Revolutionary Drugs for Diabetes, Obesity and Overweight: Disrupting the Worlds Largest Chronic Disease Landscape

Authored by: Biohedge team, 2023-07-04

Type	Scientific Due Diligence
Depth	Overview, Screening
Client	NGO
Availability	Public
Conclusion	Field leaders: Eli Lilly, Novo Nordisk, Zealand Pharma, Viking Therapeutics, Altimmune. Highest potential: Retatutride, Tirzepatide.

Content

1. A global health crisis: the obesity and diabetes pandemic
2. Overview
3. Definition of obesity
4. Type 2 diabetes and obesity
5. Definition of diabetes
6. Unsuspected finding in diabetes trials
7. Incretins: beyond blood sugar control
8. Descriptive statistics
9. Obesity
10. Overweight
11. Type 2 diabetes
12. The incretin era: redefining blockbuster drugs
13. The biology of incretins
14. Incretins and pleiotropic effects
15. Fat tissue and energy expenditure
16. Incretin in obese with- or without diabetes
17. Incretin hormones and cardiovascular disease
18. Approved medications for obesity
19. Non-hormonal therapy
20. Hormonal therapy (incretins)
21. Clinical trials: GLP-1 receptor agonists
22. GLP-1: heart disease in patients with diabetes
23. GLP-1: treatment for obesity and overweight
24. Liraglutide
25. Semaglutide
26. STEP 1–8
27. Safety and regain of weight loss
28. Expansion of therapeutic indications
29. Tirzepatide (GLP-1 + GIP)
30. Larger weight loss with Tirzepatide in type 2 diabetes (SURMOUNT 1–2)
31. The full effect of tirzepatide (SURMOUNT 3–4)
32. Retatrutide – a tripple hormone incretin (GLP-1 + GIP + GCA)
33. Weight loss pills on the horizon
34. Rybelsus (oral GLP-1)
35. Orforglipron (oral GLP-1)
36. Danuglipron (oral GLP-1)
37. How big could the overall market become?
38. Predictions and market leaders
39. Market leaders (tickers)
40. Eli Lilly and Novo Nordisk investment opportunities
41. How much do these drugs cost, and who will pay?
42. The North American market
43. The European market
44. What could go wrong with weight loss therapies?
45. The potential for cardiovascular risk factor improvement
46. Side effects and complications
47. Gastrointestinal side effects of GLP-1R
48. Pancreatitis and pancreatic cancer concerns
49. Conclusions

A global health crisis: the obesity and diabetes pandemic

Overview

Diabetes, a chronic metabolic disorder, exerts its impact on a vast global populace, affecting approximately 500 million individuals. Additionally, nearly 500 million people grapple with pre-diabetes or impaired glucose tolerance (IGT), which signifies the early stages in the development of type 2 diabetes. There are also several hundred million more individuals who contend with a related condition known as metabolic syndrome.

Interestingly, around 85-90% of all those afflicted with diabetes, pre-diabetes, or IGT, are destined to develop or have already developed the variant recognized as type 2 diabetes. The notable surge in these conditions over recent decades finds its roots in a significant cause—the obesity pandemic. Obesity and overweight were once deemed untreatable conditions, but transformative research has finally constructed a group of drugs that effectively and safely reduce body fat.

Pharmaceutical, biotechnology, medical technology, and digital health companies focusing on type 2 diabetes are now turning their attention to the emerging medical field of obesity and overweight which has enormous potential. This new domain offers promising insights and therapeutic opportunities for several large public health disorders.

Definition of obesity

Obesity is a medical condition characterized by excessive accumulation of body fat and represents a significant risk factor for a wide range of leading causes of mortality and morbidity worldwide. The condition is defined as a body mass index (BMI) that reaches or exceeds 30 kg/m², while overweight is defined as a BMI of 25 kg/m² or higher.

Large observational studies have indicated that individuals with obesity or overweight experience a reduction in life expectancy ranging from 5 to 20 years, depending on the severity of the condition.

Diabetes is a chronic disease that significantly increases our susceptibility to several life-threatening medical conditions. Various forms of diabetes exist, however, type 2 diabetes accounts for approximately 85-90% of all diabetes cases worldwide.

Type 2 diabetes and obesity

The incidence of type 2 diabetes has risen in parallel with the global obesity pandemic, as obesity and being overweight are intricately associated with type 2 diabetes. In fact, obesity or overweight is prevalent in more than 80% of all cases of type 2 diabetes and is considered the causal factor for the development of diabetes.

To comprehend the intricate link between obesity, overweight, diabetes, and chronic diseases, it is essential to grasp the biological effects (pathophysiological) that excessive and dysfunctional fat tissue has on specific organs and tissues in the human body.

More than energy imbalance

A reasonably accurate portrayal of the accumulation of excessive fat tissue is that it arises from a surplus of energy intake coupled with insufficient energy expenditure, leading to the storage of biochemical energy (fat and sugar) within fat cells.

Over time, prolonged exposure to elevated energy levels, and the diminishing ability to effectively manage biochemical energy waste products, give rise to the development of insulin resistance, beta-cell failure, and impaired metabolism of fat and sugar in vital organs like the liver, skeletal muscles, brain, fat tissue, and pancreas.

These metabolic processes are triggered early on and are prevalent in nearly all individuals grappling with obesity and being overweight. Intriguingly, these processes serve as causal factors for the onset of various other serious health conditions such as diabetes, heart disease, cancer, dementia, autoimmune diseases, musculoskeletal issues, and numerous other age-related ailments.

A nuclear analog

Dysfunctional metabolism and cellular disequilibrium mirrors the perilous state of a neglected nuclear power plant, wherein the reactors house depleted nuclear energy, and unattended nuclear waste indiscriminately corrodes its surroundings

 

Unsuspected finding in diabetes trials

A notable revelation arising from clinical trials investigating patients with type 2 diabetes illuminated that those individuals receiving active treatment experienced a noteworthy decrease in blood glucose levels and cardiometabolic risk factors.

Particularly striking was the reduction observed in body weight, fat mass, and waist circumference among the active treatment group compared to those administered with a placebo. These pivotal findings set in motion an array of subsequent clinical trials and research endeavors that have repeatedly demonstrated the immense potential harbored within a group of hormones known as incretins.

Incretins: beyond blood sugar control

While these hormones are naturally synthesized within the human body, primarily from cells that coat the inside of our intestines, the administration of exogenous treatment with these hormones has demonstrated several favorable effects on metabolism. Consequently, these hormones have now emerged as groundbreaking drugs with the potential to revolutionize the medical landscape in the forthcoming decades.

Descriptive statistics

Obesity

The prevalence of obesity and overweight demonstrates notable disparities across diverse geographical regions. European and North American countries typically report prevalence rates surpassing 40%, with certain countries and regions nearing the 60% threshold.

Furthermore, the prevalence of obesity and overweight is on the rise within all socioeconomic strata. Projections indicate that by 2035, over half of the global population will fall within the obese or overweight classification. Consequently, it becomes evident that tackling the issues of obesity and overweight stands as one of the paramount public health challenges of our era.

Table 1. Change in prevalence of obesity (BMI ≥30 kg/m2) in adults (>18 years)
	2020	2025	2030	2035
America
Men	32%	36%	41%	47%
Women	37%	40%	45%	49%
Economic impact (US$ at 2019 value) (billions)	870$	1030$	1230$	1470$
Eastern Mediterranean
Men	20%	23%	27%	31%
Women	30%	34%	37%	41%
Economic impact (US$ at 2019 value) (billions)	70$	92$	122$	163$
Europe
Men	26%	30%	34%	39%
Women	28%	30%	32%	35%
Economic impact (US$ at 2019 value) (billions)	516$	596$	691$	807$
Africa
Men	7%	9%	11%	13%
Women	18%	22%	26%	31%
Economic impact (US$ at 2019 value) (billions)	23$	30$	40$	53$
South-East Asia
Men	4%	6%	7%	10%
Women	8%	10%	13%	16%
Economic impact (US$ at 2019 value) (billions)	65$	102$	162$	254$
Western Pacific
Men	8%	11%	14%	19%
Women	9%	11%	13%	16%
Economic impact (US$ at 2019 value) (billions)	412	625	984	1560
Global economic cost	1960$	2470$	3230$	4320$
Economic impact (US$ at 2019 value) (billions)

 

Overweight

As depicted in Figure 1, the findings indicate that a significant majority of adults worldwide already fall into the overweight category (BMI ≥25 kg/m²). Notably, the rise in overweight cases is more pronounced than the increase observed in obesity cases. While the risk of obesity-related complications tends to escalate in a non-linear manner for various diseases, the risk of developing these conditions rises above a BMI threshold of ≥25 kg/m².

Consequently, discussions pertaining to obesity also encompass considerations of being overweight, and vice versa. Thus, obesity and diabetes are the largest public health concerns of our time since they are reaching pandemic levels and resulting in numerous life-threatening diseases.

Type 2 diabetes

• According to the International Diabetes Foundation (IDF) Diabetes Atlas 10th Edition, the number of individuals aged 20-79 years with diabetes reached 537 million in 2021. Projections indicate that this figure will climb to 645 million by 2030 and further to 780 million by 2045.

• Diabetes is responsible for a substantial proportion of all cases of heart disease, stroke, heart failure, kidney disease, dementia, cancer, and several other age-related diseases.

• The economic impact of diabetes manifests in total healthcare expenditures amounting to approximately 1 trillion dollars, a cost that is expected to increase by over 300% over the past 15 years, as indicated by the IDF.

• Roughly 550 million individuals exhibit metabolic conditions such as impaired glucose tolerance (IGT), with several hundred million presenting impaired fasting glucose (IFG). These individuals are classified as having pre-diabetes and are at a heightened risk of developing obesity and diabetes.

The incretin era: redefining blockbuster drugs

Significant advancements have been achieved in the past five decades concerning the management of diseases intricately linked with excessive body weight, such as hypertension, diabetes, and dyslipidemia. Nonetheless, addressing obesity as an independent condition has posed considerable challenges, often resulting in limited effectiveness and uncertain safety outcomes.

However, a transformative shift has recently occurred. Within the realm of pharmacological interventions, a plethora of options exist for treating diabetes. In this report, the primary focus will be on novel biopharmaceutical interventions, as they constitute the fundamental building blocks of all treatment modalities targeting obesity and diabetes.

Among the novel treatment options for type 2 diabetes and obesity, four particularly noteworthy contenders are the following:

1. Sodium-Glucose Co transporter-2 (SGLT2 inhibitors) (not incretin hormone)
2. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) (incretin)
3. Gastric inhibitory polypeptide (GIP) treatment (incretin)
4. Glucagon receptor agonists (GRA) treatment (incretin)

The biology of incretins

Incretin hormones are released from the cells in our intestine after meals and play a vital role in stimulating insulin and glucagon secretion by the pancreas. The pancreas, liver, skeletal muscles, and fat tissue are the most important metabolic regulators in the human body.

Incretins are becoming the primary therapeutic option for a wide range of patient cohorts afflicted with obesity and type 2 diabetes, these therapies hold immense promise. Among the burgeoning class of breakthrough drugs designed to combat age-related conditions, GLP-1 receptor agonists (RAs), GIP-based treatments, and GRAs emerge as notable contenders.

As of current understanding, 14 distinct incretins have been identified, with pharmaceutical interventions having been developed for three (GLP-1, GIP, GRA) of these hormonally active compounds and three (amylin, PYY, FGF21) more in the pipeline.

List of potential molecular targets

1. Glucagon-like peptide-1 (GLP-1)
2. Glucose-dependent insulinotropic peptide (GIP)
3. Gastric inhibitory polypeptide (GIP)
4. Glucagon-like peptide-2 (GLP-2)
5. Glucagon
6. Vasoactive intestinal peptide (VIP)
7. Pituitary adenylate cyclase-activating peptide (PACAP)
8. Secretin
9. Gastrin-releasing peptide (GRP)
10. Neuromedin U (NMU)
11. Ghrelin
12. Amylin
13. Peptide YY (PYY)
14. Fibroblast growth factor 21 (FGF21)

Incretins and pleiotropic effects

Beyond glucose regulation, GLP-1 influences appetite, satiety, and gastric emptying, while GIP may influence adipose tissue and bone metabolism. GLP-1 also plays a role in the hedonic control of food intake. GLP-1 mimetics decrease appetite and food intake, but individual responses may vary. Hypothalamic and brainstem responses to GLP-1R activation are critical in influencing food intake.

Fat tissue and energy expenditure

GLP-1RA has been shown to reduce white adipose tissue thickness and induce adipocyte hyperplasia in both animal and human studies. However, the effect of GIP on adipose tissue remains unclear.

GLP-1 has been shown to increase energy expenditure in animal studies. The effects of GLP-1 and GIP on energy expenditure in humans require further investigation. GLP-1 slows gastric emptying, contributing to its satiating effect. The effects of GIP on gastrointestinal motility are not fully understood.

Incretin in obese with- or without diabetes

Increased body weight is associated with reduced GLP-1 secretion and an impaired incretin effect. GIP secretion tends to be higher in obese individuals.

GLP-1 concentrations in individuals with T2DM may vary based on glucose control, disease duration, and BMI. The loss of incretin effect in diabetic subjects is primarily due to the pancreas’ impaired response to GIP and GLP-1.

Incretin hormones and non-alcoholic fatty liver disease

NAFLD is closely associated with insulin resistance. GLP-1 and GIP may play a role in the pathophysiology and treatment of NAFLD, but further research is needed.

Incretin hormones and cardiovascular disease

GLP-1 has shown beneficial effects on cardiovascular parameters beyond glycemic control. Studies on GIP’s role in cardiovascular health are emerging, suggesting its potential associations with blood pressure and vascular health.

Incretins have also resulted in improved blood pressure, blood fat, and other cardiovascular risk factors. This means that future incretin treatment also has the potential to treat other public health diseases such as cardiovascular risk factors.

The gut-brain connection

Incretins, a group of gastrointestinal hormones, establish a vital communication channel between the gut and the brain, relaying crucial information pertaining to energy intake, metabolism, energy storage, and various other essential factors.

A paradigm shift

These paradigm-shifting pharmaceutical agents are forecasted to yield substantial annual revenues ranging from several billion to hundreds of billions of dollars annually in the forthcoming years. The inexhaustible potential of these drugs stems from their profound impact on systemic metabolism, leading to a cascade of favorable biological effects.

While all the medications under discussion are also accessible for the treatment of type 2 diabetes, the scope of this report primarily centers on the burgeoning market for obesity. This deliberate focus is driven by the recognition that the global market for obesity presents significantly greater dimensions, necessitating a specialized examination of the emerging opportunities and challenges within this specific domain.

Approved medications for obesity

GLP-1 treatments:

1. Liraglutide: A glucagon-like peptide 1 analog (GLP-1) is a novel treatment that results in weight loss by activating several physiological systems, most notably affecting appetite and feeling of saturation. The brand name is Saxenda.

Manufacturer: Novo Nordisk

• Semaglutide: A GLP-1 analog treatment that is slightly modified from Liraglutide and lasts for 165 hours. The most recent clinical trial called STEP 8 demonstrated that Semaglutide is clinically superior to Liraglutide with an average 15.8% weight reduction and 6.4% for the Liraglutide group (source: JAMA. 2022;327(2):138-150. doi:10.1001/jama.2021.23619). Sold under the brand name Wegovy.

Manufacturer: Novo Nordisk

GLP-1 and GIP combination therapy:

1. Tirzepatide: This is also a novel injectable treatment alternative that includes both GLP1 and activates another biological receptor called gastric inhibitory polypeptide (GIP) receptor. This results in a 22% weight loss from baseline. Sold under the brand name Mounjaro.

Manufacturer: Eli Lilly

Clinical trials: GLP-1 receptor agonists

GLP-1: heart disease in patients with diabetes

Long-acting GLP1 agonists have demonstrated a reduction in the incidence of specific cardiovascular diseases, as evidenced by clinical trials such as LEADER, SUSTAIN-6, Harmony Outcomes, REWIND, ELIXIA, EXSCEL, and AMPLITUDE-O. When the results of these eight cardiovascular outcome trials of GLP1 agonists are analyzed collectively, they indicate a 10% decrease in the rates of fatal and non-fatal heart attacks.

It is important to note that this beneficial effect typically requires a minimum exposure of 12 months to GLP1 agonists in most trials. However, there are some discrepancies among these trials, as certain trials show a risk reduction in stroke, while others demonstrate a risk reduction in a heart attack or a combined reduction in both.

1. LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results): Primary Outcome: Composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Hazard Ratio (HR): 0.87 (95% CI 0.78–0.97)
2. SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes): Primary Outcome: Composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Hazard Ratio (HR): 0.74 (95% CI 0.58–0.95)
3. EXSCEL (Exenatide Study of Cardiovascular Event Lowering): Primary Outcome: Composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Hazard Ratio (HR): 0.91 (95% CI 0.83–1.00)
4. Harmony Outcomes: Primary Outcome: Composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Hazard Ratio (HR): 0.91 (95% CI 0.78–1.06)
5. REWIND (Researching Cardiovascular Events with a Weekly Incretin in Diabetes): Primary Outcome: Composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Hazard Ratio (HR): 0.88 (95% CI 0.79–0.99)
6. ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome): Primary Outcome: Composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Hazard Ratio (HR): 1.00 (95% CI 0.81–1.20)

A hazard ratio below 1.0 indicates a significant risk reduction. For instance, HR 0.70 means that the risk is 30 % lower to develop events, compared to a placebo or other treatment. Thus, there is an independent risk reduction for cardiovascular complications from incretin treatment, in addition to improving cardiovascular risk factors, such as obesity.

GLP-1: treatment for obesity and overweight

The obesity and diabetes market is dominated by Novo Nordisk and Eli Lilly. These companies are at the forefront of development and will dominate the market for this decade. As evident from Figure 2, incretins and bariatric surgery are the only interventions that yield clinically significant weight loss effects (> 5%), however, bariatric surgery is not a treatment option for roughly 99% of all individuals with obesity or overweight.

Orlistat and Phentermine/topiramate also produce around 5% weight loss, however, modern GLP-1 treatments produce roughly 18% weight reduction and more than 10% is considered clinically important with large health benefits.

Liraglutide

The SCALE trials represent a pioneering endeavor in the field of weight loss-focused clinical research, examining the efficacy of GLP-1 analogs. Notably, the subsequent investigation pertaining to this class of medications reveals a noteworthy observation that holds significant implications for future sales—namely, weight regain upon discontinuation of the treatment.

The SCALE Maintenance trial, a crucial component of this research, highlights a moderate to substantial reduction in body weight ranging from 6% to 8%. The weight change outcomes with liraglutide from the trial are visually depicted in the accompanying figure (source: https://doi.org/10.1038/ijo.2013.120).

However, it is important to note that the SCALE Maintenance study indicates a relatively limited improvement in other crucial cardiometabolic risk factors, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate.

The second SCALE study included patients with obesity-related complications and showed quite similar results but slightly greater weight loss change in patients with liraglutide (source: DOI: 10.1056/NEJMoa1411892) than SCALE Maintenance. A safety and tolerability study that also included follow-up data for 2 years after discontinuing the treatment with liraglutide shows that a substantial proportion of all weight is regained (source: https://doi.org/10.1038/ijo.2011.158).

Clinical trial for Liraglutide in patients with diabetes shows an even lower weight reduction, which is typical for the GLP-1 analog group (source: doi:10.1001/jama.2015.9676). Liraglutide only achieved a 7% weight loss in individuals with obesity who also had type 2 diabetes. Suggesting that incretins are more effective in individuals that do not have advanced metabolic disease.

Having demonstrated short-term weight loss with liraglutide in obese adults, the first long-term efficacy for sustaining weight loss over 2 years, was investigated showing that weight regain is an important factor in GLP-1 treatments as a large proportion of the weight loss is regained after discontinuing treatment (source: doi: 10.1038/ijo.2011.158). The improvement for various cardiometabolic risk factors normalizes as well.

Semaglutide

The clinical trials known as STEP 1, STEP 2, STEP 3, STEP 4, STEP 5, STEP 6 and STEP 8 have investigated the impact of another GLP-1 analog developed by Novo Nordisk that is called Semaglutide. See Figure 4 for more details.

Summary of clinical findings from these STEP studies:

1. STEP 1: The STEP 1 trial assessed the efficacy of Semaglutide (2.4 mg) for weight management in individuals with overweight or obesity. The study demonstrated that Semaglutide led to significant weight loss, with participants experiencing an average weight reduction of 14.9% over a 68-week period. Secondary objectives evaluated in this trial included changes in cardiovascular risk factors, body composition, and quality of life.

• STEP 2: The STEP 2 trial investigated the efficacy of Semaglutide (2.4 mg vs Semaglutide 1.0 mg) in comparison to a placebo for weight management in individuals with obesity, overweight, and type 2 diabetes. The trial revealed a substantial weight reduction in the Semaglutide group, with participants experiencing an average weight loss of 9.6% over 68 weeks. Secondary objectives included changes in cardiometabolic risk factors and health-related quality of life. (source: https://doi.org/10.1016/S0140-6736(21)00213-0)

• STEP 3: In the STEP 3 trial, Semaglutide was evaluated for weight management in individuals with obesity but without diabetes and an initial low-calorie diet. The results revealed a notable reduction in body weight, with participants achieving an average weight loss of 16.0% over 68 weeks. Secondary endpoints encompassed various measurements related to cardiometabolic risk factors, body composition, and health-related quality of life. Virtually all factors improved significantly with Semaglutide 2.4 mg versus placebo.

• STEP 4: The STEP 4 trial investigated the effectiveness of Semaglutide in individuals with obesity but without diabetes that had a run-in period for 20 weeks and were thereafter randomized to either continued treatment or placebo. The trial demonstrated substantial weight loss, with participants experiencing an average reduction of 9.6% in body weight over 68 weeks. Secondary outcomes such as glycemic control, cardiovascular risk factors, and quality of life, continued to display lower levels after discontinued treatment. (source: doi:10.1001/jama.2021.3224)

• STEP 5: The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous Semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. This trial shows long-term data for semaglutide. The findings showed a significant decrease in body weight, with participants achieving an average weight loss of 12.6% over 104 weeks. Secondary outcomes examined in this trial included changes in cardiometabolic risk factors and health-related quality of life. Similar results are demonstrated for these risk factors. (source: https://doi.org/10.1038/s41591-022-02026-4)

• STEP 6: shows that the effect of GLP-1 is even greater in Asian populations, either superior or equivalent to effects that have been observed in European populations. (source: https://doi.org/10.1016/S2213-8587(22)00008-0)

• STEP 8: The STEP 8 trial focused on the evaluation of Semaglutide vs. Liraglutide for weight management in individuals with type 2 diabetes. The results demonstrated significant weight loss, with participants achieving an average reduction of 5.6% in body weight over 68 weeks. Secondary outcomes assessed in this trial encompassed glycemic control, cardiovascular risk factors, and quality of life. (source: DOI: 10.1001/jama.2021.23619)

As such, the Semaglutide drug has repeatedly proven to have a significant weight loss reduction in all clinical trials in addition to improving secondary outcome measures such as glycemic control, blood pressure, body composition, and quality of life.

Safety and regain of weight loss

A meta-analysis of clinical trials that included GLP-1 receptor agonists showed that these treatments are safe and may cause some feeling of nausea or gastrointestinal symptoms and around 10% of all individuals that start with GLP-1 analogs (source: https://doi.org/10.3389/fendo.2021.645563). This study shows that subcutaneous injection is associated with a slight risk increase for nausea and other side-effects such as gastrointestinal

symptoms but these are reduced after some time of ongoing treatment. The novel treatments with oral tablets of semaglutide display a similar frequency of side effects as injection therapies, a dose vs. side-effect plot is presented below from this study.

The STEP 1 study group investigated the weight regain from discontinuing the treatment of Semaglutide and demonstrated that a large proportion of the weight is regained, around two-thirds of all weight is regained (source: https://doi.org/10.1111/dom.14725).

Furthermore, as demonstrated above in the STEP 4 trial, those who switched to placebo regained a lot of weight as well, and study investigators presume that virtually all weight loss is regained if investigated over a longer period. This means that lifelong treatment is necessary to maintain weight loss.

 

Conclusions from semaglutide and liraglutide trials

The SCALE and STEP studies have demonstrated a causal relationship between incretins, type 2 diabetes, and weight loss. However, one thing is evident, the treatment must be continued to maintain improvements in cardiometabolic health and the effect is significantly lower in individuals with obesity and type 2 diabetes or obesity-related complications, compared to individuals that have just obesity and have not developed any complications.

Expansion of therapeutic indications

Novo Nordisk is expanding its GLP-1 portfolio into other serious chronic diseases such as Alzheimer’s disease, cardiovascular disease, chronic kidney disease, peripheral artery disease, heart failure, and fatty liver.

New therapeutic areas represent a patient population with high unmet medical needs. As such, semaglutide holds a plethora of therapeutic opportunities. The ongoing clinical trials with semaglutide are called FOCUS, SOUL, SELECT, STRIDE, FLOW, Alzheimer’s Disease, STEP, and Semaglutide in NASH.

The figure above shows that companies working on incretins for weight loss have already initiated clinical trials for other therapeutic indications. Currently, most trials are focused on cardiometabolic conditions, with the exception of dementia and Alzheimer’s.

Tirzepatide (GLP-1 + GIP)

Semaglutide is the main drug from Novo Nordisk for weight loss. However, Eli Lilly has developed another variant that is even more effective and substantiates the causal factor between incretins, weight loss, and diabetes.

Tirzepatide is the first combinatory dual agonist medication that includes a GLP-1 and a GIP agonist. It was examined in the clinical trial called SOURMOUNT-1 which investigated the efficacy and safety of tirzepatide. As evident from the figure, the effectiveness of double hormonal therapy is at best 22.5% weight loss reduction from the baseline value.

An important clinical difference between Novo Nordisk drugs and Tirzepatide is the dose-response effect. Tirzepatide does not demonstrate a clear advantage at the maximum tolerated dose (i.e., 10 vs. 15 mg), yet there is an increase in side effects for those who received 15 mg.

 

Tirzepatide is a single molecule that activates the body’s receptors for GIP and GLP-1, which are natural incretin hormones. Tirzepatide is in phase 3 development for adults with obesity, or overweight with weight-related comorbidity.

It is also being studied as a potential treatment for people with obesity and/or overweight with heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea (OSA), and non-alcoholic steatohepatitis (NASH). Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are also ongoing.

Larger weight loss with Tirzepatide in type 2 diabetes

The SOURMOUNT-2 clinical trial was recently published and demonstrated a greater weight loss reduction from Tirzepatide than what was observed for Semaglutide in patients with obesity, overweight, and type 2 diabetes. Keep in mind that Semaglutide has a slightly lower weight loss reduction effect in patients with type 2 diabetes, whereas Tirzepatide showed a potentially higher weight loss of 14%.

The recent SOURMOUNT-2 publication in the Lancet demonstrated least-squares mean change in body weight at week 72 with tirzepatide 10 mg and 15 mg was –12·8% (SE 0·6) and –14·7% (0·5), respectively, and –3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of –9·6% percentage points (95% CI –11·1 to –8·1) with tirzepatide 10 mg and –11·6% percentage points (–13·0 to –10·1) with tirzepatide 15 mg (all p<0·0001) (source: https://doi.org/10.1016/S0140-6736(23)01200-X). Thus, tirzepatide is more effective for both individuals with just obesity and those with type 2 diabetes who are obese, compared to semaglutide and liraglutide.

The full effect of tirzepatide

Results from SURMOUNT-3 and SURMOUNT-4 trials showcased the efficacy and safety of tirzepatide for individuals with obesity or overweight. In SURMOUNT-3, participants underwent a 12-week lifestyle intervention before being randomized to receive tirzepatide or a placebo for 72 weeks. Tirzepatide outperformed placebo in both co-primary endpoints, resulting in substantial weight loss and an increased proportion achieving ≥5% weight reduction.

SURMOUNT-4 consisted of a 36-week open-label tirzepatide lead-in period followed by a 52-week double-blind treatment phase. Tirzepatide demonstrated sustained weight loss superiority over placebo, with participants achieving significant mean weight reductions. In both trials, tirzepatide recipients experienced additional body weight loss compared to those on placebo, regardless of the estimand considered.

Overall, tirzepatide displayed promising results in aiding weight loss in participants with obesity or overweight. The full findings of the SURMOUNT-3 study are set for presentation at the ObesityWeek conference in October and subsequent peer-reviewed journal publication. These studies contribute valuable insights into the potential of tirzepatide as a treatment option for weight management.

Retatrutide – a triple hormone incretin (GLP-1 + GIP + GCA)

Retatrutide is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors. The dose–response relationships with respect to side effects, safety, and efficacy for the treatment of obesity were not known until just recently.

The difference between Retatrutide and other incretin hormone treatments is the fact that three active hormones are being targeted with this treatment. The findings from this trial are remarkable. This is the most effective injection today for weight loss. Around 22-26% of body weight is reduced from baseline after active treatment with Retatrutide.

 

Weight loss pills on the horizon

Rybelsus (oral GLP-1)

Rybelsus from Novo Nordisk is the first oral Semaglutide treatment to hit the market. Remarkably this drug demonstrated similar weight loss change in patients with obesity as did the injection treatments from Novo Nordisk and the frequency of side-effects and discontinuation of the medicine is similar to that of injections of Semaglutide. These findings were published in Lancet in the OASIS-1 trial just recently.

	Orforglipron (at week 36, oral)	Retatrutide (at highest dose, injected*)	Mounjaro (injected**)	Wegovy (at week 68, injected)	Rybelsus (at week 26, oral)
Weight loss in obesity	~14-15%	~22-24%	15-21%	15%	15%-
Weight loss in T2D	up to 9.6%	~15-17%	6.3-7.8%	9.6%	3-4%
Long-term blood glucose reduction in T2D	up to 2.1%	~2%	1.7-1.8%	–	1.2-1.4%
Notes: *at 48 weeks for obesity, and 36 weeks for T2D; **at week 72 for obesity, and week 40 for T2D. T2D = type 2 diabetes. Source: Lilly presentation, NEJM & drug labels.

Orforglipron (oral GLP-1)

The recent trial by Eli Lilly shows that the oral GLP-1 analog called Orforglipron has demonstrated similar effects to Rybelsus and other GLP-1 injection treatments with similar side effects and discontinuation frequency.

Danuglipron (oral GLP-1)

Considering the enormous market for weight loss therapies and diabetes, additional pharmaceutical companies have entered the market with Pfizer developing their one and only weight loss pill called Danuglipron. This drug also belongs to the GLP-1 analog class. The first trial demonstrated a significant weight reduction after just 16 weeks of treatment, in individuals with obesity and type 2 diabetes.

Suggesting that Pfizer’s new drug can compete with Novo Nordisk Rybelsus and Orforglipron from Eli Lilly, however, Novo and Lilly performed their first trials in individuals with just obesity, suggesting that Danuglipron might be more effective when investigated in individuals with just obesity and no obesity-related complications.

Overall market potential

During a recent investment conference, the CEO of pharmaceutical company Pfizer emphasized that the combined global market for pharmaceuticals aimed at addressing obesity and type 2 diabetes is poised to reach an astonishing $90 billion by the year 2030. This forecast finds support in the pervasive prevalence of these two conditions, with the Centers for Disease Control and Prevention reporting that 41.9% of American adults are categorized as obese, and approximately 1 in 10 individuals are affected by diabetes.

Predictions and market leaders

The table below depicts predicted sales for type 2 diabetes and obesity respectively for the two market leaders in weight loss therapies (i.e., Novo Nordisk och Eli lilly). These predictions are for Bloomberg, however, other predictions estimate that the overall weight loss market (excluding diabetes) will be worth 50-70 billion US dollars in 2030 and Novo and Eli Lilly will share this market with a slight advantage for Lilly considering their portfolio.

 

Manufacturer / Ticker (Drug)	Indication	FDA Approval	2022 Sales (bil)	2029E Sales (bil)
Eli Lilly / LLY (Mounjaro)	Type 2 diabetes	approved	$0.5	$15.8
Eli Lilly / LLY (N/A)	Obesity	Not yet approved	N/A	14.6
Novo Nordisk / NVO (Ozempic)	Type 2 diabetes	approved	8.5	16.8
Novo Nordisk / NVO (Wegovy)	Obesity	approved	0.9	11.9
Novo Nordisk / NVO (Rybelsus)	Type 2 diabetes	approved	1.6	7.1

 

Considering that these medications do not offer a definitive cure, it is anticipated that patients will necessitate long-term utilization, thereby expanding the revenue potential of these drugs. Notably, Mounjaro, which encompasses diverse formulations encompassing injectables and oral therapies targeting both diabetes and obesity, has garnered ambitious sales projections from industry analysts.

Predictions estimate impressive annual sales figures between 40–100$ billion. To contextualize these figures, even the lower end of this range surpasses the peak sales achieved by the historically best-selling therapeutic, AbbVie’s (ABBV) Humira.

 

Market leaders (tickers)

1. Eli Lilly (LLY) – exceptional portfolio with several medications launched and more in the pipeline
2. Novo Nordisk (NVO) – exceptional portfolio with several medications launched and more in the pipeline
3. Pfizer (PFE) – oral treatment with Danuglipron
4. Amgen (AMGN) – dual GLP1 and GIP treatment, Phase 3 study begins in 2024 and launch could be expected in 2026 or 2027
5. Novartis (NVS) – Versanis was started by Novartis to sell and develop Bimagrumab, an antibody that blocks activin type 2 receptors in muscles to stimulate growth, reduce fat mass, and improve glycemic control
6. Astra Zeneca (AZN) and Regeneron (REGN) – small-molecule experimentation based on genetic findings such as GPR75. Phase 1 studies have not been initiated yet.
7. Viking Therapeutics (VKTX) – oral tablet with GLP1 and GIP receptor agonists. Currently starting their Phase 2 study.
8. Structure Therapeutics (GPCR) – oral small molecule for GLP-1. In Phase 2 currently

 

Eli Lilly and Novo Nordisk investment opportunities

Lilly’s potential for substantial long-term growth is recognized by bullish investors. With a robust pipeline of forthcoming obesity market products, including the promising Mounjaro, Lilly appears poised for enduring sales opportunities over the next five to ten years. The shares of Lilly have shown impressive growth, doubling from the beginning of 2021 to the end of 2022, and this upward trend has continued.

Recently, positive results from a Phase 3 trial of its Alzheimer’s disease therapy propelled the company’s shares to an all-time high, easing concerns for investors. Similarly, Novo’s shares have also doubled over the past two years, driven by the increasing momentum of its Wegovy rollout. However, when comparing the two companies, Lilly emerges as the more promising investment opportunity within the obesity drug market.

Analysts project a compound annual rate of earnings per share growth of 23% for Lilly from 2022 to 2027, surpassing Novo’s 17% growth rate. Lilly’s edge lies in its robust drug pipeline, featuring transformative drugs in advanced development stages, including donanemab for Alzheimer’s, Jaypirca for cancer, and lebrikizumab for dermatitis. Early data also indicates that Lilly’s tirzepatide may outperform Novo’s Ozempic as a more effective weight-loss agent.

When it comes to combination therapies, Lilly’s retatritude, involving GLP-1, GIP, and glucagon receptor activation, presents a compelling option. On the other hand, Novo is exploring combination therapies involving GLP-1 and GIP, as well as GLP-1 and Amylin, which offers the potential for enhanced weight loss or blood glucose control. In terms of valuation, Lilly currently trades at 44 times its expected earnings over the next 12 months. Compared to other S&P 500 healthcare stocks.

Lilly and Novo are years ahead of other companies

Eli Lilly and Novo Nordisk have long been on the diabetes market as the main insulin producers in the world and slowly diversified the portfolio to their other companies.

How much do these drugs cost, and who will pay?

The North American market

The medications in question are typically priced around $1,000 per month in the United States, varying slightly based on indications and dosing requirements for patients with diabetes. The payment process for these drugs follows the standard procedure for most medications.

Manufacturers negotiate with pharmacy benefit managers to secure insurance coverage, which gradually expands over time. As per Lilly’s report, about 60% of individuals covered by commercial insurance plans and Medicare currently have access to Mounjaro. However, a different situation arises when these drugs are prescribed for obesity treatment. Debates regarding the classification of obesity as a disease often results in insurers excluding coverage for weight-loss medications.

Additionally, federal legislation prohibits Medicare’s prescription drug benefit from covering such drugs. Due to increasing patient demand, investors and analysts expect an expansion in insurer coverage. Private insurers have started covering Novo’s obesity drug (resulting in approximately 40 million Americans having insurance coverage for Wegovy), but not all overweight individuals are eligible.

To further support the case for insurer coverage, Lilly and Novo have yet to release study results demonstrating that their obesity drugs not only aid non-diabetic individuals in weight loss but also reduce their risk of heart disease and stroke.

Both companies are currently conducting trials to gather this data, with Novo expected to produce results in the coming months and Lilly’s results anticipated in the coming years. Positive outcomes from these trials would significantly challenge insurers’ decision to withhold coverage for these drugs as obesity treatments.

The European market

In the European market, the pricing and payment structure for these medications vary across different countries, which are divided between government insurance and private insurance systems. In countries with government insurance, the cost of these drugs is typically negotiated between drug manufacturers and national health authorities or healthcare systems.

The government or public health insurance programs often play a central role in determining the reimbursement and coverage for these medications. This can lead to a standardized approach to pricing and availability, making the medications accessible to a broader segment of the population. Conversely, in countries with private insurance systems like Germany, the pricing and payment dynamics for these drugs are influenced by private health insurance companies.

These insurers negotiate with drug manufacturers to secure coverage for specific medications, including those for diabetes and obesity. The extent of coverage and reimbursement may vary depending on the insurer’s policies and agreements with drug manufacturers. In both government insurance and private insurance scenarios, the actual payment for these drugs is primarily borne by the insurers, either government-run or private insurance companies.

However, patients may still be responsible for co-payments or out-of-pocket expenses, depending on the specific insurance plan they have. In some cases, especially for government insurance systems, co-payments may be subsidized or waived for vulnerable populations to ensure greater access to essential medications.

Overall, the landscape of drug pricing and coverage in the European market can be complex and is influenced by various factors, including government policies, negotiations with manufacturers, and the nature of the healthcare insurance system in each individual country.

What could go wrong with weight loss therapies?

The primary risk faced by pharmaceutical companies operating in the weight loss domain, such as Novo and Lilly, pertains to the possibility of their clinical trials, designed to demonstrate the drug’s efficacy in reducing stroke and heart attack rates among non-diabetic patients, yielding unfavorable results.

In such a scenario, insurance coverage for obesity indications would remain limited. While the drugs would still achieve significant commercial success, they may fall short of the lofty expectations set by many.

There are additional risks that may not be immediately apparent. One such risk is the potential impact of Medicare price negotiations, scheduled to be implemented in 2026 as part of the Inflation Reduction Act passed last year. Currently, Medicare covers both Novo and Lilly’s drugs for diabetes, and Novo’s Ozempic could become eligible for negotiation as early as 2027.

The outcome of these negotiations remains uncertain, but it is plausible that lower Medicare prices for Ozempic could have a ripple effect on the prices Lilly can command for its competing drug.

Furthermore, there are threats emanating from competitors. Should the upcoming drugs from Pfizer or Amgen match or surpass the performance of Novo and Lilly’s products, the optimistic projections put forth by analysts could face a more realistic reassessment.

The potential for cardiovascular risk factor improvement

Incretins such as GLP-1 analogs, GIP, and others will surely have a positive effect on cardiovascular risk factor improvement and cardiovascular disease and demonstrated by the recent findings from the SELECT study that is undergoing from Novo Nordisk were preliminary results demonstrated more than 20% relative risk reduction for future cardiovascular events in patients with Semaglutide treatment, irrespective of having diabetes or not.

Not only about diabetes and obesity anymore

This means that the previous label of only using Semaglutide and future incretins for individuals with type 2 diabetes is slowly eroding. These drugs will soon be required for individuals with obesity, and other metabolic conditions, and even for individuals with classic cardiovascular risk factors such as high blood pressure, poor renal function, and elevated levels of fat in the blood circulation.

Interestingly, available clinical trial data from the STEP studies demonstrate that canceling treatment with incretins results in worsening levels of cardiovascular risk factors, and in a large proportion of treated cases, the risk factors regress back to almost baseline levels. This means that continued treatment is necessary for sustained improvement of the most important risk factors.

Treatment indications will just continue to grow

It is conceivable that treatment with incretins such as semaglutide will result in an improvement for most cardiometabolic conditions, which include several public health diseases such as cancer, cardiovascular disease, renal disease, and dementia. The preclinical data suggests that these therapies should have such improvement and now clinical trial data is slowly catching up and verifying these claims with real-world data.

Side effects and complications

Gastrointestinal side effects of GLP-1R

Agonists Gastrointestinal adverse effects are common with GLP-1R agonist treatment, with nausea, vomiting, and diarrhea being the most reported. A systematic analysis of 32 clinical trials with 10,367 patients found that the risk of nausea and diarrhea increased with the dose of long-acting GLP-1R agonists. Nausea and vomiting were more common when GLP-1R agonists were combined with another common drug for diabetes (metformin). Some GLP-1R agonists, such as lixisenatide, showed lower incidences of nausea and diarrhea compared to others.

Pancreatitis and pancreatic cancer concerns

Controversy has arisen regarding a suspected association between GLP-1R agonists and pancreatitis and pancreatic cancer since their introduction in 2005. Reports from the FDA Adverse Event Reporting System (FAERS) suggested a potential link, but further reviews by the FDA and EMA found inconsistent data and no causal relationship. A meta-analysis involving 9347 patients on GLP-1R agonists and 9353 on placebo showed no increased risk of pancreatitis.

Similarly, a large retrospective cohort study with nearly one million patients initiating antidiabetic medications found no increased risk of pancreatic cancer with GLP-1R agonist use. In conclusion, GLP-1R agonists are considered safe and unlikely to cause pancreatitis or pancreatic cancer. Not all incretins are labeled as contradictory if the individual has had malignant thyroid cancer but this is a quite rare cancer thus most individuals with obesity, overweight, diabetes, and even healthy people will be eligible for the treatment.

Conclusions

There is extensive clinical evidence supporting the efficacy of incretin treatment, available in both injection and tablet forms, for addressing obesity, overweight, diabetes, and various other cardiometabolic disorders. These treatments have been proven to be safe, with manageable side effects like nausea and gastrointestinal symptoms.

Moreover, the market potential for these treatments is substantial, as currently, no therapeutic options offer clinically significant effects on weight loss. In addition, it is worth noting that these medications may play a pivotal role in managing age-related diseases such as Alzheimer’s, fatty liver disease, and cancer.

Incretin treatment could potentially be the first class of medications to effectively reverse age-related conditions, positioning them at the forefront of age-reversal therapies. At present, the market is largely dominated by two pharmaceutical companies, namely Novo Nordisk and Eli Lilly, which have a significant head start compared to other competitors such as Pfizer and Amgen, who have also entered the market.

An intriguing aspect of these drugs is that they require lifelong treatment, as the positive effects, including improved cardiometabolic risk factors, normalize after discontinuation. Consequently, the demand for these treatments will only rise, given the increasing global population affected by obesity and diabetes. These conditions are becoming major public health concerns of our time, and no “one-shot” cure is currently on the horizon.

Lastly, the companies that are at the forefront of this medical field (Novo and Lilly) have a tremendous leap compared to the third, fourth, and other competitors down the list, meaning that market dominance is expected for the foreseeable future. These companies are possibly on their way to becoming the first pure biopharma companies with a market value of one trillion dollars.