antidiabetic and antilipid drugs and renal failure dr m.mortazavi nephrologist
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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