SGLT2 inhibitors (empagliflozin, dapagliflozin)

What it is

SGLT2 stands for sodium-glucose cotransporter 2. It is located almost exclusively in the kidney, where it brings most of the filtered sugar back into the blood. Empagliflozin, approved in the EU as Jardiance since 2014, and dapagliflozin, approved as Forxiga since 2012, specifically inhibit this transporter. According to the prescribing information, empagliflozin is 5,000 times more selective for SGLT2 than for the intestinal transporter SGLT1.

Originally, both came onto the market as diabetes drugs. Today they are also approved in the EU for chronic heart failure and chronic kidney disease, including in people without diabetes. Canagliflozin belongs to the same class and has its own entry on this site, where the lifespan data from the ITP mouse program can also be found.

How it is supposed to work

The direct effect is measurable and well understood. When the transporter is blocked, sugar ends up in the urine. In type 2 diabetes, this was on average about 78 g per day in the approval studies. That means a loss of calories, less body fat and somewhat less weight. In a 24-week study, body weight under empagliflozin was 1.93 kg lower than under placebo, and systolic blood pressure 2.6 mmHg lower. At the same time, the kidney excretes more sodium, which relieves the circulation and the heart.

Beyond this, a second mechanism is under discussion. A much-cited hypothesis paper in Diabetes Care formulated the idea in 2020 that SGLT2 inhibitors put cells into a fasting-like state, with energy-deficiency signals otherwise known from calorie restriction. That would explain why the benefit for the heart and kidneys is greater than the lowering of blood sugar alone would suggest. This fasting mimicry has not been proven in humans, but it is the core of the longevity interest.

Why the longevity scene is paying attention

Three findings from the laboratory fuel the curiosity. In the Interventions Testing Program, canagliflozin extended the life of male mice. A paper in Nature Aging showed in 2024 that SGLT2 inhibition reduces senescent cells in abdominal fat by helping the immune system recognize them better, and that mice with premature aging lived longer. Another mouse study in 2024 found a 5.9 percent longer median survival of male mice under empagliflozin, along with better learning and motor performance. In addition, a large Korean cohort showed a lower risk of dementia under SGLT2 inhibitors compared with another class of diabetes drugs. In user circles, the class is therefore discussed as a candidate for healthspan, alongside metformin and acarbose.

What the studies show

DAPA-HF: heart failure with and without diabetes

4,744 people with heart failure and an ejection fraction of up to 40 percent received dapagliflozin 10 mg or placebo in addition to standard therapy. After a median of 18.2 months, the primary endpoint of worsening heart failure or cardiovascular death occurred in 16.3 versus 21.2 percent, HR 0.74. All-cause mortality also fell, 11.6 versus 13.9 percent. People without diabetes benefited similarly to people with diabetes.

DAPA-CKD and EMPA-KIDNEY: kidney protection

In DAPA-CKD, 4,304 people with kidney disease received dapagliflozin or placebo. The trial was stopped early because of clear efficacy: the primary kidney endpoint occurred after a median of 2.4 years in 9.2 versus 14.5 percent, and 4.7 versus 6.8 percent had died. EMPA-KIDNEY confirmed this with 6,609 patients for empagliflozin, 13.1 versus 16.9 percent for the primary endpoint; all-cause mortality did not differ significantly there.

DECLARE-TIMI 58: the sober counter-check

17,160 people with type 2 diabetes, most of them without existing vascular disease, received dapagliflozin or placebo for a median of 4.2 years. Heart attack, stroke and cardiovascular death did not become less frequent, 8.8 versus 9.4 percent. Hospital stays for heart failure and kidney events, on the other hand, fell. This shows: the benefit depends strongly on the baseline risk.

Dementia in a Korean cohort

In Korean health insurance data, 110,885 pairs of 40- to 69-year-olds with type 2 diabetes who started either an SGLT2 or a DPP-4 inhibitor were compared. Under SGLT2 inhibitors, dementia was diagnosed less often, HR 0.65, and 0.70 after correction for residual bias. The authors themselves stress that observational data can overestimate the effect and that randomized trials are needed.

Where the data stop

All large trials enrolled patients, with diabetes, heart failure or kidney disease. For healthy people without these diagnoses, there is no randomized trial with hard endpoints or with aging markers. Life extension has so far been shown only in mice, and not consistently there either: in the ITP, only male animals benefited from canagliflozin; for empagliflozin and dapagliflozin we found no published ITP data, and the empagliflozin mouse study is a single paper. The dementia finding comes from observational data. The question of muscle is also open: a meta-analysis of 18 studies found, besides 1.16 kg less fat mass, also 1.01 kg less skeletal muscle mass, whereas an analysis of 5 long-term studies over at least 12 months found no significant loss of fat-free mass. For people in training who want to build muscle, there are no data.

Status, approval and legal

Empagliflozin and dapagliflozin are approved, prescription-only medicines in Germany and the EU, approved for type 2 diabetes, chronic heart failure and chronic kidney disease. In the US, both have been approved since 2014. Any use without these diagnoses, for example for longevity or weight loss, is off-label and belongs in the hands of a physician. The heart and kidney trials used 10 mg once daily; this is a figure from the studies, not a recommendation. SGLT2 inhibitors are not named on the 2026 Prohibited List of the World Anti-Doping Agency.

Safety

Safety is well described through approval studies and more than a decade of use. The most common are fungal infections in the genital area, in 4.0 percent under empagliflozin 10 mg versus 1.0 percent under placebo, and under dapagliflozin in women 8.4 versus 1.2 percent. In addition, there are urinary tract infections, increased urination, fluid deficiency and a drop in blood pressure, especially from age 75 and with diuretics. The most important rare complication is ketoacidosis, an acidification by ketone bodies, which can occur even with near-normal blood sugar and, according to the prescribing information, has also been reported in people without diabetes. Risk factors are restricted food intake, severe fluid losses, surgery, acute illness and alcohol. Anyone who fasts or follows a ketogenic diet should know this. Very rare is a severe infection in the perineal area, Fournier’s gangrene. The drugs are not suitable in type 1 diabetes, during pregnancy and breastfeeding. Together with insulin or sulfonylureas, the risk of hypoglycemia increases.

Sources

• Zinman et al., N Engl J Med 2015 – EMPA-REG OUTCOME
• McMurray et al., N Engl J Med 2019 – DAPA-HF
• Anker et al., N Engl J Med 2021 – EMPEROR-Preserved
• Heerspink et al., N Engl J Med 2020 – DAPA-CKD
• EMPA-KIDNEY Collaborative Group, N Engl J Med 2023 – EMPA-KIDNEY
• Wiviott et al., N Engl J Med 2019 – DECLARE-TIMI 58
• Nuffield Department of Population Health Renal Studies Group, Lancet 2022 – kidney meta-analysis
• Shin et al., BMJ 2024 – dementia risk, Korean cohort
• Katsuumi et al., Nat Aging 2024 – SGLT2 inhibition and senescent cells in mice
• EMA – Jardiance, product information (German)