Anti-obesity & Type 2 Diabetes Therapies — Quick Reference

Module outlines

• Module 1: Treatment strategies for type 2 diabetes
• Module 2: Development of pharmacotherapies for weight loss
• Module 3: Bariatric surgery and weight loss

Diabetes complications

• Complications common in long-standing diabetes; management aims to reduce risk
• Postprandial hyperglycemia a strong predictor of cardiovascular disease
• Neuropathy affects about half of people with long-standing diabetes and includes sensory loss, pain, burning, and autonomic issues
• Retinopathy is a leading cause of blindness in industrialized countries
• Nephropathy can progress to end-stage renal disease
• Ulcers and non-healing wounds are common feet/skin complications

Treatment goals for T2DM

• Improve overall glycemic control
• Reduce peak postprandial glucose excursions
• Minimize risk of microvascular and macrovascular complications
• Individualize targets based on patient factors

Metformin: introduction and status

• First-line pharmacological therapy for T2DM globally
• Widely prescribed due to safety and tolerability
• Prevents progression from impaired glucose tolerance to T2DM

Metformin: mechanism of action

• AMPK activation is central to metformin action
• Increases glucose uptake in skeletal muscle
• Reduces hepatic glucose production
• Effects largely insulin-independent
• Reduces glucose absorption from the gut; may influence gut microbiota

Metformin: effects on glucose tolerance and absorption

• Improves glucose tolerance without requiring increased insulin levels
• Anti-hyperglycemic effects involve liver, muscle, and gut pathways
• Gut absorption reduction contributes to lower postprandial glucose

Metformin: long-term outcomes and legacy effect

• 10-year follow-up of intensive glucose control shows long-term benefits beyond the trial period
• Early intensive therapy is associated with improved long-term outcomes in type 2 diabetes

Metformin: summary of action

• Increases glucose uptake in skeletal muscle $- ext{enhances peripheral glucose disposal}$
• Reduces hepatic glucose production $- ext{lower hepatic gluconeogenesis}$
• Independent of insulin action, via AMPK activation
• Reduces gut glucose absorption and may modulate gut microbiota

GLP-1 receptor agonists

• Exenatide, Liraglutide, and other long-acting GLP-1 receptor agonists (e.g., Ozempic/semaglutide)
• Exenatide is a synthetic version of exendin-4 from Gila monster saliva; longer half-life than native GLP-1
• Enhance glucose-dependent insulin secretion; improve glycemic control with weight loss
• Often used as add-on therapy to metformin, sulfonylureas, thiazolidinediones, or combinations

Exenatide: pharmacology and use

• Mechanism: GLP-1 receptor agonist; increases insulin release in a glucose-dependent manner
• Quick onset of insulin effects (roughly within minutes to hours), insulin levels fall after peak
• Adjunct therapy for glycemic control in type 2 diabetes

Exenatide: effects on glycemic control and weight (30 weeks study)

• Glycemic control improved over 30 weeks when added to metformin
• Weight loss observed in a dose-dependent manner
• Adverse events common with GLP-1 RAs include nausea and vomiting; incidence higher with active treatment than placebo
• Dose-related adverse events and tolerability data:
  • Nausea: Placebo $23\%$, Exenatide 5 μg $36\%$, Exenatide 10 μg $45\%$
  • Diarrhea: Placebo $8\%$, Exenatide 5 μg $12\%$, Exenatide 10 μg $16\%$
  • Other adverse events occurred with varying frequency; overall tolerability acceptable for many patients
• Weight change data (illustrative):
  • Placebo: $-0.3 \text{ kg}$
  • Exenatide 5 μg: $-1.6 \text{ kg}$
  • Exenatide 10 μg: $-2.8 \text{ kg}$

GLP-1 receptor agonists: Ozempic (semaglutide)

• Semaglutide is a long-acting GLP-1 receptor agonist with decreased renal clearance and increased half-life relative to native GLP-1
• Used for glycemic control and has notable weight loss benefits

Learning objectives (summary of key takeaways)

• Describe clinical goals of type 2 diabetes therapies
• Understand metformin’s effects on glycemic control and its proposed mechanisms of action
• Describe effects of new-generation GLP-1 receptor agonists on glycemic control and weight
• Recognize the long-term impact of early intensive glycemic control (legacy effects) from major trials