SGLT2 Inhibitors and GLP-1s Together: What the Combination Trials Show About Weight, Blood Sugar and Kidneys

Can you take an SGLT2 inhibitor and a GLP-1 together? In adults with type 2 diabetes, yes: the pairing has been tested in several randomized trials, and it lowers blood sugar and body weight further than either drug class alone. What the trials have not shown is that the combination protects the kidneys or heart better than one drug on its own.

SGLT2 inhibitors are daily tablets such as dapagliflozin, empagliflozin and canagliflozin. GLP-1 receptor agonists include semaglutide, dulaglutide, exenatide and, with an added GIP action, tirzepatide. Plenty of people end up on both, often because a doctor prescribed the tablet for diabetes, heart or kidney reasons before the injection came along.

This article walks through the combination trials one at a time: SUSTAIN 9, AWARD-10, DURATION-8, the SGLT2 subgroup of FLOW and a 2026 network meta-analysis. Every trial here studied standard doses in type 2 diabetes. None tested a GLP-1 microdose alongside an SGLT2 inhibitor, and that gap is part of the story.

Why would an SGLT2 inhibitor and a GLP-1 work well together?

Two different routes, one appetite problem

The two drug classes lower glucose and weight by unrelated routes, so their effects can add up. An SGLT2 inhibitor blocks glucose reabsorption in the kidney, and the sugar that would have been recycled leaves in the urine along with its calories. A GLP-1 medicine acts on the gut and brain, slowing digestion and reducing how much a person wants to eat.

The calorie loss from an SGLT2 inhibitor triggers a response that GLP-1 medicines are well placed to blunt. Polidori, Hall and colleagues used data from a 52-week trial of canagliflozin in 153 patients, published in Obesity in 2016, to calculate how eating changed as weight came off. They estimated that appetite rose enough to drive eating about 100 kcal a day above baseline for each kilogram lost, more than three times the matching drop in energy expenditure.

That finding explains why SGLT2 inhibitors on their own tend to produce modest weight loss. It also makes a GLP-1 a logical partner, since dampened appetite is what GLP-1 drugs do best. The logic is sound, but it is a mechanism argument. No trial has measured appetite as a primary outcome of the combination. Our article on hunger hormones on a GLP-1 covers the appetite side in more depth.

What happens when semaglutide is added to an SGLT2 inhibitor?

The SUSTAIN 9 trial

Adding semaglutide to an SGLT2 inhibitor lowered both blood sugar and weight substantially in SUSTAIN 9. Zinman and colleagues randomized 302 adults with type 2 diabetes who had been on an SGLT-2 inhibitor for at least 90 days to weekly semaglutide or placebo at 61 centres. The results were published in Lancet Diabetes & Endocrinology in 2019. Semaglutide started at 0.25 mg for 4 weeks, rose to 0.5 mg for 4 weeks and then stayed at 1.0 mg until week 30.

Compared with placebo, semaglutide lowered HbA1c by a further 1.42 percentage points and body weight by a further 3.81 kg. The SGLT-2 inhibitor stayed in place throughout, and 71.5% of participants were also on metformin.

The cost was mostly digestive. Gastrointestinal adverse events affected 37.3% of the semaglutide group and 13.2% of the placebo group. Serious adverse events were similar, at 4.7% and 4.0%. Of the 16 people who stopped treatment early because of an adverse event, 13 were on semaglutide. Readers interested in how a slower start changes that picture can see the gentle ramp.

Does a lower GLP-1 dose still add benefit on top of an SGLT2 inhibitor?

The AWARD-10 trial and its two dulaglutide doses

Yes, in the one trial that tested two doses, the lower dose delivered most of the glucose benefit with far less nausea. AWARD-10, led by Ludvik and published in Lancet Diabetes & Endocrinology in 2018, randomized 424 adults whose diabetes was not controlled on an SGLT2 inhibitor to weekly dulaglutide 1.5 mg, dulaglutide 0.75 mg or placebo for 24 weeks at 40 sites.

HbA1c fell by 1.34 percentage points on 1.5 mg, 1.21 on 0.75 mg and 0.54 on placebo. Nausea was reported by 15% of the 1.5 mg group, 5% of the 0.75 mg group and 4% of the placebo group. Diarrhoea did not follow the same pattern: 6%, 10% and 3%. For anyone curious about lower-dose GLP-1 use, this is the nearest data point in the combination literature, though 0.75 mg is an approved dose, not a microdose.

Is starting both drugs at once better than starting one?

DURATION-8: combination versus each drug alone

Starting both at once beat either drug alone on every glucose measure, on weight loss and on systolic blood pressure in DURATION-8. Frías and colleagues randomized 695 adults on metformin to weekly exenatide 2 mg plus daily dapagliflozin 10 mg, exenatide alone or dapagliflozin alone, across 109 sites, reporting in Lancet Diabetes & Endocrinology in 2016. Mean baseline HbA1c was high, at 9.3%.

After 28 weeks, HbA1c had fallen by 2.0 percentage points on the combination, 1.6 on exenatide and 1.4 on dapagliflozin. Adverse events were recorded in 57%, 54% and 52% of the three groups, and no major or minor hypoglycaemia was reported in any group.

The advantage held over 2 years. In the 104-week extension reported in Diabetes Care in 2020, the HbA1c reductions were 1.70, 1.29 and 1.06 points. Only 62.0% of participants completed treatment to that point, and the authors called the 104-week results exploratory, so the long-term figures describe the people who stayed rather than everyone who started.

What about tirzepatide with an SGLT2 inhibitor?

SURPASS-3 allowed it as background therapy

Tirzepatide has not had a dedicated SGLT2 add-on trial, but SURPASS-3 enrolled people on metformin with or without an SGLT2 inhibitor. Ludvik and colleagues randomized 1,444 people to tirzepatide 5, 10 or 15 mg or insulin degludec for 52 weeks, publishing in the Lancet in 2021. HbA1c fell by 1.93, 2.20 and 2.37 points on tirzepatide, and weight dropped by 7.5 to 12.9 kg, while insulin degludec added 2.3 kg. The abstract does not split those results by SGLT2 use, so the trial shows the drugs can be used together rather than how much the tablet adds.

Does a GLP-1 protect the kidneys further in someone already on an SGLT2 inhibitor?

The SGLT2 subgroup of the FLOW trial

It is not yet known. FLOW tested semaglutide in people with type 2 diabetes and chronic kidney disease, and Mann and colleagues split the results by SGLT2 inhibitor use in Nature Medicine in 2024. Across everyone, semaglutide lowered the risk of the primary outcome, a composite of kidney failure, a 50% or greater fall in eGFR, or kidney or cardiovascular death, by 24%.

In the 2,983 participants not taking an SGLT2 inhibitor, the primary outcome occurred in 290 of 1,490 on semaglutide and 372 of 1,493 on placebo, a hazard ratio of 0.73. In the 550 who were taking one, the numbers were 41 of 277 and 38 of 273, a hazard ratio of 1.07. The interaction test, which asks whether the two groups truly differ, gave p = 0.109, which is not statistically significant.

The authors concluded that kidney benefits were consistent with and without SGLT2 inhibitors, while noting that power was limited to detect smaller but clinically relevant effects. Put plainly, the SGLT2 subgroup was too small to show whether semaglutide adds kidney protection on top of the tablet. Our article on GLP-1s and kidney function covers eGFR and what it measures.

Is the combination better for the heart than either drug alone?

A 2026 network meta-analysis

The best available pooled evidence finds no clear advantage for heart attacks, strokes, cardiovascular death or kidney events, with a possible advantage for heart failure. Chuang and colleagues combined 12 randomized trials with 99,683 participants in a network meta-analysis published in CMAJ in 2026.

For major adverse cardiovascular events, the risk ratio for the combination was 0.86 against SGLT2 inhibitors alone and 0.95 against GLP-1 drugs alone, neither significant. For major kidney events the ratios were 1.05 and 0.86, also not significant. Heart failure admissions were lower on the combination, with risk ratios of 0.72 and 0.62.

Every one of these estimates was rated very low certainty, because almost no trial randomized people to the combination against each single drug for hard outcomes. The comparisons are indirect. The authors called for trials that compare combined therapy with monotherapy directly. Our overview of GLP-1s and cardiovascular health covers the single-drug outcome trials.

What are the safety issues when combining an SGLT2 inhibitor and a GLP-1?

Stomach, blood sugar and ketoacidosis

The trials found no new safety problems from the pairing itself; the risks are those of each drug. The GLP-1 brings the digestive side effects seen in SUSTAIN 9 and AWARD-10. Low blood sugar was uncommon: DURATION-8 recorded none, and in SUSTAIN 9 it affected 2.7% of the semaglutide group, where 12.9% of participants also took a sulphonylurea. Our piece on hypoglycemia on a GLP-1 explains which drug pairings raise that risk.

The SGLT2 inhibitor brings a rarer but more serious risk: ketoacidosis, sometimes with blood sugar that looks close to normal. He and colleagues searched the FDA Adverse Event Reporting System and, in Acta Diabetologica in 2023, described 10,195 reports of ketoacidosis linked to SGLT-2 inhibitors, 1,680 of them the euglycemic type. Reporting odds ratios were about 16.69 and 16.44 compared with other glucose-lowering drugs, median onset was 31 days and about 75.6% of patients needed hospital care.

Spontaneous reports cannot give a true rate, and the authors described the event as rare. Still, GLP-1 medicines reduce how much people eat, and anyone on both drugs should ask their prescriber how to handle days of illness, vomiting or very low food intake, and which symptoms mean stopping the tablet and getting checked. The hydration guide covers the fluid side, since both drug classes can affect it.

What does this mean for someone microdosing a GLP-1 who also takes an SGLT2 inhibitor?

Reading trial data across to low doses

The honest answer is that the combination evidence comes from standard doses in type 2 diabetes, and none of it tested a microdose. The closest hints are indirect. SUSTAIN 9 started semaglutide at 0.25 mg and 0.5 mg, the range many low-dose protocols sit in, but it reported outcomes only after a 30-week course that ended at 1.0 mg. AWARD-10 showed that dulaglutide 0.75 mg kept most of the HbA1c effect of 1.5 mg with a third of the nausea.

The pairing with metformin has its own trial history, covered in metformin and GLP-1s together.

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