Drug: SGLT2-Hemmer

What It Is

SGLT2 inhibitors are oral diabetes drugs that block one kidney transporter, so glucose leaves in the urine. SGLT2 stands for sodium-glucose cotransporter 2, a protein in the proximal tubule of the kidney.

Three SGLT2 inhibitors carry most of the evidence: empagliflozin, dapagliflozin and canagliflozin, sold as Jardiance, Farxiga and Invokana. Their generic names all end in -gliflozin. They were approved to lower blood sugar, and large outcome trials changed that standing. Heart and kidney specialists now prescribe them mainly for organ protection.

The disease these drugs treat is largely manufactured, driven by ultra-processed food heavy in sugar, fat and salt. In the Nurses' Health Study, about 90% of type 2 diabetes cases traced to modifiable factors like diet and weight.

What It Does

The result that changed the class came from EMPA-REG OUTCOME. The trial set out only to show that empagliflozin did not harm the heart. Instead, in people with type 2 diabetes and established heart disease, it cut death from cardiovascular causes by 38% and death from any cause by 32%. That cut in cardiovascular death held up when the separate class trials were pooled, but its size varied from one to the next. Unlike the heart-failure and kidney results, it is not a uniform property of the class.

Two benefits then repeat across the class in separate randomized trials: fewer hospital admissions for heart failure, and a slower loss of function in chronic kidney disease. DAPA-HF, DAPA-CKD and CREDENCE are the trials that pinned them down.

The pivotal trials were paid for by the companies that sell the drugs. Boehringer Ingelheim and Eli Lilly funded EMPA-REG OUTCOME; AstraZeneca funded DAPA-HF and DAPA-CKD; Janssen funded CREDENCE and CANVAS. That funding does not overturn the findings, because the same benefits repeat across separate drugs, separate companies and independent analyses. Manufacturer-funded trials also tend to report effects at the favorable edge.

A separate and far thinner line of evidence links the class to the biology of aging, and it rests on a single animal result.

The Research & Studies

Everything here is based on the research we have collected and checked, sorted into groups and ordered with the strongest evidence first. Click any claim to open the studies behind it.

Heart And Vascular

Empagliflozin cut cardiovascular death 38% and all-cause death 32% (EMPA-REG)Strong

In plain terms

In people with type 2 diabetes who already had heart disease, empagliflozin lowered the rate of dying from heart causes by nearly two-fifths and cut heart-failure hospital stays by about a third.

In detail

In EMPA-REG OUTCOME, empagliflozin reduced cardiovascular death by 38% (HR 0.62), all-cause death by 32% (HR 0.68) and hospitalization for heart failure by 35% (HR 0.65) over a median 3.1 years in adults with type 2 diabetes and established cardiovascular disease. Measured in: 7,020 adults with type 2 diabetes and established cardiovascular disease, mean age 63, about 71% men, median follow-up 3.1 years.. The trial enrolled people who already had cardiovascular disease, so it shows benefit in that higher-risk group, not in the general population, and participants were about 71% men.

Who this may not transfer to:Trial population was people with type 2 diabetes and established heart disease, about 71% men, so the benefit is shown in that higher-risk group.

The study · 1

Zinman et al., empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME) · N Engl J Med 2015;373:2117-2128

Counts once: this finding and 1 other here come from the same source, so they are one body of evidence, not separate confirmations.

Dapagliflozin cut worsening heart failure or cardiovascular death 26%, with or without diabetes (DAPA-HF)Strong

In plain terms

In people with a weak heart, dapagliflozin lowered the rate of heart failure getting worse or of dying from heart causes by about a quarter, and it worked just as well in those who did not have diabetes.

In detail

In DAPA-HF, dapagliflozin reduced the primary composite of worsening heart failure or cardiovascular death by 26% (HR 0.74) over a median 18.2 months in people with heart failure and reduced ejection fraction, and the benefit was consistent whether or not they had type 2 diabetes. Measured in: 4,744 adults with heart failure and reduced ejection fraction, about 42% with type 2 diabetes, about 77% men, median follow-up 18.2 months.. The trial studied heart failure with reduced ejection fraction specifically, and participants were about 77% men, so the sex balance is skewed.

Who this may not transfer to:Heart failure with reduced ejection fraction, about 77% men; the benefit held with and without diabetes.

The study · 1

McMurray et al., dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF) · N Engl J Med 2019;381:1995-2008

The whole class lowers heart attacks, heart-failure hospitalization and kidney decline (pooled trials)Strong

In plain terms

Pooling the big trials, the whole class reliably lowers heart attacks and strokes, heart-failure hospital stays, and kidney decline, so this is a property of the class and not of a single drug.

In detail

A meta-analysis of six large SGLT2 inhibitor outcome trials in type 2 diabetes (46,969 patients) found the class reduced major adverse cardiovascular events, hospitalization for heart failure and kidney disease progression, with the heart-failure and kidney benefits the most consistent across the drugs; the reduction in cardiovascular death was significant overall but varied between the trials. Measured in: Pooled participants from large cardiovascular and renal outcome trials of SGLT2 inhibitors in type 2 diabetes.. The pooled trials enrolled people with type 2 diabetes at elevated cardiovascular or kidney risk, so the class effect is established in that population, not in low-risk or non-diabetic general populations.

Who this may not transfer to:Pooled from diabetes outcome trials at elevated cardiovascular or kidney risk; not tested in low-risk or non-diabetic general populations.

The study · 1

McGuire et al., association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis · JAMA Cardiol 2021;6:148-158

Kidney Disease

Dapagliflozin cut kidney-disease progression and related death 39% (DAPA-CKD)Strong

In plain terms

In people with chronic kidney disease, dapagliflozin slowed the loss of kidney function and cut the risk of kidney failure by about two-fifths, and it helped those without diabetes too.

In detail

In DAPA-CKD, dapagliflozin reduced the primary composite of a sustained fall in kidney function, end-stage kidney disease, or renal or cardiovascular death by 39% (HR 0.61) in people with chronic kidney disease, with benefit whether or not they had type 2 diabetes. Measured in: 4,304 adults with chronic kidney disease, about 67% with type 2 diabetes, about 67% men, trial stopped early for benefit.. The trial was stopped early for clear benefit, which can modestly overstate effect size, and participants were about 67% men.

Who this may not transfer to:Chronic kidney disease, about 67% men; the benefit held with and without diabetes.

The study · 1

Heerspink et al., dapagliflozin in patients with chronic kidney disease (DAPA-CKD) · N Engl J Med 2020;383:1436-1446

Canagliflozin cut kidney failure and related death 30% in diabetic nephropathy (CREDENCE)Strong

In plain terms

In people with diabetes whose kidneys were already spilling protein, canagliflozin cut the risk of kidney failure and related death by about a third.

In detail

In CREDENCE, canagliflozin reduced the primary composite of end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death by 30% (HR 0.70) in people with type 2 diabetes and albuminuric chronic kidney disease. Measured in: 4,401 adults with type 2 diabetes and albuminuric chronic kidney disease, about 66% men, trial stopped early for benefit.. This trial was in people with diabetes and existing kidney damage, so it establishes benefit in that population, and it was stopped early for efficacy.

Who this may not transfer to:People with type 2 diabetes and albuminuric kidney disease, about 66% men.

The study · 1

Perkovic et al., canagliflozin and renal outcomes in type 2 diabetes and nephropathy (CREDENCE) · N Engl J Med 2019;380:2295-2306

How it works

Blocking SGLT2 in the kidney spills 50 to 80 grams of glucose a day into the urineModerate · mixed

In plain terms

These drugs stop the kidney from reclaiming glucose, so instead of returning to the blood it leaves in the urine, which lowers blood sugar without needing more insulin.

In detail

SGLT2 inhibitors block the sodium-glucose cotransporter 2 in the proximal tubule of the kidney, which normally reabsorbs about 90% of filtered glucose. Blocking it causes roughly 50 to 80 grams of glucose per day to be excreted in the urine, lowering blood sugar independently of insulin, with mild osmotic diuresis and small reductions in weight and blood pressure. The blood-sugar lowering is modest and does not account for the size of the heart and kidney benefits, which are thought to come from fluid unloading, reduced pressure in the kidney filter, and a shift toward ketone metabolism.

Who this may not transfer to:Mechanism of the drug class; applies to anyone taking one.

The study · 1

Peters et al., euglycemic diabetic ketoacidosis: a potential complication of treatment with SGLT2 inhibition · Diabetes Care 2015;38:1687-1693

Blood Sugar

Empagliflozin lowered HbA1c only about 0.3 to 0.5 points, a modest glucose effectModerate

In plain terms

The drop in long-term blood sugar these drugs produce is small, smaller than what metformin or a GLP-1 drug delivers, and it does not explain the heart and kidney gains.

In detail

In EMPA-REG OUTCOME, empagliflozin lowered HbA1c by roughly 0.3 to 0.5 percentage points more than placebo over the trial, alongside small reductions in body weight and blood pressure, a modest glucose effect compared with the size of the cardiovascular benefit. Measured in: 7,020 adults with type 2 diabetes and established cardiovascular disease, mean age 63, about 71% men.. This is the between-group HbA1c difference in a cardiovascular outcome trial where background diabetes treatment was adjusted, so it reflects the modest add-on glucose effect, not a head-to-head glucose-lowering comparison.

Who this may not transfer to:Add-on glucose effect measured in a diabetes cardiovascular trial, about 71% men.

The study · 1

Zinman et al., empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes (EMPA-REG OUTCOME) · N Engl J Med 2015;373:2117-2128

Counts once: this finding and 1 other here come from the same source, so they are one body of evidence, not separate confirmations.

Longevity And Mortality

Canagliflozin extended male-mouse median lifespan about 14%, with no effect in femalesPreliminary

In plain terms

In a careful animal study, a canagliflozin diet let male mice live about 14% longer on average, while female mice got no benefit.

In detail

In the Interventions Testing Program, a rigorous multi-site study in genetically heterogeneous mice, canagliflozin extended median lifespan in males by about 14% but had no significant effect on female lifespan. This is a rodent result and the benefit appeared only in males, so it does not establish any effect on human lifespan and does not transfer to women even at the animal level.

Who this may not transfer to:Rodent result in male mice only; it does not transfer to humans, or to females even at the animal level.

The study · 1

Miller et al., canagliflozin extends life span in genetically heterogeneous male but not female mice · JCI Insight 2020;5:e140019

Counts once: this finding and 1 other here come from the same source, so they are one body of evidence, not separate confirmations.

No completed human trial shows these drugs extend healthy lifespanPreliminary · mixed

In plain terms

There is no human trial showing these drugs help healthy people live longer; the proven human benefits are for people who already have heart, kidney or blood sugar disease.

In detail

No completed randomized trial tests an SGLT2 inhibitor for extending healthy lifespan or healthspan in people. The human evidence establishes reductions in cardiovascular and kidney disease outcomes in people who already have those conditions, not lifespan extension in healthy adults. The longevity interest rests on a single animal lifespan result in male mice and on mechanism, with no human outcome data for a healthy-aging use.

Who this may not transfer to:No human outcome data for a healthy-aging use; the proven human benefits are in people who already have heart, kidney or blood sugar disease.

The study · 1

Miller et al., canagliflozin extends life span in genetically heterogeneous male but not female mice · JCI Insight 2020;5:e140019

Counts once: this finding and 1 other here come from the same source, so they are one body of evidence, not separate confirmations.

How It Works

Anatomy

1What SGLT2 does, and what blocking it means

SGLT2 sits in the proximal tubule of the kidney and normally reclaims filtered glucose back into the blood. These drugs block it, so that glucose passes into the urine. Beyond lowering blood sugar, the loss pulls a little water and sodium out too. That produces small drops in weight and blood pressure.

2Why the heart and kidney benefits are larger than the glucose effect

The glucose effect is modest, so it does not explain the heart and kidney results. Three ideas lead. Mild fluid loss eases the load the heart must pump against. Lower pressure inside the kidney filter protects it over time. A shift toward burning ketones may give the heart a more efficient fuel. Which matters most is still being worked out, though the outcome data are large and consistent.

3The longevity question

The Interventions Testing Program, a rigorous multi-site animal aging study, found canagliflozin extended median lifespan in male mice by about 14% and did nothing measurable in females. The proposed reasons include the daily loss of glucose calories acting as a mild caloric restriction, and a metabolic switch toward ketones. No completed human trial tests any of these drugs for healthy aging, so this remains a hypothesis grounded in one animal result.

The kidney filters roughly 180 grams of glucose a day and, in a healthy person, reabsorbs nearly all of it. About 90% of that reabsorption runs through SGLT2, so blocking it lets 50 to 80 grams a day leave in the urine. That lowers blood sugar without pushing the pancreas to release more insulin. For the metabolic system these drugs act on, see insulin and glucose handling.

How to Approach It

The strongest evidence for these drugs is in heart failure, chronic kidney disease and type 2 diabetes. What to weigh before the longevity idea comes up:

1

Start with the basics a pill does not replaceFreeModerate

The foundations of metabolic and cardiovascular health are exercise, whole foods, sleep and keeping muscle, and no drug substitutes for them. See [resistance training](/go/integrative/practice/resistance-training) for holding muscle with age and [sleep environment](/go/integrative/practice/sleep-environment) for the rest of the foundation.

2

If you have heart failure, kidney disease or diabetes, this is where the drugs are strongestVariesEasy

For heart failure, chronic kidney disease and type 2 diabetes, these drugs have large randomized trials behind them. This is the core of what they are for.

3

If you take one, agree a sick-day rule in advanceFreeEasy

With your prescriber, plan to pause the drug during serious illness, dehydration or before surgery. That single step heads off the most dangerous situation on the label.

4

Treat the longevity question as not yet tested in peopleFreeEasy

For a healthy person without heart, kidney or blood-sugar disease, taking one to slow aging runs ahead of the evidence. So far that evidence is one mouse study, with no completed human trial and no established dose. Anyone drawn to it for aging can raise it with a prescriber before acting.

Go Deeper

• Insulin and glucose handling: how the body regulates blood sugar, and why moving glucose out of the blood matters.
• The biology of aging: the science behind the longevity claim.
• Metformin: the other old diabetes drug at the center of the same longevity question.
• GLP-1 Medications: the newer diabetes and weight drugs weighed alongside this class.
• Resistance training: the free, self-directed lever for holding muscle and metabolic health with age.
• Sleep environment: the rest of the foundation no pill replaces.

The Chinese Medicine View

SGLT2 inhibitors are products of modern chemistry, developed over roughly the past 20 years. No classical Chinese text lists one, no channel, no temperature, no flavor, and no traditional formula that contains it.

Classical Chinese medicine does describe a pattern that maps loosely onto diabetes: Xiao Ke, the wasting-and-thirsting disorder. It reads the heavy urination and constant thirst of that pattern as Yin depletion with Heat, a state the tradition works to resolve.

From that starting point the tradition would raise a caution. These drugs deliberately increase the loss of a refined substance, glucose, through the urine, and pull body fluid out along with it. A tradition built around preserving fluids and Yin would see deliberately causing that loss, in someone already dry and thirsty, as the wrong move. The volume-depletion and dehydration risk on the label lines up with that concern.

The tradition would not read a deliberate loss of glucose as strengthening anything. It treats these drugs as acting on the downstream picture: high blood sugar, heart strain, kidney decline. Its own aim, a body that transforms and holds its own fluids, is a different task the drug does not address. The case for the drugs rests on their own trials. For heart and kidney disease, those trials are extensive. Nothing here suggests any herb or formula reproduces what they do.

Cautions

Everything to be aware of is here, in one place. This practice suits most healthy people; a few situations call for real care.

Genital yeast infections rise in both men and women, most often early on

In the CANVAS program, canagliflozin increased genital mycotic infections in both women and men compared with placebo, a consistent effect of putting glucose into the urine and seen across the drug class. Rates come from a diabetes population, and genital infections were common but generally treatable, not severe.Neal et al., canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS Program)

Ketoacidosis can strike while blood glucose reads close to normal, which makes it easy to miss

A case series described diabetic ketoacidosis occurring during SGLT2 inhibitor treatment while blood glucose read close to normal, not markedly elevated, so-called euglycemic ketoacidosis, precipitated by surgery, acute illness, dehydration, insulin reduction and low-carbohydrate intake. This is a small case series, not a rate from a controlled trial, so it establishes that the event happens and its triggers, not a precise incidence.Peters et al., euglycemic diabetic ketoacidosis: a potential complication of treatment with SGLT2 inhibition

Canagliflozin verdoppelte Amputationen der unteren Extremitäten annähernd, 6.3 vs. 3.4 pro 1,000 Patientenjahre (CANVAS)

Im CANVAS-Programm war Canagliflozin im Vergleich zu Placebo mit etwa der doppelten Rate an Amputationen der unteren Extremitäten verbunden (6.3 vs. 3.4 pro 1,000 Patientenjahre; HR 1.97), hauptsächlich auf Höhe der Zehen oder des Metatarsus. Eine spätere Canagliflozin-Nierenstudie konnte das gleiche Amputationssignal nicht reproduzieren, das Risiko ist also nicht abschließend geklärt, und es wurde in einer Hochrisiko-Diabetespopulation untersucht.Neal et al., canagliflozin and cardiovascular and renal events in type 2 diabetes (CANVAS Program)

Fournier-Gangrän, eine perineale Infektion: 55 Postmarketing-Fälle innerhalb der Klasse

Eine Überprüfung von Postmarketing-Berichten identifizierte 55 Fälle von Fournier-Gangrän, einer nekrotisierenden Infektion des Damms, bei Menschen, die über etwa sechs Jahre SGLT2-Hemmer einnahmen, ein seltenes, aber ernstes Ereignis, das in der gesamten Medikamentenklasse beobachtet wurde. Dies sind spontane Postmarketing-Berichte, die keine Inzidenzrate festlegen oder beweisen können, dass das Medikament jeden Fall verursacht hat, aber das Signal war konsistent genug, um einen Klassenwarnhinweis auszulösen.Bersoff-Matcha et al., Fournier gangrene associated with SGLT2 inhibitors: a review of spontaneous postmarketing cases

A prescription drug, and the decision sits with a clinician

These are prescription medicines. Whether one fits, and how it interacts with your kidney function, blood pressure and other medicines, is a decision made with a prescriber. No dose is given, because there is no safe general dose outside the diseases these drugs are approved to treat.

Ketoacidosis at near-normal blood sugar

These drugs can cause diabetic ketoacidosis, a dangerous buildup of acid in the blood. It can happen while blood sugar reads close to normal. The risk rises around surgery, serious illness, dehydration, heavy alcohol use, and very low-carbohydrate eating. The standard guidance is to pause the drug during those situations, a plan a prescriber sets in advance.

Genital yeast and urinary infections

Because the drugs put sugar into the urine, they raise the rate of genital yeast infections in men and women, most often early in treatment. They can also contribute to urinary tract infections. These are usually treatable, and common enough to expect and plan for before starting.

Volume depletion and low blood pressure

The mild diuretic effect can tip into dehydration and low blood pressure, especially in older adults, in people already on other diuretics, and during illness with poor fluid intake. Staying well hydrated and reviewing other blood-pressure and fluid medicines with a prescriber is part of using these drugs safely.

Fournier gangrene, rare but serious

A rare but severe infection of the tissue around the genitals and perineum, called Fournier gangrene, has been reported across this drug class in postmarketing surveillance. It needs emergency care.

The amputation signal with canagliflozin

In the CANVAS trial, canagliflozin was linked to about twice the rate of lower-limb amputation, mostly of toes and the mid-foot. Later trials of the same drug did not show an effect that large, so the picture is not settled. It is still a specific reason to raise foot care and any existing foot problems with a prescriber.

Not a do-it-yourself longevity drug

No completed human trial establishes a benefit or a dose for these drugs as a way to slow aging in a healthy person. The research is a single result in mice. A prescriber can weigh the trade-offs for an individual case.

Start slow, be smart, read the research, and consult a professional if you have any concerns. This is here to inform your choice, not make it for you.

When to See Someone

Most people who take these drugs for the right reason do well. Two problems are emergencies because they can look milder than they are. If either fits, get seen without waiting.

• Nausea, vomiting, abdominal pain, deep or rapid breathing, unusual drowsiness or confusion, even when a home glucose reading looks normal. This can be diabetic ketoacidosis. The normal-looking blood sugar is what makes it easy to miss, so get urgent assessment.(seek urgent care)
• Severe pain, swelling, redness or tenderness of the genitals or the perineum, especially with fever or feeling very unwell. This can be Fournier gangrene, a fast-spreading infection. Get emergency care.(seek urgent care)

These drugs have a strong record in heart and kidney disease. Both are treatable when caught early and dangerous when missed. Any change to a prescribed medicine goes through your prescriber.

Common Questions

What do SGLT2 inhibitors actually do?

They block the kidney's reabsorption of glucose, so it leaves in the urine. Normally the kidney reclaims almost all the glucose it filters through the SGLT2 transporter. These drugs block that transporter, so 50 to 80 grams of glucose leave in the urine each day. That lowers blood sugar and produces small drops in weight and blood pressure.

The larger reason they are prescribed is protection of the heart and kidneys, beyond what the blood-sugar change alone would predict.

Do they help people who do not have diabetes?

Yes, for two conditions. In DAPA-HF, dapagliflozin cut worsening heart failure or cardiovascular death in people with a weak heart. In DAPA-CKD, it slowed chronic kidney disease. In both trials the benefit held whether or not the person had diabetes. That is why cardiologists and kidney specialists prescribe them beyond diabetes care. The benefit is established in people who already have heart or kidney disease, not in an otherwise healthy person.

Do SGLT2 inhibitors extend lifespan?

In people, that is not known. The evidence is one animal result: in the Interventions Testing Program, the drug raised median survival in male mice by roughly 14%, with no measurable effect in females. The proposed reasons are the daily loss of glucose calories and a shift toward burning ketones. No completed human trial tests any of these drugs for slowing aging. The established human benefit is protection of the heart and kidney in people who already have disease.

What are the main risks?

Ketoacidosis is the one that can begin while blood sugar reads near normal, so the drugs are paused around illness and surgery. Genital yeast infections are common early, from the sugar in the urine. The mild diuretic effect can also cause volume depletion and low blood pressure, most of all in older adults on other diuretics. Rarer and serious is Fournier gangrene, a fast-spreading infection in the genital and perineal tissue. Canagliflozin also carried an amputation signal in the CANVAS trial.