The SGLT2 inhibitors have had a profound effect on chronic disease management, in particular, in those living with chronic kidney disease, heart failure, or seeking to reduce cardiovascular risk in type 2 diabetes.

There has been a quiet but profound shift in how we understand and use them. What began as a class of glucose-lowering agents has become central to the management of chronic kidney disease and heart failure. Most clinicians now recognize their role in slowing kidney decline and reducing cardiovascular events.

And yet, when kidney function falls into the low 20s – or below – many of us still hesitate.

That hesitation is not unreasonable. It reflects how these drugs were originally studied and how their use was first framed. But it is increasingly at odds with what we now understand about how they work and where their benefits lie.

How the Threshold Entered Practice

The commonly cited eGFR “floor” for SGLT2 inhibitors comes from the major clinical trials – CREDENCE, DAPA-CKD, and EMPA-KIDNEY.

Each of these studies required a minimum eGFR for enrollment, generally in the range of 20 to 30 mL/min/1.73 m². That decision has often been interpreted as implying that the drugs are ineffective or unsafe below those levels.

In reality, those thresholds were pragmatic. At the time these trials were designed, SGLT2 inhibitors were still largely viewed through a glycemic lens, and there was understandable caution about introducing them in advanced CKD. Trial populations also need to be bounded to allow for interpretable results.

Over time, however, those entry criteria have taken on a life of their own. What began as a study design choice has come to feel like a biological boundary.

What the Trials Actually Tell Us

One detail that tends to receive less attention is what happened after patients entered these trials.

Kidney function did not remain static. Many participants experienced progressive decline in eGFR, often falling well below the initial enrollment threshold. In general, however, they were not required to discontinue therapy as this occurred. Regulatory summaries of these trials now make this explicit, noting that patients in studies such as DAPA-CKD and related programs continued therapy even as eGFR declined below the entry criteria.

Importantly, there was no signal that benefit disappeared once a patient crossed an arbitrary eGFR value. Nor was there a late-emerging safety concern specific to lower levels of kidney function.

This creates a situation that is difficult to reconcile clinically. A patient who began treatment at an eGFR of 28 and has since declined to 17 is typically continued on therapy without much debate. A patient who first presents at an eGFR of 17, however, may be considered a less appropriate candidate to start.

The physiology in these two situations is the same. The difference lies in how the evidence was generated, not in how the drug behaves.

Moving Beyond the Glycemic Frame

Part of the persistence of this threshold comes from the way these drugs were originally conceptualized.

It remains true that the glucose-lowering effect of SGLT2 inhibitors diminishes as eGFR falls. With less filtered glucose, there is less glycosuria, and HbA1c reductions become modest.

But the outcomes that have driven their widespread adoption in CKD are not primarily related to glycemic control.

The more relevant mechanism is hemodynamic. By inhibiting sodium reabsorption in the proximal tubule, these agents increase sodium delivery to the macula densa, restore tubuloglomerular feedback, and reduce intraglomerular pressure. This results in a functional “unloading” of the glomerulus.

That mechanism does not appear to switch off at a specific eGFR. It is active in moderate CKD and, based on both physiology and trial experience, likely remains operative in more advanced stages as well.

Once one accepts that the benefit is largely independent of glucose lowering, the rationale for a strict lower threshold becomes less clear.

Interpreting the Early Rise in Creatinine

The initial rise in serum creatinine that accompanies SGLT2 inhibitor initiation continues to generate concern, particularly in patients with more advanced CKD.

At lower baseline eGFR, even a modest increase can feel consequential. It is often interpreted, understandably, as a sign that the kidney is being harmed.

However, in most cases, this early change reflects a reduction in intraglomerular pressure rather than structural injury. The same principle underlies the rise in creatinine seen with initiation of ACE inhibitors or ARBs – a phenomenon that is now widely accepted as part of their renoprotective effect.

Seen in that light, the early “dip” in eGFR is less a complication than an expected physiological response. It requires clinical judgment, particularly in patients at risk of volume depletion or other competing insults, but it should not automatically be viewed as a reason to avoid or discontinue therapy.

Where the Benefit May Be Greatest

Another important consideration is how treatment effect translates into clinical benefit across different levels of kidney function.

Meta-analyses, including large collaborative work led by David Neuen, suggest that relative risk reductions for kidney outcomes are broadly consistent across eGFR strata. However, because baseline risk is substantially higher in patients with more advanced CKD, the absolute benefit may be greater in this group.

In practical terms, a modest slowing of decline at an eGFR of 20 may translate into a meaningful delay in the need for dialysis. That is often of greater consequence to patients than a similar relative effect earlier in the disease course.

This raises an important question: are we withholding therapy from the very patients who stand to gain the most?

The Evolving Position of Guidelines

Guidelines have begun to reflect this shift in understanding.

KDIGO recommends SGLT2 inhibitors in patients with diabetes and CKD down to an eGFR of 20 mL/min/1.73 m² and explicitly notes that the reversible fall in eGFR after initiation is generally not a reason to stop therapy.

Diabetes Canada (2025 update) supports their use in patients with eGFR 20–45, even in the absence of significant albuminuria in many cases.

American Diabetes Association similarly recommends SGLT2 inhibitors for patients with CKD down to an eGFR of 20 for kidney and cardiovascular protection.

At the same time, regulatory labeling remains somewhat heterogeneous. For example, Jardiance (empagliflozin) does not specify a strict lower eGFR threshold for heart failure indications, whereas Farxiga (dapagliflozin) continues to advise against initiation below eGFR 25 while permitting continuation if kidney function later declines.

Taken together, this reflects a field in transition. The conceptual model has shifted, but the practical boundaries have not fully aligned.

A Practical Way to Approach the Patient at Low GFR

When considering whether to initiate an SGLT2 inhibitor in a patient with advanced CKD, it may be helpful to reframe the question.

Rather than focusing primarily on whether the patient meets the entry criteria of a particular trial, one might ask:

• Is the underlying mechanism of benefit still relevant at this level of kidney function?

• Is there evidence, direct or indirect, that benefit persists as eGFR declines?

• Would I be comfortable continuing this therapy if the patient had already been on it?

If the answer to the last question is yes, it is worth examining why initiation feels different.

That difference may be more reflective of how the evidence was generated than of any meaningful change in biology.

Conclusion

SGLT2 inhibitors are no longer best understood as glucose-lowering drugs. Their primary role in CKD is to modify intraglomerular hemodynamics and reduce the downstream consequences of hyperfiltration and injury.

The eGFR thresholds that continue to shape prescribing patterns originated as pragmatic decisions in clinical trial design. Over time, they have been interpreted as markers of biological effectiveness.

As evidence accumulates and guidelines evolve, that interpretation is becoming harder to sustain.

For clinicians, the challenge is not simply to follow thresholds, but to understand where they came from – and when it may be reasonable to look beyond them.

References

1. de Boer IH, Khunti K, Sadusky T, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2022;102(5):974-989. doi:10.1016/j.kint.2022.08.012.

2. Herrington WG, Staplin N, Wanner C, et al; EMPA-KIDNEY Collaborative Group. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127. doi:10.1056/NEJMoa2204233.

3. EMPA-KIDNEY Collaborative Group. Effects of Empagliflozin on Progression of Chronic Kidney Disease: A Prespecified Secondary Analysis from the EMPA-KIDNEY Trial. Lancet Diabetes Endocrinol. 2024;12(1):39-50. doi:10.1016/S2213-8587(23)00321-2.

4. Nuffield Department of Population Health Renal Studies Group; SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of Diabetes on the Effects of Sodium Glucose Co-Transporter-2 Inhibitors on Kidney Outcomes: Collaborative Meta-Analysis of Large Placebo-Controlled Trials. Lancet. 2022;400(10365):1788-1801. doi:10.1016/S0140-6736(22)02074-8.

5. Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria. JAMA. 2026;335(3):233-244. doi:10.1001/jama.2025.20834.

6. Chatur S, Fletcher RA, Yeung E, et al. SGLT2 Inhibition in Patients With Type 2 Diabetes and CKD Experiencing a Deterioration in Estimated Glomerular Filtration Rate to <20 mL/min/1.73 m². J Card Fail. 2026. doi:10.1016/j.cardfail.2026.01.020.

7. Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117-S314. doi:10.1016/j.kint.2023.10.018.

8. American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes – 2026. Diabetes Care. 2026;49(Suppl 1):S246-S260. doi:10.2337/dc26-S011.

9. Diabetes Canada Clinical Practice Guidelines Expert Committee. Chronic Kidney Disease in Diabetes: 2025 Update. Diabetes Canada Clinical Practice Guidelines. 2025.

10. Cherney DZI, Odutayo A, Aronson R, Ezekowitz J, Parker JD. Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;74(20):2511-2524. doi:10.1016/j.jacc.2019.09.022.

A recent Twitter thread:

As a Canadian nephrologist, relevant & active national debate in light of CADTH draft guidelines which suggest finerenone not be funded if on an SGLT2i.

We know from CREDENCE, DAPA-CKD and EMPA-KIDNEY that SGLT2i + ACEi or ARB (aka RAASi) is safe and effective at reducing renal/CV endpoints.

Finerenone was studied in FIDELIO and FIGARO & enrolled when SGLT2i were not yet standard care.

These trials showed that finerenone + RAAS blockade reduced cardiovascular and renal endpoints There are no trials yet that evaluate triple therapy (Finerenone + SGLT2i + RAASi) vs dual therapy (SGLT2i + RAASi).

Even in patients in the active treatment arm in CREDENCE, DAPA-CKD and EMPA-KIDNEY, there was significant residual risk of adverse events While treatment with dual therapy is good, it is not sufficient

2022 KDIGO guidelines indicate that finerenone can be added to a RAS inhibitor and SGLT2 inhibitor for treatment of CKD and T2D.

“the most logical application of finerenone is to patients with high residual risks of CKD progression and [CV} events, as evidenced by the presence of albuminuria (ACR >30 mg/g [>3 mg/mmol]) despite lifestyle modifications and first-line drug therapies” – KDIGO 2022 CPG

KDIGO takes into account the 877 FIDELIO/FIGARO participants on an SGLT2i at baseline and the complementary mechanisms of action which suggest that benefits of SGLT2i and finerenone may be additive

KDIGO specifically notes the pre-specified individual patient-level combined analysis of the FIDELIO and FIGARO trials shows no significant heterogeneity in the cardiovascular or renal benefit in those using an SGLT2i at baseline

KDIGO notes the possibility that concurrent use of finerenone with SGLT2 inhibitor may reduce hyperkalemia.

When the Twitter community was asked: “Would you add finerenone to patients w/ diabetes, CKD and persistent proteinuria ( w/ normal K+) despite RAASi & SGLT2i & lifestyle changes (ie offer triple therapy)?”, survey results were as follows:

This is a highly subjective list, but these trials have been included as they have had a meaningful impact on guidelines, patients and clinicians at a global scale.

1. IDNT: Irbesartan Diabetic Nephropathy Trial

A randomized, blinded, placebo-controlled trial designed to assess whether irbesartan or amlodipine slow the progression of nephropathy in patients with type 2 diabetes, independent of effects on systemic blood pressure (BP) lowering.

The primary outcome, a composite of doubling of serum creatinine, onset of end-stage renal disease, serum creatinine ≥6.0 mg/dl, or death from any cause, was reduced by 23% compared to the amlodipine group (32.6% vs. 41.1%, p=0.006).

The authors found that the angiotensin-II–receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

https://www.nejm.org/doi/full/10.1056/nejmoa011303

2. RENAAL: Reduction in End Points in NIDDM with the Angiotensin II Antagonist Losartan study

In this study, it was shown that losartan reduced the incidence of a doubling of the serum creatinine concentration and end-stage renal disease. The benefit exceeded that attributable to changes in blood pressure.

It was published at the same time as the IDNT study.

https://www.nejm.org/doi/full/10.1056/nejmoa011161

3. The Effect of Angiotensin-Converting-Enzyme Inhibition on Diabetic Nephropathy

This was a randomized, controlled trial comparing captopril with placebo in patients with type 1 diabetes mellitus who had protein in the urine of ≥ 500 mg per day.

This was an important study as it showed that captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death, dialysis, and transplantation. Notably, it was significantly more effective than blood-pressure control alone.

https://www.nejm.org/doi/full/10.1056/NEJM199311113292004

4. CREDENCE: Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

The first study to show that an SGLT2i can reduce kidney outcomes in patients with diabetes and kidney disease.

This study showed that in patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group.

https://www.nejm.org/doi/full/10.1056/nejmoa1811744

5. DAPA-CKD: Dapagliflozin in Patients with Chronic Kidney Disease

The first study to show that an SGLT2i can reduce kidney outcomes in both people with and people without diabetes.

Specifically, the authors found that 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.

https://www.nejm.org/doi/full/10.1056/NEJMoa2024816

6. FIDELIO: Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes

While MRAs, including finerenone (a nonsteroidal, selective mineralocorticoid receptor antagonist) had been shown to reduce albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes, long-term benefits on kidney and cardiovascular outcomes were unknown.

This was the first study that showed that in patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo.

https://www.nejm.org/doi/full/10.1056/NEJMoa2025845

7. EMPA-KIDNEY: Empagliflozin in Patients with Chronic Kidney Disease

The first study to show that an SGLT2i can reduce kidney and cardiovascular outcomes in both people with and people without diabetes, independent of whether albuminuria is present.

Specifically, the authors found that among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin led to a lower risk of progression of kidney disease or death from cardiovascular causes.

https://www.nejm.org/doi/full/10.1056/NEJMoa2204233

EMPA-KIDNEY was a clinical trial testing whether taking a single pill of empagliflozin every day prevents worsening of kidney disease or deaths from heart disease in people who have chronic kidney disease (CKD). The trial was stopped early due to evidence of efficacy and was reported in November 2022 at the American Society of Nephrology ‘Kidney Week’ meeting and simultaneously published in the New England Journal of Medicine

1. Further solidifies SGLT2 inhibitors as the standard of care in managing CKD

Based on CREDENCE and DAPA-CKD, guidelines already recommend SGLT2i in chronic kidney disease. The American Diabetes Association and Diabetes Canada clinical practice guidelines recommend the use of SGLT2 inhibitors in people living with T2D and CKD as Grade A, Level 1 evidence.

The 2022 KDIGO (Kidney Disease Improving Global Outcomes) guidelines recommend the use of SGLT2 inhibitors when eGFR is ≥20 ml/min. This trial should further solidify this position.

2. Increase comfort starting SGLT2i treatment with a GFR as low as 20 ml/min

In the trial, patients were eligible for the study if they were adults with eGFR of at least 20 ml per minute (notably, regardless of the level of albuminuria)

Clinicians remain hesitant to start SGLT2i at lower GFRs so this study should help reassure the safety and efficacy at lower values.

3. Increase comfort continuing an SGLT2i below a GFR of 20 ml/min, even all the way down to dialysis initiation.

Like the CREDENCE and DAPA-CKD trials, EMPA-KIDNEY had patients remain on treatment all the way down to dialysis

Many clinicians get worried about continuing an SGLT2i when GFR is < 20 ml/min. There are now 3 kidney trials showing this strategy is both safe and effective.

4. Adds Empagliflozin as an SGLT2i with primary evidence of benefit in chronic kidney disease

Prior to EMPA-KIDNEY, we knew from primary outcome trials that dapagliflozin and canagliflozin had kidney protective effects. Empagliflozin has now been added to this list.

5. SGLT2i will be more widely used in patients without diabetes

This is now the 2nd major trial (after DAPA-CKD) which shows benefit in CKD whether or not someone has diabetes.

6. SGLT2 inhibitors may have beneficial effects even in the absence of protein in the urine

EMPA-KIDNEY included patients with CKD but without albumin in the urine (albuminuria). The primary outcome was not remarkably impacted in this subgroup, though this isn’t entirely surprising as the trial was stopped early and events are just less common in patients without albuminuria. There was, however, an impact on slope of GFR – this suggests there may be more impact on kidney outcomes over a longer period of time.

7. Another argument why SGLT2i may be the statins of the 21st century

Dr. Eugene Braunwald has called the SGLT2i class ‘the statins of the 21st century’ (Eur Heart J, 2022, qxmd.com/r/34741610/). This study showed impressive reductions in cardiovascular events, a repeated finding in multiple studies of SGLT2 inhibitors.

The SPRINT trial made waves in the field of hypertension, showing evidence for reduced hard clinical endpoints (a combined outcome of myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, or death from cardiovascular causes) in those patients with a BP target of 120 mm Hg systolic.

At the same time, it was clearly shown that more intensive blood pressure control drove increased risk of adverse events, including hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure.

The challenge with randomized clinical trials is that the results, while considered valid for the total population studied, may not apply to individual patients who simply meet the enrolment criteria for the study.

Some of those patients would derive more benefit and less harm, while others will see more harm and fewer benefits.  As the world moves towards personalized medicine, it would be ideal to be able to individualize how we apply the results of a clinical trial.

The CREBP Journal Club reviewed SPRINT and made the comment (which they shared in their PubMed Commons post):

Whether the interventions are beneficial for an individual patient appears to be dependent on the individual clinical circumstances and the preferences of the patient. We would strongly recommend the development of methods for improving shared decision making with patients on this topic before recommending this intervention be part of routine practice.

Well, enter the SPRINT data analysis challenge, and researchers like  Noa Dagan, MD, MPH, the head of data at Clalit Research Institute, Rahul Aggarwal, Boston University School of Medicine, and Joseph Rigdon, PhD from Stanford University.

Researchers like these re-analyzed the SPRINT data, made available by the NIH and its researchers, in order to derive more specific recommendations for individual patients.

Each researcher had a unique approach to personalizing the trial to individual patients or subgroups of patients.  Perhaps most fascinating was the approach taken by contest winner Dr. Dagan and her group, where they adapted the concept of the Number Needed to Treat (NNT) and calculated iNNT – the individualized number needed to treat (or harm).  Unlike the NNT which suggests how many all-comers would need to be treated to see a benefit of treatment, the iNNT represents the number of people, identical to the person in front of you, who would need to be treated to see one of them benefit.

Attempts to individualize treatment recommendations based on the balance of benefit vs harm obviously requires some subjective evaluation of how much real patients might value a potential benefit versus fear a potential harm.

It is clear that this type of analyses will require more patient input on the values, wishes and beliefs which would determine acceptability of treatment.  That being said, it is exceptionally exciting to see raw clinical trial being opened to the public, with researchers finding novel ways to personalize the applicability of a landmark clinical trial.

See the winning presentations at the SPRINT Data Analysis Challenge.

On a personal note, as medical director of QxMD, I’m eager to collaborate with researchers doing this type of work to adapt personalized decision support tools into the app Calculate by QxMD, so that we can make the results of this work accessible to the 1.5 million clinicians who use our platform every year.

SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. PMID: 26551272.

At last week’s Medicine rounds at the Royal Columbia Hospital, I presented the results from the recently published SPRINT trial.

SPRINT Research Group, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, Kimmel PL, Johnson KC, Goff DC Jr, Fine LJ, Cutler JA, Cushman WC, Cheung AK, Ambrosius WT. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov 26;373(22):2103-16. PMID: 26551272.

In short, my thoughts are that this is a very well done study with no concerning methodologic issues that affect the validity of the results.

With a clinically and statistically significant reduction cardiovascular outcomes and mortality, the benefits of a systolic BP target of <120 mm Hg appear to be quite meaningful in the population studied, despite the high NNTs.

It should be clearly noted that this study excludes those with prior stroke, diabetes, nursing home residents, among others.

That being said, it appears to be broadly applicable (with ~17 million Americans fitting the enrollment criteria), including the elderly and many with chronic kidney disease.

As a nephrologist, I was really encouraged to see that almost 30% of patients enrolled had CKD (with GFR 20-60 ml/min, with the exclusion of PKD, GN requiring immunosuppression, and proteinuria > 1 gm/day).  My clinical practice is certainly made up of plenty of patients who would satisfy the inclusion and exclusion criteria of the study.

Caution should be taken before applying the findings of this study to all patients who meet the enrollment criteria given the increased rate of serious adverse events in the intensive BP control arm (<120 mm Hg systolic), especially given that in the real world, adverse events can be higher than in clinical trials.

I take particular note that worsening GFR and acute kidney injury were more common in the intensive BP control arm, though chronic dialysis was not increased.  The rates of temporary dialysis in AKI were not reported, and it would be important to ensure this was not significantly increased in the intensive BP arm.

It’s also important to point out that in real world clinical practice (ie outside a clinical trial), even achieving a BP target of  <140 mm Hg can be quite hard (with at least 1/3 of hypertensive Americans above target), so shooting for a target of  <120 mm Hg may not be achievable in many patients.

All this being said, in those patients who I feel I can safely monitor and follow closely, I will be offering intensive BP control, after reviewing the risks, benefits and alternative.  As with any therapy that offers both potential advantages and risks, a decision on which BP target to use will require a careful discussion with our patients.

For those interested, here are my slides: