Antidiabetic Medications

High blood glucose

1. Defective beta cell functionDiminished phase 1 insulin releaseDelayed phase 2 insulin release

2. Overproduction of glucagon

Impaired GI motility

1. Tissues less sensitive to insulin2. Liver produces excess glucose

Type 2 Diabetes

Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE Type 2 Video from diabetes.com

Metformin

Biguanides

Biguanides

Metformin Glucophage 500, 850, 1000 mg tablets

Glucophage XR 500, 750 mg XR tablets

Indication

Type II Diabetes Mellitus, Antipsychotic-induced weight gain

MOA

Decrease hepatic glucose production, decrease intestinal absorption of

glucose and increase insulin sensitivity therefore increasing peripheral

glucose uptake

Depends upon Presence of insulin

Power Decreases HbA1c 1% to 2%

Dosing One to three times daily

Biguanides

Patient InfoN/V/DUpset stomach/dyspepsia – take with foodMetallic tasteMinimal Weight LossAlcohol may increase likelihood of lactic acidosisDoes not cause hypoglycemia

Biguanides

Special Population Considerations:Geriatric: limited data suggests starting doses should be 33% lower for geriatric patients than that of an adult dose. Titration should also to a lower limit.

Cautions/Severe Adverse ReactionsBlack Box Lactic Acidosis: D/C immediately and notify practitioner if: myalgia, malaise, hyperventilation, unusual somnolence. Alcohol potentiates this reaction. Advise patients not to consume excessive amounts of alcohol.

Biguanides

CONTRAINDICATIONSRenal disease or renal dysfunction (Scr > 1.5 mg/dL in males, >1.4 mg/dL in females)Abnormal Scr from any cause including: shock, acute MI, or septicemiaMetabolic acidosis (including diabetic ketoacidosis (DKA))Heart failure requiring pharmacologic therapy; active liver failure

Sulfonylureas

Tolbutamide Acetohexamide

ChlorpropamideTolazamide

Glyburide

Glimepiride

Glipizide

Sulfonylureas

Glimepiride Amaryl 1, 2, 4 mg tablets

Glipizide Diamicrom, Diamicrom XL)

(2.5), 5, 10 mg (XL)

tablets

Glyburide (DiaBeta) 1.25, 2.5, 5 mg tablets

Indications Adjuncts to diet and exercise to lower blood glucose in patients w/ type II diabetes mellitusMOAStimulating insulin release from beta-cells of pancreatic isletsOnset glucose lowering effect: 30 minutes with peak at 1.5-3 hours lasting 24 hours

Sulfonylureas

Sulfonylureas

SU

SU

sulphonylurea receptor

KATP channel

KATP channel closes

membrane depolarisation

calcium entryinsulin secretion

Ca2+

Ca2+

insulin

insulin

insulin

pancreaticbeta cell

SU

Sulphonylureas allow for insulin release at lower glucose threshold

Adverse Effects– Hypoglycemia– Nausea and

vomiting– Cholestatic jaundice– Agranulocytosis– Anemia– Hypersensitivity– Dermatological rxns– Drug interactions– Dizziness– Weight gain

Contraindications– Type I diabetes– Pregnancy/

lactation– Hepatic/renal

failure– Diabetes

complicated by ketoacidosis

Sulfonylureas

Special Population Considerations:Pediatric: safety and efficacy not established for pts under age 16Hepatic/Renal Dysfunction: conservative dosing and titration recommended.

Caution/Severe Adverse ReactionsSyndrome of Inappropriate Anti-diuretic Hormone (SIADH)

Sulfonylureas

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Vildagliptin Galvus 50 mg tablets

Vildagliptin/metformin Galvusmet 50/500, 50/1000 mg

tablets

Sitagliptin (Januvia) 25, 50, 100 mg tablets

Sitagliptin/metformin (Janumet) 50/500, 50/1000 mg

tablets

Saxagliptin (Onglyza) 2.5, 5 mg tablets

Saxagliptin/metformin (Kombiglyze XR)

2.5/1000, 5/500, 5/1000 mg

Tablets

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Indications Diabetes Mellitus Type II  MOA  Inhibits the breakdown of GLP-1 by DPP-4

therefore increasing GLP-1 levels resulting in increased glucose-dependent insulin release and decreased level of circulating glucagon and hepatic glucose production

Patient InfoN/VHypoglycemiaWeight neutralNasopharyngitis/URIHeadacheOnset: Reduction in postprandial serum glucose: 60 minutes

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

Special Population Considerations:Renal Impairment: avoid combo drugs w/ metformin

– For sitagliptin: CrCl 30-50 mL/min : 50 mg daily CrCl < 30 mL/min: 25 mg daily End Stage Renal Disease Requiring dialysis: 25 mg

dailyGeriatric: caution due to age related renal function decreases

Cautions/Severe Adverse ReactionsAcute pancreatitisRash (Stevens-Johnson syndrome)

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

GLP-1 receptor agonist

It is 97% similar to endogenous GLP-1 (7-37). It provides powerful and sustained reductions in A1C

for adults with type 2 diabetes and has direct and indirect effects in multiple organ systems that affect glucose homeostasis

Liraglutide Victoza Once daily Injection

Exenatide Byetta Once daily Injection

GLP-1 receptor agonist

It slows gastric emptying It reduces glucagon secretion, helping to lower hepatic glucose

output from the liver It impacts beta-cell function and improves insulin secretion in

the pancreas Structural modifications increase the stability against DPP-4

and promote plasma protein binding. 13-hour half-life because an amino acid substitution and a fatty

acid attachment make it stable against degradation by DPP-4. suitable for once-daily administration.

Thiazolidinediones (TZD)

Pioglitazone (Actos) 15, 30, 45 mg tablets

Rosiglitazone (Avandia) 2, 4, 8 mg tablets

IndicationsAs adjunct to diet and exercise for type II diabetes MOAIncrease insulin sensitivity by affecting PPAR-γ (peroxisome proliferators-activated receptor) at adipose tissue, skeletal muscle and in the liver.

Special Alert February 2011: Addition of Risk Evaluation and Mitigation Strategy to rosiglitazone. The medication is restricted to those patients already on rosiglitazone for fails pioglitazone or cannot be managed by other oral antidiabetic medications.

TZD (cont)

Patient InfoWeight gainEdemaHypoglycemia esp. when used with other antidiabetic medications and insulin (not w/ metformin)May cause or exacerbate heart failure with risk of fluid retentionURI, sinusitis, pharyngitisMyalgiaHeadache

TZD (cont)

Cautions/Severe Adverse ReactionsBlack Box: Heart Failure (for all thiazolidinediones, mainly due to rosiglitazone)Hepatic failureAnemiaBone lossOvulation in premenopausal womenPregancy Cat: C

TZD (cont)

Special Populations Considerations:Congestive Heart Failure: should be initiated at lowest approved dose with longer intervals between dose increases for NYHA class II. Use is not recommended in patients with NYHA Class III or IV CHF

CONTRAINDICATIONSNYHA Class III-IV heart failureActive liver disease (ALT > 2.5 upper limit of normal)

Insulin

Indications

Type I diabetes mellitus, type II diabetes mellitus, hyperkalemia, DKA/diabetic coma

MOA

Stimulating peripheral glucose uptake and inhibiting hepatic glucose production

Patient Info Hypoglycemia (BG < 70 mg/dL) esp with higher doses

– Anxiety, blurred vision, palpitations, shakiness, slurred speech, sweating

Weight gain

Insulin (cont)

Administration:Subcutaneous injectionRotate siteCheck blood sugars regularly

Storage:Refrigerate until useOnce vial is punctured, it is good for 28 days and can be left at room temperature (except for glargine which is 90 days)

Insulin (cont)

Dosing:Starting daily dose: 0.5-1 unit/kg/day in divided dosesAdjust according to fasting (premeal) blood glucose of 80-130 mg/dL and peak postprandial blood glucose < 180 mg/dLProvide 50% as long acting insulin and 50% as prandial insulin1 unit of can account for 30 grams of carbohydrate (14-50)1 unit can lower 50 mg/dL blood glucose (10-100)

Special Population Consderations:Renal dysfunction

– CrCl 10-50 mL/min: 75% of normal dose– CrCl < 10 ml/min: 25-50% of normal dose; monitor closely

Exercise??? ---- Acute Stress???

Insulin Action

Rapid/immediate

Fast

Intermediate

Slow

0 2 4 6 8 10 12 14 16 18 20 22 24

Blo

od c

once

ntra

tion

Time (hr)

Insulin Dosing

Normal insulin secretion

Long-acting

Long-acting &Short-acting

70/30 pre-mixed

Insulin Administration

Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9

Insulin (cont)

Cautions/Severe Adverse ReactionsSevere hypoglycemia (seizure/coma) (BG < 40 mg/dL)EdemaLipoatrophy or lipohypertropy at injection site

CONTRAINDICATIONSSevere hypoglycemiaAllergy or sensitivity to any ingredient of the product

Insulin Comparison Chart

courses.washington.edu/pharm504/Insulin%20Chart.pdf

Adjunctive Therapy in Diabetes Mellitus Type II

Hypoglycemia– Complication of treatment!– Make sure patients inform the people around them of

these symptoms and what to do!– Symptoms: Anxiety, blurred vision, palpitations,

shakiness, slurred speech, sweating– Treatment: glucose/simple sugars: 3-4 glucose tablets,

½ can of soda (NOT diet!)– Treatment: glucagon injection

Dose: 1 mg IM, IV, SQ; may repeat in 20 minutes if needed

Adjunctive Therapy (cont)

Energy balance, diet, exercise– Low-carb, low-fat, calorie-restricted diet is recommended

Cardiovascular disease/Hypertension– Systolic blood pressure goal < 130 mm Hg– Angiotensin Converting Enzyme II Inhibitor (ACE-I) is first

line Renal protective Angiotensin Receptor Blockers (ARB) can be used if

patient fails or is intolerant to ACE-I

Adjunctive Therapies (cont)

Dislipidemia– Patients with type II diabetes have an LDL goal < 100

mg/dL– Weight loss– First line therapy: statins (i.e. atorvastatin, simvastatin,

rosuvastatin etc.)– Fiber, omega-3 fatty acids (fish oils) can be used as adjunct

therapy

Antiplatelet agents– Consider starting daily low dose aspirin (81 mg) to prevent

ischemic events

Adjunctive Therapies (cont)

Smoking cessation Regular Screening for Cardiovascular Diseases and Coronary

Artery Disease Depression/Stress/Anxiety/Other psychosocial conditions need

to be screen for regularly Diabetic neuropathies especially in extremities need to be

screened for on a regular basis– Fastidious foot care– Regular foot exams (annually)

Eye exams Monitor kidney function