GLP-1 (Weight-Loss) Drugs' Indication Cascade: From Diabetes to Obesity, Heart and Kidney
In this article
From Diabetes to the Heart, From the Liver to the Kidney: Why Do GLP-1 Drugs Always Win Approval in the Same Order?
GLP-1 drugs began in 2005 as type 2 diabetes medicines. Today in the United States they are also approved for obesity, reducing cardiovascular events, sleep apnea, fatty liver disease (MASH) and chronic kidney disease. What stands out is that almost every new molecule follows the same path: diabetes first, then obesity, then the heart and other organs. In this article I explain why this order, the "indication sequence", exists, which studies decided each link, and where the evidence thins out. I covered the properties of the individual drugs in my semaglutide (Ozempic) and tirzepatide (Mounjaro) articles (in Turkish).
- What is happening? Incretin drugs produce three primary effects through a single mechanism: blood sugar control, weight loss and organ effects that are partly independent of weight. Each effect opens the door to a separate family of diseases.
- Why always the same order? The first approval comes from diabetes, through a surrogate endpoint such as HbA1c that can be measured quickly. Weight is the common denominator; the more closely a disease is tied to weight, the greater the chance of a new indication. But every new label requires its own phase 3 trial.
- Where is the evidence strong? In diabetes, obesity, cardiovascular events, sleep apnea, MASH and kidney disease there are hard-endpoint or approval-grade studies. In heart failure the FDA asked for an additional study.
- Where is it weak? As you move away from metabolism. In Alzheimer's disease two large trials (EVOKE, EVOKE+) were negative; in addiction, psoriasis and polycystic ovary syndrome the data are at an early stage.
Why does this topic matter?
GLP-1 drugs are the most talked-about drug class of recent years. Every week brings a new study, a new headline, sometimes an exaggerated claim. A question I often hear from my patients is: "I hear this drug is good for the heart and the kidney too; does it prevent Alzheimer's as well?" To answer it properly, you need to know the difference between saying a drug "may work" in a disease and the drug being "approved" for it (little-known effects of GLP-1 drugs, in Turkish).
Understanding the indication sequence is useful in two ways. First, it helps us tell which uses rest on strong evidence and which on hope. Second, approval, reimbursement and the disease for which a drug may be promoted all depend on which link of the sequence has been reached. Given how common obesity and diabetes are in our country, this information concerns millions of people (diabetes in the world and in Türkiye, obesity in the light of science; both in Turkish).
What is the indication sequence?
The indication sequence is the expansion of a drug's uses in a particular order. GLP-1 drugs are approved first in type 2 diabetes, then in obesity; reducing cardiovascular events, obesity-related diseases and organ protection follow. Each link requires its own phase 3 trial and its own approval.
This order is no coincidence. The biology of the drug, the rules of clinical research and the economics of drug development all push in the same direction. The figure below summarizes how a single mechanism leads to three different effects and how these effects lead to different disease families.
One mechanism, three primary effects
GLP-1 is a hormone released from the gut after eating. In the pancreas it increases insulin secretion and suppresses glucagon when blood sugar is high. In the brain it reduces appetite and the sense of reward from food. It slows the emptying of the stomach. Its receptors are also found in blood vessel walls, the kidney and other tissues. Newer-generation drugs act on GIP, glucagon or amylin receptors in addition to GLP-1, which increases weight loss (diabetes and insulin resistance, in Turkish).
This multi-directional action produces three primary outcomes. The first is blood sugar control: HbA1c falls. The second is weight loss: about 15% with single-acting drugs, up to 20-28% with dual and triple drugs. The third is effects that appear partly independent of weight: inflammation in the body decreases, the process of arterial hardening slows, and blood pressure and kidney circulation improve (what is inflammation?, in Turkish).
Figure 1 · One mechanism, three primary effects
From incretin receptor agonism to disease families
Link by link
Figure 2 · The six links of the indication sequence
US approvals, November 2026
① Type 2 diabetes: the entry door
Every incretin drug begins life as a diabetes drug. The reason is that in diabetes, efficacy can be measured with a surrogate endpoint such as HbA1c. HbA1c changes within a few months, a trial of a few hundred patients is enough, and its fall is linked to a reduction in the risk of long-term complications. For this reason diabetes is the door through which a molecule can enter the market by the shortest and cheapest route. Exenatide (Byetta, 2005), liraglutide (Victoza, 2010), semaglutide (Ozempic, 2017) and tirzepatide (Mounjaro, 2022) came in through this door (dulaglutide (Trulicity)). I explained what HbA1c means and why it matters so much in my HbA1c article.
② Obesity: the "side effect" became the main indication
In the diabetes trials it was noticed right away that patients lost weight. Over time this "side effect" became one of the drug's main uses. Liraglutide 3 mg (Saxenda) was approved for obesity in 2014, semaglutide 2.4 mg (Wegovy) in 2021 and tirzepatide (Zepbound) in 2023. In December 2025 oral semaglutide, and in April 2026 orforglipron (Foundayo), which needs no injection and has no fasting or food restrictions, were approved (Wegovy, Saxenda).
With each new generation, weight loss increased. Average loss of 8-15% with single-acting GLP-1 drugs reached 21% with the dual agonist tirzepatide and 28% with the triple agonist retatrutide. In placebo groups the loss generally stayed at 1-3%. The absolute difference should also be kept in mind: for a person weighing 100 kg, a 15% loss means about 15 kg.
Average weight loss from generation to generation
Highest dose of each drug in its obesity trial; average reduction in body weight, %.
The trials lasted 56-80 weeks. Weight loss in placebo arms was 1-3%. The trials were reported with different statistical approaches (whether participants who stopped treatment were included); the values are approximate. Retatrutide, CagriSema and survodutide are not approved in the US as of November 2026. Comparison across different trials is indirect; patient groups, prior treatments and follow-up times differ.
③ Reducing cardiovascular events: a safety study showed benefit
In 2008, after debate that some diabetes drugs might raise the risk of heart attack, the FDA required new diabetes drugs to show cardiovascular safety in large trials (CVOTs). The aim of these trials was to say "it does no harm". But with GLP-1 drugs the result was better than expected: in LEADER liraglutide and in SUSTAIN-6 semaglutide reduced the composite endpoint of heart attack, stroke and cardiovascular loss of life. With these results Victoza received a cardiovascular indication in 2017 and Ozempic in 2020 (what is cardiovascular disease?, in Turkish).
The real turning point was the SELECT trial. In 17,604 people without diabetes, with cardiovascular disease and overweight or obesity, semaglutide 2.4 mg lowered major cardiovascular events from 8.0% to 6.5% over about 3.3 years (20% relative reduction; 1.5 points absolute). Thus Wegovy became the first obesity drug to receive an indication for reducing cardiovascular events, in March 2024. Tirzepatide, in SURPASS-CVOT, showed it was not worse than dulaglutide for cardiovascular events (obesity and cardiovascular disease).
Major event rates in cardiovascular outcome trials
Heart attack, stroke or cardiovascular loss of life; drug (colored) and placebo (gray), %.
LEADER and SUSTAIN-6 were done in people with type 2 diabetes (3.8 and 2.1 years), SELECT in overweight or obese people without diabetes (3.3 years). The relative risk reduction was 13% in LEADER (HR 0.87), 26% in SUSTAIN-6 (HR 0.74) and 20% in SELECT (HR 0.80). The absolute difference is about 1.5-2.3 events per 100 people. Some of these trials were in fact designed to show safety. Comparison across different trials is indirect; patient groups, prior treatments and follow-up times differ.
④ Obesity-related diseases: the more weight matters, the higher the chance
The more tightly a disease is tied to excess weight, the more likely a weight-reducing drug is to work in that disease. The successes in this link bear that out:
| Disease | Pivotal trial | Result | Status (US, November 2026) |
|---|---|---|---|
| Obstructive sleep apnea | SURMOUNT-OSA (tirzepatide) | Number of breathing pauses per hour fell markedly compared with placebo | Zepbound approved (December 2024); an application is planned for orforglipron |
| MASH (fatty liver inflammation) | ESSENCE (semaglutide 2.4 mg) | Liver inflammation regressed in 62.9% versus 34.3% of patients; fibrosis improved in 36.8% versus 22.4% | Wegovy approved (August 2025, accelerated approval) |
| Heart failure with preserved ejection fraction | STEP-HFpEF (semaglutide), SUMMIT (tirzepatide) | Symptoms and exercise capacity improved; in SUMMIT worsening of heart failure decreased | Tirzepatide application withdrawn in 2025; the FDA asked for an additional study |
| Knee osteoarthritis | STEP 9 (semaglutide 2.4 mg) | Knee pain fell markedly compared with placebo | Not on the label |
The link between fatty liver disease and cancer makes this link important from an oncology standpoint as well (fatty liver and cancer risk, liver cancer related to fatty liver; both in Turkish). However, the MASH approval is an accelerated approval based on improvement in liver biopsy; it has not yet been shown to prevent cirrhosis or liver cancer.
⑤ Organ protection: a separate hard-endpoint trial for each organ
Some effects appear partly independent of weight. In the FLOW trial, in 3,533 people with type 2 diabetes and chronic kidney disease, semaglutide reduced by 24% the composite endpoint of kidney failure, marked loss of kidney function, or kidney and cardiovascular loss of life (HR 0.76). With this result Ozempic received a kidney indication in January 2025 (kidney failure, in Turkish). In the STRIDE trial, in 792 people with diabetes and peripheral artery disease, semaglutide increased maximum walking distance in one year by about 13% compared with placebo. This indication was recommended for addition to the label in Europe in 2025; in the US it is at the application stage.
⑥ The discovery frontier: the further from metabolism, the weaker the evidence
At the outermost link of the sequence, the evidence clearly weakens. In observational studies, GLP-1 users were reported to have a lower risk of dementia. But the EVOKE and EVOKE+ trials, which tested oral semaglutide in 3,808 people with early Alzheimer's disease, showed in November 2025 that it did not slow disease progression. This is a good example of why observational data should not be relied on until confirmed by a randomized trial (what is a clinical trial?, in Turkish).
Early-stage studies are continuing in areas such as alcohol and substance use disorders, psoriasis and polycystic ovary syndrome (diseases caused by alcohol, in Turkish). Whether the risk of obesity-related cancers falls is also a question I am curious about from an oncology standpoint; today the data on this are only observational and not enough for a firm judgment (cancer and diabetes, in Turkish). I discussed the debate about the effects of these drugs on mental health in my article on GLP-1 drugs and depression.
The three engines driving the sequence
1. Fast entry through a surrogate endpoint. The first approval comes from diabetes because HbA1c is measured quickly and with few patients. The molecule enters the market by the lowest-cost route; this revenue funds expensive outcome trials in which thousands of patients are followed for years. I would like to remind you that surrogate endpoints do not always translate into real benefit, something I often discuss in oncology too (lowering LDL versus the hard-endpoint difference, in Turkish).
2. Weight is the common denominator. Obesity is the cause of many diseases. In diseases tightly tied to weight, such as sleep apnea, fatty liver and knee osteoarthritis, the chance of a new indication is high. In diseases where the link is weak, such as Alzheimer's, trials may not succeed (abdominal fat and risk).
3. Every label requires its own randomized trial. For a drug to be approved for a particular disease, reimbursed and promoted for that disease, a separate phase 3 trial with a hard endpoint is required. Heart failure is a good example: although the SUMMIT trial was positive, the FDA did not find a single trial sufficient and the tirzepatide application was withdrawn in May 2025. It should not be forgotten that failed outcome trials are also a natural part of this process (an example of an outcome trial with a negative result).
Figure 3 · The three engines driving the sequence
Science, statistics and economics
Molecule generations: each new generation walks the sequence again, but faster
Newer-generation drugs add other hormone receptors to GLP-1. Every new molecule has to walk the sequence from the beginning; but it moves faster thanks to the road opened by earlier generations. For example, tirzepatide was approved in obesity only a year and a half after its diabetes approval (2022), and in sleep apnea two and a half years after.
| Generation | Example | Status (US, November 2026) |
|---|---|---|
| Single-acting GLP-1 | Exenatide, liraglutide, semaglutide | Diabetes, obesity, cardiovascular, MASH, kidney |
| Dual GIP/GLP-1 | Tirzepatide | Diabetes, obesity, sleep apnea |
| GLP-1 + amylin | CagriSema | Obesity application filed in December 2025; decision awaited |
| Dual GLP-1/glucagon | Survodutide, mazdutide | Survodutide phase 3 (SYNCHRONIZE); mazdutide approved in China |
| Triple GIP/GLP-1/glucagon | Retatrutide | Phase 3 (TRIUMPH); application expected in 2026 |
| Oral small molecule | Orforglipron | Approved for obesity (April 2026) |
Figure 4 · Molecule generations
From single-acting to triple agonists and pills
What does this sequence mean for patients?
- Approved use and hope are different things. News that a drug "does good" in a disease usually comes from observational studies or early-stage data. Decisions about use should rest on randomized trials and approval status.
- Same molecule, different product, different label. Semaglutide is sold as Ozempic in diabetes and as Wegovy in obesity, at different doses. Which indication is on which product's label determines how the drug can be prescribed and whether it will be reimbursed.
- Labels in Türkiye may differ. The approval dates in this article are for the US; the indications approved by the European Medicines Agency and TİTCK, whether products are available in Türkiye, and SGK reimbursement may differ. I track the current situation in my articles on the individual drugs.
- It does not replace lifestyle change. In all trials these drugs were used together with dietary changes and physical activity. Adequate protein and exercise are important to limit muscle loss (diabetes remission with diet and exercise).
- Side effects are real. The most common are nausea, vomiting, diarrhea and constipation. Gallstones, pancreatitis and muscle loss from rapid weight loss are also things to watch for. These drugs should not be used without a doctor's advice and monitoring.
Questions you can ask your doctor
- Will this drug be used in my case for an approved indication?
- Is there a proven benefit for me for the heart, kidney or liver?
- Which product and dose suit me; is it available in Türkiye, and is it reimbursed?
- What should my nutrition and exercise plan be to prevent muscle loss?
- What happens to my weight and other gains if I stop the drug?
- "GLP-1 drugs are good for every disease." No. The evidence is strong in diabetes, obesity, cardiovascular disease, kidney disease and some weight-related diseases; in Alzheimer's the large trials were negative.
- "Ozempic and Wegovy are the same drug, the same thing." The active ingredient is the same but the doses, approved uses and labels differ.
- "The benefit to the heart comes only from losing weight." Partly. In SELECT the benefit appears partly independent of the size of the weight loss; effects on inflammation and on blood vessels may also play a role.
- "If there is a positive trial, the drug is approved for that disease." Not always. As in heart failure, regulators may ask for additional studies.
- "Newer-generation drugs are always better." They may produce more weight loss; but long-term safety and hard-endpoint data are more mature for the older generations.
Frequently Asked Questions
- Which diseases are GLP-1 drugs approved for?
- As of November 2026, in the US there are approved products for type 2 diabetes, obesity, reducing cardiovascular events, obstructive sleep apnea, fatty liver inflammation (MASH) and chronic kidney disease with type 2 diabetes. Approvals vary by product and country; labels in Türkiye may differ.
- Why do GLP-1 drugs win approval in diabetes first?
- In diabetes, efficacy can be measured with HbA1c within a few months and in relatively few patients. This lets a drug enter the market by the fastest and lowest-cost route. Later indications such as obesity, heart and kidney require separate trials of thousands of patients lasting years.
- Do GLP-1 drugs prevent Alzheimer's?
- No, current evidence does not support that. Although observational studies look promising, in the EVOKE and EVOKE+ trials involving 3,808 people with early Alzheimer's disease, oral semaglutide did not slow disease progression.
- When will retatrutide and CagriSema come into use?
- As of November 2026 neither is approved in the US. The application for CagriSema was filed in December 2025 and a decision is awaited. The triple agonist retatrutide showed weight loss of up to 28% in phase 3; an application is expected in 2026. It may take longer for them to reach Türkiye.
Glossary
- Incretin
- Hormones released from the gut after eating that increase insulin secretion; GLP-1 and GIP are among them.
- GLP-1
- Glucagon-like peptide-1; a hormone that increases insulin and reduces appetite and stomach emptying.
- Agonist
- A drug that stimulates a receptor and mimics the action of the natural hormone.
- Indication
- The use for which a drug is officially approved.
- Surrogate endpoint
- An indicator measured in place of the real clinical outcome that changes faster (for example HbA1c).
- Hard endpoint
- Outcomes experienced directly by the patient, such as heart attack, stroke, kidney failure or loss of life.
- CVOT
- Cardiovascular outcomes trial; a large trial that measures the safety and benefit of a drug on the heart and blood vessels.
- HbA1c
- A test reflecting average blood sugar over the last 2-3 months.
- MASH
- Fatty liver inflammation due to metabolic dysfunction; it can progress to cirrhosis.
- HFpEF
- Heart failure with preserved ejection fraction; the heart's contraction is normal but its relaxation is impaired.
DROZDOGAN Academy Commentary
The story of GLP-1 drugs shows how a single biological discovery, through well-asked questions and rigorous trials, turned step by step into a broad treatment field. But the same story teaches us to be careful about the perception that "it is good for everything".
⚡ Why it matters
Alongside diabetes and obesity, we now have a proven drug class that protects organs such as the heart, kidney and liver. The course of many weight-related diseases may change with these drugs.
✅ Strengths
Large randomized hard-endpoint trials at every link; an effect that increases from generation to generation in weight loss; absolute and relative reductions in cardiovascular and kidney events.
⚠️ Limits
The absolute benefit varies with the level of risk and is modest in some areas. When the drug is stopped, most of the weight may return. Evidence is weak in diseases far from metabolism; the Alzheimer's trials were negative. Cost and access are a major problem.
🩺 In practice
When I talk with my patients, I first clarify for which indication and on what evidence the drug is being recommended. I also state separately the expectations based on observational studies. In my patients who are receiving cancer treatment or have survived cancer, I assess weight, muscle mass and nutritional status together.
❓ Open questions
Does the risk of obesity-related cancers fall? What additional evidence will be enough for approval in heart failure and knee osteoarthritis? Should the drugs be used for life? What is the long-term safety of the new generations?
Conclusion: The indication sequence of GLP-1 drugs is the result of biology, research rules and economics pushing in the same direction. Evidence is strong in diseases close to metabolism and weaker the further away you go. Every new claim should be judged by which link it stands at and which trial it rests on.
- This article was prepared in November 2026. Its framework is based on our infographic titled "Why do incretin drugs always follow the same indication sequence?".
- Approval dates are according to the US FDA; labels from the European Medicines Agency and TİTCK may differ. Information on CagriSema and retatrutide is based on company statements and news at the time of writing.
- The values in the weight-loss chart are taken from different trials and cannot be compared directly; the trials used different statistical approaches.
- The diagrams are simplified. The Academy commentary is mine.
- This article is not medical advice; make decisions about your health together with your doctor.
Sources
- Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes (LEADER). N Engl J Med 2016;375:311-322. doi:10.1056/NEJMoa1603827. nejm.org
- Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes (SUSTAIN-6). N Engl J Med 2016;375:1834-1844. doi:10.1056/NEJMoa1607141. nejm.org
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med 2023;389:2221-2232. doi:10.1056/NEJMoa2307563. nejm.org
- Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes (FLOW). N Engl J Med 2024;391:109-121. doi:10.1056/NEJMoa2403347. nejm.org
- Bonaca MP, Catarig AM, Houlind K, et al. Semaglutide and walking capacity in people with symptomatic peripheral artery disease and type 2 diabetes (STRIDE). Lancet 2025. doi:10.1016/S0140-6736(25)00509-4. doi.org
- Sanyal AJ, Newsome PN, Kliers I, et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis (ESSENCE). N Engl J Med 2025;392:2089-2099. doi:10.1056/NEJMoa2413258. nejm.org
- Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the treatment of obstructive sleep apnea and obesity (SURMOUNT-OSA). N Engl J Med 2024;391:1193-1205. doi:10.1056/NEJMoa2404881. nejm.org
- ConscienHealth. Lilly withdraws tirzepatide application to FDA for heart failure (May 2025). conscienhealth.org
- Consultant360. FDA approves orforglipron (Foundayo) for chronic weight management (April 2026). consultantlive.com
- Pharmacy Times. FDA approves first oral GLP-1 for weight management (December 2025). pharmacytimes.com
- Pharmacy Times. Retatrutide delivers bariatric-level weight loss in pivotal phase 3 TRIUMPH-1 trial (May 2026). pharmacytimes.com
- Drug Topics. CagriSema did not meet primary end point of noninferiority to tirzepatide (February 2026). drugtopics.com
- PharmaTimes. Survodutide delivers 16.6% weight loss in major phase 3 obesity trial (April 2026). pharmatimes.com
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