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Oral Hypoglycemic Agents in T2DM

Oral Hypoglycemic Agents in T2DM. MALBOOSBAF, Ramin. MD. 17 JAN 2018. Overview of the pathogenesis of T2DM. Insulin secretory dysfunction Insulin resistance (muscle, fat, liver) Increased endogenous glucose production Decreased incretin effect Reduced renal glucose excretion

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Oral Hypoglycemic Agents in T2DM

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  1. Oral Hypoglycemic Agents in T2DM MALBOOSBAF, Ramin. MD. 17 JAN 2018

  2. Overview of the pathogenesis of T2DM • Insulin secretory dysfunction • Insulin resistance (muscle, fat, liver) • Increased endogenous glucose production • Decreased incretin effect • Reduced renal glucose excretion • Deranged adipocyte biology

  3. Multiple, Complex Pathophysiological Abnormalities in T2DM incretin effect pancreatic insulin secretion pancreatic glucagon secretion ? _ gut carbohydrate delivery & absorption HYPERGLYCEMIA _ + peripheral glucose uptake renal glucose excretion hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

  4. Multiple, Complex Pathophysiological Abnormalities in T2DM GLP-1R agonists Insulin incretin effect pancreatic insulin secretion Glinides S U s DPP-4 inhibitors pancreatic glucagon secretion Amylin mimetics ? _ DA agonists gut carbohydrate delivery & absorption A G I s HYPERGLYCEMIA T Z D s _ Metformin Bile acid sequestrants + peripheral glucose uptake renal glucose excretion hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

  5. Glycemic Control and Diabetes Complications • Diabetic patients are at high risk for cardiovascular events. • Simply focusing on glycemic control will nothave a major impact to reduce cardiovascular risk. • We favor a therapeutic approach • on weight, • blood pressure, • lipids, • cardiovascular protection, • and side effect profile, especially hypoglycemia

  6. Antihyperglycemic Therapy in Adults with T2DM Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

  7. Antihyperglycemic Therapy in Adults with T2DM Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes - 2018. Diabetes Care 2018; 41 (Suppl. 1): S73-S85

  8. ADA 2018 • Metformin monotherapy should be started at diagnosis of type 2 diabetes unless there are contraindications. • Metformin is effective, safe and inexpensive, and may reduce risk of cardiovascular events and death .

  9. MECHANISMS OF ACTION • Decrease hepatic glucose output ( inhibiting gluconeogenesis) • Increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver) • Antilipolyticeffect that lowers serum free fatty acid concentrations, thereby reducing substrate availability for gluconeogenesis • Decrease food intake and body weight

  10. Expected HbA1c reduction according to intervention Nathan DM, et al. Diabetes Care 2009;32:193-203.

  11. WEIGHT LOSS &lipid-lowering activity • In those who are obese, metformin promotes modest weight reduction or at least weight stabilization • ↓Triglyceride and free fatty acid concentrations • ↓LDL (a small ) • ↑HDL (very modest )

  12. The Diabetes Prevention Program Research Group

  13. Effectiveness safety profiles Side effects Cost Patient satisfaction Extraglycemic effect

  14. Cardiovascular benefits ?!

  15. Average Dose 2000 mg/day Vascular Protection After Chronic Exposure UKPDS: Global Clinical Outcomes in Overweight Patients 60% at 16 y Conventional Diet 60 Any diabetes-related endpoint 21 fatal/non-fatal complications Insulin or Sulphonylureas Metformin Met v Diet p=0.0023 40 Proportion of Patients with Events Met v SUs or Insulinp=0.0034 20 15% at 6 y 0 0 6 9 12 16 3 Time from Randomisation (years) UKPDS Group. Lancet 1998; 352: 854-865

  16. UKPDS: Clinical Outcomes* for Metformin Stroke Heart Attack Diabetes Deaths  39% Reduction  41% Reduction  42% Reduction * vs conventional therapy UKPDS 34. Lancet 1998; 352:854–65

  17. Diabetes Related Deaths All Cause Mortality 15 25 12 20 9 15 Incidence (Deaths per 1000 Patient Years) Incidence (Deaths per 1000 Patient Years) 6 10 3 0 5 UKPDS : Improved Survival outcomes with metformin p=0.017 p=0.011 NS NS p=0.021 42% Reduction 36% Reduction Lifestyle Insulin Metformin Lifestyle Insulin Metformin UKPDS Group. Lancet 1998; 352: 854-865

  18. 1997 2002 2007 Clinic Questionnaire 2118 SU/Insulin 1010 SU/Insulin Clinic Questionnaire 880 Lifestyle 379 Lifestyle Questionnaire Clinic 279 Metformin 136 Metformin Holman RR et al. NEJM 2008; 359:1577–89

  19. -30% -27% -33% CV Complications reduced and Survivalincrease maintained Lessons from UKPDS:Legacy Effect of Earlier Metformin Therapy UKPDS Trial Intervention 1977–1997 POST-Trial Monitoring 1997–2007 Diabetes-related deaths -42% All –Cause Mortality -36% Myocardial Infarction -39% CV Complications reduced and Survivalincreased versus othertherapies UKPDS 34. Lancet 1998; 352:854–65 UKPDS 80. NEJM 2008; 359:1577–89

  20. CANCER INCIDENCE • Observational studies reduced risk of • All cancers (relative risk [RR] 0.61, 95% CI 0.54-0.70) • Colorectal cancer (RR 0.64, 95% CI 0.54-0.76) • Cancer mortality (RR 0.66, 95% CI 0.49-0.88) • Clinical Trials • Did not defined as outcome • Short duration (< 4 Y)

  21. SIDE EFFECTS • Gastrointestinal: • Metallic taste in the mouth • Mild anorexia • Nausea • Abdominal discomfort, • Soft bowel movements or diarrhea • 5% of study subjects discontinuemetformin because of the gastrointestinal side effects

  22. Vitamin B12 deficiency • Reduces intestinal absorption of vitamin B12 in up to 30 % of patients • Lowers serum vitamin B12concentrations in 5-10 % • Peripheral neuropathy may precede the development of megaloblastic anemia. • Only rarelycauses megaloblasticanemia • Periodic testing of vitamin B12 levels should be considered in metformin-treated patients, especially in those with anemia or peripheral neuropathy

  23. Lactic acidosis • incidence 9 cases per 100,000 person-years of exposure

  24. CONTRAINDICATIONS • eGFR<30 mL/min • Concurrent active or progressive liver disease • Active alcohol abuse • Unstable heart failure

  25. Metformin Dosing • Startwith 500 mg once daily with the evening meal and, if tolerated, add a second 500 mg dose with breakfast. • The dose can be increased slowly (one tablet every 1-2 weeks) as necessary • The usual effective dose is 1500-2000mg/day. • Take with food using a divided dosage schedule.

  26. Monitoring • Serum creatinineannually • Check Hb, HCT, and red cell indices • at diagnosis • if symptoms suggestive of • anemia, • neuropathy

  27. Renal failure & OHA • eGFR: • The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is generally preferred (ADA 2017). • eGFR is routinely reported by laboratories with serum Cr, • eGFR calculators are available from http://www.nkdep.nih.gov.

  28. Renal failure & Metformin • Kidney function be assessed using (eGFR) instead of blood creatinine concentration. • Metformin may be safely used in patients with eGFR ≥30 mL/min/1.73 m2.

  29. USE of Metformin based on eGFR

  30. Heart failure & Metformin

  31. Heart failure & Metformin Conclusions: • Metformin is at least as safe as other glucose lowering treatments in patients with diabetes and HF, even in those with reduced LVEF or concomitant CKD. • Metformin should be considered the treatment of choice for those with diabetes and HF.

  32. ADA 2017 • In patients with DM-2 with stable CHF, metformin may be used if eGFR > 30 mL/min, • But should be avoided in unstable or hospitalized patients with CHF.

  33. Insulin Secretagogues • SulfonylUreas • First Generations • Chlorpropamide • Second Generations • Glibenclamide • Gliclazide • Non SulfonylUreas • Repaglinide • Nateglinide

  34. Mechanism of action • (ATP)-sensitive potassium channel (K-ATP channel) in the pancreatic beta cells

  35. Cardiovascular effects • The cardiovascular safety of sulfonylureas is uncertain • Does not appear to be an increased risk of cardiovascular events with second-generationsulfonylureas. • Meta-analysis of 47 trials (of at least one-year duration) comparing second-generation sulfonylureaswith diet, placebo, or an active comparator, were not associated with an increased risk of overall mortality, cardiovascular mortality, MI, or stroke.

  36. Choice of sulfonylurea •  For patients with CVD, we prefer to use glimepiride or gliclazide, which are selective for the over the cardiac receptors

  37. Gliclazide: • Gliclazide seems the most selective with respect to pancreatic receptor stimulation. • Based on evidence from observational studies showing • lower hypoglycemia • Cardiovascular benefits of Gliclazide over other SUs • Proposed explanations for a more favorable cardiovascular safety profile • Haemorheological and fibinolytic properties • A lower incidence of hypoglycemic events • Less weight gain

  38. Antihyperglycemicmedication prescriptions 2002–2013. Clemens KK, et al. PLoSONE. 2015; 10(9): e0137596. doi:10.1371/journal.pone.0137596

  39. Gliclazide:Method of Administration • The total daily dose 40 to 320 mg/d. • If ≥ 160 mg/dare required, tablets should be taken twice daily. Summary of product characteristics; Gliclazide 80 mg

  40. Gliclazide MR • 1 tablet of Gliclazide MR 30 mg is comparable to 1 tablet of Gliclazide 80 mg Tablets. • The recommended starting dose is 30 mg daily; taken orally in a single intake at breakfast time. • The maximum recommended daily dose is 120 mg. • The safety and efficacy in children and adolescents have not been established. • There is no or limited amount of data (less than 300 pregnancy outcomes) from the use of gliclazide in pregnant women. • it is preferable to avoid the use of Gliclazide during pregnancy. • It is unknown whether gliclazide or its metabolites are excreted in human milk. • Given the risk of neonatal hypoglycaemia, the product is therefore contra-indicated in breast-feeding mothers.

  41. Renal failure & Glibenclamide • Glibenclamide (glyburide) is metabolized in the liver and excreted by the kidneys equally and intestine. • Hypoglycemia may be serious and lasting more than 24 h in CKD. • The drug is contraindicated in eGFR < 60 mL/min.

  42. Renal failure & Gliclazide • Gliclazide is metabolized by the liver to inactive metabolites that are eliminated in the urine. • Thus, gliclazide causes less hypoglycemia than other sulfonylureas. • In eGFR > 30 mL/min gliclazide can be used.

  43. MEGLITINIDES • Repaglinide and Nateglinide, • Short-acting glucose-lowering drugs for therapy of patients with type 2 diabetes • They are administered with meals to reduce postprandial hyperglycemia

  44. Renal failure & Repaglinide • Repaglinide is exclusively metabolized in the liver to inactive metabolites and secreted in the bile. • Repaglinide can be used even in CKD stages 4 and 5 without dose reduction. • In patients with a GFR ≤30 ml/min/1.73 m2 starting with a 0.5 mg does before each meal and gradually increasing the dose.

  45. Dosing and monitoring • Starting dose of repaglinide is • Initial therapy 0.5 mg before each meal • Add-on therapy & A1C is ≥8% 1 or 2 mg prior to each meal • The maximum dose is 4 mg before each meal • The dose should be skippedif the meal is missed.

  46. Acarbose • Starting dose • 25-50 mg before each meal • The maximum dose is 100 mg before each meal

  47. Renal failure & Acarbose • Acarbose is contraindicated in liver cirrhosis and IBD (inflammatory bowel disease). • The National Kidney Foundation (NKF) advise avoiding acarbose if the GFR <30 ml/min/1.73 m2.

  48. Thiazolidinediones • Increase insulin sensitivity by acting on adipose, muscle, and liver • As monotherapy, ↓ A1C by approximately 1-1.5% • the cost and side effects of thiazolidinediones make them less appealing as initial therapy

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