2025: a Banner Year for Health?
The most common causes of mortality for Americans in 2023 were largely unchanged compared to prior years. Heart disease and cancer take the top two spots. Familiar faces like strokes, diabetes, kidney disease, and liver disease also make appearances.
We know that lifestyle modifications can greatly dampen risk of mortality from all of these disease states. Obtaining enough physical activity, eating optimal amounts of fiber, and lowering cholesterol levels not only promote a longer existence but ensure a higher quality of life.
At the same time, pharmacotherapy can be a vital component of preventing and managing chronic disease.
The latter half of 2025 will see the conclusion of several important Phase 3 trials, which may prove to be the beginning of the end for ASCVD and diabetes as well as the majority of kidney and liver disease.
TL;DR
New pills that lower cholesterol (PCSK9 inhibitors) as well as treat diabetes and promote weight loss (GLP-1 agonists) may be introduced to the market following the release of new data in late 2025.
In the United States, pharmaceutical development undergoes investigation in four “phases” of clinical trials, from proof of concept to safety testing to comparing the medication against placebos and current treatments.
Following results of a Phase 3 trial, the manufacturer can apply to the Food and Drug Administration (FDA) to obtain market approval for the pharmacotherapy. Once approved, prescriptions can be written and patients can begin to receive the medication.
GLP-1 Agonists
Many are now familiar with Ozempic, the injectable form of semaglutide, a glucagon-like peptide-1 (GLP-1) agonist, or activator.
The GLP-1 hormone is normally secreted by the small intestine. Among its various effects, GLP-1 stimulates insulin secretion, reduces glucagon release (which increases blood sugar), and slows emptying of the stomach into the small intestine. These medications are proven to lower blood sugar, blood pressure, and total cholesterol.
The current popularity of GLP-1s, however, mainly stems from their effect on weight loss. Weekly treatment with injectable semaglutide over 15 months can decrease body mass as much as 17.4 per cent.
The first oral GLP-1 agonist was approved in 2019. Rybelsus, the oral form of semaglutide, is currently approved only for treatment of type 2 diabetes in the United States. Both Ozempic and Rybelsus are sold by Novo Nordisk.
Compared to data for Ozempic, Rybelsus contributes to about half as much weight loss, although both forms have comparable effects on lowering HbA1c, a major marker for diabetes.
Phase II trial data for a novel oral GLP-1 agonist called orforglipron showed higher amounts of weight loss (-13.3kg at maximum dose after 26 weeks) compared to Phase III data for Rybelsus (-3.7 kg at maximum dose after 26 weeks)
Orforglipron is manufactured by Eli Lilly, which also sells a competitor to semaglutide called tirzepatide under the name Mounjaro® (for diabetes) and Zepbound™ (for obesity).
Tirzepatide is an agonist for both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors. GIP has similar effects to the GLP-1 hormone on blood sugar and stomach emptying. Activation of both types of receptors contributes to an additive effect—indeed, recent research finds that tirzepatide might be more efficacious than semaglutide at promoting weight loss.
In late 2025, Lilly aims to conclude two Phase 3 trials studying orforglipron for the treatment of obesity (ATTAIN trials) and diabetes (ACHIEVE trials). If approved, oforglipron (sure to be marketed with a more palatable name) could represent a major breakthrough in treatment of overweight and obesity as well as diabetes, in turn preventing scores of heart, vascular, kidney, and liver disease.
To be sure, oforglipron will likely carry a hefty price tag in the United States if approved. Monthly out-of-pocket costs for injectable semaglutide average between $970 to $1350 for Americans while German and British patients are charged less than $100 per month.
PCSK9 Inhibitors
PCSK9 (proprotein convertase subtilisin/kexin type 9) is a molecule that promotes degradation of receptors for low-density lipoproteins (LDL) on the liver. LDL is a major carrier for cholesterol, called LDL-C.
LDL-C is normally removed from the blood by attaching to its receptor. With fewer receptors, LDL-C remains in the bloodstream for longer, contributing to the formation of cholesterol plaques that cause heart attacks, strokes, and peripheral limb disease.
Inhibiting PCSK9 preserves LDL-C receptors, allowing more cholesterol to be removed from the blood.
There are currently three injectable forms of PCSK9 inhibitors, alirocumab, sold under the name Praluent® by Regeneron, evolocumab, sold as Repatha® by Amgen, and inclisiran, sold as Leqvio® by Novartis. When used without any additional cholesterol-lowering medications (e.g., statins), PCSK9 inhibitors may reduce LDL-C by 45 to 65 per cent.
As with GLP-1 agonists, the requirement to inject PCSK9 inhibitors might limit their broader appeal among patients.
In September 2025, the pharmaceutical company Merck plans to conclude two Phase 3 trials for an oral PCSK9 inhibitor called MK-0616. (Instead of a flashy, vaguely Scandinavian name like orforglipron, Merck chose a moniker that sounds eerily like a certain CIA program.)
Phase 2 trial data for MK-0616 suggests similar efficacy to its injectable counterparts, with reductions in LDL-C of 40 to 60 per cent.
Out-of-pocket costs for PCSK9 inhibitors may again limit their accessibility. While a 30-day supply of a statin may cost as little as $3, the price for an injectable PCSK9 inhibitor is about 25 times as high.
Taken together, the availability of highly effective oral treatments for high cholesterol levels, diabetes, and obesity may lead to a sea change in the health of Americans. Cost of these novel therapies, however, will remain a substantial barrier to their accessibility.
Over the next few years, as market changes and governmental policy promote downward pressure on price, these medications will be within reach for a broader range of patients.
We may finally—and permanently—move the needle on mortality rates from heart disease, stroke, diabetes, kidney disease, and liver disease.