SGLT2 inhibitors in diabetic kidney disease: the complete guide

Few medication classes in my career have changed the picture in a chronic disease the way SGLT2 inhibitors have changed the picture in diabetic kidney disease. In clinic I now have this conversation with almost every patient with diabetes and kidney involvement. This article sets out what I tell them.

Diabetic kidney disease has been one of the most challenging conditions in medicine for decades. It is the leading cause of kidney failure worldwide. For many years, despite blood pressure control and tight glucose control, patients continued to progress to dialysis. The arrival of SGLT2 inhibitors changed the picture in a way that few medication classes ever do. The benefit was large, consistent across trials, and additive to existing treatments. For most patients with diabetic kidney disease today, the question is no longer whether to use an SGLT2 inhibitor but when.

This guide walks through what SGLT2 inhibitors are, the evidence supporting their use, who benefits, the practical considerations when starting them, and what to expect over the long term.

The SGLT2 inhibitors are a class of oral medications that block the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule of the kidney. SGLT2 is the protein responsible for reabsorbing the great majority of the glucose that the kidneys filter from the blood. By blocking it, the medications cause glucose to be lost in the urine rather than reabsorbed. This produces several effects: blood glucose falls, the body loses some of the calories it would otherwise retain, urine volume increases modestly, and a degree of natural diuresis develops.

The SGLT2 inhibitors available in Ireland include empagliflozin (Jardiance), dapagliflozin (Forxiga), and canagliflozin (Invokana). They were developed in the 2010s as glucose-lowering medications for type 2 diabetes. The cardiovascular and kidney benefits that have transformed their use came as surprises, identified initially in cardiovascular safety trials that were required by regulators for all new diabetes medications after the rosiglitazone safety controversy of the late 2000s.

The pivotal trials for kidney disease are the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials. CREDENCE (published 2019) studied canagliflozin in patients with type 2 diabetes and chronic kidney disease with significant albuminuria. The trial was stopped early because of the magnitude of benefit. Kidney failure and cardiovascular events were reduced by around 30 per cent compared to placebo. DAPA-CKD (2020) studied dapagliflozin in a broader population including patients without diabetes and confirmed similar benefits. EMPA-KIDNEY (2022) studied empagliflozin and extended the evidence to lower eGFR thresholds and more varied causes of kidney disease.

The results across these trials are remarkably consistent. SGLT2 inhibitors slow the rate of kidney function decline. They reduce the risk of kidney failure. They reduce hospitalisation for heart failure. They reduce cardiovascular death. The benefits are present in patients with type 2 diabetes, patients without diabetes, patients with preserved and reduced cardiac ejection fraction, and patients across a wide range of starting kidney function. Few medication classes have shown this breadth of benefit.

The mechanism of benefit goes well beyond glucose lowering. The current understanding is that several effects contribute. SGLT2 inhibition reduces the pressure inside the glomerular filtering units, a mechanism similar to how ACE inhibitors and ARBs work. It reduces albuminuria. It produces modest weight loss. It modestly lowers blood pressure. It improves sodium and fluid balance. It may have direct effects on inflammation and on cellular metabolism in kidney and heart tissue. The combined effect is greater than any single mechanism would explain.

Who should be on an SGLT2 inhibitor? The current recommendations are broad. Most patients with type 2 diabetes and chronic kidney disease, particularly those with albuminuria, are candidates. Most patients with chronic kidney disease and proteinuria, regardless of whether they have diabetes, are candidates. Most patients with heart failure, regardless of ejection fraction or diabetes status, are candidates.

The eGFR thresholds for starting and continuing therapy have been progressively lowered as the evidence has accumulated. Most patients with an eGFR above 20 mL/min are now eligible. The medication can usually be continued even as eGFR falls further, although the glucose-lowering effect diminishes at lower kidney function.

The practical considerations when starting an SGLT2 inhibitor include several points.

Before starting, check kidney function and ensure the patient is not in an acutely dehydrated state. Patients with significantly reduced fluid intake or active diarrhoea or vomiting are not the right candidates for starting a new diuretic-like medication.

Review other medications. Patients on insulin or sulfonylureas may need dose adjustments to avoid hypoglycaemia once the SGLT2 inhibitor takes effect. Patients on diuretics may need diuretic dose reduction because the SGLT2 inhibitor itself contributes to fluid loss. Patients on ACE inhibitors and ARBs continue these as normal.

Discuss the expected initial drop in eGFR. Most patients have a small drop of around 3 to 5 mL/min in the first few weeks. This is expected, reflects the haemodynamic mechanism of the medication, and does not represent kidney damage. The long-term effect is to slow decline. The initial drop should not lead to stopping the medication.

Discuss the side effects. The most common issues are urinary tract infections and genital fungal infections, both more common in women. Most of these are treatable and do not require stopping the medication. Adequate hydration, good hygiene, and prompt treatment of any infection reduce recurrence. A small number of patients develop recurrent severe infections that lead to stopping.

Discuss euglycaemic diabetic ketoacidosis. This is a rare but important complication, mainly affecting patients with diabetes. Unlike typical diabetic ketoacidosis, the blood glucose may not be markedly elevated, which can lead to diagnostic delay. Patients should be alert to symptoms including nausea, vomiting, abdominal pain, lethargy, and difficulty breathing. The condition is more likely during episodes of acute illness, surgery, or prolonged fasting, which is why the medication is typically paused during these periods. Patients are advised to pause the medication for any illness with significant fluid loss or for any planned surgery, typically restarting once they have recovered and resumed normal eating and drinking.

A further small risk is Fournier’s gangrene, a rare but serious infection of the perineum. The risk is very low but warranted a label warning. Patients with new genital pain, swelling, or fever should seek medical attention promptly.

Follow-up after starting includes a check of kidney function and electrolytes at 4 to 6 weeks. Blood pressure should be reassessed because of the small effect of the medication. Patients on diuretics may need ongoing dose adjustment.

Long-term, the benefits accumulate. The trials showed clear benefits within the first 6 to 12 months of treatment, and the benefits continued to grow over subsequent years. The expectation is that patients on long-term SGLT2 inhibitor therapy have slower decline in kidney function, lower rates of heart failure hospitalisation, lower cardiovascular event rates, and improved survival.

For patients with diabetic kidney disease, the current standard combination is an ACE inhibitor or ARB, an SGLT2 inhibitor, and (where indicated) finerenone. Each of these works through different mechanisms and provides additive benefits. The triple combination has transformed the long-term outlook for many patients with diabetic kidney disease compared to a decade ago.

The practical message for patients is clear. If you have diabetic kidney disease and you are not on an SGLT2 inhibitor, ask your GP or specialist whether you are a candidate. For most patients, the answer is yes. The benefits are substantial. The side effect profile is generally well tolerated. The accumulated evidence is strong. Few medications in this generation have changed the course of a chronic disease as substantially.

I see private patients at Blackrock Clinic, The Beacon Hospital, Bon Secours Dublin, the Hermitage Medical Centre, and St Vincent’s Private Hospital. If you would like a consultation about your kidney health, you or your GP can contact my secretary through drrorymcquillan.ie. Most patients are seen within two to three weeks of referral.