Objectives. Insulin Resistance. Understanding the Basic Pharmacology of Medications for Type 2 Diabetes

Transcription

1 Understanding the Basic Pharmacology of Medications for Type 2 Diabetes Alan P. Agins, Ph.D. President, PRN Associates, Ltd Continuing Medical Education Tucson, AZ Objectives Describe the pathogenesis and pathophysiology of Type 2 Diabetes Explain the basic and clinical pharmacology of the major classes of drugs used for managing Type 2 diabetes Insulin Resistance & the Metabolic Syndrome Insulin resistance Hyperinsulinemia Impaired glucose tolerance Hypertriglyceridemia Decreased HDL-C Essential hypertension Clinical diabetes Accelerated atherosclerosis Which of the two is responsible for Type 2 Diabetes? Insulin Resistance approx 85% of patients Beta cell dysfucntion approx 15% of patients Insulin Resistance Not an issue of loss of insulin receptors Loss of coupling of insulin-receptor complex to intracellular signalling pathways Graphic credit: Insulin action : alila 123rf.com Inability to activate insulin receptors leads to hyperglycemia and high levels of free fatty acids in circulation... Leading to gluco/lipotoxicity in beta cells Graphic credit Pancreatic islet normal and diabetic : alila 123rf.com Alan P. Agins, Ph.D

2 Normal Glucose Uptake in Peripheral Tissues GLUT 4 transporter Lower amounts of insulin due to beta cell dysfunction result in hyperglycemia and higher FFAs in circulation leading to.... Lipotoxicity and glucotoxicity and further beta cell dysfunction and death Muscle (Elbow joint anatomy) : andegro4ka 123rf.com Fat Cells from white adipose tissue : designua 123rf.com Effect of Insulin on glucose uptake : alila 123rf.com Insulin Resistance & GLUT 4 transporter Normal Insulin Action in Liver GLUT2 is bi-directional depending on concentration gradient Insulin promotes cellular utilization of glucose Concentration gradient is inward Insulin Resistance in Liver Normal Beta Cell Function No signal to turn on cellular glucose utilization or storage Shift in biochemical pathways to glucose production Concentration gradient outward Inward flow (only) of glucose through GLUT2 Initiates series of steps leading to membrane depolarization and insulin release Well coupled to glucose concentration in serum Alan P. Agins, Ph.D

3 Events leading to Beta Cell Dysfunction and Death Targets for Medications Pancreatic islet normal and diabetic : alila 123rf.com Liver (with bile passage) : alila 123rf.com Kidney : oguzaral 123rf.com Digestive system : 3drenderings 123rf.com Row of bottles and pills : Adrian Brockwell 123rf.com Metformin Effects in Liver Metformin Effects in Muscle Decreases normal energy by interfering with mitochondria Increases activity of back up pathway to restore energy AMP Kinase pathway flips cell to utilizing glucose / turns off gluconeogenesis AMP-Kinase pathway also turns on Instrumental in shuttling GLUT4 to membrane surface Upregulates Adiponectin in adipose tissue decreases inflamation also increase glucose uptake for use in making triglycerides (decreases FFAs) Alan P. Agins, Ph.D

4 Metformin Can reduce A1c 1 1.5% Advantages Low risk of hypoglycemia Generally well tolerated Potential positive effect on lipids (LDL, TGs) Can be useful in Pre-diabetes - reduces risk of future diabetes by 25% to 30% May confer 2 o benefits: CV mortality, risk of dementia??? No pharmacokinetic interactions Synergistic with others combination products Low cost Metformin * Metformin and B12 Screening It is clinically plausible to screen for vitamin B12 deficiency prior to initiation of metformin And annually (especially among elderly patients or other high risk patients) Use of metformin ( 3-4 years) Use of high doses of metformin ( 2 g/day) Clinically worsening diabetic distal polyneuropathy in the presence or absence of hematological abnormalities Concentrations <200 pg/ml are usually diagnostic of vitamin B12 deficiency while concentrations 400 pg/ml confirm absence of vitamin B12 deficiency New FDA Recommendations for use of Metformin in Renal Impairment (April 2016) J Diabetes Metab Disord. 2013; 12: 17. Thiazolidinediones (TZDs or Glitazones) pioglitazone Thiazolidinediones (TZDs or Glitazones) Agonists of PPAR gamma receptors Decrease circulating free fatty acids (FFAs) Increase glucose / lipid utilization within peripheral tissues. Enhance glucose uptake (w insulin) Suppress hepatic glucose production Adiponectin FFA FFA FFA TGs Decreased Lipotoxicity to other tissues Low risk of hypoglycemia Prevents future development of diabetes in 60% to 75% of pre-diabetic subjects Slight increase in HDLs May decrease triglycerides Convenient dosing Generally well tolerated Alan P. Agins, Ph.D

5 Thiazolidinediones (TZDs or Glitazones) Higher risk of heart failure Weight gain (5 to 10 pounds) Fluid retention, edema Bone fractures in females Increase in bad (LDL) cholesterol Slower onset of action (weeks months) Increased risk of bladder cancer?? Block K + channel increase depolariztion and insulin secretion Sulfonylureas Powerful / Long acting A1c ~ 1.5% Benefits on both FG and PPG May cause less wt gain than TZDs or insulin Inexpensive Sulfonylureas Hypoglycemia Weight gain May not work in 10% of patients May stop working over time P450 Drug Interactions Potential for hypersensitivity (low) Sulfonylureas Potential drug interactions Cleared via CYP2C9 Inhibitors include cotrimoxizole, metronidazole, fluconazole and other azole antifungals Also highly protein bound (Albumen) Caution with warfarin, phenytoin, valproate, lamotrigine, gemfibrozil. NSAIDs (higher doses) Rapid onset short half-life Same action as sulfonylureas Weaker binding affinity + faster dissociation from receptor = shorter duration of activity Alan P. Agins, Ph.D

6 Meglitinides Repaglinide Interactions Potential for weight gain Frequent dosing / prn w meals More expensive than sulfonylureas Potential for hypoglcemia (< sulfonylureas) Cytochrome P450 interactions Pancreatic islet normal and diabetic : alila 123rf.com Alan P. Agins, Ph.D

7 Comparison of short-acting versus long-acting GLP-1 receptor agonists lixisenatide (Adlyxin) 0.8%-1.2% Once DAILY Meier, J. J. (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus Nat. Rev. Endocrinol. doi: /nrendo GLP-1 agonists Lower A1c 1 1.5% Significantly improve PPG levels May be effective in preventing diabetes and restoring normoglycemia in pre-diabetics Low incidence of hypoglycemia No weight gain / may cause weight loss Direct benefits to other organs beyond benefit on glycemic control GLP-1 receptors found in many tissues including endothilium, myocardium, brain, muscle, adipose GLP-1 agonists In addition to effects on beta cells: Increase insulin sensitivity in both skeletal muscle & adipose tissue, with substantial improvement of insulin-mediated glucose uptake Also promote increased glucose uptake in target tissues via insulin-independent mechanisms (activates AMP Kinase pathway- as do metformin ond exercise) GLP-1 agonists Injection only Expensive!! Nausea, vomiting common Potential for profound hypoglycemia with insulin or oral secretagogue Possibility of Pancreatitis (rare but serious) Possibility of Thyroid C-cell tumors (boxed-warning) Alan P. Agins, Ph.D

8 Gliptins Orally available No weight gain Little risk of hypoglycemia Few drug interactions Generally well tolerated Available in combinations with metformin and pioglitazone Gliptins Weaker than most - A1C reductions ~0.7% Dizziness, headache, nasopharyngitis Expensive No weight loss (like GLP-1 agonists) Patients with renal insufficiencyrequire dosage adjustments (except Linagliptin) Potential for pancreatitis (rare but serious) Increased risk of heart failure???? SGLT2 inhibitors Block glucose reabsorption in proximal tubule = increased glucose elimination = decreased hyperglycemia SGLT2 Inhibitors Lower both fasting and post-prandial Do not produce hypoglycemia (as monotherapy) Can lower SBP (3 to 5 mm Hg) Weight loss (robust in some) Available in rational fixed-dose combinations with metfomin and linagliptin Generally well tolerated SGLT2 Inhibitors A1c reduction <1% (less than most classes) Vaginal yeast infection (7 10%) Balantitis (~ 5%) Urinary tract infections Increased risk of hypotension Increased risk of renal impairment Slight elevation in LDL cholesterol Expensive Alan P. Agins, Ph.D

9 SGLT2 inhibitors & Diabetic Ketoacidosis (DKA) AACE Recommendations w SGLT2 inhibitors AVOID: Excessive alcohol intake Low carbohydrate diet Ketogenic diet Statins Link to diabetes? JUPITER - 1st placebo-controlled clinical trial to formally document increased risk of diabetes in statin patients Statistically significant 27% relative increase in risk in pts treated with rosuvastatin Sub-group analysis - 48% increased risk of diabetes among women Analysis of PROVE-IT, A to Z, TNT, IDEAL, and SEARCH showed that high-dose statin therapy increased the risk of diabetes by 12% Statin treatment increased the risk of type 2 diabetes by 46%, attributable to decreases in insulin sensitivity and insulin secretion Statins and Diabetes Risk CoQ10, Mitochondria and Diabetes Pancreatic Beta Cell Type 2 Diabetes Questions? 25 Million diabetics Estimated million pre-diabetics More than likely that mitochondrial damage is occuring during prediabetic phase leading to further gluco- and lipotoxicity Thanks for listening Alan Alan P. Agins, Ph.D