PROSPER-Issue 2

Issue 2: Beyond Keto: The Real Science of Insulin Resistance

Metabolism isn’t just about calories in, calories out. It’s an economy in itself — one that billions of dollars in food, pharma, supplements, and biotech now flow through. Where your mitochondria go, markets follow.

Foods and Drinks

The “keto” craze turned grocery aisles into metabolic branding exercises. Snack bars, shakes, “low-carb breads,” and keto-labeled treats are everywhere. Most aren’t ketogenic in the clinical sense, but that hardly matters for sales. For food companies, “keto” is shorthand for premium pricing and consumer aspiration. The same has happened with “low-glycemic” drinks, probiotic sodas, and now “metabolic teas” spiked with cinnamon or berberine. In consumer packaged goods, physiology is less important than narrative plus packaging.

Supplements

This is the Wild West of metabolism monetization.

• Exogenous ketones are marketed as brain fuel, fat burners, or endurance boosters. Revenues are climbing, projected to surpass $600M by 2030, but the science is mixed at best.
• MCT oils remain a staple in the wellness space — ubiquitous, cheaper, and less potent than ketone esters.
• Metabolic boosters like berberine (“nature’s Ozempic”) and NAD+ precursors (nicotinamide riboside, NMN) pull in hundreds of millions annually, even as regulatory battles loom.

For investors, the supplement industry thrives on speed to shelf, marketing claims, and consumer churn. Few products survive a 10-year cycle, but the margins are high.

Drugs

This is where the real money is made ($$$)!

• SGLT2 inhibitors (dapagliflozin, empagliflozin) are the success story: drugs designed for diabetes that turned into billion-dollar blockbusters in heart failure and kidney disease. Their ability to shift substrate use and mildly raise ketones is part of a larger story of metabolic remodeling.
• GLP-1 receptor agonists (semaglutide, tirzepatide) represent the metabolic market’s moonshot, with tens of billions in annual sales projected. These don’t raise ketones but show how aggressively pharma is monetizing “metabolic reset” narratives.
• Cancer metabolism: Beyond glucose and ketones lies the oncology gold rush. Drugs targeting tyrosine kinases (e.g., imatinib, erlotinib, osimertinib) have redefined cancer care by interrupting growth signaling. More recently, biotech is chasing cancer’s metabolic addictions — glutamine dependence, altered TCA cycle enzymes, even ketone utilization in certain tumors. The field of cancer metabolism is a rising frontier in drug development.

Devices

Metabolism can also be tracked, gamified, and monetized through devices.

• Continuous glucose monitors (CGMs): Once for type 1 diabetes, now pushed to wellness consumers who want to “hack” their metabolism. Startups like Levels and Nutrisense have built subscription models around interpreting glucose curves.
• Breath acetone analyzers: Sold as at-home “keto meters,” these devices are niche but growing. Accuracy varies, but they appeal to consumers who want data without fingersticks.
• Wearables: Oura, WHOOP, and Apple are layering sleep, HRV, and activity into “metabolic health dashboards,” turning physiology into a subscription business.

Investment Lens

• Foods & drinks: Fast cycle, low regulatory barrier, brand-driven. Winners are marketing machines, not science leaders.
• Supplements: High margin, volatile, and hype-driven. A trader’s market more than a long-term investor’s.
• Drugs: The most capital-intensive but also the most transformative. The GLP-1 + SGLT2 + cancer metabolism triad represents a multi-trillion-dollar reshaping of global pharma pipelines.
• Devices: Steady growth, especially as insurance begins to cover CGMs more broadly. The consumer wellness play may consolidate into a few dominant platforms.

Takeaway

Metabolism has moved from lab bench to shopping cart to Wall Street. Food and supplement companies ride the wave of consumer fads. Pharma is making long-term bets on metabolic pathways as the master regulators of chronic disease and cancer. Devices monetize our appetite for numbers. The investor who understands metabolism isn’t just following nutrition trends are tracking the next trillion-dollar category of human health markets.

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The Metabolic Drug Pipeline—Who’s Building What (and Why It Matters)

1) Next-gen incretins (obesity/diabetes/CV–renal)

Eli Lilly

• Retatrutide (GIP/GLP-1/Glucagon triple agonist) — Phase 3 underway across obesity, T2D and CV indications; Phase 2 in NEJM showed ~24% mean weight loss over 48 weeks. Triple agonists are increasingly viewed as the “top of the pyramid” for efficacy.
• Orforglipron (oral, small-molecule GLP-1) — Multiple Phase 3 successes in 2025; Lilly signaling global submissions. Head-to-head data vs oral semaglutide favor orforglipron on A1C/weight. This could be the first broadly approved oral GLP-1 that scales like an oral statin.
• Tirzepatide lifecycle (marketed) continues, but Lilly also explored bimagrumab (anti-ActRII) combos to preserve lean mass—one T2D study was halted in 2025 (strategy, not necessarily science). Expect more “lean-mass sparing” combos across the class.

Novo Nordisk

• CagriSema (cagrilintide + semaglutide) — amylin + GLP-1 co-therapy in Phase 3; positioned as a high-efficacy alternative that may better preserve lean mass. Novo’s Q1’25 pipeline deck keeps it front-and-center.
• Amycretin (GLP-1 + amylin co-agonist) — Early-/mid-stage readouts show up to ~24% weight loss at 36 weeks (injectable) and double-digit loss with an oral form; Phase 3 planned. Mechanistically interesting because it couples satiety (amylin) with GLP-1.
• High-dose oral semaglutide / icosema / once-weekly insulin icodec — portfolio breadth gives Novo multiple shots on goal.

Amgen

• MariTide (AMG-133; GIPR antagonist/GLP-1 agonist) — Phase 2: ~12–20% mean weight loss at 52 weeks (placebo ~2–3%); efficacy good but investor reactions were mixed vs very high bar set by GLP-1 class. Phase 3 is moving forward.

Boehringer Ingelheim + Zealand

• Survodutide (BI-456906; GLP-1/Glucagon dual) — ~19% weight loss in Phase 2 obesity; Phase 3 in MASH (NASH) and obesity now running; FDA Breakthrough in MASH. Dual GLP-1/GCGR is the leading bet for liver disease plus weight loss.

Viking Therapeutics

• VK2735 (dual GLP-1/GIP) — Injectable Phase 2 showed up to ~14–15% weight loss at 13 weeks; oral VK2735 Phase 2 met endpoints with up to ~12% at 13 weeks—one to watch among “challenger” orals.

Roche

• CT-388 (dual GLP-1/GIP) — Moving to Phase 3; part of a broader obesity build (Carmot deal) and paired-asset strategy.
• Petrelintide (long-acting amylin) — $5.3B co-dev deal with Zealand; signals a serious push into non-incretin satiety biology and combo potential (e.g., CT-388 + petrelintide).

Pfizer

• Danuglipron (oral GLP-1) discontinued in 2025 after a liver injury case and earlier tolerability issues; pivoting via M&A (e.g., Metsera) to stay in the game. Expect alternative oral mechanisms or new GLP-1s from BD.

Altimmune

• Pemvidutide (GLP-1/Glucagon) — Mixed optics: obesity data have been less competitive; focus shifting to MASH where Phase 2b/3 signals look more differentiated (steatohepatitis effects).

Investor read: Incretin next-gens are de-risked as a category, but winners will be (1) oral scale, (2) triple/dual efficacy with tolerability, and (3) organ-specific labels (HF, MASH). Lilly and Novo own the high ground; Roche and BI/Zealand are credible fast followers; Viking is a dark horse in orals.

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2) Liver & cardio-metabolic disease beyond incretins (MASH/NAFLD)

FGF21 analogs (metabolic remodeling + anti-fibrosis)

• Akero – Efruxifermin (EFX): Phase 3 SYNCHRONY program enrolling (F2–F3 and compensated cirrhosis). Signals on fibrosis improvement accrue over longer windows; 36-week fibrosis endpoint missed in one cirrhosis study, but 96-week data/analyses suggest potential longer-term benefit; Lancet paper in 2025 supports continued development.
• 89bio – Pegozafermin: Phase 3 ENLIGHTEN MASH and ENTRUST SHTG active; Breakthrough/PRIME designations; Roche acquisition announced Sept 2025 to fold MASH/SHTG into its cardio-metabolic build.

GLP-1/Glucagon for liver

• Survodutide (BI/Zealand) in Phase 3 MASH as above; AstraZeneca’s cotadutide remains a relevant dual in NASH with supportive early signals on hepatic fat and metabolic parameters.

Investor read: FGF21 analogs are the lead non-incretin bet in MASH and severe hypertriglyceridemia, now validated by big-pharma M&A (Roche–89bio). Dual GLP-1/GCGR agents (survodutide, cotadutide) could straddle weight + liver labels.

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3) “Metabolism-adjacent” oncology (reprogramming tumor fuel)

IDH pathway (oncometabolites)

• Approved: ivosidenib (IDH1), enasidenib (IDH2) in AML; vorasidenib (dual IDH1/2) approved in IDH-mutant glioma. This is the cleanest example of targeting cancer metabolism with real-world impact.

Glutamine addiction

• Telaglenastat (CB-839; glutaminase-1 inhibitor): mixed history; RCC Phase 2 failed primary endpoint, but combinations (e.g., with azacitidine or IO) continue to be explored; new analyses keep the door ajar. Category remains scientifically compelling but clinically hard.

Pyrimidine synthesis (DHODH)

• Multiple DHODH inhibitors active in AML/MDS early phases; overall field is noisy and early, with limited efficacy to date. Still a plausible metabolism target for select heme malignancies.

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4) Cardiometabolic “systems” drugs

• SGLT2/SGLT1-2 inhibitors: Outcome benefits across HF (reduced and preserved EF) and CKD are now standard of care; the metabolic-remodeling narrative (mild endogenous ketosis, improved energetics, cardio-renal effects) continues to attract combo studies with GLP-1s and beyond. (Context from earlier section in this issue.)
• Non-steroidal MRAs (finerenone) and next-gen reno-cardio agents continue to extend the cardio-renal-metabolic stack.

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What to watch (2025–2027 catalysts)

• Oral GLP-1 approvals (Lilly’s orforglipron) could unlock statin-scale adherence and market size.
• Triple agonists (Lilly retatrutide) — first Phase 3 readouts, including osteoarthritis and CV metabolic endpoints, will define “beyond GLP-1.”
• Amylin resurgence (Novo amycretin; Roche/Zealand petrelintide) — potential for better satiety/lean-mass profiles and powerful combo playbooks.
• FGF21 Phase 3s (Akero, 89bio/Roche) — first approvable non-incretin metabolic drugs for MASH/SHTG would broaden the franchise beyond weight loss.
• Challenger orals (Viking VK2735-O) — proof that small-company innovation can compete if tolerability and efficacy line up.
• PFizer’s BD after danuglipron exit (e.g., Metsera deal) — expect aggressive moves to re-enter obesity with differentiated mechanisms.

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References

1. Jastreboff AM, et al. “Tirzepatide and weight loss.” NEJM. 2022.
2. Coskun T, et al. “Triple agonists for metabolic disease.” Cell Metab. 2022.
3. Wilding JP, et al. “Semaglutide for obesity.” NEJM. 2021.
4. Zelniker TA, et al. “SGLT2 inhibitors & CV/renal outcomes.” Lancet. 2019.
5. Talukdar S, et al. “FGF21 biology & therapeutics.” Cell Metab. 2016.
6. Sanyal AJ, et al. “Efruxifermin (EFX) in NASH.” Lancet. 2020.
7. Pavlova NN & Thompson CB. “The emerging hallmarks of cancer metabolism.” Cell Metab. 2016.
8. Faubert B, et al. “Glutamine metabolism in cancer.” Nature. 2017.
9. Ward PS & Thompson CB. “IDH mutations in cancer.” Cancer Cell. 2012.
10. Zhao B, et al. “TKIs and metabolic rewiring.” Nat Rev Cancer. 2021.
11. Poff AM, et al. “Ketone supplementation in therapy — review.” Front Nutr. 2021.

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