ORAL AGENTS OLD & NEW FOR THE MANAGEMENT OF T2DM

Transcription

1 ORAL AGENTS OLD & NEW FOR THE MANAGEMENT OF T2DM ECHO-Diabetes July 21, 2016 VERONICA BRADY, PHD, FNP-BC, BC-ADM, CDE

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4 OBJECTIVES Overview of Diabetes Oral hypoglycemic agents Define various classes of medications Describe mechanisms of action Define indications/contraindications for use Q & A

5 DIABETES THE FACTS 29.1 million in US ( 9.3% of population) Nearly 1/3 (27.8%) unaware that they have diabetes 7 th leading cause of death in the US in 2010 More than 234,051 death certificates list diabetes as underlying cause in 2010 Cost of care $245 billion 2.3 x higher medical expenditures for people with DM Increasing prevalence in children and adults CDC.gov/diabetes, 2014

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

7 TYPE 2 DM Formerly Non-insulin Dependant Diabetes (NIDDM) Heterogeneous disorder Variable plasma insulin levels-low or high Peripheral insulin resistance Associated with increased CV risk

8 PATHOPHYSIOLOGIC DEFECTS IN T2DM Diagram used in talk in 2008

9 PATHOPHYSIOLOGIC DEFECTS IN T2DM Pancreas Intestine Adipose Tissue Kidney Liver Brain Muscle DeFronzo,R Diabetes

10 Kendall. GLP-1 based therapies, Medscape. Accessed

11 TARGETS FOR THERAPY IN DIABETES Evans, J.L & Rushakoff, R.J, 2010, Endotext.org

12 Medication Class Route Year HbA1c % reduced The OLD Sulfonylurea PO Alpha-glucosidase inhibitor PO Biguanide PO Meglitinides PO Thiazolidinedione PO The NEW DPP-4 inhibitors PO Bile acid sequestrin PO with metformin Dopamine agonist PO The NOVEL SGLT2 inhibitor PO

13 ORAL HYPOGLYEMIC AGENTS (OHA)

14 SULFONYLUREAS 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

15 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 Hypoglycemia, weight gain effects Cautious Use Impaired renal and hepatic function, adrenal or pituitary insufficiency, elderly, malnourished Contraindications Ketoacidosis

16 SULFONYLUREAS Considerations: Lead to progressive decline in β-cell function No protective effect against atherosclerotic cardiovascular complications Within 3 years most patients require 2 nd anti-diabetic medication Defronzo, Diabetes

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

18 ALPHA-GLUCOSIDASE INHIBITORS Inhibits enzyme that facilitates breakdown of complex sugars to glucose in the small intestine, causes malabsorption of carbohydrates

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

20 ALPHA-GLUCOSIDASE INHIBITORS Usual Start Dose Name Dose Available mg mg Max Dose mg Acarbose (Precose) 25, 50, tid Max Dose: Adult: 150/d < 60 kg, 300/d > 60 kg Miglitol (Glyset) 25, 50, tid Max Dose: 300

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

22 BIGUANIDES Lowers HbA1c 1.5% Main Benefits Common adverse effects Cautious Use Contraindications Decreases blood glucose without causing hypoglycemia or weight gain, low cost Nausea, vomiting, diarrhea, flatulence, low serum B12. May cause ovulation in anovulatory and premenopausal PCOS patients Malnourished, debilitation, infection-induced stress, fever, trauma, elderly 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

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

24 BIGUANIDES Considerations: May be safe for use in patients with slightly elevated Cr if it has been stable ( mg/dL), patient does not drink alcohol and dose not have large areas of tissue damage May be used in patients with IFG/IGT Metformin is not metabolized and most of drug is excreted in the urine (Barieri, et al Uptodate)

25 MEGLITINIDES 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%)

26 MEGLITINIDES Lowers HbA1c 1-1.5% Main Benefits Common adverse effects Cautious Use Contraindications 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. Hypoglycemia (less risk compared to sulfonylureas) Renal insufficiency, liver disease, use with insulin, adrenal insufficiency, surgery, trauma, elderly, pituitary insufficiency, malnourished Ketoacidosis, allergy to medication, Type 1 diabetes, used with gemfibrozil results in increased repaglinide plasma concentrations 8-fold and may result in severe hypoglycemia

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

28 THIAZOLIDINEDIONES 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

29 THIAZOLIDINEDIONES Lowers HbA1c 0.8-1% Main Benefits Common adverse effects Cautious Use Contraindications Improves blood glucose control without hypoglycemia Bladder cancer risk (not significant), increased risk of fracture in females, may causes ovulation in females in some premenopausal anovulatory women, weight gain, edema If ALT increases to 3 x UNL, stop treatment, if 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 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)

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

31 DIPEPTIDYL PEPTIDASE 4 INHIBITOR Increases and prolongs incretin hormone activity that is inactivated by DPP-4 activity; metabolism limited, primarily by CYP3A4 Reduces fasting and post prandial glucose concentrations by increasing insulin release and decreasing glucagon concentration.

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

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

34 BILE ACID SEQUESTRANT 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.

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

36 BILE ACID SEQUESTRANT Name Dose Available mg Usual Start Dose Max Dose Colesevelam (Welchol) tab bid, or 6 tab qd Max Dose: 7 tab/day

37 DOPAMINE AGONIST 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.

38 DOPAMINE AGONIST Lowers HbA1c % 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

39 DOPAMINE AGONIST Name Dose Available mg Usual Start Dose Max Dose mg mg Bromocriptine (Cycloset) 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: qd

40 SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) 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

41 SODIUM-GLUCOSE CO-TRANSPORTER 2 (SGLT2) Lowers HbA1c 0.8% with the 100 dose 1.03% with the 300 dose Main Benefits Common adverse effects Cautious Use Contraindications Weight loss, low risk of hypoglycemia Female genital mycotic infections, urinary tract infection, increased urination (bone fractures 104 weeks) 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 Ketoacidosis, dialysis, renal failure, type 1 diabetes

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

43 COMBINATION ORAL AGENTS Name Dose Available mg Usual Start Dose mg Max Dose Glipizide + metformin (Metaglip) 2.5/250; 2.5/500; 5/ /250 qd If BG mg /dl start 2.5/500 bid Max Dose: 20/2000 Glyburide + metformin (Glucovance) 1.25/250; 2.5/500; 5/ /250 qd or bid Max Dose: 20/2500 Linagliptin + metformin (Jentadueto) 2.5/500; ; 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

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

45 COMBINATION ORAL AGENTS Repaglinide + 1/500; 2/500 1/500 with meals Max Dose: metformin 10/2500 (PrandiMet) 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

46 COMBINATION ORAL AGENTS Sitagliptin 50/500; 50/ /500 bid Max Dose: phosphate + 100/2000 metformin (Janumet) Sitagliptin phosphate + metformin XR (Janumet XR) 50/500; 50/1000; 100/ /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

47 COMBINATION ORAL AGENTS Saxagliptin + 5/500; 5/1000; Take daily in the Max: 5/2000 metformin XR 2.5/1000 evening (Kombiglyze XR)

48 KEY POINTS (ADA-EASD) DIABETES CARE, DIABETOLOGIA. 19 APRIL 2012 Glycemic targets & BG-lowering therapies must be individualized. Diet, exercise, & education: foundation of any T2DM therapy program Unless 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.

49 KEY POINTS (CONT) 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.

50 QUESTIONS?