- GLP-1, initially touted as a therapy for diabetes, have proven successful for weight loss, CV event reduction, and with beneficial effects in HFpEF.
- Weight is gained after patients stop taking GLP-1 medication and the majority of patients discontinue drugs after 1 year. Less frequent doses are often more convenient and see better adherence. Yet, weight loss drugs in development are moving in opposite direction - to daily orals.
- Weight-loss drugs might limit the upside of pump players to penetrate type 2 patients and thus limit growth prospects. However, type 1 diabetes and mealtime insulin users will not be impacted.
- GLP-1 will compete with the existing NASH-related therpaies in earlier stages of NASH. Although obesity treatments will not replace the need for NASH-related therapies, they will add to an already crowded NASH pipeline.
GLP-1s continue to report strong data in cardiovascular and metabolic indications as a result of the significant weight loss associated with taking the drugs. This has adversely impacted obesity related markets such as NASH and insulin pumps. This note will cover the latest GLP-1 updates, impact on parallel markets and caveats.
Data Continues Supporting GLP-1
CV Outcomes Data
In early August, Novo Nordisk (NVO) announced that semaglutide reduced the risk of cardiovascular death, heart attack, or stroke by 20%. The study, called SELECT, involved 17,500 overweight or obese people with a history of heart disease aged 45 years or older with no prior history of diabetes.
By demonstrating that weight management translates into a reduction in cardiovascular events – and thus saves lives – Novo now has crucial data to convince payers for broad reimbursement coverage and access for their anti-obesity drug. This is important because insurance does not currently cover weight-loss treatment, but that could change with the cardiovascular outcomes data from SELECT.
Heart Failure Data
Last week, Novo presented semaglutide data that demonstrated reduction in heart failure symptoms in patients with Heart Failure with Preserved Ejection Fraction (HFpEF) and obesity. HFpEF comprises roughly half of all heart failure cases. 80% of people with HFpEF are also obese. The trial, called STEP-HFpEF trial tested GLP-1 semaglutide against placebo in 529 adults with obesity and HFpEF.
Results were presented at ESC Congress 2023 and suggested statistically significant change (p<0.001) in symptoms and physical limitations associated with heart failure (KCCQ-CSS). For change in body weight, results suggested the mean percentage change in body weight was −13.3% with semaglutide and −2.6% with placebo (p<0.001).
Bottom Line: GLP1 agonists, initially touted as a therapy for diabetes, have proven successful for weight loss (SURMOUNT Trial), CV event reduction (SELECT Trial), and with beneficial effects in HFpEF and obesity (STEP-HFpEF Trial). This additional data will help Novo with label expansion and reimbursement coverage.
GLP-1 Come with Caveats
Although GLP-1 seem like miracle class of drugs for cardiology and metabolism, they do have a few caveats. The current standards of care are weekly injectables from Novo’s Ozempic/Wegovy to Lilly’s Mounjaro. A study looked at compliance rate for a daily GLP-1 injection and weekly injection.
Results showed that 43% of patients receiving once-weekly GLP-1 injections and 36% of patients on daily injections persisted with treatment for 12 months. The majority of patients (>50%) did not continue treatment after 12 months. This is important because weight is regained when patients stop taking GLP-1 medication.
Generally, for people who take medication over a prolonged time, less frequent doses are often more convenient and see better adherence. The trend in obesity drug development is moving in the opposite direction, towards daily orals. Pfizer, for example, decided to advance danuglipron into Phase 3 studies. Danuglipron is a twice daily pill. Both Lilly (orfoglipron) and Novo (semaglutide) have one-daily oral GLP-1s in Phase 3.
Interestingly, Lilly announced that it was discontinuing its oral GIP/GLP-1. No details were shared on the reason. Lilly’s weekly injectable Mounjaro is a GIP/GLP-1 drug that has shown superior weight loss to Novo’s GLP-1 injection semaglutide. It doesn’t seem that an oral GIP/GLP-1 will be moving forward, which could read through to Viking (VKTX)’s oral GIP/GLP-1 program. Amgen’s AMG-133 is a monthly injection currently engaged in Phase 2 that will also include patients with type 2 diabetes.
Bottom Line: Weight is gained after patients stop taking GLP-1 medication. Studies have shown that the majority of patients discontinue drugs after 1 year. For maximum effect, patients need to take GLP-1 over a prolonged time. Less frequent doses are often more convenient and see better adherence. Yet, weight loss drugs in development are mostly moving in opposite direction - to daily orals. It will be interesting to see how GLP-1 compliance holds up in the medium-long term.
GLP-1 Impact on Related Markets
Insulin Pumps
Pure-play insulin pump companies Insulet (PODD) and Tandem (TNDM) are down 31% and 39% YTD, respectively. Although share performance is not directly correlated to the success of GLP-1 drugs, the insulin pump market will see a smaller share of overall diabetics as a result of GLP-1 drugs.
GLP-1 drugs were originally approved for controlling diabetes as the drug class is effective in managing blood sugar levels. GLP-1 drugs will help many type 2 diabetes patients, which account for over 90% of all diabetes patients. As a result, GLP-1 can delay the use of daily mealtime insulin delivery and, ultimately, fewer people on pumps.
Diabetes, however, is a progressive disease and at some point in their life, type 2 patients will eventually benefit from insulin pumps. So, GLP-1 drugs will move the need for pumps later on, but not evaporate the market.
Type 1 diabetes patients are not impacted by GLP-1. The majority of existing business for pump players PODD and TNDM come from type 1 diabetes patients. Weight-loss drugs might limit the upside of pump players to penetrate type 2 patients and thus limit growth prospects.
There are approximately 7M diabetes patients that need pumps, regardless of GLP-1 drugs. Today, only about 20% are using pumps. This leaves a large enough market, approximately 5.5M patients, that are still in need of pump technologies.
Bottom Line: Weight-loss drugs might limit the upside of pump players to penetrate type 2 patients and thus limit growth prospects. However, type 1 diabetes and mealtime insulin users are still only 20% penetrated, which gives pump players sufficient growth runway.
Nonalcoholic steatohepatitis (NASH)
NASH is the most severe form of nonalcoholic fatty liver disease (NAFLD), a condition in which the liver builds up excessive fat deposits. 25% of Americans (83 million) are suspected to have a fatty liver, however the vast majority does not have any liver injury. About 15% (13 million) of this patient population has fat buildup in the liver that leads to inflammation and scarring (“fibrosis”).
The stages of NASH-associated fibrosis range from F0 (without fibrosis) to F4 (cirrhosis). See below.
Losing weight can help reduce fat, scarring, and inflammation in the liver. As a result, it is believed that weight loss drugs will eat into NASH without fibrosis (F0) and NASH with mild fibrosis (F1 & F2) markets. This leaves F3 and F4 stages for NASH companies, cutting the addressable population from 13M to 3.3M. This is what the market is predicting. Whether it will actually play out like this is to be determined.
Several arguments can be made in favor of NASH-specific treatments:
- NASH’s pathological hallmarks include chronic inflammation, fibrosis & cirrhosis of the liver. GLP-1s have not demonstrated benefit on these endpoints. At least not yet. In a Phase 2 study, semaglutide was tested on F1, F2 and F3 stage patients and demonstrated a significantly higher percentage of patients had NASH resolution. However, it did not show a significant difference in the percentage of patients with an improvement in fibrosis stage.
- Combination of off-label usage of GLP-1 and NASH-related therapies will be used to augment responses. As a result, GLP-1 will obviate, but not replace, the need for NASH-related therapies in F1 and F2 stages.
- Not all NASH patients are obese (BMI >30), so GLP-1 does not apply to this subgroup.
Arguably, the most important point is that GLP-1 will shrink the pie for an already competitive NASH indication. There is a plethora of treatments in development, all targeting a similar patient population and with comparable data. Madrigal (MDGL) is in Phase 3, Akero (AKRO) and 89bio (ETNB) entering Phase 3, Viking (VKTX) and Terns (TERN) in Phase 2.
GLP-1 will compete with the existing NASH-related therpaies in earlier F1 & F2 stages of fibrosis. Although obesity treatments will not replace the need for NASH-related therapies, they will add to an already crowded NASH pipeline.
Propthink contributors hold no position in any of the names mentioned above
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