Antidiabetic and Antilipid drugs and renal failureDR M.MORTAZAVI

NEPHROLOGIST

Goal

To understand the use and side effects of anti-diabetic medications and be able to educate patients.

Guidelines for Glycemic, BP, & Lipid Control American Diabetes Assoc. Goals

HbA1C < 7.0% (individualization)

Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l)

Postprandial glucose < 180 mg/dL

Blood pressure < 130/80 mmHg

Lipids

LDL: < 100 mg/dL (2.59 mmol/l) < 70 mg/dL (1.81 mmol/l) (with overt CVD)HDL: > 40 mg/dL (1.04 mmol/l) > 50 mg/dL (1.30 mmol/l)TG: < 150 mg/dL (1.69 mmol/l)

ADA. Diabetes Care. 2012;35:S11-63HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.

Nine to Know

Brand & Generic Name Mechanism of action Therapeutic effect Relevant pharmacokinetics and pharmacodynamics Dosing by route Adverse reactions and contraindications Monitoring parameters Drug-drug and drug food interactions Comparisons between agents w/in the same class

of drugs

+

-

-

peripheralglucose uptake

hepatic glucose production

pancreatic insulinsecretion

pancreatic glucagonsecretion

Main Pathophysiological Defects in T2DM

gutcarbohydratedelivery &absorption

incretineffect

HYPERGLYCEMIA

?

Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Type 2 Diabetes

High blood glucose

1. Defective beta cell function• Diminished phase 1 insulin release• Delayed phase 2 insulin release2. Overproduction of glucagon

Impaired GI motility

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

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

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

3. ANTI-HYPERGLYCEMIC THERAPY

• Therapeutic options: Oral agents & non-insulin injectables

- Metformin

- Sulfonylureas

- Thiazolidinediones

- Meglitinides

- a-glucosidase inhibitors

- Bile acid sequestrants

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

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 

Biguanides (cont)

Patient Info

Upset stomach/dyspepsia – take with food

Metallic taste

Minimal Weight Loss

Alcohol may increase likelihood of lactic acidosis

Does not cause hypoglycemia

Biguanides (cont)

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 Reactions Black Box Lactic Acidosis: D/C immediately and

notify practitioner if: myalgia, malaise, hyperventilation, unusual somnolence.

Alcohol potentiates this reaction

Biguanides (cont)

CONTRAINDICATIONS Renal 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 septicemia Metabolic acidosis (including diabetic

ketoacidosis (DKA)) Heart failure requiring pharmacologic

therapy; active liver failure

Sulfonylureas

Gliclazid 80 mg

Glipizide (Glucotrol, Glucotrol 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 mellitus MOA

Stimulating insulin release from beta-cells of pancreatic islets

Where does it work?

Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE

Sulfonylureas (cont)

Patient Info

Hypoglycemia

GI upset/abdominal pain

Dizziness

Weight gain

Heartburn/epigastric fullness

Onset: glucose lowering effect: 30 minutes with peak at 1.5-3 hours lasting 24 hours

Sulfonylureas (cont)

Special Population Considerations:

Pediatric: safety and efficacy not established for pts under age 16

Hepatic/Renal Dysfunction: conservative dosing and titration recommended.

Caution/Severe Adverse Reactions

Syndrome of Inappropriate Anti-diuretic Hormone (SIADH)

CONTRAINDICATIONS

Diabetes complicated by ketoacidosis

Type I DM

Diabetes w/ pregnancy. Pregnancy Cat: C (except glyburide: B)

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.

Where does it work?

Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE

TZD (cont)

Patient Info Weight gain Edema Hypoglycemia esp. when used with other

antidiabetic medications and insulin (not w/ metformin)

May cause or exacerbate heart failure with risk of fluid retention

Myalgia Headache

TZD (cont)

Cautions/Severe Adverse Reactions Black Box: Heart Failure (for all thiazolidinediones,

mainly due to rosiglitazone) Hepatic failure Anemia Bone loss Ovulation in premenopausal women Pregancy 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

CONTRAINDICATIONS NYHA Class III-IV heart failure Active 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

Indication for insulin therapy:

Where does it work?

Image Obtained From: Diabetes 101: Overview of Drug Therapy by Jennifer Danielson, RPh, CDE Insulin: the Movie from diabetes.org

Insulin (cont)

Administration:

Subcutaneous injection

Rotate site

Check blood sugars regularly

Storage:

Refrigerate until use

Once 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 doses

Adjust according to fasting (premeal) blood glucose of 80-130 mg/dL and peak postprandial blood glucose < 180 mg/dL

Provide 50% as long acting insulin and 50% as prandial insulin

1 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???

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

Long (Detemir)

Rapid (Lispro, Aspart, Glulisine)

Hours

Long (Glargine)

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

Short (Regular)

Hours after injection

Insu

lin le

vel

3. ANTI-HYPERGLYCEMIC THERAPY

•Therapeutic options: Insulin

Intermediate (NPH)

Insulin Dosing

Normal insulin secretion

Long-acting

Long-acting &Short-acting

70/30 pre-mixed

Insulin Comparison Chart

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

Class Mechanism Advantages Disadvantages CostBiguanides • Activates AMP-kinase

• Hepatic glucose production

• Extensive experience• No hypoglycemia• Weight neutral• ? CVD

• Gastrointestinal• Lactic acidosis• B-12 deficiency• Contraindications

Low

SUs / Meglitinides

• Closes KATP channels• Insulin secretion

• Extensive experience• Microvasc. risk

• Hypoglycemia• Weight gain• Low durability• ? Ischemic preconditioning

Low

TZDs • PPAR-g activator• insulin sensitivity

• No hypoglycemia• Durability• TGs, HDL-C • ? CVD (pio)

• Weight gain• Edema / heart failure• Bone fractures• ? MI (rosi)• ? Bladder ca (pio)

High

a-GIs • Inhibits -a glucosidase• Slows carbohydrate absorption

• No hypoglycemia• Nonsystemic• Post-prandial glucose• ? CVD events

• Gastrointestinal• Dosing frequency• Modest A1c

Mod.

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages

Cost

DPP-4inhibitors

• Inhibits DPP-4• Increases GLP-1, GIP

• No hypoglycemia• Well tolerated

• Modest A1c • ? Pancreatitis• Urticaria

High

GLP-1 receptor agonists

• Activates GLP-1 R• Insulin, glucagon• gastric emptying• satiety

• Weight loss• No hypoglycemia• ? Beta cell mass• ? CV protection

• GI• ? Pancreatitis• Medullary ca• Injectable

High

Amylin mimetics

• Activates amylin receptor• glucagon• gastric emptying• satiety

• Weight loss• PPG

• GI• Modest A1c • Injectable• Hypo w/ insulin• Dosing frequency

High

Bile acid sequestrants

• Bind bile acids• Hepatic glucose production

• No hypoglycemia• Nonsystemic• Post-prandial glucose• CVD events

• GI• Modest A1c• Dosing frequency

High

Dopamine-2agonists

• Activates DA receptor• Modulates hypothalamic control of metabolism• insulin sensitivity

• No hypoglyemia• ? CVD events

• Modest A1c• Dizziness/syncope• Nausea• Fatigue

High

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages CostInsulin • Activates insulin

receptor• peripheral glucose uptake

• Universally effective• Unlimited efficacy• Microvascular risk

• Hypoglycemia• Weight gain• ? Mitogenicity• Injectable• Training requirements• “Stigma”

Variable

Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone & CVD events

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Metformin: May use unless condition is unstable or severe

Avoid TZDs

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Increased risk of hypoglycemia Metformin & lactic acidosis

US: stop @SCr ≥ 1.5 (1.4 women)

UK: dose @GFR <45 & stop @GFR <30

Caution with SUs (esp. glyburide)

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia

Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis Insulin best option if disease

severe

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM

4. OTHER CONSIDERATIONS•Comorbidities

-Coronary Disease

-Heart Failure

-Renal disease

-Liver dysfunction

-Hypoglycemia Emerging concerns regarding

association with increased mortality

Proper drug selection in the hypoglycemia prone

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Antilipid Drugs

DR.M.MORTAZAVI

NEPHROLOGIST

Lipoproteins Low-density lipoproteins (LDL):

Elevation of LDL: Atherosclerotic plaque formation Increases the risk for heart disease

High-density lipoproteins (HDL): Take cholesterol from the peripheral cells and transport it to

the liver

Cholesterol Levels

HDL cholesterol: Protects against heart diseases Higher the LDL level: Greater the risk for heart disease Drugs used to treat hyperlipidemia:

Bile acid sequestrantsHMG-CoA reductase inhibitorsFibric acid derivativesNiacin

HMG-CoA Reductase Inhibitors: Actions

Statins**

HMG-CoA reductase:

An enzyme that is a catalyst during the manufacture of cholesterol

Inhibits the manufacture of cholesterol or promotes the breakdown of cholesterol

Lowers the blood levels of cholesterol and serum triglycerides

Increases blood levels of HDLs

HMG-CoA Reductase Inhibitors: Uses

As adjunct to diet in the treatment of hyperlipidemia

For primary prevention of coronary events

MI For secondary prevention of cardiovascular events

TIA/stroke

HMG-CoA Reductase Inhibitors:

Adverse Reactions

Central nervous system reactions: Headache, blurred vision, dizziness, insomnia

Gastrointestinal reactions: Flatulence, abdominal pain, cramping, constipation, nausea

Other: Elevated CPK level, Rhabdomyolysis with possible renal failure

Pharyngitis with use of rosuvastatin/Crestor

HMG-CoA Reductase Inhibitors: Contraindications And Precautions

Contraindicated in patients:

With hypersensitivity to the drugs, serious liver disorders

During pregnancy and lactation Used cautiously in patients with:

History of alcoholism, acute infection, hypotension, trauma, endocrine disorders, visual disturbances, and myopathy

Nursing alert

Pts taking cyclosporine, Asians and those with severe renal insufficiency are at risk for myopathy/rhabdomyolysis when taking rosuvastatin/Crestor

HMG-CoA Reductase Inhibitors: Interactions

Interactant Drug Effect of Interaction

Macrolides, erythromycin, clarithromycin

Increased risk of severe myopathy or rhabdomyolysis

Amiodarone Increased risk for myopathy and for severe myopathy or rhabdomyolysis

Niacin Increased risk for severe myopathy or rhabdomyolysis

Bile Acid Sequestrants: Actions and Use

Bile: Manufactured, secreted by liver

-Stored in the gallbladder, emulsifies fat, lipids

Used to treat: Hyperlipidemia; Pruritus associated with partial biliary obstruction

Bile Acid Sequestrants: Adverse

Reactions Constipation Aggravation of hemorrhoids Abdominal cramps Nausea Increased bleeding tendencies related to vitamin K

malabsorption, and vitamin A and D deficiencies

Bile Acid Sequestrants:

Contraindications And Precautions

Contraindicated in patients :

With known hypersensitivity to the drugs With complete biliary obstruction With liver disease

Used cautiously in patients:

With liver disease, kidney diseaseDuring pregnancy and lactation

Bile Acid Sequestrants : Interactions

Drug Interactant Effect of Interaction Anticoagulants Decreased effect of the

anticoagulant (cholestyramine)

Thyroid hormone Loss of efficacy of thyroid; also hypothyroidism (particularly with cholestyramine)

Ursodiol Reduced absorption of ursodiol (particularly cholestyramine and colestipol)

Fibric Acid Derivatives: Actions

Clofibrate:

Stimulates liver to increase breakdown of very–low-density lipoproteins (VLDLs) to low-density lipoproteins (LDLs); Decreases liver synthesis of VLDLs and inhibites cholesterol formation

Fenofibrate:

Reduces VLDL; Stimulates catabolism of triglyceride-rich lipoproteins; Decreases plasma triglyceride, cholesterol

Fibric Acid Derivatives: Actions (cont’d)

Gemfibrozil:

Increases excretion of cholesterol in the feces

Reduces the production of triglycerides by the liver

Lowers serum lipid levels

Fibric Acid Derivatives: Uses

Clofibrate and gemfibrozil:

Used to treat individuals with very high serum triglyceride levels who are at risk for abdominal pain, pancreatitis

Fenofibrate:

Used as adjunctive treatment for reducing LDL, total cholesterol, triglycerides in patients with hyperlipidemia

Fibric Acid Derivatives

Adverse Reactions:

Nausea, vomiting, GI upset, diarrhea, cholelithiasis or cholecystitis

Contraindicated in patients:

With hypersensitivity to the drugs and those with significant hepatic or renal dysfunction or primary biliary cirrhosis

Used cautiously in patients with:

Peptic ulcer disease, diabetes, during pregnancy and lactation

Miscellaneous Antihyperlipidemic Drugs: Niacin

Action: Lowers blood lipid levels Uses: Adjunctive therapy for lowering very high

serum triglyceride levels in patients who are at risk for pancreatitis

Adverse reactions:Gastrointestinal reactions: Nausea, vomiting,

abdominal pain, diarrhea Other reactions: Severe generalized flushing

of the skin, sensation of warmth,

Miscellaneous Antihyperlipidemic Drugs:

Contraindications And Precautions

Contraindicated in patients:

With known hypersensitivity to niacin, active peptic ulcer, hepatic dysfunction, and arterial bleeding

Used cautiously in patients with:

Renal dysfunction, high alcohol consumption, unstable angina, gout, pregnancy

Thank you