GLP-1 medications compared: every approved drug

Complete guide: GLP-1 drugs: a complete guide to semaglutide and beyond

The search "GLP-1 medications" actually covers a family of molecules with different histories and properties. This physician-oriented reference sorts the GLP-1 receptor agonists (GLP-1RAs) by origin, structure and duration of action, and sets them against what has been published: cardiovascular safety trials, weight trials and head-to-head comparisons. It contains no doses and no use recommendations; it is a map of the evidence. For the broader picture of the class, see the complete GLP-1 guide.

What counts as a GLP-1 medication, and what does not

GLP-1 is a gut hormone (an incretin) that stimulates glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying and acts on satiety centers in the brain¹. The natural hormone lasts only minutes in the blood because the enzyme DPP-4 degrades it, so no medication uses it unchanged: all are modified analogs or related molecules that resist that degradation²⁴.

Within the class it helps to separate three groups. The pure GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, dulaglutide, albiglutide, semaglutide) activate a single receptor⁴. The dual agonists (tirzepatide) also activate the glucose-dependent insulinotropic polypeptide (GIP) receptor¹⁶¹⁷. And the oral non-peptide drugs, which are not analogs of the hormone, are another chapter: see orforglipron and non-peptide oral GLP-1s. This guide covers the first two groups, all of them peptides.

Structure and duration: how the molecules differ

The practical difference between these medications is mostly how they avoid degradation and renal clearance. There are three strategies⁴:

• Origin in exendin-4. Exenatide is the synthetic version of exendin-4, a peptide found in Gila monster saliva that resists DPP-4 without much modification⁴. Lixisenatide is also derived from exendin-4⁴. Exenatide exists in a weekly extended-release formulation, whose five-year results were published in DURATION-1⁵.
• Acylation to bind albumin. Liraglutide adds a fatty acid to a modified human GLP-1; that tail sticks to plasma albumin and extends action enough to allow once-daily administration². Semaglutide uses the same principle, with an optimized linker and fatty diacid and changes that protect it from DPP-4, and is designed for once-weekly administration³.
• Fusion to a large protein. Dulaglutide fuses a GLP-1 analog to an immunoglobulin Fc fragment; albiglutide was fused to albumin. The size slows renal filtration and allows weekly administration⁴¹⁰.

Tirzepatide, the dual agonist, is a peptide that activates GIP and GLP-1 receptors and is also given once a week¹⁶¹⁷. To understand why a second receptor changes the size of the effect, see tirzepatide mechanism of action: GIP, GLP-1, the paradox.

Cardiovascular safety: what the trials showed, molecule by molecule

Since regulators began requiring cardiovascular safety data for type 2 diabetes drugs, each GLP-1RA has had its large trial. The results are not uniform, and it is a mistake to speak of a "class effect" without nuance⁴:

• Lixisenatide (ELIXA): in patients with a recent acute coronary syndrome it met non-inferiority but showed no superiority: a neutral result⁶.
• Liraglutide (LEADER): reduced the major cardiovascular outcome with HR 0.87 (95% CI 0.78–0.97), and cardiovascular death with HR 0.78⁷.
• Weekly semaglutide (SUSTAIN-6): HR 0.74 (95% CI 0.58–0.95) for major events, with an increase in retinopathy complications (HR 1.76) that called for monitoring⁸.
• Weekly exenatide (EXSCEL): non-inferior, with HR 0.91 (95% CI 0.83–1.00), without statistical superiority⁹.
• Albiglutide (HARMONY): HR 0.78 in patients with established cardiovascular disease¹⁰.
• Dulaglutide (REWIND): HR 0.88 (95% CI 0.79–0.99) in a population with many patients without prior cardiovascular disease¹¹.
• Oral semaglutide (PIONEER 6): non-inferior, with no superiority on the composite outcome and lower cardiovascular mortality as a secondary finding (HR 0.49)¹².
• Efpeglenatide (AMPLITUDE-O): HR 0.73 for major events and 0.68 for a renal composite; it is not a marketed medication, but it illustrates that the benefit is not limited to one molecule¹³.

More recently, SELECT tested semaglutide in people with overweight or obesity and prior cardiovascular disease without diabetes, with a reduction in major events (HR 0.80; 95% CI 0.72–0.90)¹⁹. That result moved the discussion from a diabetes class to a class with benefit in obesity. For the broader picture of hard outcomes, see GLP-1s beyond weight.

Weight and glucose: what the trials and head-to-heads show

In obesity, the scale of weight loss grows with the potency of the molecule. Liraglutide 3.0 mg, in SCALE, produced a mean loss of 8.4 kg versus 2.8 kg with placebo at 56 weeks¹⁴. Semaglutide 2.4 mg, in STEP 1, achieved −14.9% of body weight at 68 weeks versus −2.4% with placebo¹⁵. And tirzepatide, in SURMOUNT-1, reached up to −20.9% at 72 weeks at the highest dose¹⁷.

The most reliable data for comparison are head-to-head trials. In type 2 diabetes, SURPASS-2 randomized tirzepatide or semaglutide 1 mg; every tirzepatide dose lowered HbA1c more (differences of −0.15, −0.39 and −0.45 percentage points) and weight more (−1.9, −3.6 and −5.5 kg)¹⁶. In obesity without diabetes, SURMOUNT-5 compared tirzepatide with semaglutide: −20.2% versus −13.7% of weight at 72 weeks¹⁸. So far, these two trials are the strongest direct evidence between the two most used molecules.

Adverse effects common to the whole class

Gastrointestinal effects (nausea, diarrhea, vomiting, constipation) are the most frequent in every trial of the class and are usually more marked when treatment starts or the dose is escalated¹⁶¹⁸. In SURPASS-2, for example, nausea occurred in 17% to 22% with tirzepatide and in 18% with semaglutide¹⁶. An insurance-claims analysis of people who used GLP-1RAs for weight loss described more pancreatitis, gastroparesis and bowel obstruction than with another obesity drug; it is observational and does not prove causality, but it justifies vigilance²⁰. Thyroid safety is covered separately in GLP-1s and thyroid cancer, and the tirzepatide profile in tirzepatide side effects.

How to read these comparisons without error

A table that puts each cardiovascular trial's HR side by side invites ranking the drugs from best to worst, but it is a trap. Populations differ (LEADER and SUSTAIN-6 enrolled very high-risk patients; REWIND, many at moderate risk), durations and outcome definitions vary, and the trials were not designed to compare⁴⁷⁸¹¹. Only head-to-head trials allow two drugs to be compared, and even those answer for one specific population and duration¹⁶¹⁸. Anyone reading an "effectiveness" table should always ask: against which comparator, and in which population.