ECHO-Diabetes July 21, 2016 Veronica Brady, PhD, FNP-BC, BC-ADM, CDE - PowerPoint Presentation

ECHO-Diabetes July 21, 2016 Veronica Brady, PhD, FNP-BC, BC-ADM, CDE Oral Agents— Old & New for the Management of T2DM

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Overview of DiabetesOral hypoglycemic agentsDefine various classes of medicationsDescribe mechanisms of action Define indications/contraindications for useQ & AObjectives

CDC.gov/diabetes, 201429.1 million in US ( 9.3% of population) Nearly 1/3 (27.8%) unaware that they have diabetes7th leading cause of death in the US in 2010More than 234,051 death certificates list diabetes as underlying cause in 2010Cost of care $245 billion—2.3 x higher medical expenditures for people with DM Increasing prevalence in children and adults Diabetes – The Facts

As many as 1 in 3 US adults could have diabetes by 2050 CDC.gov/diabetes

Formerly Non-insulin Dependant Diabetes (NIDDM)Heterogeneous disorder Variable plasma insulin levels-low or highPeripheral insulin resistanceAssociated with increased CV risk Type 2 DM

Diagram used in talk in 2008 Pathophysiologic Defects in T2DM

DeFronzo,R . 2009 Diabetes Intestine Kidney Liver Muscle Brain Pancreas Adipose Tissue Pathophysiologic Defects in T2DM

Kendall. GLP-1 based therapies, Medscape. Accessed 9-7-14

Evans, J.L & Rushakoff, R.J, 2010, Endotext.org Targets for Therapy in Diabetes

Medication Class Route Year HbA1c % reduced   The OLD     Sulfonylurea PO 1946 1.5 Alpha-glucosidase inhibitor PO 1995 0.5-0.8 Biguanide PO 1995 1.5 Meglitinides PO 1997 1-1.5 Thiazolidinedione PO 1999 0.8-1.0   The NEW     DPP-4 inhibitors PO 2006 0.5-0.8 Bile acid sequestrin PO 2008 0.5 with metformin Dopamine agonist PO 2009 0.5-0.9   The NOVEL     SGLT2 inhibitor PO 2013 0.91-1.16

OraL HYPOGLYEMIC AGENTS (oha)

Increases insulin secretion in people with capacity to produce insulin, may also decrease the rate of hepatic glucose production, and increase insulin receptor sensitivity and increase the number of insulin receptors   Sulfonylureas

Lowers HbA1c   1.5%Main Benefits   Can be used as monotherapy or in combination with other oral agents (with the exception of glinides ) or with insulin   Common adverse effects   Hypoglycemia, weight gain Cautious Use   Impaired renal and hepatic function, adrenal or pituitary insufficiency, elderly, malnourished   Contraindications   Ketoacidosis Sulfonylureas

Considerations:Lead to progressive decline in β-cell functionNo protective effect against atherosclerotic cardiovascular complicationsWithin 3 years most patients require 2nd anti-diabetic medicationDefronzo , 2009. DiabetesSulfonylureas

Name Dose Available mg Usual Start Dose mg Max Dose mg Glimepiride (Amaryl) 1, 2, 4 1–2 qd Max Dose: 8 Glipizide (Glucotrol) 5, 10 5 qd Max Dose: 20 qd Glipizide ext-rel (Glucotrol XL) 5, 10 5 qd Max Dose: 20 qd Glyburide (Diabeta) 1.25, 2.5, 5 2.5 – 5; 1.25 for elderly Max Dose: 20 qd Glyburide (Glynase Pres Tab) 1.5, 3, 6 2.5 – 5; 1.25 for elderly Max Dose: 20 qd Sulfonylureas

Inhibits enzyme that facilitates breakdown of complex sugars to glucose in the small intestine, causes malabsorption of carbohydrates Alpha-Glucosidase Inhibitors

Lowers HbA1c   0.5-0.8%Main Benefits   Improves postprandial blood glucose. Does not cause hypoglycemia or weight gain Common adverse effects   Abdominal pain, diarrhea, elevated serum transaminases, flatulence Cautious Use   Concurrent use with sulfonylureas, If hypoglycemia occurs, treat with oral dextrose not sucrose Contraindications   Hypersensitivity, diabetic ketoacidosis, cirrhosis, inflammatory bowel disease, colonic ulceration, partial intestinal obstruction   Alpha- Glucosidase Inhibitors

Name Dose Available mg Usual Start Dose mg Max Dose mg   Acarbose ( Precose )   25, 50, 100 25 tid Max Dose: Adult: 150/d < 60 kg, 300/d > 60 kg Miglitol (Glyset) 25, 50, 100 25 tid Max Dose: 300 Alpha- Glucosidase Inhibitors

Decreases hepatic glucose production, decreases GI glucose absorption, increase target cell insulin sensitivity, reduces appetite, improves glucose uptake by fat/muscles Biguanides

Lowers HbA1c   1.5% Main Benefits   Decreases blood glucose without causing hypoglycemia or weight gain, low cost Common adverse effects   Nausea, vomiting, diarrhea, flatulence, low serum B12. May cause ovulation in anovulatory and premenopausal PCOS patients   Cautious Use   Malnourished, debilitation, infection-induced stress, fever, trauma, elderly Contraindications   BLACK BOX WARNING: lactic acidosis is rare but potentially severe Do not use /discontinue in unstable , acute CHF if risk of hypoperfusion and hypoxemia, renal dysfunction (creatinine > 1.4 in women, and > 1.5 in men, dehydration, sepsis, surgery, tests involving the injection of dye, hepatic disease, excessive or chronic alcohol consumption, hypersensitivity, DKA metabolic acidosis   Biguanides

Name   Dose Available mg  Usual Start Dose mg   Max Dose mg   Metformin (Glucophage)   500, 850, 1000 500 bid or 850 qd Max Dose: 2550 qd ; Contra: renal/hepatic disease Metformin Ext-rel (Glucophage XR, Fortamet 500, 750 500 bid or 850 qd Max dose: 2500; Contra in renal/hepatic disease   Metformin Oral Solution (Riomet) 100/ml 500 bid or 850 qd Max Dose: 2550 qd ; Contra in renal/hepatic disease Biguanides

Considerations:May be safe for use in patients with slightly elevated Cr—if it has been stable (1.4-1.7mg/dL), patient does not drink alcohol and dose not have large areas of tissue damageMay be used in patients with IFG/IGTMetformin is not metabolized and most of drug is excreted in the urine (Barieri, et al. 2014. Uptodate) Biguanides

Increases insulin secretion by binding to K+ channels on beta islet cells. Repaglinide is metabolized by the liver enzymes CYP3A4 & CYP2C8. Nateglinide is metabolized by hepatic cytochrome P450 CYP2Cp (70%) and CYP34A (30%)   Meglitinides

Lowers HbA1c   1-1.5%Main Benefits   Increases insulin levels for a short period of time compared to sulfonylurea agents. Meglitinides have a lower risk of hypoglycemia compared to sulfonylureas. Good for those who skip meals .   Common adverse effects   Hypoglycemia (less risk compared to sulfonylureas) Cautious Use   Renal insufficiency, liver disease, use with insulin, adrenal insufficiency, surgery, trauma, elderly, pituitary insufficiency, malnourished   Contraindications   Ketoacidosis, allergy to medication, Type 1 diabetes, used with gemfibrozil results in increased repaglinide plasma concentrations 8-fold and may result in severe hypoglycemia   Meglitinides

Name   Dose Available mg  Usual Start Dose mg   Max Dose mg   Nateglinide ( Starlix ) 60, 120 120 tid ; Max Dose: 360 qd ; Can start at 60 tid if A1c near target Caution: hepatic/renal impairment   Repaglinide (Prandin) 0.5, 1, 2 0.5 ac if A1c < 8 Max Dose: 16 qd ; Caution :hepatic impairment Meglinitides

Improves target cell response to insulin, Increases glucose uptake by muscle and fat and decreases hepatic gluconeogenesis. Metabolized to active metabolites by hepatic CYP2C8 & CYP34A  Thiazolidinediones

Lowers HbA1c   0.8-1% Main Benefits   Improves blood glucose control without hypoglycemia Common adverse effects   Bladder cancer risk (not significant) , increased risk of fracture in females, may causes ovulation in females in some premenopausal anovulatory women, weight gain, edema   Cautious Use   If ALT increases to 3 x UNL, stop treatment, if 1.5-3 x ULN retest weekly until normal or until 3 x UNL and need to discontinue, dyspnea, rapid weight gain, combination with used with insulin or other oral diabetes agents   Contraindications   BLACK BOX WARNING: Active bladder cancer. Do not use if NYHA class III or IV heart failure, diabetic ketoacidosis, hypersensitivity, type 1 diabetes, moderate-severe hepatic impairment (ALT > 2.5 UNL)   Thiazolidinediones

Name   Dose Available mg  Usual Start Dose mg   Max Dose mg   Pioglitizone (Actos) 15, 30, 45 15 or 30 qd Max Dose: 45 qd ; Contra in Class III or IV HF   Rosiglitizone (Avandia) 2, 4, 8 4 qd or 2 bid Max dose: 8 qd Thiazolidinediones

Increases and prolongs incretin hormone activity that is inactivated by DPP-4 activity; metabolism limited, primarily by CYP3A4Reduces fasting and post prandial glucose concentrations by increasing insulin release and decreasing glucagon concentration. Dipeptidyl peptidase 4 inhibitor

Lowers HbA1c   0.5-0.8%Main Benefits   Improves blood glucose control without risk of hypoglycemia or weight gain, can be use with SU, Biguanides, TZDs, & insulin Common adverse effects   Few, comparable to placebo, abdominal pain, diarrhea, nasopharyngitis , nausea headache, URI ( sciatic nerve pain) Cautious Use   Renal impairment, acute pancreatitis, use with insulin or sulfonylureas Contraindications   Type 1 diabetes, diabetic ketoacidosis; do not use with GLP-1 analog Dipeptidyl peptidase 4 inhibitor

Name Dose Available mg Usual Start Dose mg Max Dose mg   Sitagliptin Phosphate (Januvia)   25, 50, 100 100 qd Max Dose 100; Cr Cl 30-50: 50 qd , Cr Cl < 30: 25 qd Saxagliptin (Onglyza)   2.5, 5 2.5-5 qd Reduce to 2.5 if CrCl < 50 5 Linagliptin ( Tradjenta ) 5 5 1 dose for all. No adjustments for renal failure Alogliptin ( Nesina ) 6.25, 12.5, 25 25 25 CrCl 30-59; 12.5 CrCl <30:6.25 Dipeptidyl peptidase 4 inhibitor

Binds with bile acids in the intestine thereby impeding their reabsorption. As the bile acid pool is depleted, the hepatic enzyme, cholesterol 7-alpha-hydroxylase is upregulated , which increases the conversion of cholesterol to bile acids. The mechanism of action for reducing blood glucose is unknown.   Bile Acid Sequestrant

Lowers HbA1c   0.5-0.6%  Main Benefits   Lowers both HbA1c and LDL Common adverse effects   Constipation, dyspepsia, nausea, dysphagia Cautious Use   Biliary obstruction, breast-feeding, children, cholelithiasis , coagulopathy, constipation, dysphagia, gastroparesis , hemorrhoids, ileus, phenylketonuria, pregnancy, surgery, vitamin K deficiency   Contraindications   Ketoacidosis, GI obstruction, hypertriglyceridemia, pancreatitis Bile Acid Sequestrant

Name Dose Available mg Usual Start Dose Max Dose Colesevelam (Welchol) 625 3 tab bid, or 6 tab qd Max Dose: 7 tab/day Bile Acid Sequestrant

Synthetic dopamine agonist. The mechanism of action is not understood but thought that stimulating dopamine receptors in the brain at certain times of the day “resets” the biological clock and improves metabolism. Dopamine Agonist

Lowers HbA1c   0.3-0.5% Main Benefits   Postprandial glucose concentrations were improved without increasing plasma insulin concentrations   Common adverse effects   GI upset, fatigue, dizziness, headache, hypotension, syncope, somnolence, hypoglycemia Cautious Use   Abrupt discontinuation, acute MI, angina, bipolar disorder, cardiac arrhythmias, cardiac disease, children coronary artery disease, dementia, depression, driving or operating machinery, geriatric, GI bleed, hepatic disease, hypotension, peptic ulcer disease, peripheral vascular disease, pregnancy, pulmonary fibrosis, renal disease, renal impairment, retroperitoneal fibrosis, schizophrenia, surgery   Contraindications   Ketoacidosis, type 1 diabetes, basilar/hemiplegic migraine, breast-feeding, eclampsia, ergot alkaloid hypersensitivity, hypertension, preeclampsia   Dopamine Agonist

Name Dose Available mg Usual Start Dose mg Max Dose mg Bromocriptine (Cycloset) 0.8 0.8 qd in the morning within 2 hours of waking, increase the dose by 0.8/d no more frequently than every 1 week Max Dose: 1.6-4.8 qd Dopamine Agonist

Blocks the reabsorption of glucose by the kidneys which results in increased glucose excretion and lower blood glucose concentrations in patients with type 2 diabetes   Sodium-Glucose Co-Transporter 2 (SGLT2)

Lowers HbA1c   0.8% with the 100 dose 1.03% with the 300 dose   Main Benefits   Weight loss, low risk of hypoglycemia Common adverse effects   Female genital mycotic infections, urinary tract infection, increased urination (bone fractures 6% @ 104 weeks) Cautious Use   Adrenal insufficiency, balanitis , breast-feeding, children, dehydration, diabetic ketoacidosis, fever, geriatric, hepatic disease, hypercholesterolemia, hypercortisolism , hyperglycemia, hyperkalemia, hyperthyroidism, hypoglycemia, vaginitis, renal impairment, pregnancy, pituitary insufficiency, neonates, malnutrition, infants   Contraindications   Ketoacidosis, dialysis, renal failure , type 1 diabetes Sodium-Glucose Co-Transporter 2 (SGLT2 )

Name Dose Available mg Usual Start Dose mg Max Dose mg Canaglidlozin ( Invokana ) 100, 300 100 qd taken before 1 st meal of the day Max Dose: 300 qd Dapagliflozin ( Farxiga ) 5,10 5 10 Do not use if CrCl <60 Empagliflozin ( Jardiance ) 10,25 10 25 Sodium-Glucose Co-Transporter 2 (SGLT2)

Name   Dose Available mg Usual Start Dose mg Max Dose Glipizide + metformin (Metaglip) 2.5/250; 2.5/500; 5/500 2.5/250 qd If BG 280-320 mg /dL start 2.5/500 bid   Max Dose: 20/2000 Glyburide + metformin (Glucovance)   1.25/250; 2.5/500; 5/500   1.25/250 qd or bid Max Dose: 20/2500 Linagliptin + metformin (Jentadueto) 2.5/500; 2.5 850; 2.5/1000 If new to metformin: 2.5/500 bid; previously on metformin: 2.5/current dose of metformin bid   Max Dose: 2.5/1000 bid Combination Oral Agents

Pioglitizone + glimepiride (Duetact )  30/2; 30/4 If on previously start with usual dose. If not, start 30/2 or 30/4 daily   Max dose: 30/4 Pioglitizone + metformin (Actoplus Met)   15/500, 15/850 15/500 qd or bid; 15/850 qd or bid Max Dose: 45/2550 Pioglitizone + metformin XR (Actoplus Met XR)   15/500, 15/ 850 15/500 qd or bid; 15/850 qd or bid Max Dose: 45/2550 Combination Oral Agents

Repaglinide + metformin (PrandiMet )  1/500; 2/500 1/500 with meals Max Dose: 10/2500 Rosiglitizone + glimepiride (Avandaryl)   4/1; 4/2; 4/4 4/1 qd Max Dose: 4 /4 Rosiglitizone + metformin (Avandamet) 1/500; 2/500; 4/500; 2/1000; 4/1000   2/500 qd or bid Max Dose: 8/2000; Conta in Class III or IV HF Combination Oral Agents

Sitagliptin phosphate + metformin (Janumet )  50/500; 50/1000 50/500 bid Max Dose: 100/2000 Sitagliptin phosphate + metformin XR (Janumet XR)   50/500; 50/1000; 100/1000 50/500 bid Max Dose: 100/2000 Sitagliptin + simvastatin (Juvisync) 50/10; 50/20; 50/40; 100/10; 100/20; 100/40 100/40 qd. If already on simvastatin: 100/current simvastatin dose   100/40 Combination Oral Agents

Saxagliptin + metformin XR (Kombiglyze XR)5/500; 5/1000; 2.5/1000 Take daily in the evening Max: 5/2000 Combination Oral Agents

Glycemic targets & BG-lowering therapies must be individualized. Diet, exercise, & education: foundation of any T2DM therapy programUnless contraindicated, metformin = optimal 1st-line drug. After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable; minimize side effects.KEY POINTS (ADA-EASD) Diabetes Care, Diabetologia. 19 April 2012

Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control.All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values.)Comprehensive CV risk reduction - a major focus of therapy. Key Points (cont)

Questions?