulin Glargine in Patients with Type 2 Diabetes and Moderate-to-Severe CKD trial, albeit not a kidney outcome trial, dulaglutide slowed annual eGFR decline by 5 ml/min per 1.73 m2 when compared with insulin glargine in individuals with moderate to severe CKD (17). The kidney outcome trial of semaglutide for kidney failure prevention in patients with macroalbuminuria and CKD (a Research Study to See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and CKD; Clinicaltrials.gov identifier NCT03819153) is ongoing.

In summary, SGLT2i is preferred over GLP-1 RA for kidney failure prevention in patients with albuminuria and eGFR≥30 ml/min per 1.73 m2, on the basis of the overall strength and abundance of placebo-controlled, clinical trials data, but not on head-to-head comparison. GLP-1 RA should be considered when SGLT2i is contraindicated, especially in patients with eGFR<30 ml/min per 1.73 m2.

SGLT2i May Reduce the Risk of AKI

Patients with reduced eGFR and high-grade albuminuria are at higher risk for AKI (33). AKI is associated with worsening proteinuria (34) and CKD progression (35). Prevention of AKI is important to slow CKD progression and to avert acute complications such as hyperkalemia and volume overload. In contrast to the common concerns of SGLT2i increasing AKI risk owing to volume depletion, SGLT2i has consistently shown reduction of AKI risk in observational studies (36,37) and clinical trials (20,38). The exact mechanism by which SGLT2i reduces AKI risk is under investigation. SGLT2i may attenuate ischemic-reperfusion injury to the kidney (39) and reduce tubular injury markers (40). Randomized clinical trials testing SGLT2i in preventing AKI are warranted. Currently, there are no clinical data in support of GLP-1 RA for AKI prevention.

SGLT2i Reduces Heart Failure Hospitalization More than GLP-1 RA

The rate of heart failure hospitalization is high in CKD (41). Reduced eGFR and albuminuria compound the risk of heart failure hospitalization and mortality (41). Prevention of heart failure hospitalization can reduce the risk of CKD progression and death (42). The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes tool, which includes prior history of heart failure, atrial fibrillation, coronary artery disease, eGFR, and albuminuria, is a validated clinical tool for heart failure risk stratification. A score of ≥2 identifies patients with a high risk for heart failure hospitalization (43).

SGLT2i consistently reduces the risk of heart failure hospitalization by approximately 30% across the spectrum of heart failure risk (44), in patients with and without diabetes (DAPA-HF trial) (7), and in systolic heart failure (7) and, potentially, diastolic heart failure (45,46). Dedicated SGLT2i trials for prevention of heart failure hospitalization in diastolic heart failure, including Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (testing dapagliflozin; Clinicaltrials.gov identifier NCT03619213) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (testing empagliflozin; Clinicaltrials.gov identifier NCT03057951), are currently underway. The risk reduction of heart failure hospitalization is more pronounced in patients with cardiovascular disease and CKD (47).

In prospective observational studies, SGLT2i was associated with 40%–50% less heart failure hospitalizations compared with other antidiabetic agents in participants with a low prevalence of cardiovascular disease (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL 2]) (48) and those with established cardiovascular disease (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World) (49). In contrast, GLP-1 RA showed no benefit or harm on heart failure hospitalization in individual clinical trials. In a meta-analysis (21), GLP-1 RA showed only a modest risk reduction in heart failure hospitalization (hazard ratio, 0.91; 95% confidence interval, 0.83 to 0.99). When SGLT2i and GLP-1 RAs were compared in population-based cohort studies, SGLT2i users had a 30%–40% lower risk of heart failure hospitalization compared with GLP1-RA users (50). Thus, SGLT2i is preferred over GLP-1 RA in patients at high risk of heart failure hospitalization.

Both SGLT2i and GLP-1 RA Reduce the Risk of Cardiovascular Events

Atherosclerotic cardiovascular diseases include coronary artery disease, cerebrovascular disease, and peripheral and aortic arterial disease. SGLT2i and GLP-1 RA similarly reduce nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (referred to as a three-point major adverse cardiovascular event) by 12%–14% in patients with established cardiovascular disease (51).

Some studies suggest potential benefits of SGLT2i and GLP-1 RA as primary preventions for cardiovascular disease. In a meta-analysis of four major SGLT2i trials (the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose, the Multicenter Canagliflozin Cardiovascular Assessment Study, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58, and CREDENCE), SGLT2i reduced myocardial infarction, stroke, and cardiovascular death irrespective of established cardiovascular disease, heart failure, or baseline kidney function (19). SGLT2i may also reduce atrial fibrillation (52) and protect against stroke in individuals with reduced kidney function (19). The global observational study CVD-REAL 2 demonstrated that SGLT2i reduced risk of myocardial infarction by 19% and stroke by 32% compared with other glucose-lowering agents despite a lower percentage (27%) of participants with preexisting cardiovascular disease and shorter follow-up duration (approximately 12–13 months) than the SGLT2i cardiovascular outcome trials. The CVD-REAL 2 study complements the SGLT2i cardiovascular outcome trials and supports the use of SGLT2i for primary prevention of atherosclerotic cardiovascular disease. For GLP-1 RA, in the REWIND trial, where only 31% of the participants had established cardiovascular disease, dulaglutide reduced three-point major adverse cardiovascular events by approximately 12%, regardless of preexisting atherosclerotic cardiovascular disease (12).

In summary, both SGLT2i and GLP-1 RA are recommended for patients with atherosclerotic cardiovascular disease or with high-risk factors, such as diabetes, hypertension, smoking, dyslipidemia, and left ventricular hypertrophy. GLP-1 RA is recommended by the ADA as the preferred agent for patients with established cardiovascular disease; SGLT2i is noted as an alternative if an oral medication is preferred (22).

GLP-1 RA Is Superior to SGLT2i in Reducing Metabolic Risks

Metabolic comorbidities like uncontrolled diabetes and obesity are prevalent in patients with CKD, and should be considered when choosing between a SGLT2i or GLP-1 RA. Intensive glucose control, commonly by insulin and sulfonylureas in patients with CKD (53), reduces risk of CKD progression in the early stages of CKD (preserved eGFR without macroalbuminuria) (23), but not in moderate to severe CKD. In the Action to Control Cardiovascular Risk in Diabetes trial, even those with early CKD had higher risks of hypoglycemia (54), cardiovascular events, and death (55). To maintain glycemic control and avoid severe hypoglycemia is challenging, especially in patients with CKD, where the choices of glucose-lowering agents are often limited (56) and the risk of severe hypoglycemia is exponentially increased (57). Severe hypoglycemia increases risk of cardiovascular events (58), heart failure hospitalization (59), and mortality (60). Minimizing hypoglycemia is imperative for improving cardiovascular outcomes. GLP-1 RAs are highly effective in reducing hemoglobin A1c with low risk of hypoglycemia (61) (as opposed to insulin or sulfonylureas) and volume expansion (as opposed to thiazolidinediones), and remain efficacious and safe in moderate CKD (17) (as opposed to metformin), which makes it an ideal glucose-lowering agent for patients with CKD. When compared head to head, GLP-1 RA is superior than SGLT2i for glycemic control and weight loss (62), especially in patients with reduced eGFR (63). Combining GLP-1 RA and SGLT2i further reduces hemoglobin A1c and weight (64). Oral GLP-1 RA (semaglutide) is now approved by the US Food and Drug Administration, serving as an alternative if an oral medication is preferred.

Integrated Algorithm to Consider SGLT2i and GLP-1 RA in Patients with Diabetic Kidney Disease

Herein, we summarize our stepwise algorithm for prescribing SGLT2i and/or GLP-1 RA (Figure 1) on the basis of the clinical evidence above. First, if patients have UACR≥300 mg/g and eGFR is ≥30 ml/min per 1.73 m2, an SGLT2i should be initiated for kidney failure prevention and continued even when eGFR falls below 30 ml/min per 1.73 m2. GLP-1 RA should be considered as an add-on therapy in patients with uncontrolled metabolic risks, and as an alternative to SGLT2i for kidney failure prevention when UACR is ≥300mg/g and eGFR is <30 ml/min per 1.73 m2.

When UACR is <300 mg/g, an SGLT2i should be initiated if patients have a high risk of heart failure hospitalization. In the absence of a high risk of CKD progression and/or heart failure hospitalization, an SGLT2i or GLP-1 RA should be prescribed for those with established or at high risk for cardiovascular disease. GLP-1 RA is preferred for those with coexisting, uncontrolled metabolic risks.

In patients without heart failure or established cardiovascular disease but with low-grade albuminuria, it is reasonable to initiate SGLT2i for kidney failure prevention if eGFR is ≥30 ml/min per 1.73 m2. GLP-1 RA could be introduced to patients with uncontrolled metabolic risks or as an alternative to SGLT2i if eGFR is <30 ml/min per 1.73 m2 or the patient is intolerant of SGLT2i.

If patients have uncontrolled metabolic risks, GLP-1 RA is preferred over SGLT2i for greater efficacies in glucose lowering and weight loss across a broad range of eGFRs in the absence of albuminuria, heart failure, or cardiovascular disease. If medication cost is a concern, SGLT2i and GLP-1 RA are not recommended by the ADA in the absence of albuminuria, heart failure, atherosclerotic cardiovascular disease, or uncontrolled metabolic risks. There are insufficient data at this time to support the combined use of SGLT2i and GLP-1 RA for further cardiovascular and kidney failure risk reduction.

Monitoring and Mitigating Adverse Effects of SGLT2i and GLP-1 RA

When deciding to treat patients with SGLT2i or GLP-1 RA agents, the risk of adverse events should be weighed against the risk of kidney disease progression. The frequent common adverse effects of SGLT2i and GLP-1 RA are transient and reversible. Patients should be monitored for the severe but infrequent adverse events, and proactive mitigating strategies can be taken (Table 3).

Table 3. - Strategies to mitigate the adverse effects of SGLT2i and GLP1-RA
Adverse Effects Frequency Severity Mitigating Strategies
SGLT2i
 Genital fungal infection a Low Keep genital area dry and clean. Prophylactic topical treatment for fungal infection in high-risk patients
 Volume depletion a Low Proactive dose reduction of diuretics in euvolemic patients. Hold SGLT2i when patients have nausea, vomiting, or diarrhea. Implement “Sick day protocol”
 UTI b Low Use with caution. Avoid in patients at high risk of recurrent UTI (e.g., indwelling foley catheter or self-catheterization)
 DKA c High Patient education on early recognition and implement “STOP DKA” protocol (stop SGLT2i, test for ketones, maintain intake of fluid and carbohydrates, and use maintenance and supplemental insulin)
 Amputation b High Encourage self-examination by patients or caregivers. Foot examination by health care provider at clinic visits. Temporarily hold SGLT2i when having an open wound or infection of the foot
 Bone fracture b High Caution in patients with risk of fall. Monitor PTH and vitamin D
GLP-1 RA
 Nausea/vomiting/diarrhea a Low Patient education on symptom recognition. Start at low dose and slowly uptitrate over 2–4 wk
 Cholelithiasis and cholecystitis b High Patient education on recognition of symptoms
 Acute pancreatitis d High Caution in patients with history of pancreatitis
SGLT2i, sodium glucose co-transporter 2 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; UTI, urinary tract infection; DKA, diabetic ketoacidosis; PTH, parathyroid hormone.
aCommonly reported in multiple, large clinical trials.
bIncreased risk reported in a single, large clinical trial.
cIncreased risk reported in meta-analysis of clinical trials.
dReported in small clinical trials or case series.

Adverse Effects of SGLT2i and Mitigation Strategies

One of the most common adverse effects of SGLT2i is genital fungal infection. Maintaining good genital hygiene can reduce this risk. Individuals with immobility, incontinence, intertrigo in the groin region, chronic diarrhea, or inability to maintain genital hygiene should avoid the use of SGLT2i because of increased risk for perineal necrotizing fasciitis (65). Prophylactic topical antifungal medication could be used in high-risk patients.

Another common adverse effect is volume depletion. Baseline diuretic use is an independent factor for eGFR decrease >10% with empagliflozin, which often leads to premature discontinuation of SGLT2i. When an SGLT2i is added to a maintenance dose of diuretics in patients with euvolemia, proactive reduction of diuretics and monitoring for volume depletion can avoid an acute decline in eGFR.

Euglycemic diabetic ketoacidosis (DKA) is a rare but severe adverse effect of SGLT2i, occurring in patients on insufficient insulin, reduced carbohydrate intake, volume depletion, excessive alcohol use, or concomitant infections (66). Educating patients on the signs and symptoms of DKA and following the STOP DKA protocol (67) (stop SGLT2i, test for ketones, maintain intake of fluid and carbohydrates, and use maintenance and supplemental insulin) are keys to mitigating the risk of euglycemic DKA.

Amputation was seen in the CANVAS trial but not in other large SGLT2i trials. Foot examination should be performed daily by the patient and at every clinic visit by health care providers. Temporarily holding SGLT2i should be considered when patients have an open wound or infection of the foot.

Although the risk of urinary tract infection (UTI) from SGLT2i was not significantly increased in a large population-based cohort (68), in patients with history of recurrent severe UTI (i.e., UTI or pyelonephritis that requires hospitalization), alternatives to SGLT2i should be considered.

A higher risk of bone fracture was seen in the CANVAS trial (4) but not in other large SGLT2i trials. The magnitude and variability of SGLT2is on bone mineral adverse effects are yet to be determined. It is advisable to monitor the patient’s parathyroid hormone level when on SGLT2i and treat with active vitamin D analogs if the parathyroid hormone level uptrends above goal. SGLT2i should be used with caution in patients at high risk for falls.

Adverse Effects of GLP-1 RA and Mitigation Strategies

The most common adverse effects of GLP-1 RA are nausea, vomiting, and diarrhea, which are often self-limited after 2–4 weeks of use. These gastrointestinal side effects may be ameliorated by starting at the lowest dose and slowly increasing the dose over the course of several weeks. GLP-1 RA may increase heart rate because of sympathetic stimulation (69) but is not associated with the development of atrial fibrillation (70). Coadministration of a β-blocker can mitigate this effect on heart rate.

GLP-1 RA increases the risk of acute biliary disease, such as cholelithiasis and cholecystitis, but does not increase the risk of acute pancreatitis (71). GLP-1 RA should be used with caution in patients with a history of cholelithiasis or pancreatitis.

GLP-1 RA is associated with risk of medullary thyroid cancer in rodents but not in primates (72). GLP-1 RA is contraindicated in patients with medical history or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2.

Conclusion

Cardiovascular diseases, heart failure, and kidney failure are the leading morbidities in patients with diabetic kidney disease. Treatments that reduce cardiovascular events, heart failure hospitalization, and CKD progression are critical. SGLT2i and GLP-1 RA reduce cardiovascular events similarly. SGLT2i is preferred for patients with heart failure and CKD, whereas GLP-1 RA is preferred for patients with uncontrolled metabolic risks and in moderate to severe CKD, particularly when eGFR is <30 ml/min per 1.73 m2. Meticulous patient selection by a comprehensive risk assessment algorithm and proactive strategies to mitigate adverse effects can facilitate the adoption of SGLT2i and GLP-1 RA for heart and kidney protection. The combined use of SGLT2i and GLP-1 RA in improving cardiovascular and kidney outcomes merits further investigation.

Disclosures

All authors have nothing to disclose.

Funding

J. Li is supported by the Ben J. Lipps Research Fellowship from the American Society of Nephrology. M. Zhuo is supported by National Institute of Diabetes and Digestive and Kidney Diseases award T32-DK007199. J. Paik is supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases award R01-AR075117.

Published online ahead of print. Publication date available at www.cjasn.org.

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Keywords:

chronic kidney disease; sodium-glucose cotransporter 2 inhibitor; glucagon-like peptide-1 receptor agonist; prescribing algorithm; diabetic kidney disease; Glucagon-Like Peptide 1; Diabetic Nephropathies; Glucagon-Like Peptide-1 Receptor; Cardiovascular Diseases; Blood Glucose; obesity; heart failure; kidney; Renal Insufficiency; Risk Assessment; Health Care Costs; Algorithms; Decision Making; Symporters

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