SGLT2 Inhibitors: From Glycaemia to Heart Failure and Chronic Kidney Disease

CLINICALIQ DRUG CLASS EXPLAINERS
Episode 02: SGLT2 Inhibitors
Host: Sarah Mitchell | Expert: Dr Anzal Qurbain, Pharmaceutical Physician
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[HOST] Welcome back to ClinicaliQ Drug Class Explainers. I'm Sarah Mitchell, and joining me again is Dr Anzal Qurbain, pharmaceutical physician. Today we're moving on to SGLT2 inhibitors — a drug class that started out as a diabetes treatment and somehow ended up changing cardiology and nephrology as well. Anzal, where do we even begin with these?

[EXPERT] I think we begin with the kidney, because that's the whole trick. The kidneys filter an enormous amount of glucose every day — about 180 grams — and almost all of it gets reabsorbed back into the bloodstream via a transporter called SGLT2, which sits in the proximal tubule. SGLT2 inhibitors block that transporter, so the glucose can't get back in. It just passes out in the urine.

[HOST] So you're literally making the body pee out sugar.

[EXPERT] Exactly. And that sounds almost too simple, but the consequences are surprisingly wide-reaching. You lower blood glucose, you lose some calories, blood pressure drops slightly because of osmotic fluid loss, and — and this is the part that surprised everyone — you get profound benefits in the heart and kidney that go well beyond glucose lowering.

[HOST] Before we get to those benefits, let's name the drugs. Which ones are we actually talking about?

[EXPERT] The three main ones in UK practice are empagliflozin, brand name Jardiance; dapagliflozin, brand name Forxiga; and canagliflozin, brand name Invokana. There's also ertugliflozin, Steglatro, but it's used less commonly. Each has slightly different licensed indications, which matters clinically.

[HOST] And they're all doing the same basic thing — blocking SGLT2?

[EXPERT] Yes, the mechanism is the same. The differences are mainly about which trials they've been studied in, which indications they have, and some minor pharmacokinetic differences. In practice, dapagliflozin has probably the broadest licence in the UK right now, covering type 2 diabetes, heart failure with reduced ejection fraction, and chronic kidney disease — regardless of whether the patient has diabetes.

[HOST] That last bit is interesting. You said regardless of diabetes. So these aren't just diabetes drugs anymore?

[EXPERT] That's the major shift. The DAPA-HF trial, published in 2019, enrolled patients with heart failure with reduced ejection fraction — HFrEF — and about half of them didn't have diabetes. Dapagliflozin reduced the combined endpoint of worsening heart failure and cardiovascular death by about 26%. Then the EMPEROR-Reduced trial did the same with empagliflozin and found a similar result. So NICE now recommends these drugs in HFrEF regardless of diabetes status.

[HOST] Why do they help the heart? That doesn't seem obvious from a kidney transporter.

[EXPERT] That's the question everyone asked, and honestly it's still not fully settled. Several mechanisms have been proposed — the osmotic diuresis reduces preload, there may be direct myocardial effects, they reduce inflammation, they improve mitochondrial function in cardiac cells. The leading theory is that they produce something called a "metabolic shift" where the heart starts burning ketone bodies more efficiently. But the honest answer is it's probably a combination of effects.

[HOST] And the kidney data — what did that show?

[EXPERT] The DAPA-CKD trial and the CREDENCE trial with canagliflozin both showed that SGLT2 inhibitors significantly slow the progression of chronic kidney disease and reduce the risk of needing dialysis. DAPA-CKD was particularly striking because it included patients with CKD who didn't have diabetes at all. NICE now recommends dapagliflozin in CKD with albuminuria, again regardless of diabetes.

[HOST] So who is the ideal patient for an SGLT2 inhibitor in everyday clinical practice?

[EXPERT] In type 2 diabetes, the NICE guidelines now push for early use in patients who have established cardiovascular disease, heart failure, or CKD — or who are at high risk of those things. It's moved from being a "third or fourth line add-on" to being something you consider early in the pathway alongside, or even instead of, some older agents. And then separately, in HFrEF, it goes in regardless of diabetes as part of the standard quadruple therapy alongside an ACE inhibitor or ARNi, a beta-blocker, and a mineralocorticoid receptor antagonist.

[HOST] Let's talk about side effects, because I imagine there are some. You're deliberately making someone pee out sugar — that has to cause problems.

[EXPERT] The most common one is genital thrush — candidal infections. Because there's more glucose in the urine, it creates a warm, sugary environment that Candida loves. It happens in maybe 10 to 15 percent of patients, more common in women, and usually responds to a standard antifungal. It's worth warning patients upfront so they're not alarmed.

[HOST] That makes sense. What else?

[EXPERT] Urinary tract infections are slightly more common, though the data is more mixed than for thrush. The osmotic diuresis can cause volume depletion — so patients can feel lightheaded, especially elderly patients or those on diuretics. You need to review their other medications when you start.

[HOST] And there's a more serious one — DKA?

[EXPERT] Yes, diabetic ketoacidosis, and specifically what's called euglycaemic DKA — that's the important one to know about. Normally with DKA you expect very high blood glucose, but with SGLT2 inhibitors, the glucose is being excreted in the urine, so glucose levels can appear almost normal. A patient can be in DKA and not flagged by a routine glucose check. So if someone on an SGLT2 inhibitor comes in feeling unwell with nausea, vomiting, abdominal pain — you must check blood ketones or arterial blood gas, not just a glucose.

[HOST] How common is that?

[EXPERT] It's rare — probably around 1 in 1,000 patient-years — but it's life-threatening if missed. It's more of a risk in type 1 diabetes, which is why these drugs are generally not recommended in type 1 outside specialist settings. In type 2, the main precipitants are illness, prolonged fasting, alcohol excess, or very low carbohydrate diets.

[HOST] Which brings us to the sick day rules?

[EXPERT] This is the key clinical pearl. SGLT2 inhibitors should be stopped — temporarily — whenever a patient is acutely unwell, significantly dehydrated, has a gastrointestinal illness where they're not eating or drinking, or is going for a surgical procedure requiring fasting. The mnemonic that's sometimes used is "SADMAN" — Surgery, Anaesthesia, Diarrhoea, vomiting, low caloric intake, and so on — but the key message is simple: if you're not eating and drinking normally, stop the tablet until you're recovered.

[HOST] And before surgery specifically?

[EXPERT] Yes. Current guidance — and this came out of a patient safety alert — recommends stopping SGLT2 inhibitors at least 3 days before elective surgery. The concern is perioperative euglycaemic DKA. Anaesthetists should be checking for this, and the patient's medication list needs to be accurate.

[HOST] What about drug interactions more broadly? Anything else to watch for?

[EXPERT] The main interactions are pharmacodynamic rather than pharmacokinetic. Combining with diuretics increases the risk of dehydration and hypotension. Combining with insulin or sulfonylureas increases hypoglycaemia risk — you may need to reduce those doses when you start an SGLT2 inhibitor. There aren't major cytochrome P450 interactions to worry about.

[HOST] What about renal function itself? If these drugs work on the kidney, do they harm it in the long run?

[EXPERT] There's often a small initial dip in eGFR when you start — usually 3 to 5 mL/min — and this can worry clinicians. But it's generally a haemodynamic effect, not structural damage, and it stabilises. The long-term trajectory is actually better kidney function preserved over time compared to placebo. The dip is analogous to what you see when you start an ACE inhibitor. Current guidance says you can initiate dapagliflozin for CKD or HF down to an eGFR of 25, though the glucose-lowering effect is minimal below about 45.

[HOST] So should clinicians be concerned if they see that initial eGFR dip?

[EXPERT] Not unless it's very large or unexpected. Recheck at 2 to 4 weeks, and if the dip is modest and stable, continue. If there's a severe drop or ongoing deterioration, stop and review. The key is having a baseline eGFR before you start.

[HOST] Let me try to pull all this together. SGLT2 inhibitors block a kidney transporter, cause glucose to be excreted in urine, lower blood sugar, reduce weight and blood pressure slightly, and — more importantly — protect the heart and kidneys through mechanisms we don't fully understand. They're now recommended early in type 2 diabetes with risk factors, and in heart failure regardless of diabetes. The main side effects are thrush, volume depletion, and rare but serious euglycaemic DKA. The sick day rule is stop them if you're unwell or fasting. Have I got that right?

[EXPERT] That's a very good summary. I'd just add one practical point: patients often don't understand why they've been given a "diabetes tablet" when they don't have diabetes, or when their diabetes is well controlled. It's worth taking a minute to explain that this drug is doing something different — it's protecting your heart or your kidneys — otherwise you get poor adherence.

[HOST] That's a really important point. Patients need to understand the "why." Anzal, thank you — this has been genuinely eye-opening. I had no idea these drugs had moved so far beyond diabetes.

[EXPERT] They're probably the most exciting class to come out of diabetes medicine in a generation, and we're still learning. There are trials ongoing in heart failure with preserved ejection fraction, in acute kidney injury prevention, even in metabolic liver disease. The story isn't finished.

[HOST] Something to look forward to. That's all for this episode of ClinicaliQ Drug Class Explainers. In our next episode, we'll be looking at JAK inhibitors — the oral drugs that have transformed inflammatory diseases from rheumatoid arthritis to eczema, and come with a safety profile that every prescriber needs to understand. Until then, I'm Sarah Mitchell — keep learning.

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