Antidiabetic and Antilipid
drugs and renal failure
DR 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
Preprandial
glucose
Postprandial
glucose
< 7.0% (individualization)
70-130 mg/dL (3.9-7.2 mmol/l)
< 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)
HDL = high-density lipoprotein; LDL = low-density
lipoprotein; PG = plasma glucose; TG = triglycerides.
ADA. Diabetes Care. 2012;35:S11-63
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
Main Pathophysiological Defects in T2DM
pancreatic
insulin
secretion
incretin
effect
-
gut
carbohydrate
delivery &
absorption
pancreatic
glucagon
secretion
?
HYPERGLYCEMIA
+
hepatic
glucose
production
peripheral
glucose
uptake
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Type 2 Diabetes
High blood glucose
Impaired GI motility
1. Defective beta cell function
•
•
Diminished phase 1 insulin release
Delayed phase 2 insulin release
2. Overproduction of glucagon
1. Tissues less sensitive to insulin
2. 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
Indications
As adjunct to diet and exercise for type II diabetes
MOA
Increase 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
3. ANTI-HYPERGLYCEMIC THERAPY
• Therapeutic options: Insulin
Insulin level
Rapid (Lispro, Aspart, Glulisine)
Short (Regular)
Intermediate (NPH)
Long (Detemir)
Long (Glargine)
0
2
4
6
8
Hours
10 12 14 16
Hours after injection
18
20
22
24
Insulin Dosing
Long-acting
Long-acting &
Short-acting
Normal insulin secretion
70/30
pre-mixed
Insulin Comparison Chart
courses.washington.edu/pharm504/Insulin%20Chart.pdf
Class
Mechanism
Advantages
Disadvantages
Cost
Biguanides
• 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 aglucosidase
• Slows carbohydrate
absorption
• No hypoglycemia
• Gastrointestinal
• Nonsystemic
• Dosing frequency
•  Post-prandial glucose • Modest  A1c
• ?  CVD events
Table 1. Properties of anti-hyperglycemic agents
Mod.
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Class
Mechanism
Advantages
Disadvantages
Cost
DPP-4
inhibitors
• 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
• GI
• Nonsystemic
• Modest  A1c
•  Post-prandial glucose • Dosing frequency
•  CVD events
High
Dopamine-2
agonists
• 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
Insulin
Mechanism
• Activates insulin
receptor
•  peripheral glucose
uptake
Advantages
• Universally
effective
• Unlimited efficacy
•  Microvascular
risk
Table 1. Properties of anti-hyperglycemic agents
Disadvantages
• Hypoglycemia
• Weight gain
• ? Mitogenicity
• Injectable
• Training
requirements
• “Stigma”
Cost
Variable
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of
Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Comorbidities
 Metformin: CVD benefit (UKPDS)
- Coronary Disease
 Avoid hypoglycemia
- Heart Failure
 ? SUs & ischemic preconditioning
- Renal disease
 ? Pioglitazone &  CVD events
- Liver dysfunction
- Hypoglycemia
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
 Metformin: May use unless
- Heart Failure
condition is unstable or severe
 Avoid TZDs
- Renal disease
- Liver dysfunction
- Hypoglycemia
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
 Increased risk of hypoglycemia
- Renal disease
 Metformin & lactic acidosis
- Liver dysfunction
- Hypoglycemia
 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 sequestrants
 HMG-CoA reductase inhibitors
 Fibric acid derivatives
 Niacin
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:


Gastrointestinal reactions:


Headache, blurred vision, dizziness, insomnia
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
Macrolides, erythromycin,
clarithromycin
Amiodarone
Niacin
Effect of Interaction
Increased risk of severe
myopathy or
rhabdomyolysis
Increased risk for
myopathy and for
severe myopathy or
rhabdomyolysis
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 disease
 During
pregnancy and lactation
Bile Acid Sequestrants : Interactions
Drug Interactant
Anticoagulants
Thyroid hormone
Ursodiol
Effect of Interaction
Decreased effect of the
anticoagulant
(cholestyramine)
Loss of efficacy of thyroid; also
hypothyroidism (particularly
with cholestyramine)
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 lowdensity 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
 Reduces
liver
 Lowers
excretion of cholesterol in the feces
the production of triglycerides by the
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