oral agents—the old and new in the management of t2dm · echo -diabetes. july 21, 2016. veronica...

ECHO-DiabetesJuly 21, 2016

VERONICA BRADY, PHD, FNP-BC, BC-ADM, CDE

ORAL AGENTS— OLD & NEW FOR THE

MANAGEMENT OF T2DM

Overview of Diabetes Oral hypoglycemic agents Define various classes of medications Describe mechanisms of action Define indications/contraindications for use

Q & A

OBJECTIVES

CDC.gov/diabetes, 2014

29.1 million in US ( 9.3% of population)

Nearly 1/3 (27.8%) unaware that they have diabetes

7th 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

DIABETES – THE FACTS

As many as 1 in 3 US adults could have diabetes by 2050

C DC . g ov / d ia betes

Formerly Non-insulin Dependant Diabetes (NIDDM)

Heterogeneous disorder

Variable plasma insulin levels-low or high

Peripheral insulin resistance

Associated with increased CV risk

TYPE 2 DM

Diagram used in talk in 2008

PATHOPHYSIOLOGIC DEFECTS IN T2DM

DeFronzo,R. 2009 Diabetes

Intestine

Kidney

Liver MuscleBrain

Pancreas AdiposeTissue

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

HbA1c % Medication Class Route Year

reducedThe OLD

Sulfonylurea PO 1946 1.5Alpha-glucosidase inhibitor

PO 1995 0.5-0.8

Biguanide PO 1995 1.5Meglitinides PO 1997 1-1.5Thiazolidinedione PO 1999 0.8-1.0

The NEWDPP-4 inhibitors PO 2006 0.5-0.8Bile acid sequestrin PO 2008 0.5 with metforminDopamine agonist PO 2009 0.5-0.9

The NOVELSGLT2 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 Hypoglycemia, weight gaineffects

Cautious Use Impaired renal and hepatic function, adrenal or pituitary insufficiency, elderly, malnourished

Contraindications Ketoacidosis

SULFONYLUREAS

Considerations: Lead to progressive decline in β-cell function

No protective effect against atherosclerotic cardiovascular complications

Within 3 years most patients require 2nd anti-diabetic medication

Defronzo, 2009. Diabetes

SULFONYLUREAS

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 causehypoglycemia 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


Usual Start Dose Max Dose mgName Dose Available mg 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


Decreases hepatic glucose production, decreasesGI glucose absorption, increase target cell insulinsensitivity,reduces appetite, improves glucoseuptake by fat/muscles

BIGUANIDES

Lowers HbA1c 1.5%

Main Benefits 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

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 Max Dose mgmgUsual Start Dose

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.


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

Usual Start Dose Name Dose Available mg Max Dose mgmg

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


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 CYP3A4

Reduces fasting and post prandial glucose concentrations by increasing insulin release and decreasing glucagon concentration.

DIPEPTIDYL PEPTIDASE 4 INHIBITOR


Main Benefits 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 Renal impairment, acute pancreatitis, use with insulin or sulfonylureas

Contraindications Type 1 diabetes, diabetic ketoacidosis; do not use with GLP-1 analog


Name Dose Available Usual Start Dose mg Max Dose mgmg

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 qdReduce 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 25CrCl 30-59; 12.5CrCl <30:6.25


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


Main Benefits Lowers both HbA1c and LDL


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


Name Dose Available mg Usual Start Dose Max Dose

Colesevelam(Welchol)

625 3 tab bid, or 6 tab qd

Max Dose: 7 tab/day


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


Main Benefits Postprandial glucose concentrations were improved without increasing plasma insulin concentrations


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 Max Dose mgmg

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


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


Name Dose Available mg Usual Start Dose Max Dose mgmg

Canaglidlozin(Invokana)

100, 300 100 qd taken before 1st meal of the day

Max Dose: 300 qd

Dapagliflozin(Farxiga)

5,10 5 10Do not use if CrCl<60

Empagliflozin(Jardiance)

10,25 10 25


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 + 30/2; 30/4 If on previously Max dose: 30/4glimepiride start with usual (Duetact) dose. If not, start

30/2 or 30/4 daily

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


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


Sitagliptin 50/500; 50/1000 50/500 bid Max Dose: phosphate + 100/2000metformin (Janumet)

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


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


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.

KEY POINTS (ADA-EASD)DIABETES CARE, DIABETOLOGIA . 19 APRIL 201 2

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?

oral agents—the old and new in the management of t2dm · echo -diabetes. july 21, 2016. veronica...

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