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New Diabetes Medications

Sniffy Insulin and Lizard Spit. New Diabetes Medications. Hilary Suzawa & Anoop Agrawal September 2008. Money! Money! Money!. Diabetic drug market $15 billion today Expected to be $25 billion in 2011 Cost $1500-2000 per year per patient for the new medications. Normal Physiology.

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New Diabetes Medications

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  1. Sniffy Insulin and Lizard Spit New Diabetes Medications Hilary Suzawa & Anoop Agrawal September 2008

  2. Money! Money! Money! • Diabetic drug market $15 billion today • Expected to be $25 billion in 2011 • Cost $1500-2000 per year per patient for the new medications

  3. Normal Physiology • Throughout the day, especially between meals, we rely upon hepatic glucose production to sustain normal glucose levels. • When you eat a meal, an insulin surge occurs in order to deal with the glucose load and deposit it into tissues – known as ‘insulin demand.’ • To keep the incoming glucose load in balance with the endogenous glucose production, the liver needs to be suppressed.

  4. Normal Physiology • It’s more than just insulin – it’s glucagon that suppresses the liver’s production! • Also, an oral glucose load stimulates higher insulin secretion than an equal or higher IV glucose load… • …So, something in the GI tract is stimulating the pancreas to increase serum insulin, suppressing glucagon release

  5. What could it be??? • It’s the other hormones known as the Incretins! • Incretin hormones are peptide hormones secreted by enteroendocrine cells (the L cells) that line the small intestine. • The incretins stimulate the β-cell of the pancreas.

  6. Incretins • Stimulate glucose-dependentinsulin secretion • Increase insulin in response to meals • Lower risk of hypoglycemia • Suppresses inappropriate glucagon secretion by α-cells • Increases β-cell growth and replication, decrease β-cell apoptosis • Slows gastric emptying • May decrease food intake (satiety)

  7. Pathophysiology: hormonal imbalance

  8. Who are the Incretins? • GI secreted –Incretins • Gastric inhibitory peptide (GIP) - aka glucose-dependent insulinotropic peptide • Glucagon-like peptide-1 and -2 (GLP-1, GLP-2) • GLP-1 is normally rapidly inactivated by enzyme dipeptidyl peptidase-IV (DPP-IV) • In DM type II • GIP levels are normal but peptide loses its ability to stimulate insulin secretion (function) • GLP-1 levels are decreased (quantity)

  9. One more hormone: amylin • Produced by the β-cell and is co-secreted with insulin. • Suppresses glucagon secretion • especially postprandial • Decreases postprandial hepatic GLC production • Decreases postprandial GLC levels • Reduces gastric emptying time • Centrally-mediated induction of satiety • In DM type II, amylin secretion is delayed and decreased (quantity)

  10. Amylin & Insulin Secretion from β-cells

  11. Glucose-Regulating Hormones • In total, glucose control is dependent upon a complex interaction of multiple peptides: • Insulin (β-cells) • Glucagon (α-cells) • Incretins: GLP-1 and 2; GIP (L-cells) • Amylin (β-cells)

  12. New Kids on the Block

  13. Exenatide (Byetta): GLP-1 mimic • Approved 6/2004 • Synthetic version of exendin-4 (isolated from the toxic venom of the Gila monster) • Mechanism: Binds to GLP-1 receptor (mimic) • Resistant to DPP-IV and so has increased half-life

  14. Exenatide (Byetta) • Injection (subcutaneous) • Pre-filled pen; 250 mcg/ml • Dose • 5 mcg BID within 60 minutes prior to a meal • After one month may increase to 10 mcg BID • Currently BID but may soon have a weekly formulation (Exenatide LAR)

  15. Exenatide (Byetta) • Most common side effect: Nausea • Benefits • Weight loss • Low risk of hypoglycemia • Animal studies—may help pancreas re-grow cells • Efficacy • When added to sulfonylureas or metformin additional lowering of HbA1c by 0.5-1% • Renal excretion

  16. Gliptins (DPP-IV inhibitor) • (Vildagliptin) Galvus & (Sitagliptin) Januvia • Inhibits the destruction of GLP-1 (DPP-IV inhibitor; dipeptidyl peptidase IV inhibitor) • Raise levels of the hormone GLP-1 • Causes the pancreas to produce more insulin • Not as efficacious as metformin • Use as adjunct instead of sulfonylureas (avoid hypoglycemia and weight gain)

  17. vildagliptin (Galvus) • Dose • 50 mg po daily or 50 mg po BID • Increased GLP-1 and GIP in DM type I and DM type II • Decrease triglycerides • Improved insulin sensitivity • Most common side effect: • Mild hypoglycemia

  18. sitagliptin (Januvia) • Dose • 100 mg po daily or 200 mg po daily • Renal excretion • Is currently available on the market

  19. Flew Under the Radar • pramlintide (Symlin) • amylin mimic • FDA approved 3/2005

  20. pramlintide (Symlin) • Synthetic analog of human amylin • Mechanism: Supresses glucagon • Adjunctive therapy • Decrease insulin dose by 50% when add Symlin • Impact: approximately 1% reduction in A1c • Administration: • subcutaneous injection • cannot be mixed with insulin

  21. pramlintide (Symlin) • Use and dosing: only for patients on insulin • Type I: 15 mcg immediately before meals, increase to target 30-60 mcg • Type II: 60 mcg immediately before meals, increase to target 120 mcg • Side effects • Hypoglycemia (*boxed warning) • Nausea • Headache • Benefits • Weight loss

  22. Inhaled Insulin (Exubera) • FDA approved 1/2006 • Inhaled • Dose • 0.05 mg/kg (round down) TID within 10 minutes of a meal • 1 mg and 3 mg blisters • Three 1 mg blisters gives higher level than one 3 mg blister • Give two 1 mg blisters instead of one 3 mg blister if need to substitute

  23. Inhaled Insulin (Exubera) • Side Effects • Respiratory sx, decreases in PFTs (baseline recommended) • Chest pain • Hypoglycemia • Xerostomia and Rash • Otitis media and ear pain (pediatrics) • If current smoker or quit within past 6 months then increased absorption may lead to increased risk of hypoglycemia • Renal excretion

  24. Key Points • New medications are adjuncts and do not replace insulin or glucophage (Metformin) as mainstays of treatment • Many of the medications are given with meals • exenatide (Byetta) may help with weight loss • sitagliptin (Januvia) is available; vildagliptin (Galvus) not yet on the market • Must decrease insulin dose 50% if add pramlintide (Symlin) because of hypoglycemia • These new therapies may alter the natural history of β-cell decline and hence delay progression of diabetes…these studies are in progress.

  25. Bibliography • Berenson, A. 4 Diabetes Drugs are Seen Raising Hope and Profit. New York Times June 22, 2006. • Cefalu, W. T. Incretin-Based Therapeutics Strategies: A Clinical Perspective. Medscape. • Jeha G and Heptulla R. Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations. Pediatric Diabetes 2006: 7: 122-138. • Trujillo J. Incretin hormones in the treatment of type 2 diabetes. Formulary March 2006: 41: 130-141 • Up to Date • http://www.glucagon.com

  26. The End

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