SGLT2 inhibitors (empagliflozin, dapagliflozin)
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How this letter has changedLatest: August 2026 · First graded.
EMPA-REG OUTCOME (PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 26378978), DAPA-HF (PMID 31535829) and DAPA-CKD (PMID 32970396) are three independent randomized trials in three different populations, all on hard clinical outcomes. That is the replicated-hard-outcome route to Grade A. The record states the boundary in the same breath as the letter: every one of those trials enrolled people who already had cardiovascular, cardiac or renal disease. No trial has given an SGLT2 inhibitor to a healthy adult to see whether they live longer.PMID 26378978 PMID 31535829 PMID 32970396
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SGLT2 inhibitors are prescription pills first used for diabetes. Two common ones are empagliflozin and dapagliflozin. Three large studies, each in a different group of patients, found fewer deaths from heart disease, fewer hospital stays for heart failure, and slower loss of kidney function. Everyone in those studies was already sick, with heart disease and diabetes, a weak heart, or long-term kidney disease. No study has given these drugs to healthy adults to slow aging. Genital yeast infections and loss of body fluid were more common on the drugs. A rare but serious acid buildup in the blood is a known risk.
Funding: Both randomized trials replicating this Grade A were funded by industry: EMPA-REG OUTCOME (PMID 26378978) by Boehringer Ingelheim and Eli Lilly, the makers of the drug it tested; DAPA-HF (PMID 31535829) by AstraZeneca, the maker of the drug it tested. The funder's role in design and analysis is not stated here, because the full trial reports could not be read. The letter stands because each trial met the grading rules on its own; the funding is stated here so it can be weighed alongside it. Investigators: Both randomized trials replicating this Grade A were run by investigators employed by, founded by, or belonging to the organization that developed, sells or teaches the intervention (Boehringer Ingelheim and Eli Lilly, the drug makers, whose employees are among the authors; AstraZeneca, the drug maker, whose employees are among the authors). The funder may read non-commercial; the people who ran the trials are part of the organization whose intervention they tested, which is stated here so it can be weighed alongside the letter.
A letter describes the human evidence, not the product, the manufacturer, or the intervention's worth.
Why this gradeThe reasoning, and what the grade does not cover.
Grade A by the replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. hard-outcome route, and unusually well replicated: three randomized trials in three different disease populations, on cardiovascular death, heart-failure hospitalization and kidney-failure progression.
WHAT THIS GRADE DOES NOT COVERevery one of those trials enrolled people who were already sick, with established cardiovascular disease and diabetes, heart failure with reduced ejection fraction, or chronic kidney disease. That is where the A is earned and it does not travel. Nothing in this evidence says an SGLT2 inhibitor extends life in a healthy adult, and no trial has given one to healthy adults for aging. The grade also attaches to the specific drugs and doses studied, not to the drug class as an idea.
Shared endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score.: Cardiovascular death, heart-failure hospitalization or kidney-failure progression
- EMPA-REG OUTCOME (Zinman): Lower cardiovascular death with empagliflozin, type 2 diabetes with cardiovascular disease. PMID 26378978 · Funding: manufacturer-funded (Boehringer Ingelheim and Eli Lilly)
- DAPA-HF (McMurray): Fewer heart-failure worsening events or cardiovascular deaths with dapagliflozin, reduced ejection fraction. PMID 31535829 · Funding: manufacturer-funded (AstraZeneca)
What the replication does not cover: The class grade rests on two different drugs from two different sponsors.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
Reduction of cardiovascular death, heart-failure hospitalization and kidney-failure progression, replicated across three separate randomized populations. No trial has tested them for longevity in healthy adults.
Replicated randomized human trials on a hard clinical outcome, an objectively measured function, or a validated scale scored by a clinician blinded to treatment.
Every trial enrolled a disease population: cardiovascular disease with type 2 diabetes, heart failure with reduced ejection fraction, or chronic kidney disease. No trial has given these drugs to healthy adults for aging.
Prescription only; requires physician management. Kidney function and volume status are what the trials monitored.
Genital mycotic infection and volume depletion A fall in a nutrient's level caused by a medication, for example through reduced absorption or increased loss. were more frequent on treatment across these trials, and euglycemic diabetic ketoacidosis is a labeled risk.
- PMID 26378978 →Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes
- PMID 31535829 →Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
- PMID 32970396 →Dapagliflozin in Patients with Chronic Kidney Disease.
Primary evidenceThree papers, each linked to its PubMed record.
Zinman et al., EMPA-REG OUTCOME (New England Journal of Medicine, 2015; PMID 26378978): randomized, placebo-controlled, empagliflozin 10 mg or 25 mg daily added to standard care in patients with type 2 diabetes at high cardiovascular risk, with cardiovascular death, non-fatal myocardial infarction and non-fatal stroke as the primary composite. McMurray et al., DAPA-HF (New England Journal of Medicine, 2019; PMID 31535829): phase 3 randomized trial of dapagliflozin 10 mg daily in patients with heart failure and reduced ejection fraction, with and without diabetes. Heerspink et al., DAPA-CKD (New England Journal of Medicine, 2020; PMID 32970396): 4,304 participants with chronic kidney disease, with and without type 2 diabetes. Three independent randomized trials, three different populations, all on hard clinical outcomes, which is the replicated-hard-outcome route to Grade A. The same caution that applies to semaglutide applies here and is the more important half of this record: the A is earned in people who already have cardiovascular, cardiac or renal disease. Nothing in this evidence says an SGLT2 inhibitor extends life in a healthy adult, and no trial has asked.
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