Breakthrough Clinical Results
Novo Nordisk announced positive results from two early-phase clinical trials of amycretin, a novel investigational obesity treatment, published in The Lancet. Both subcutaneous and oral formulations will proceed to Phase 3 development. The Phase 1b/2a trial of subcutaneous amycretin showed significant weight loss (up to 24.3% at the highest dose) compared to placebo, with mostly mild or moderate side effects. The Phase 1 trial of oral amycretin also demonstrated significant weight loss compared to placebo. Novo Nordisk is advancing both formulations based on these results and regulatory feedback.
Key Highlights
- Positive Phase 1b/2a and Phase 1 clinical trial results for amycretin published in The Lancet.
- Both subcutaneous and oral formulations of amycretin will advance to Phase 3 clinical development.
- Significant weight loss observed in both trials compared to placebo.
- Amycretin is a unimolecular long-acting GLP-1 and amylin receptor agonist.
Incidence and Prevalence
Global Obesity Epidemiology: Current Prevalence and Trends
Global Prevalence Estimates
The prevalence of obesity has grown to an alarming level of at least 300 million people worldwide. However, there are some discrepancies in the estimates, as current estimates of the global prevalence exceed 250 million. The worldwide prevalence of overweight and obesity has doubled since 1980 to an extent that nearly a third of the world's population is now classified as overweight or obese.
In one global study, the overall prevalence of obesity was 4%, and the prevalence of ≥3 h/d of sedentary behavior was 26%. However, estimates of the prevalence of obesity in developed countries vary depending on the definitions used. For example, one recent survey reported that the prevalence of obesity in the US is 15%, while another survey found it to be 26%.
Regional and Demographic Variations
Prevalence rates for overweight and obese people are very different in each region with the Middle East, Central and Eastern Europe and North America having higher prevalence rates. The prevalence of obesity and sedentary behavior were found to be lowest in low-income countries and highest in upper-middle-income countries.
Regional data shows varying prevalence rates: - In Trabzon city, Turkey, the prevalence of obesity (BMI ≥ 30) was 6.0% among those ≥20 years of age - In Tanzania, the age-adjusted prevalence of obesity (BMI ≥ 30) was 13% among men and 35% among women - In Saudi Arabia, the prevalence of obesity among pregnant women was 23.9%, with extreme obesity (BMI > 40 kg/m²) at 4.7% - In urban Shanghai, Chinese men aged 40-75 had an obesity prevalence of 10.5% (using WHO Asian criteria of BMI ≥ 27.5) - In Taiwan, the overall prevalence of obesity (defined as BMI ≥ 27 kg/m²) was 19.2% in men and 13.4% in women
In Latin America and the Caribbean, obesity was most prevalent among women in Mexico and least prevalent among women in Haiti. Urban residents consistently had a larger obesity burden than their rural counterparts in most Latin American and Caribbean countries.
Demographic Patterns
Obesity rates have increased in all ages and both sexes irrespective of geographical locality, ethnicity or socioeconomic status. The prevalence of obesity is generally greater in older persons and women. This trend was similar across regions and countries, although absolute prevalence rates of overweight and obesity varied widely.
Frequency of obesity is influenced by age, sex, race and has increased during the last 30 years. Massive obesity (BMI > 40) corresponds to an increase in mortality ratio. The frequency of massive obesity differs among countries with important incidence in USA (13 million subjects), Finland, and South Africa.
Recently an increase in superobesity in childhood has been observed, especially in the United States. Asians have greater percent body fat than Caucasians for the same BMI. BMI has low sensitivity and there is large inter-individual variability in percent body fat for any given BMI value, partly attributed to age, sex, and ethnicity.
Trends and Future Outlook
Obesity is at last being recognized as a major public health problem of global significance. Rates are already high and increasing in most parts of the world. For some developed countries, the prevalence rates of obesity seem to have levelled off during the past few years. However, obesity is now a serious, emerging problem in developing countries.
Overweight and obesity are becoming more prevalent worldwide, not only in developed nations, but also in the populations of developing countries. This increase is possibly as a result of urbanization, migration, new eating habits and recent affluence. Obesity is usually now associated with poverty even in developing countries.
The first formal World Health Organization Consultation on obesity concluded that the global epidemic is an unintended consequence of modernization, economic development, urbanization and other societal changes. Since modernization appears to be an inevitable process throughout the world, there is every reason to expect that the epidemic of overweight and obesity will extend globally in the future.
More quality national obesity prevalence data are urgently needed, as well as research to identify and promote diets that protect individuals from obesity and type 2 diabetes.
Risk Factors and Comorbidities
Risk Factors and Comorbidities for Obesity
Top Risk Factors
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Genetic factors play a crucial role in obesity development:
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Responsible for up to 40% of causes leading to primary obesity
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578 human genes have been identified as controlling feeding behavior or body weight regulation
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Specific genetic variants associated with obesity include ADRB3 rs4994, FTO rs9939609, ADRB2 rs1042714, IL6 rs1800795, and MTHFR rs1801133
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Both polygenic and monogenic influences are recognized
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Genetic predisposition to obesity is intertwined with genetic predisposition to type 2 diabetes
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Environmental and lifestyle factors:
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Sedentary lifestyle and decline in daily energy expenditures show a close relationship with body fat content
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Factors associated with modernization and lifestyle changes contribute significantly
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Dietary patterns play a key role, with unhealthy dietary intake patterns showing significant environmental correlation with BMI
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High carbohydrate intake (>260g/day) was associated with increased obesity risk in individuals with certain genotypes
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Physiological and metabolic factors:
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Positive energy balance (consuming more calories than expended) is a fundamental cause
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Leptin resistance characterized by increased leptin blood levels is present in most individuals with obesity
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Maternal nutrition during pregnancy may have long-term metabolic consequences in offspring
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Prenatal nutrition can shape future susceptibility through alterations in leptin sensitivity
Additional risk factors include: - Family history of type 2 diabetes - Puberty - Intrauterine exposure to diabetes - Female gender - Certain ethnicities (particularly African American, Mexican American, Native American, and Asian American populations) - Age - Marital status - Education level (women with low education had significantly greater risk)
Major Comorbidities
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Metabolic disorders:
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Type 2 diabetes mellitus is strongly associated with obesity, described as "perhaps the most significant risk factor" for type 2 diabetes in children and youth
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Polycystic ovarian syndrome (PCOS) is exacerbated by the persistence of obesity
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Cardiovascular issues:
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Atherosclerotic plaques
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Hypertension (with 53% prevalence in one study population)
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Adverse lipid profile (dyslipidemia)
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Coronary heart diseases
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Other significant comorbidities:
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Various types of cancer are linked to obesity
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Idiopathic intracranial hypertension (IIH) shows a significant relationship with obesity, with a relative risk of 8 (95%CI: 2,29)
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Inflammatory bowel disease (IBD)
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Non-communicable diseases
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Poor self-image that limits participation in physical activity, creating a negative feedback loop
Mechanisms and Connections
- Proinflammatory cytokines (IL-1, IL-6, and TNF) may be elevated in obesity, potentially causing serious consequences
- Polymorphisms located in cytokine genes may affect protein expression levels
- Tracking of obesity from childhood to adulthood is significant
- Inflammation plays a role in the pathophysiology of obesity and diabetes
- The intestinal microbiota may play a role in the development of both obesity and IBD
- Adipose tissue produces pro-inflammatory adipokines, providing a potential mechanism linking obesity and inflammatory conditions
- Waist circumference is a significant risk parameter, with almost 90% of individuals with BMI > 35 kg/m² above the cut-off point
Tirzepatide: Non-Obesity Indications and Clinical Trial Designs
Indications Beyond Obesity
Tirzepatide is currently approved for the treatment of type 2 diabetes (T2D) and obesity in the US and EU. Beyond these approved indications, tirzepatide is being investigated for:
- Metabolic dysfunction-associated fatty liver disease (MAFLD)
- Potential to reduce hepatic steatosis, lobular inflammation, liver cell damage, fibrosis, and total liver triglyceride levels
- Cardiovascular outcomes in patients with diabetes (in the SURPASS-CVOT trial)
- Kidney function preservation in T2D (suggested by post hoc analysis)
The drug has demonstrated significant benefits in reducing the prevalence of metabolic syndrome compared to placebo and other treatments. It enhances lipid metabolism, reduces blood pressure, and lowers liver fat content.
Clinical Trial Intervention Models and Study Designs
Two major clinical trial designs have been implemented for tirzepatide in non-obesity type 2 diabetes:
SURPASS-1
- 40-week, double-blind, randomized, placebo-controlled, phase 3 trial
- Conducted at 52 medical research centers and hospitals in India, Japan, Mexico, and the USA
- Used a computer-generated random sequence to assign participants (1:1:1:1) to once-weekly tirzepatide (5, 10, or 15 mg) or placebo
- Masking: All participants, investigators, and the sponsor were masked to treatment assignment
- Registered with ClinicalTrials.gov (NCT03954834)
Insulin Degludec Comparison Trial
- Open-label, parallel-group, multicentre, multinational, phase 3 study
- Conducted at 122 sites across 13 countries
- Compared tirzepatide versus titrated insulin degludec in people with type 2 diabetes inadequately controlled by metformin with or without SGLT2 inhibitors
- Randomization: Participants were randomly assigned (1:1:1:1) using an interactive web-response system
- Intervention: Once-weekly subcutaneous injection of tirzepatide (5, 10, or 15 mg) or once-daily subcutaneous injection of titrated insulin degludec
- Stratification: By country, HbA1c, and concomitant use of oral antihyperglycemic medications
Primary and Secondary Endpoints
SURPASS-1
- Primary endpoint: Mean change in glycated hemoglobin (HbA1c) from baseline at 40 weeks
Insulin Degludec Comparison Trial
- Primary efficacy endpoint: Non-inferiority of tirzepatide 10 mg or 15 mg, or both, versus insulin degludec in mean change from baseline in HbA1c at week 52
In addition to these specific endpoints, tirzepatide studies have evaluated its effects on: - Liver fat content - Lipid metabolism - Blood pressure - Metabolic syndrome prevalence - Cardiovascular safety - Kidney function