Added to metformin, GLP-1 medicines usually lower A1c by 1% to 2% or more, with a low risk of lows unless taken with insulin or a sulfonylurea. Here is how semaglutide, dulaglutide, liraglutide and tirzepatide work, what the major trials found, and which side effects and sick-day risks matter.
GLP-1 medicines lower blood sugar in type 2 diabetes. Added to metformin, they usually bring A1c down by 1% to 2% or more 3, which by a standard formula means an average glucose about 1.6 to 3.2 mmol/L (29 to 57 mg/dL) lower 8. They boost the body’s own insulin when glucose is high and curb the rise after meals 1, and because the insulin boost fades as glucose returns to normal 9, they carry a low risk of lows on their own 3.
This article explains how semaglutide, dulaglutide, liraglutide and tirzepatide work, what the trials found, what changes in your readings, the side effects, and where guidelines place them. It is education, not advice; decisions about any medicine belong with you and your care team.
GLP-1 medicines are diabetes drugs that copy GLP-1 (glucagon-like peptide-1), a hormone the gut releases when you eat 10. They mainly help manage blood sugar in type 2 diabetes, and some can also help treat obesity 11. Doctors call them GLP-1 receptor agonists (GLP-1 RAs). An agonist is a medicine that switches on a receptor, the “lock” a hormone fits into.
Cleveland Clinic lists these generic names and how often each is usually taken 11:
Brand names include Ozempic, Rybelsus and Wegovy (semaglutide), Trulicity (dulaglutide), Victoza and Saxenda (liraglutide) 12, and Mounjaro and Zepbound (tirzepatide) 2. As Yale Medicine puts it, the injections are “not insulin,” and most are given once a week 13.
GLP-1 medicines lower blood sugar in four ways: they increase insulin release when glucose is high, hold back glucagon (a pancreatic hormone that pushes blood sugar up), slow the emptying of the stomach and reduce appetite 1.
The ADA and the European Association for the Study of Diabetes (EASD) describe the insulin boost as glucose-dependent 1. A 1993 experiment showed what that means. Researchers gave an infusion of GLP-1 to 10 people with type 2 diabetes whose fasting glucose averaged 13.1 mmol/L (236 mg/dL) 9. Within four hours, glucose fell to a normal 4.9 mmol/L (88 mg/dL), which did not happen with placebo. Once glucose was normal, insulin fell back toward its starting level and glucose held steady 9.
Slower stomach emptying curbs the rise in glucose after meals 1. As Yale Medicine explains, sugar “isn’t absorbed as fast in the bloodstream” 13. The medicines also act in the brain to reduce hunger 10, which lowers how much people eat and, over time, body weight 1.
In plain terms: These medicines turn up your own insulin when glucose is high and ease off as it returns to normal. They also slow how fast a meal reaches your blood and take the edge off hunger. That is why, on their own, they seldom push glucose too low, and why rises after meals tend to be smaller.
Added to metformin, GLP-1 medicines and tirzepatide usually lower A1c by 1% to 2% or more 3. A fall from 8.3% to 6.3% is 2 percentage points; our guide to A1c, GMI and average glucose explains what A1c measures. The ADA’s 2026 Standards of Care rate the glucose-lowering effect of GLP-1 RAs as “high to very high” and of tirzepatide as “very high,” with weight loss for both 3.
| Trial and medicine | Who and how long | A1c change | Weight change |
|---|---|---|---|
| SURPASS-2: tirzepatide 5, 10 or 15 mg vs semaglutide 1 mg, weekly | 1,879 adults with type 2 diabetes, 40 weeks | −2.01 to −2.30 points vs −1.86 | 1.9 to 5.5 kg more loss with tirzepatide 4 |
| SUSTAIN FORTE: semaglutide 2.0 mg vs 1.0 mg, weekly | People with type 2 diabetes, 40 weeks | −2.1% vs −1.9% (−23 vs −21 mmol/mol) | −6.4 vs −5.6 kg 1 |
| AWARD-11: dulaglutide 4.5 mg vs 1.5 mg, weekly | People with type 2 diabetes on metformin, 36 weeks | −1.77% vs −1.54% | −4.6 vs −3.0 kg 1 |
| LEADER: liraglutide vs placebo, daily | 9,340 adults at high cardiovascular risk, median 3.8 years | 0.40 points lower than placebo at 36 months | 2.3 kg more loss 6 |
SURPASS-2 participants started at an average A1c of 8.28% (67 mmol/mol) 4. Compared with placebo, tirzepatide 5, 10 and 15 mg lowered A1c by 1.91, 1.93 and 2.11 percentage points, with mean weight reductions of 7 to 9.5 kg, the ADA/EASD report says 1.
For weight, the STEP 2 trial tested semaglutide 2.4 mg weekly with a lifestyle program in people with type 2 diabetes. They lost 9.6% of their body weight, 6.2 percentage points more than with placebo and 2.7 more than with semaglutide 1.0 mg 1.
Day to day, GLP-1 medicines tend to show up as smaller rises after meals and a lower average glucose 1, 3. The A1c-Derived Average Glucose (ADAG) study, which collected about 2,700 readings from each of 507 people, found that average glucose (mg/dL) = 28.7 × A1c − 46.7 8. By that formula, each percentage point of A1c is worth about 1.6 mmol/L (29 mg/dL), so a fall of 1 to 2 points matches an average about 1.6 to 3.2 mmol/L (29 to 57 mg/dL) lower.
The effect is not limited to meals: in the 1993 infusion study, GLP-1 brought high fasting glucose down to normal 9. A meal can still rise differently from one day to the next, for reasons covered in same meal, different spike.
These medicines are started low and raised in steps, because gradual increases help limit stomach side effects 1. In SURPASS-2, each higher tirzepatide dose lowered A1c a little more 4, and SURPASS-2, SUSTAIN FORTE and AWARD-11 reported their main A1c results at 36 to 40 weeks 1, 4. If you wear a CGM, our guides to time in range and AGP reports explain how to read shifts over weeks rather than days.
The ADA recommends adding a GLP-1 medicine when insulin is used, for better glucose control with benefits for weight and the risk of lows. It says insulin dosing should be reassessed when one is added or its dose is raised 3. Eating less matters too: Mayo Clinic notes that lows can follow a delayed or missed meal, or being unable to eat because of nausea or vomiting 2. Any change to insulin is a decision for your care team.
On their own, GLP-1 medicines and tirzepatide carry a low risk of low blood sugar, but lows become more likely when they are combined with insulin or a sulfonylurea 3, 11. The ADA’s 2026 summary table lists no hypoglycemia risk for either class 3, and Mayo Clinic’s drug pages say semaglutide and tirzepatide do not cause lows by themselves 2, 5.
In SURPASS-2, glucose below 3.0 mmol/L (54 mg/dL) was reported in 0.2% to 1.7% of people on tirzepatide and 0.4% on semaglutide 4. In LEADER, severe lows occurred in 2.4% of people on liraglutide and 3.3% on placebo 6.
Combinations are different. Cleveland Clinic warns that lows “can become a serious risk” with other glucose-lowering medicines, “like sulfonylureas or insulin” 11. The ADA therefore recommends that when a new glucose-lowering medicine is started, care teams reassess the need for, and dose of, sulfonylureas, meglitinides and insulin 3. How your own plan changes is for your prescriber to decide. Our article on low blood sugar covers warning signs and treatment.
Nausea, vomiting and diarrhea are the most common side effects of GLP-1 medicines; they tend to occur when starting or raising the dose and fade over time 1. In SURPASS-2, nausea affected 17% to 22% of people on tirzepatide and 18% on semaglutide, diarrhea 13% to 16% and 12%, and vomiting 6% to 10% and 8%, mostly mild to moderate 4. In LEADER, 9.5% of people on liraglutide and 7.3% on placebo stopped because of side effects, mainly stomach and bowel problems 6. The ADA says GLP-1 RAs are not recommended for people with gastroparesis, in which the stomach empties too slowly 3.
Mayo Clinic says tirzepatide “may cause dehydration which can lead to acute kidney injury,” a sudden drop in kidney function 2. Its semaglutide page lists vomiting and increased thirst among possible signs of dehydration 5, and Cleveland Clinic lists acute kidney injury among severe but rare side effects 11. For people with reduced kidney function who report severe stomach and bowel reactions, the ADA advises monitoring kidney function when the medicine is started or the dose raised 3.
Harvard Health says “you should immediately seek medical attention” for severe vomiting and diarrhea, severe pain or tenderness in your belly, being unable to pass gas or move your bowels, or yellow skin (jaundice) 10. Our article on high blood sugar covers sick days more broadly.
The ADA says acute pancreatitis “has been reported, but causality has not been established” 3. In LEADER, it occurred in 18 people on liraglutide and 23 on placebo, while acute gallstone disease affected 145 and 90 6. The ADA advises close eye monitoring for people at high risk of diabetic retinopathy 3. The ADA/EASD report linked extra retinopathy complications with semaglutide in the SUSTAIN-6 trial to large, fast A1c falls in people who already had retinopathy 1. Thyroid C-cell tumours have been found in rodents; their relevance to people has not been determined 3.
The ADA’s 2026 Standards note case reports of pulmonary aspiration, where stomach contents get into the lungs, under general anesthesia and deep sedation. People taking a GLP-1 RA are more likely to have food left in the stomach 14. Advice has moved from holding weekly doses for at least seven days, as the American Society of Anesthesiologists first advised, toward a more personal approach: several societies now let people at low risk of delayed stomach emptying continue the medicine before elective surgery, with a liquid diet for 24 hours beforehand 14. The ADA recommends a personalized approach and notes that holding a weekly medicine for one week “is likely insufficient” to lower the risk 14. Harvard Health advises telling your doctor that you take a GLP-1 drug if you are having surgery or a procedure with general anesthesia 10.
The ADA’s 2026 Standards recommend a GLP-1 RA, an SGLT2 inhibitor or both, with proven benefit, for adults with type 2 diabetes who have chronic kidney disease or who have, or are at high risk of, atherosclerotic cardiovascular disease (heart attack, stroke and other disease of narrowed arteries), whatever their A1c 3. It prefers GLP-1–based therapy to insulin when treatment is started or added, unless glucose is severely high. In advanced kidney disease (eGFR below 30), it prefers a GLP-1 RA for glucose management because of the lower risk of lows 3. For adults with obesity and heart failure with preserved ejection fraction, it recommends a dual GIP and GLP-1 RA with proven benefit 3.
Diabetes Canada’s 2020 update says metformin should usually be chosen before other agents 15. For adults with atherosclerotic cardiovascular disease, it says treatment should include agents with proven heart or kidney benefit, giving its strongest grade to liraglutide and dulaglutide and a lower one to injected semaglutide 15. It suggests a GLP-1 RA as an add-on when weight loss is a priority, and for people on insulin before insulin is intensified. It does not cover tirzepatide 15.
Heart trials count major adverse cardiovascular events (MACE): cardiovascular death, nonfatal heart attack or nonfatal stroke 6. A hazard ratio below 1 means fewer events with the medicine.
The ADA’s 2026 table lists cardiovascular benefit for dulaglutide, liraglutide and semaglutide (injected and oral), and for the dual GIP and GLP-1 RA, “under investigation” 3.
In the US, the FDA has not approved GLP-1 medicines for type 1 diabetes 11. In the largest type 1 trials, liraglutide brought modest A1c falls of about 0.4%, about 5 kg of weight loss and lower insulin doses, but the ADA says “higher rates of DKA and gastrointestinal side effects have limited their use in type 1 diabetes” 3. DKA, diabetic ketoacidosis, is a dangerous build-up of acids called ketones.
For pregnancy, the ADA says GLP-1 RAs and dual GIP and GLP-1 RAs should be stopped before pregnancy, with contraception used while taking them 16. Prescribing information advises stopping semaglutide at least 2 months before a planned pregnancy, and Canadian prescribing information for tirzepatide at least 1 month. Several months are usually needed to clear the medicine and reach pre-pregnancy glucose goals with treatment approved for pregnancy 16.
Yes, and it does more. Tirzepatide acts on the receptors for two gut hormones, GIP and GLP-1, so it is called a dual GIP and GLP-1 receptor agonist 2, 11. In a 40-week head-to-head trial, it lowered A1c and weight more than semaglutide 1 mg 4.
On their own, rarely: the ADA lists no hypoglycemia risk for the class 3. The risk rises when they are taken with insulin or a sulfonylurea, and the ADA asks care teams to reassess those medicines when a new one is started 3, 11.
Common, especially early on. In SURPASS-2, 17% to 22% of people on tirzepatide and 18% on semaglutide had nausea, mostly mild to moderate 4. Stomach side effects tend to occur when starting or raising the dose and fade over time 1.
It depends, and the advice has changed. The ADA’s 2026 Standards recommend a personalized approach because of a risk of aspiration under anesthesia, and note that some societies now let people at low risk continue with a 24-hour liquid diet before elective surgery 14. Harvard Health advises telling your doctor that you take one before surgery 10.
A new or changed medicine is easier to understand when you can look at several weeks of readings together. In Glyve’s day view, the glucose line shows your own target range, with logged meals, insulin, exercise, sleep and stress on the same timeline, so you can see after-meal rises and fasting readings in context. You can log by typing, by voice or with a photo of a meal, a nutrition label or a barcode, and every estimate is a draft you check before saving. The week view shows whether a pattern repeats. Glyve reads glucose from Apple Health, from Dexcom and FreeStyle Libre through your Dexcom Share or LibreLinkUp follower account (readings can arrive later than in the CGM’s own app), or from meter readings you type in. A PDF summary, CSV or AGP report lets you share those weeks with your care team when you choose. Glyve is not a medical device: it gives no medical advice and recommends no doses, so questions about your medicines stay with your care team.
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