Is Farxiga (dapagliflozin) a safe and efficacious agent for Type 2 DM and CKD.

Comment by InpharmD Researcher

Evidence from the DAPA-CKD trial and its subgroup analyses supports Farxiga (dapagliflozin) for reducing kidney disease progression and cardiovascular events in patients with T2DM and CKD, with generally favorable safety findings. These benefits are consistent with current clinical guidelines, although risks such as volume depletion, genital mycotic infections, and diabetic ketoacidosis warrant consideration. Notably, DAPA-CKD enrolled patients with a UACR of 200-5,000 mg/g, limiting the direct applicability of its findings to patients with lower levels of albuminuria.

A literature search was conducted using PubMed and Google Scholar to identify studies evaluating the efficacy and safety of Farxiga (dapagliflozin) in patients with type 2 diabetes mellitus and chronic kidney disease. Search terms included “Farxiga,” “dapagliflozin,” “SGLT2 inhibitors,” “type 2 diabetes mellitus,” “chronic kidney disease,” “DAPA-CKD,” “renal outcomes,” “cardiovascular outcomes,” “efficacy,” and “safety,” alone and in various combinations. Relevant clinical practice guidelines from the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO), along with FDA prescribing information, were also reviewed.

Background

The 2026 American Diabetes Association (ADA) Standards of Care recommend sodium-glucose cotransporter-2 (SGLT2) inhibitors with demonstrated kidney and cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Specifically, recommendation 11.7a (Grade A) recommends initiating SGLT2 inhibitors in patients with an estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m² to reduce CKD progression and cardiovascular events, with treatment continued until kidney failure if tolerated. The guidelines emphasize that SGLT2 inhibitors slow kidney function decline and reduce albuminuria through mechanisms that appear independent of glucose lowering. [1]

Regarding efficacy, the guidelines highlight the DAPA-CKD trial (see Table 1 for an overview of DAPA-CKD and Tables 2-3 for relevant subgroup analyses), which evaluated Farxiga (dapagliflozin) in 4,304 patients with CKD, approximately 67.5% of whom had T2DM. Participants had a mean baseline eGFR of 43.1 mL/min/1.73 m² and a median urinary albumin-to-creatinine ratio (UACR) of 949 mg/g. Dapagliflozin significantly reduced the primary composite outcome of sustained ≥50% decline in eGFR, kidney failure, or kidney or cardiovascular death compared with placebo (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.51 to 0.72; p <0.001). Significant reductions were also observed in the kidney-specific composite outcome (HR 0.56; 95% CI 0.45 to 0.68; p<0.001) and the composite of cardiovascular death or hospitalization for heart failure (HR 0.71; 95% CI 0.55 to 0.92; p= 0.009). [1]

Regarding safety, the guidelines acknowledge concerns about acute kidney injury (AKI) associated with SGLT2 inhibitor–induced volume depletion, particularly when combined with diuretics or other medications affecting kidney hemodynamics. However, an increased risk of AKI has not been observed in randomized controlled trials. An initial increase in serum creatinine may occur following SGLT2 inhibitor initiation because of hemodynamic changes and generally does not warrant discontinuation. Additionally, the guidelines cite a post hoc analysis of DAPA-CKD demonstrating that dapagliflozin's effects in patients with stage G4 CKD and albuminuria were consistent with those observed in the overall trial, without evidence of increased risks. [1]

Overall, the guidelines support the use of SGLT2 inhibitors, including dapagliflozin, to reduce kidney disease progression and cardiovascular complications in patients with T2DM and CKD. The guidelines also emphasize that treatment selection should consider kidney function, cardiovascular and kidney risks, adverse effects, comorbidities, patient preferences, and cost. [1]

Consistent with the ADA recommendations summarized above, the 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guideline strongly recommends SGLT2 inhibitors for patients with T2DM, CKD, and an eGFR ≥20 mL/min/1.73 m² (Grade 1A), primarily for kidney and cardiovascular protection rather than glycemic control alone. Dapagliflozin 10 mg once daily is specifically identified among agents with demonstrated benefits. The guideline cites several randomized controlled trials supporting this recommendation, including DAPA-CKD, which demonstrated significant reductions in kidney disease progression and cardiovascular outcomes, as previously discussed. KDIGO notes that evidence is particularly strong in patients with elevated albuminuria and reduced kidney function, consistent with populations enrolled in major kidney outcome trials. For safety, KDIGO highlights genital mycotic infections, volume depletion, and diabetic ketoacidosis as important risks associated with SGLT2 inhibitors. Hypoglycemia risk may also increase when these agents are combined with insulin or sulfonylureas. The guideline recommends assessing volume status, considering adjustments to concomitant diuretics or glucose-lowering medications when appropriate, and temporarily withholding treatment during prolonged fasting, surgery, or critical illness. An initial reversible decline in eGFR generally does not warrant discontinuation, and treatment may be continued if eGFR falls below 20 mL/min/1.73 m² unless poorly tolerated or kidney replacement therapy is initiated. Notably, the eGFR threshold is a class-level recommendation rather than dapagliflozin-specific prescribing guidance. [2]

Relevant Prescribing Information

Indications and Usage [3]
FARXIGA is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated:
To reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular (CV) death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression.
To reduce the risk of CV death, hospitalization for heart failure, and urgent heart failure visit in adults with heart failure.
To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors.
As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus.

Limitations of use [3]
Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus.
Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m2. FARXIGA is likely to be ineffective in this setting based upon its mechanism of action.
Not recommended for the treatment of chronic kidney disease in patients with polycystic kidney disease or patients requiring or with a recent history of immunosuppressive therapy for the treatment of kidney disease. FARXIGA is not expected to be effective in these populations.

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Is Farxiga (dapagliflozin) a safe and efficacious agent for Type 2 DM and CKD.

Level of evidence

A - Multiple high-quality studies with consistent results Read more→

Please see Tables 1-3 for your response.

Dapagliflozin in Patients with Chronic Kidney Disease
Design	Randomized, double-blind, placebo-controlled, multicenter clinical trial; DAPA-CKD trial N= 4304
Objective	To assess the long-term efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes
Study Groups	Dapagliflozin (n= 2152) Placebo (n= 2152)
Inclusion Criteria	Adults with or without type 2 diabetes, estimated GFR of 25 to 75 ml/min/1.73 m2, urinary albumin-to-creatinine ratio of 200 to 5000, receiving a stable dose of an ACE inhibitor or ARB for at least 4 weeks before screening
Exclusion Criteria	Documented diagnosis of type 1 diabetes, polycystic kidney disease, lupus nephritis, or antineutrophil cytoplasmic antibody-associated vasculitis; received immunotherapy for kidney disease within 6 months before enrollment
Methods	Participants were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo. Randomization was stratified by type 2 diabetes diagnosis and urinary albumin-to-creatinine ratio. Follow-up visits were conducted at 2 weeks, 2, 4, and 8 months, and every 4 months thereafter. The primary outcome was a composite of a sustained decline in estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes
Duration	February 2017 to June 2020
Outcome Measures	Primary: Composite of a sustained decline in estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes Secondary: Composite of decline in estimated GFR of ≥50%, end-stage kidney disease, or death from renal causes; composite of death from cardiovascular causes or hospitalization for heart failure; death from any cause
Baseline Characteristics		Dapagliflozin (n= 2152)	Placebo (n= 2152)
	Age, years	61.8±12.1	61.9±12.1
	Female sex, %	32.9	33.3
	White, %	52.2	54.2
	Black, %	4.8	4.0
	Asian, %	34.8	33.4
	Other, %	8.1	8.4
	Weight, kg	81.5±20.1	82.0±20.9
	Body-mass index	29.4±6.0	29.6±6.3
	Current smoker, %	13.2	14.0
	Systolic blood pressure, mm Hg	136.7±17.5	137.4±17.3
	Diastolic blood pressure, mm Hg	77.5±10.7	77.5±10.3
	Estimated GFR, ml/min/1.73 m2	43.2±12.3	43.0±12.4
	Type 2 diabetes, %	67.6	67.4
Results		Dapagliflozin (n= 2152)	Placebo (n= 2152)	Hazard Ratio (95% CI)	p-Value
	Primary composite outcome	197/2152 (9.2%)	312/2152 (14.5%)	0.61 (0.51–0.72)	<0.001
	Decline in estimated GFR of ≥50%	112/2152 (5.2%)	201/2152 (9.3%)	0.53 (0.42–0.67)	-
	End-stage kidney disease	109/2152 (5.1%)	161/2152 (7.5%)	0.64 (0.50–0.82)	-
	Death from cardiovascular causes	65/2152 (3.0%)	80/2152 (3.7%)	0.81 (0.58–1.12)	-
	Composite of death from cardiovascular causes or hospitalization for heart failure	100/2152 (4.6%)	138/2152 (6.4%)	0.71 (0.55–0.92)	0.009
	Death from any cause	101/2152 (4.7%)	146/2152 (6.8%)	0.69 (0.53–0.88)	0.004
Adverse Events	The incidences of adverse events and serious adverse events were similar overall in the dapagliflozin and placebo groups. Diabetic ketoacidosis was not reported in any participants who received dapagliflozin and in two participants who received placebo. There was one confirmed case of Fournier’s gangrene in the placebo group and none in the dapagliflozin group.
Study Author Conclusions	Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo.
Critique	The study was well-designed as a randomized, double-blind, placebo-controlled trial, providing strong evidence for the efficacy of dapagliflozin in reducing renal and cardiovascular outcomes in chronic kidney disease patients. However, the trial was stopped early due to efficacy, which may have reduced the power for some secondary outcomes. Additionally, the trial did not collect estimated GFR values after completion, limiting the understanding of long-term effects post-treatment.

Table 1 References:
[4] Heerspink HJL, Stefnsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816

Effects of Dapagliflozin on Major Adverse Kidney and Cardiovascular Events in Patients with Diabetic and Non-diabetic Chronic Kidney Disease: A Pre-specified Analysis from the DAPA-CKD Trial
Design	Randomized controlled trial N= 4,304
Objective	To examine whether the presence or absence of type 2 diabetes at baseline and the underlying aetiology of kidney disease modified the effects of dapagliflozin on these clinical outcomes
Study Groups	Dapagliflozin (n= 2,152) Placebo (n= 2,152)
Inclusion Criteria	Type 2 diabetes, established atherosclerotic cardiovascular disease or multiple risk factors for atherosclerotic cardiovascular disease, HbA1c between 6.5%-12%, chronic kideny disease (eGFR 25-75 mL/min/1.73m²)
Exclusion Criteria	Diagnosis of type 1 diabetes, polycystic kidney disease, lupus nephritis, or anti-neutrophil cytoplasmic antibody-associated vasculitis, receiving immunotherapy for primary or secondary kidney disease within the prior six months
Methods	After an initial 4-8 week run-in period, patients were randomized (1:1) to receive dapagliflozin 10 mg once-daily or matching placebo. Study visits occurred at 2 weeks, 2, 4, and 8 months, and every 4 months thereafter.
Duration	Median follow-up: 2.4 years
Outcome Measures	Primary: composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney or cardiovascular death Secondary: kidney composite (primary without cardiovascular death)
Baseline Characteristics		Type 2 diabetes		Without diabetes
		Dapagliflozin (n= 1,455)	Placebo (n= 1,451)	Dapagliflozin (n= 697)	Placebo (n= 701)
	Age, years	64.1 ± 9.8	64.7 ± 9.5	56.9 ± 14.6	56 ± 14.6
	Female	34%	32.5%	30.8%	35%
	White Black or African American Asian Other	51.6% 5.2% 33.1% 10.1%	54.4% 4.2% 31.1% 10.3%	53.5% 4% 38.5% 4.0%	53.6% 3.7% 38.1% 4.6%
	Weight, kg	83.2 ± 20.9	83.8 ± 21.2	77.9 ± 17.8	78.3 ± 19.9
	Estimate GFR, mL/min/1.73 m² ≥ 60 45 to < 60 30 to < 45 < 30	12.3% 30.9% 43.7% 13.1%	11.6% 32.3% 41.6% 14.5%	7.9% 28.1% 49.2% 14.8%	7.3% 30.5% 45.1% 17.1%
Results	Endpoint	Dapagliflozin (n= 2,152)	Placebo (n= 2,152)	Hazard ratio (HR) (95% confidence interval [CI])
	Primary composite outcome, event per 100 patient-years	5.2	8	0.64 (0.52 to 0.79)
	Secondary kidney composite outcome, HR (95% CI)	0.57 (0.45 to 0.73)	0.51 (0.34 to 0.75)
Adverse Events	Any serious adverse event: without diabetes, dapagliflozin 21.6% vs. placebo 23.9%%; Type 2 diabetes, 33.2% vs. 38.8% (p= 0.48) Discontinuation due to adverse event: without diabetes, 5.2% vs. 4.1%; Type 2 diabetes, 5.6% vs. 6.5% (p= 0.2) Adverse events of interest Without diabetes: amputation (0 vs. 0.1%); fracture (2.9% vs. 2.6%); renal related adverse event (4.9% vs. 5.7%); volume depletion (5% vs. 2.7%) Type 2 diabetes: amputation (2.4% vs. 2.6%); diabetic keotacidosis (0 vs. 0.1%); fracture (4.5% vs. 3.5%); renal related adverse event (8.3% vs. 10.2%); major hypoglycemia (1% vs. 1.9%); volume depletion (6.3% vs. 4.9%)
Study Author Conclusions	Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic CKD
InpharmD Researcher Critique	Although the analysis was pre-specified, the study results are presented with a surprising lack of transparency. This lack of clarity hinders the ability to engage with the study and limits the reliability of the author's findings.

Table 2 References:
[5] Wheeler DC, Stefnsson BV, Jongs N, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 2021;9(1):22-31. doi:10.1016/S2213-8587(20)30369-7

Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial
Design	Multicenter, double-blind, placebo-controlled, randomized trial N= 4,304
Objective	To compare the efficacy and safety of dapagliflozin versus placebo in reducing kidney and cardiovascular outcomes in participants with chronic kidney disease (CKD) with and without diabetes, according to baseline glycemic status
Study Groups	Normoglycemia (n= 738) Prediabetes (n= 660) Type 2 diabetes (n= 2,906)
Inclusion Criteria	Participants with CKD, eGFR 25–75 mL/min/1.73 m2, and urinary albumin-to-creatinine ratio 200–5,000 mg/g
Exclusion Criteria	See the main DAPA-CKD trial. The analysis utilized the parent trial's eligibility criteria rather than a separate set of exclusions based on glycemic status
Methods	Participants were randomized 1:1 to dapagliflozin 10 mg/day or placebo. The primary endpoint was a composite of sustained eGFR decline $50%, end-stage kidney disease, or kidney or cardiovascular death. Secondary endpoints included kidney-specific outcomes, cardiovascular outcomes, and all-cause mortality. Participants were monitored for a median of 2.4 years
Duration	Median follow-up of 2.4 years
Outcome Measures	Primary: Composite of sustained eGFR decline $50%, end-stage kidney disease, or kidney or cardiovascular death Secondary: Kidney-specific composite outcome, composite cardiovascular endpoint, all-cause mortality
Baseline Characteristics		Normoglycemia (n= 738)	Prediabetes (n= 660)	Type 2 diabetes (n= 2,906)
	HbA1c, %	<5.7	5.7 to <6.5	≥6.5
Results	In this prespecified subgroup analysis of DAPA-CKD, 4,304 participants were categorized by baseline glycemic status as having normoglycemia (n=738), prediabetes (n=660), or T2DM (n=2,906). Dapagliflozin significantly reduced the primary composite outcome of ≥50% eGFR decline, end-stage kidney disease, or kidney or cardiovascular death compared with placebo (HR 0.61; 95% CI 0.51–0.72), with no significant difference in treatment effect across glycemic subgroups (p for interaction=0.19). Similar consistency was observed for the kidney-specific composite outcome (p for interaction=0.42), cardiovascular death or hospitalization for heart failure (HR 0.71; 95% CI 0.55–0.92; p for interaction=0.43), and all-cause mortality (p for interaction=0.25). Among participants with T2DM, dapagliflozin produced a modest reduction in HbA1c compared with placebo (between-group difference −0.1%; 95% CI −0.2 to 0.0; p=0.0378).
Adverse Events	Serious adverse event rates were similar between treatment groups across glycemic subgroups (p for interaction=0.18). No diabetic ketoacidosis events occurred in dapagliflozin-treated participants, compared with two events in placebo-treated participants with T2DM. Major hypoglycemia occurred in fewer dapagliflozin-treated participants with T2DM than placebo-treated participants (14 vs 28), while no events occurred among dapagliflozin-treated participants with normoglycemia or prediabetes. No between-treatment or glycemic subgroup differences were observed for fractures, amputations, or kidney-related adverse events, and no significant interaction by glycemic status was observed for volume depletion.
Study Author Conclusions	Dapagliflozin safely reduced kidney and cardiovascular events independent of baseline glycemic status, supporting its use in CKD patients regardless of glycemic status.
Critique	The study's strengths include its large sample size and robust design as a multicenter, double-blind, placebo-controlled trial. However, the early termination of the trial may limit the statistical power to examine other endpoints, and the findings may not be generalizable to patients with lower levels of albuminuria or an eGFR <25 mL/min/1.73 m2.

Table 3 References:
[6] Persson F, Rossing P, Vart P, et al. Efficacy and Safety of Dapagliflozin by Baseline Glycemic Status: A Prespecified Analysis From the DAPA-CKD Trial. Diabetes Care. 2021;44(8):1894-1897. doi:10.2337/dc21-0300