SGLT2 inhibitors are a class of medications that lower blood sugar by blocking the kidneys from reabsorbing glucose back into the bloodstream. Originally developed for type 2 diabetes, they’ve become some of the most important drugs in cardiology and nephrology because of their ability to protect the heart and kidneys independently of blood sugar control. Five are currently available: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and bexagliflozin.
How SGLT2 Inhibitors Work
Your kidneys filter about 180 grams of glucose from your blood every day, and under normal conditions, nearly all of it gets reabsorbed back into the bloodstream through a protein called SGLT2 in the kidney’s filtration tubes. SGLT2 inhibitors block that protein, preventing 30% to 60% of that filtered glucose from being reabsorbed. The glucose leaves your body through urine instead.
This mechanism has a cascade of secondary effects. Along with glucose, sodium reabsorption is also reduced. The extra sodium delivered further along the kidney’s filtration system triggers changes in how the kidney regulates blood flow and pressure within itself. The result is lower pressure inside the kidney’s filtering units, which protects them from long-term damage. The shift in sodium handling also suppresses a hormonal system (the same one targeted by ACE inhibitors and ARBs) that drives fluid retention and blood vessel constriction.
Conditions They Treat
SGLT2 inhibitors were first approved for type 2 diabetes, where they lower HbA1c by an average of 0.5% to 0.8% as a standalone treatment or when added to other medications. That’s a moderate effect compared to some diabetes drugs, but the real story is what happens beyond blood sugar.
These medications are now approved and widely used for heart failure, including in people who don’t have diabetes at all. They’re also approved for chronic kidney disease. Current guidelines from major kidney and cardiology organizations recommend them for patients with kidney disease and a kidney filtration rate (eGFR) of 20 or above, and for heart failure patients regardless of how much kidney function they’ve lost. Their benefits for kidney and heart protection tend to appear within the first several months of treatment.
Heart Protection
The cardiovascular benefits of SGLT2 inhibitors have been remarkably consistent across large trials. In patients with reduced heart function, SGLT2 inhibitors cut the combined risk of dying from cardiovascular causes or being hospitalized for heart failure by 26%. Recurrent heart failure hospitalizations dropped by 25%. These reductions are significant for a single drug class and hold up whether or not the patient has diabetes.
Part of the heart benefit comes from mild fluid loss. By blocking sodium and glucose reabsorption, these drugs act as gentle diuretics, reducing the volume of fluid the heart has to pump. They also lower systolic blood pressure by an average of about 3.6 mmHg and diastolic pressure by about 1.7 mmHg, comparable to a low-dose water pill. This combination of reduced fluid load, lower blood pressure, and hormonal changes helps a struggling heart work more efficiently.
Kidney Protection
SGLT2 inhibitors slow the progression of chronic kidney disease through a direct physical mechanism. By changing sodium delivery within the kidney, they cause the small blood vessel feeding each filtering unit to constrict slightly. This lowers the pressure inside the filter itself, reducing the kind of ongoing mechanical damage that gradually destroys kidney tissue over years. Three major trials (CREDENCE, DAPA-CKD, and EMPA-KIDNEY) all showed reductions in a composite outcome that included progression to dialysis, kidney transplant, or severe drops in kidney function.
Current international guidelines recommend starting these drugs when eGFR is 20 or above. Once started, they can generally be continued even if kidney function declines further. Benefits and safety in patients with eGFR below 20, on dialysis, or with a kidney transplant are still being studied.
Common Side Effects
The most predictable side effect is genital yeast infections, a direct consequence of having extra glucose in the urine. Sugar-rich urine creates an environment where yeast thrives. In major trials, genital infections were roughly three to four times more common in people taking SGLT2 inhibitors than in those on placebo. In the CANVAS trial program, for example, rates were about 69 per 1,000 patient-years in women taking the drug compared to about 18 per 1,000 patient-years on placebo. Men were also affected, though at lower rates.
Urinary tract infections, despite early concerns, don’t appear to be significantly more common with these drugs. Most large trials showed nearly identical UTI rates between treatment and placebo groups.
Because SGLT2 inhibitors cause mild fluid loss, some people experience increased urination, thirst, or occasional lightheadedness, especially when starting the medication or when combined with other diuretics.
Euglycemic Ketoacidosis
The most serious risk to be aware of is a rare condition called euglycemic diabetic ketoacidosis. Normal ketoacidosis happens when the body breaks down fat for energy and produces dangerously high levels of acids called ketones, usually accompanied by very high blood sugar. With SGLT2 inhibitors, the same dangerous acid buildup can happen while blood sugar stays normal or only mildly elevated (below 250 mg/dL). This makes it harder to recognize.
Symptoms include nausea, vomiting, abdominal pain, fatigue, loss of appetite, and shortness of breath. Some people develop deep, rapid breathing as the body tries to compensate for the acid buildup, or a fruity smell on the breath from excess ketones. Because blood sugar readings look fine, this condition can be missed if you’re not aware it exists. It’s most likely to occur during illness, surgery, prolonged fasting, or significant dehydration, situations where the body is already under metabolic stress.
What to Expect on These Medications
SGLT2 inhibitors are taken once daily as a pill. Most people notice increased urination in the first few days as the body adjusts to excreting more glucose and fluid. Blood sugar effects are modest compared to insulin or some older diabetes drugs, which also means the risk of low blood sugar is very low when these drugs are used alone.
You can expect a small amount of weight loss from the calorie loss through urinary glucose and the mild diuretic effect, though this varies from person to person. Blood pressure typically drops modestly without additional medication changes. For people taking them primarily for heart failure or kidney disease rather than diabetes, the blood sugar lowering effect is minimal and generally not a concern.
Staying well-hydrated and maintaining good genital hygiene can reduce the likelihood of the most common side effects. If you’re scheduled for surgery or become significantly ill, your prescribing team will typically have you pause the medication temporarily to reduce the risk of ketoacidosis.