LK

The Incretin/GLP-1 Revolution in Obesity Treatment: Comprehensive Notes

Outline of the Presentation

  • History of anti-obesity medicines and the growing incidence of obesity.

  • Discovery of incretins: initial research and physiological markers.

  • Therapeutic development: leveraging unusual sources like Gila monster saliva.

  • The clinical surprise: remarkable weight loss observed with these agents.

  • Emerging applications beyond weight loss, such as addiction, kidney disease, and cognitive effects.

  • Important limitations and unresolved problems related to incretin-based treatments.

  • Lessons learned about drug discovery from this experience.

The Dismal History of Anti-Obesity Medicines and Growing Incidence

  • Historical context of anti-obesity drugs: The path to effective obesity treatments has been fraught with challenges. Many older medications were plagued by significant side effects, limited efficacy, or difficult tolerability, often leading to their withdrawal from the market. Examples include early amphetamine-based drugs with addiction potential, fen-phen (fenfluramine/phentermine) withdrawn due to cardiac valve damage, sibutramine (recalled due to cardiovascular risks), and rimonabant (recalled due to psychiatric side effects).

  • Global Prevalence of Obesity: Projected to reach over 50\% by 2035.

  • Number of People (aged >5 years) with Overweight or Obesity (BMI \ge 25\text{ kg/m}^2) (millions):

    • 2020: 2,603

    • 2025: 3,041

    • 2030: 3,507

    • 2035: 4,005

  • Number of People with Obesity (BMI \ge 30\text{ kg/m}^2) (millions):

    • 2020: 988

    • 2025: 1,249

    • 2030: 1,556

    • 2035: 1,914

  • Proportion of Population with Overweight or Obesity (BMI \ge 25\text{ kg/m}^2):

    • 2020: 38\%

    • 2025: 42\%

    • 2030: 46\%

    • 2035: 51\%

  • Proportion of Population with Obesity (BMI \ge 30\text{ kg/m}^2):

    • 2020: 14\%

    • 2025: 17\%

    • 2030: 20\%

    • 2035: 24\%

    Note: For children and adolescents, overweight and obesity are defined using WHO classification of +1\text{SD} and +2\text{SD} above median growth reference.

  • Prevalence of Obesity in the US:

    • Overall Obesity (BMI \ge 30): Has significantly increased from 1990 to 2010, with projections for 2030 showing continued rise.

    • Severe Obesity (BMI > 35): Also shows a sharp increase from 1990 to 2010, with similar projections for 2030.

  • Why Most Diets Fail (to keep weight lost off):

    • The human body is programmed to defend its body weight (often referred to as a 'set point') by reducing calories burned (energy expenditure) when weight is lost and intake is reduced. This physiological adaptation, known as adaptive thermogenesis, can significantly lower basal metabolic rate.

    • This defense mechanism also includes increasing appetite and hunger signals, driven by hormonal changes (e.g., decreased leptin, increased ghrelin, and alterations in peptide YY and cholecystokinin), which make adherence to reduced calorie intake extremely difficult.

    • Bodies actively work against attempts to achieve and maintain a lower weight, making sustained weight loss a biological challenge rather than simply a matter of willpower.

    • High weight can be defended for many years, indicating that fat stores have a strong biological defense mechanism.

Discovery of Incretins

  • Definition and Role: Incretins are gut-derived hormones (primarily Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP)) secreted in response to nutrient intake.

  • The Incretin Effect: This refers to the phenomenon where oral glucose administration elicits a significantly greater insulin response than an equivalent amount of intravenous glucose, demonstrating the role of gut factors in potentiating insulin secretion.

  • Physiological Action: Incretins stimulate insulin release from pancreatic beta cells in a glucose-dependent manner, meaning they only work when blood glucose levels are elevated. They also suppress glucagon secretion, slow gastric emptying, and promote satiety.

Therapeutic Development: Leveraging Unusual Sources like Gila Monster Saliva

  • Exendin-4 Discovery: A pivotal moment in incretin-based therapy came with the discovery of exendin-4, a peptide found in the saliva of the Gila monster (a venomous lizard native to the southwestern US and Mexico).

  • Structural Similarity and Resistance to Degradation: Exendin-4 was found to be structurally similar to human GLP-1 but possesses a key advantage: it is resistant to degradation by the enzyme dipeptidyl peptidase-4 (DPP-4). Human GLP-1 is rapidly degraded by DPP-4, limiting its therapeutic utility in its native form.

  • Development of GLP-1 Receptor Agonists: This unique property of exendin-4 made it an ideal lead compound for developing long-acting GLP-1 receptor agonists. The first drug in this class, exenatide (synthetic version of exendin-4), mimicked the actions of GLP-1, leading to improved glycemic control and, notably, weight loss.