- All four lower blood sugar in type 2 diabetes. Compared with placebo in meta-analyses, SGLT2 inhibitors cut A1C by about 0.66 points, DPP-4 inhibitors by 0.74, metformin by 1.12 and tirzepatide by 2.10.3,5,6,8
- GLP-1 drugs cause the most weight loss, SGLT2 inhibitors a little, and DPP-4 inhibitors and metformin are about weight neutral.2,5,8
- A DPP-4 inhibitor protects the body's own GLP-1, raising it about 2-fold. A GLP-1 agonist supplies far higher, drug-level amounts.9,10
- The 2026 ADA/EASD consensus report advocates earlier use of SGLT2 inhibitors and GLP-1-based drugs, potentially from diagnosis.1
What is the difference between GLP-1 agonists, SGLT2 inhibitors, DPP-4 inhibitors and metformin?
They are four classes of type 2 diabetes medicines, each lowering blood sugar a different way. Metformin mainly acts on the liver. SGLT2 inhibitors make the kidneys pass extra sugar into urine. DPP-4 inhibitors and GLP-1 agonists both work through the gut hormone GLP-1, but at very different strengths.
A1C, used below, is a blood test of your average blood sugar over about three months.
Agonist vs antagonist: what do the words mean?
A receptor is a "lock" on a cell that a hormone fits like a key. An agonist is a drug that fits the lock and turns it, switching on the same signal as the body's own hormone. An antagonist fits the lock but blocks it, so nothing happens. An inhibitor blocks an enzyme or a transporter (a working protein) instead. GLP-1 medicines are agonists. The Ozempic label says semaglutide "selectively binds to and activates the GLP-1 receptor."11
Metformin
How it works. Metformin is a pill used daily by more than 200 million people. It lowers blood sugar mainly by acting on the liver, though a 2023 review says its exact mechanisms are still not fully understood and the gut may also play a part.4 Brand example: Glucophage.
Effect. In a 2012 meta-analysis of 35 trials, metformin alone lowered A1C by 1.12 percentage points compared with placebo.3 The 2022 ADA/EASD report describes it as weight neutral with potential for modest weight loss, with low risk of low blood sugar and low cost.2
Main side effects. Nausea and diarrhea were more common with metformin than with DPP-4 inhibitors in a 2012 BMJ meta-analysis.7 It may lower vitamin B12 levels, and the 2022 report says it should not be used when kidney function (eGFR) is below 30.2
SGLT2 inhibitors
How they work. SGLT2 is a transporter in the kidney that pulls sugar back into the blood. SGLT2 inhibitors are pills that block it, so more sugar leaves in the urine.2 Examples: empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana).
Effect. In a 2013 meta-analysis of 45 placebo-controlled trials (11,232 people), they lowered A1C by 0.66 points vs placebo. Compared with other diabetes drugs, they lowered weight by about 1.8 kg and systolic blood pressure by about 4.5 mm Hg.5 Large outcome trials found they reduce heart failure hospitalizations and protect the kidneys in people at high risk.2
Main side effects. Genital yeast infections (about 5 times the odds) and urinary tract infections (1.4 times) were more common.5 Diabetic ketoacidosis, a dangerous buildup of blood acids, is rare: 0.1–0.6% in heart outcome trials vs under 0.1–0.3% on placebo.2
DPP-4 inhibitors
How they work. DPP-4 is an enzyme that breaks down the body's own GLP-1 quickly. DPP-4 inhibitors are pills that block that enzyme, so more of your own GLP-1 stays active. This raises insulin and lowers glucagon (a hormone that raises blood sugar) when blood sugar is high.2 Examples: sitagliptin (Januvia), linagliptin (Tradjenta), saxagliptin (Onglyza), alogliptin (Nesina).
Effect. In a 2007 JAMA meta-analysis, DPP-4 inhibitors lowered A1C by 0.74 points vs placebo and were weight neutral.6 As a first drug, they lowered A1C 0.20 points less than metformin, with about 1.5 kg less weight loss.7
Main side effects. They are generally well tolerated with little risk of low blood sugar. Four showed heart safety but no heart benefit in trials, and saxagliptin raised the risk of heart failure hospitalization, which is on its label.2 The 2007 review found slightly more stuffy nose and sore throat (risk ratio 1.2) and headache (1.4).6
GLP-1 receptor agonists
How they work. These are man-made versions of GLP-1 built to resist DPP-4 and last much longer. They raise insulin and lower glucagon only when blood sugar is high, and slightly slow how fast the stomach empties.11 They also reduce appetite and food intake.2 Tirzepatide (Mounjaro) is a dual agonist that also switches on the receptor for a second gut hormone, GIP.11 Examples: semaglutide (Ozempic injection, Rybelsus tablet), dulaglutide (Trulicity), liraglutide (Victoza), tirzepatide (Mounjaro).
Effect. In the 2007 review of early GLP-1 drugs, A1C fell 0.97 points and weight 1.4 kg vs placebo.6 Newer drugs do more. In the SUSTAIN FORTE trial, semaglutide 1.0 mg lowered A1C by 1.9 points and weight by 5.6 kg from baseline over 40 weeks.2 A 2024 BMJ network meta-analysis of 76 trials (39,246 people) found tirzepatide lowered A1C by 2.10 points and weight by 8.47 kg vs placebo, the most of the drugs it compared.8
Main side effects. Nausea, vomiting and diarrhea, mostly when starting or raising the dose.2 In the 2007 review, nausea was 2.9 times and vomiting 3.2 times as likely as on placebo.6 Gallbladder problems are more common, and these drugs are not used in people with a personal or family history of medullary thyroid cancer or with MEN 2.2 More in GLP-1 nausea and stomach side effects and GLP-1 weight loss in type 2 diabetes.
GLP-1 vs DPP-4 inhibitor: why are they so different?
Both work through GLP-1, but the dose is very different. In a 2006 study of 58 adults with type 2 diabetes, near-maximal effect of sitagliptin came with active GLP-1 (and GIP) levels raised 2-fold or more after a sugar drink.9 GLP-1 agonists, by contrast, circulate at drug-level concentrations far above what the body makes.10 Think of a bathtub: a DPP-4 inhibitor slows the drain so a bit more of your own water stays in, while a GLP-1 agonist opens a much bigger tap. The analogy has limits, since the hormone acts on many organs. In head-to-head trials, DPP-4 inhibitors lowered A1C 0.49 points less and weight 1.56 kg less than GLP-1 agonists, but caused less nausea.7
Side-by-side comparison
| Class | Form | A1C vs placebo | Weight | Main side effects |
|---|---|---|---|---|
| Metformin | Pill | −1.12 points (alone) | Neutral, maybe modest loss | Nausea, diarrhea; low B12 |
| SGLT2 inhibitors | Pill | −0.66 points | About −1.8 kg vs other drugs | Genital and urinary infections; rare ketoacidosis |
| DPP-4 inhibitors | Pill | −0.74 points | Neutral | Usually mild; heart failure warning for saxagliptin |
| GLP-1 agonists | Mostly weekly or daily injection; one pill | −0.97 (early drugs) to −2.10 (tirzepatide) | −1.4 kg (early drugs) to −8.47 kg (tirzepatide) | Nausea, vomiting, diarrhea; gallbladder |
Where does each sit in the guidelines?
The 2022 ADA/EASD consensus report said metformin "remains the agent of choice" for lowering blood sugar in most people, because of its effect, safety and low cost. It also said GLP-1 agonists and SGLT2 inhibitors should be considered for people with, or at high risk of, heart disease, heart failure or kidney disease, whether or not they take metformin.2
The 2026 update, published in October 2026, goes further. It advocates earlier use, potentially from diagnosis, of SGLT2 inhibitors and/or GLP-1-based therapies to protect the organs, and earlier combined use of both in people with heart disease, kidney disease or heart failure.1 The ADA also updates its Standards of Care each year; the 2026 edition has a full chapter on these medicines.12
Key terms in this article
- A1C: a blood test of average blood sugar over about three months.
- Receptor: a "lock" on a cell that a hormone switches on.
- Agonist: a drug that switches on a receptor, like the body's own hormone.
- Antagonist: a drug that blocks a receptor so it cannot be switched on.
- Inhibitor: a drug that blocks an enzyme or transporter.
- GLP-1: a gut hormone that raises insulin, lowers glucagon and reduces appetite.
- DPP-4: an enzyme that breaks down GLP-1.
- SGLT2: a kidney transporter that returns sugar to the blood.
Common questions
What is the difference between a GLP-1 agonist and a DPP-4 inhibitor?
A GLP-1 receptor agonist, such as semaglutide (Ozempic), is a man-made version of the GLP-1 hormone given at levels well above what the body makes. A DPP-4 inhibitor, such as sitagliptin (Januvia), is a pill that slows the breakdown of the body's own GLP-1; in a 2006 study of 58 adults with type 2 diabetes, sitagliptin's near-maximal effect came with active GLP-1 levels raised 2-fold or more. In a 2012 BMJ meta-analysis, DPP-4 inhibitors lowered A1C 0.49 points less than GLP-1 agonists.
Which lowers A1C more: GLP-1, SGLT2, DPP-4 or metformin?
In meta-analyses of trials in adults with type 2 diabetes, compared with placebo, SGLT2 inhibitors lowered A1C by about 0.66 percentage points, DPP-4 inhibitors by 0.74, metformin alone by 1.12, and tirzepatide, the strongest GLP-1-based drug, by 2.10. These come from different reviews, so they are a rough guide rather than a head-to-head ranking.
Do SGLT2 inhibitors cause weight loss?
Yes, modestly. In a 2013 Annals of Internal Medicine meta-analysis of adults with type 2 diabetes, SGLT2 inhibitors reduced body weight by about 1.8 kg more than other diabetes drugs. GLP-1-based drugs usually cause more weight loss, while DPP-4 inhibitors are weight neutral.
Is metformin still the first drug for type 2 diabetes?
The 2022 ADA and EASD consensus report said metformin remains the agent of choice for lowering blood sugar in most people, but that GLP-1 agonists and SGLT2 inhibitors should be considered for people with heart disease, heart failure or kidney disease regardless of metformin. The 2026 update advocates earlier use of SGLT2 inhibitors and GLP-1-based drugs, potentially from diagnosis.
Sources
- Davies MJ, Aroda VR, Bajaj M, et al. Management of Type 2 Diabetes, 2026. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2026 (online ahead of print). doi:10.2337/dci26-0141 · PubMed
- Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2022;65(12):1925-1966. doi:10.1007/s00125-022-05787-2 · Full text (PMC)
- Hirst JA, Farmer AJ, Ali R, et al. Quantifying the effect of metformin treatment and dose on glycemic control. Diabetes Care. 2012;35(2):446-454. doi:10.2337/dc11-1465 · Full text (PMC)
- Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 2023;19(8):460-476. doi:10.1038/s41574-023-00833-4 · Full text (PMC)
- Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262-274. doi:10.7326/0003-4819-159-4-201308200-00007 · PubMed
- Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194-206. doi:10.1001/jama.298.2.194 · PubMed
- Karagiannis T, Paschos P, Paletas K, et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ. 2012;344:e1369. doi:10.1136/bmj.e1369 · PubMed
- Yao H, Zhang A, Li D, et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ. 2024;384:e076410. doi:10.1136/bmj-2023-076410 · Full text (PMC)
- Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619. doi:10.1210/jc.2006-1009 · PubMed
- Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18(3):203-216. doi:10.1111/dom.12591 · Full text (PMC)
- US prescribing information, section 12.1 (Mechanism of Action): OZEMPIC (revised June 2026) and MOUNJARO (revised August 2026), DailyMed, checked November 2026.
- American Diabetes Association Professional Practice Committee for Diabetes. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2026. Diabetes Care. 2026;49(Suppl 1):S183-S215. doi:10.2337/dc26-S009 · Full text (PMC)
