Diabetes Mellitus AnnaGolovko
Introduction <ul><li>Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia resulting fro...
Epidemiology <ul><li>DM affects more than 170 million people worldwide </li></ul><ul><li>By 2010 this number will increase...
Classification of Diabetes Mellitus <ul><li>Type 1Diabetes Mellitus </li></ul><ul><ul><ul><li>Average onset is in childhoo...
Classification of Diabetes Mellitus <ul><li>Type 2 DM </li></ul><ul><ul><ul><li>Usually diagnosed after the age of 30 </li...
Classification of Diabetes Mellitus <ul><li>Secondary Diabetes </li></ul><ul><ul><ul><li>Develops as a result of other dis...
Classification of Diabetes Mellitus <ul><li>Genetic defects </li></ul><ul><ul><ul><li>MODY </li></ul></ul></ul><ul><ul><ul...
Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG) <ul><li>Not diagnostic of DM </li></ul><ul><li>Risk fa...
Pathophysiology of Type 1 DM <ul><li>Immune-mediated destruction of pancreatic  β -cells </li></ul><ul><li>Certain antibod...
Pathophysiology of Type 1 DM <ul><li>Environmental triggers </li></ul><ul><ul><ul><li>Viral infections (mumps, influenza) ...
Pathophysiology of Type 2 DM <ul><li>Multifactorial pathogenesis </li></ul><ul><ul><ul><li>Genetic mutations </li></ul></u...
Pathophysiology of Type 2 DM <ul><li>Genetic predisposition </li></ul><ul><ul><ul><li>Many genes are responsible for causi...
Pathophysiology of Type 2 DM <ul><li>Other Risk Factors for developing type 2 DM </li></ul><ul><ul><ul><li>HTN ( ≥ 140/90 ...
Pathophysiology of Type 2 DM <ul><li>Typical physiological abnormalities in type 2 DM </li></ul><ul><ul><ul><li>Increased ...
Pathophysiology of Type 2 DM <ul><li>Insulin Resistance </li></ul><ul><ul><ul><li>Strongly associated with obesity and phy...
<ul><li>Metabolic syndrome </li></ul><ul><ul><ul><li>A group of related conditions that increase the risk for CVD </li></u...
Symptoms of diabetes and a casual plasma glucose  ≥  200 mg/dl The symptoms of diabetes include polyuria, polydipsia, poly...
Screening for Type 2 DM <ul><li>Criteria for testing for diabetes in asymptomatic adult individuals </li></ul><ul><li>1.  ...
Acanthosis Nigricans   A skin disorder characterized by velvety, light-brown-to-black, markings usually on the neck, under...
Treatment  <ul><li>Desired outcomes: </li></ul><ul><ul><ul><li>Reduce risk for microvascular and macrovascular complicatio...
Specific Desired Endpoints http://guidelines.gov/summary/summary.aspx?doc_id=7212&nbr=004306&string=diabetes <ul><li>Key c...
Non- pharmacological treatment <ul><li>Diet </li></ul><ul><ul><li>Medical nutrition therapy (MNT) is recommended for all p...
Composition of diet <ul><li>Protein </li></ul><ul><ul><ul><li>15%-20% of total calories </li></ul></ul></ul><ul><ul><ul><l...
Composition of diet <ul><li>Carbohydrates </li></ul><ul><ul><ul><li>Total amount of carbohydrates is more important than t...
Composition of diet <ul><li>Fat </li></ul><ul><ul><ul><li><30% of total calories </li></ul></ul></ul><ul><ul><ul><ul><ul><...
Physical Activity <ul><li>Aerobic exercise of 20-60 minutes 3-5 times per week has been shown to improve glucose tolerance...
Pharmacologic Treatment of Type 1 DM <ul><li>The primary therapy for type 1 DM is insulin therapy </li></ul><ul><li>Functi...
 
Pharmacologic Treatment of Type 1 DM <ul><li>Mechanism of action: </li></ul><ul><ul><ul><li>Cells take up glucose only by ...
Pharmacologic Treatment of Type 1 DM <ul><li>Exogenous insulins are categorized according to their strength, onset and dur...
Pharmacologic Treatment of Type 1 DM <ul><li>Pharmacokinetics </li></ul><ul><ul><ul><li>Half-life of IV: 9 minutes </li></...
Types of Insulins http://www.clevelandclinic.org/health/health-info/docs/3300/3376.asp?index=11452 16-20 hrs 30 min.-2½hrs...
Pharmacologic Treatment of Type 1 DM <ul><li>Problems with Insulin </li></ul><ul><ul><ul><li>Lipoatrophy: loss of fat at i...
Pharmacologic Treatment of Type 1 DM <ul><li>Problems with insulin </li></ul><ul><ul><li>Hypoglycemia: </li></ul></ul><ul>...
Pharmacologic Treatment of Type 1 DM <ul><li>Foods that will provide 10g of carbs </li></ul><ul><ul><ul><li>½ cup of orang...
Diabetic Ketoacidosis (DKA) <ul><li>Diabetic ketoacidosis is usually precipitated by a stressful event such as trauma, inf...
Diabetic Ketoacidosis (DKA) <ul><li>Treatment: </li></ul><ul><ul><li>Fluid replenishment with normal saline (2-3L over fir...
Pharmacologic Treatment of Type 2 DM <ul><li>When choosing therapy, the patient’s age, weight, renal and hepatic function ...
Pharmacologic Treatment of Type 2 DM <ul><li>Sulfonylureas  </li></ul><ul><ul><ul><li>Increase insulin production in pancr...
Sulfonylureas <ul><li>First generation </li></ul><ul><ul><ul><li>Acetohexamide (Dymelor), chlorpropamide (Diabinese), tola...
Sulfonylureas <ul><li>Who is a candidate: </li></ul><ul><ul><ul><li>Normal weight type 2 DM patients </li></ul></ul></ul><...
Sulfonylureas <ul><li>Pharmacokinetics </li></ul><ul><ul><ul><li>All SUs are metabolized by the liver </li></ul></ul></ul>...
Sulfonylureas <ul><li>Drug interactions: </li></ul><ul><ul><ul><li>Clofibrate, phenylbutazone, salicylates, sulfonamides  ...
Sulfonylureas <ul><li>Glyburide  </li></ul><ul><ul><ul><li>dose: 1.25-10 mg single or divided doses </li></ul></ul></ul><u...
Sulfonylureas <ul><li>Glipizide </li></ul><ul><ul><ul><li>Dose: 2.5-20 mg QD-BID, max dose= 40mg, 20mg (XL) </li></ul></ul...
Sulfonylureas <ul><li>Glimipiride </li></ul><ul><ul><ul><li>Dose: 1-8 mg/day, max=8mg </li></ul></ul></ul><ul><ul><ul><li>...
Sulfonylureas <ul><li>Acetohexamide (Dymelor) </li></ul><ul><ul><ul><li>Dose: 0.25-1.5g single or divided doses </li></ul>...
Sulfonylureas <ul><li>Chlorpropamide (Diabinese) </li></ul><ul><ul><ul><li>Dose: 0.1-0.5g single dose, max=0.5g </li></ul>...
Sulfonylureas <ul><li>Place in therapy </li></ul><ul><ul><ul><li>Monotherapy for type 2 DM (FBG 140-160mg/dl) </li></ul></...
Meglitinides <ul><li>Non-sulfonylurea insulin secretagogues </li></ul><ul><ul><ul><li>Require glucose to work </li></ul></...
Meglitinides <ul><li>Repaglinide (Prandin) </li></ul><ul><ul><ul><li>Pharmacokinetics: </li></ul></ul></ul><ul><ul><ul><ul...
Meglitinides <ul><li>Nateglinide (Starlix) </li></ul><ul><ul><ul><li>Pharmacokinetics: </li></ul></ul></ul><ul><ul><ul><ul...
Meglitinides <ul><li>Efficacy: </li></ul><ul><ul><ul><li>HgA1c  ↓ 0.6%-1% </li></ul></ul></ul><ul><li>Adverse reaction </l...
Alpha-Glucosidase Inhibitors <ul><li>Acarbose (Precose) and Miglitol (glyset) </li></ul><ul><ul><li>Interfere with hydroly...
Alpha-Glucosidase Inhibitors <ul><li>Adverse effects </li></ul><ul><ul><ul><li>GI: flatulence, diarrhea, and abdominal pai...
Alpha-Glucosidase Inhibitors <ul><li>Can be used in combination with insulin, SU, and metformin </li></ul><ul><li>Dose: do...
Biguanides  <ul><li>Metformin (Glucophage) </li></ul><ul><ul><ul><li>Antihyperglycemic or insulin sensitizer: </li></ul></...
Biguanides <ul><li>Efficacy </li></ul><ul><ul><ul><li>Reduces FPG by 60-70 mg/dl </li></ul></ul></ul><ul><ul><ul><li>Reduc...
Biguanides <ul><li>Contrindications </li></ul><ul><ul><ul><li>Renal impairment: SCr  ≥ 1.5mg/dl for men and ≥1.4mg/dl for ...
Biguanides <ul><li>Drug interactions: </li></ul><ul><ul><ul><li>Drugs that are eliminated through renal tubular secretion ...
Biguanides <ul><li>Metformin is indicated as monotherapy as well as in combination with glitazones, alpha glucosidase inhi...
Thiazolidinediones  <ul><li>Glitazones: Rosiglitazone (Avandia) and Poiglitazone (Actos) </li></ul><ul><li>Referred to as ...
Thiazolidinediones <ul><li>Efficacy </li></ul><ul><ul><ul><li>Takes 2-3 months to see full effect </li></ul></ul></ul><ul>...
Thiazolidinediones <ul><li>Adverse effects </li></ul><ul><ul><ul><li>Serum transaminase elevations: baseline LFTs should b...
Thiazolidinediones <ul><li>Drug interactions </li></ul><ul><ul><ul><ul><li>Rosiglitazone is metabolized by Cyp2C8 and 2C9 ...
Thiazolidinediones <ul><li>Pioglitazone and rosiglitazone are both indicated for monotherapy and in combination with SU, m...
Exenatide (Byetta) <ul><li>Approved as an alternative for starting insulin therapy in type 2 diabetics who were not adequa...
Exenatide (Byetta) <ul><li>Promotes weight loss </li></ul><ul><li>Improves HgA1c values (decrease in 1.1% from baseline) <...
Medications that all diabetic patients should be on <ul><li>Aspirin (81-325mg/day) </li></ul><ul><li>Statin </li></ul><ul>...
Monitoring /Counseling <ul><li>Assess nutrition and physical activity regularly </li></ul><ul><li>Monitor HgA1c  every 3-6...
Patient case <ul><li>AD is a 70 y/o white male who presented to the ER with worsening SOB on exertion </li></ul><ul><ul><l...
<ul><li>Vital Signs: </li></ul><ul><li>Pulse: 88bpm  CrCl ~62ml/min </li></ul><ul><li>Respiration: 24bpm </li></ul><ul><li...
<ul><li>Current medications: </li></ul><ul><li>ALLOPURINOL TAB  100MG PO QD  </li></ul><ul><li>ASPIRIN (ENTERIC COATED) TA...
<ul><li>Risk factors for type 2 DM: family history, HTN, dyslipidemia, smoker, age, HgA1c? </li></ul><ul><li>Recommendatio...
<ul><li>Monitoring:  </li></ul><ul><ul><ul><li>Renal function: CrCl, serum creatinine </li></ul></ul></ul><ul><ul><ul><li>...
References: <ul><li>Hardman Joel, Limbird lee, editors. Goodman&Gilman’s the pharmacological basis of therapeutics. New Yo...
<ul><li>UptoDate.  http:// uptodateonline.com/application/topic.asp?file =diabetes/25035 </li></ul><ul><li>http:// uptodat...
Upcoming SlideShare
Loading in …5
×

D Mmajor[1]

1,848 views

Published on

Published in: Health & Medicine
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
1,848
On SlideShare
0
From Embeds
0
Number of Embeds
3
Actions
Shares
0
Downloads
60
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

D Mmajor[1]

  1. 1. Diabetes Mellitus AnnaGolovko
  2. 2. Introduction <ul><li>Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, action, or both </li></ul><ul><li>DM is associated with abnormalities in the metabolism of proteins, carbohydrates and fats. </li></ul><ul><li>DM leads to microvascular and macrovascular complications </li></ul><ul><ul><ul><li>Microvascular: retinopathy, nephropathy, and peripheral neuropathy </li></ul></ul></ul><ul><ul><ul><li>Macrovascular: coronary heart disease, stroke, and PVD </li></ul></ul></ul>
  3. 3. Epidemiology <ul><li>DM affects more than 170 million people worldwide </li></ul><ul><li>By 2010 this number will increase by as much as 50% </li></ul><ul><li>~90% of patients with diabetes have type 2 DM </li></ul><ul><li>~10% of patients have type 1 DM or other causes of diabetes </li></ul><ul><li>Racial and ethnic populations at highest risk for type 2 DM: African American, Native Americans, Hispanics, Asian Americans, and Pacific Islanders </li></ul><ul><li>Cardiovascular morbidity in type 2 DM patients is 2-4 times greater than in non-diabetic patients </li></ul>
  4. 4. Classification of Diabetes Mellitus <ul><li>Type 1Diabetes Mellitus </li></ul><ul><ul><ul><li>Average onset is in childhood or early adulthood (usually before 30 years of age) </li></ul></ul></ul><ul><ul><ul><li>Characterized by autoimmune destruction of pancreatic β -cells ->absolute insulin deficiency </li></ul></ul></ul><ul><ul><ul><li>Patients depend on exogenous insulin to sustain life </li></ul></ul></ul>
  5. 5. Classification of Diabetes Mellitus <ul><li>Type 2 DM </li></ul><ul><ul><ul><li>Usually diagnosed after the age of 30 </li></ul></ul></ul><ul><ul><ul><li>Endogenous levels of insulin may be normal, decreased, or increased </li></ul></ul></ul><ul><ul><ul><li>Insulin resistance and insulin tolerance are present in initial stages </li></ul></ul></ul><ul><ul><ul><li>Prevalence increases with age, however an increasing number of adolescents are being diagnosed as a consequence of obesity and sedentary lifestyle </li></ul></ul></ul>
  6. 6. Classification of Diabetes Mellitus <ul><li>Secondary Diabetes </li></ul><ul><ul><ul><li>Develops as a result of other disorders or treatments </li></ul></ul></ul><ul><ul><ul><ul><li>Diseases of the pancreas: chronic pancreatitis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Endocrinopathies: </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Cushing’s syndrome: ↑cortisol </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Acromegaly: ↑growth hormone </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Thyrotoxicosis: ↑thyroid hormone </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>Drug induced: glucocorticoids, pentamidine, thiazides </li></ul></ul></ul></ul>
  7. 7. Classification of Diabetes Mellitus <ul><li>Genetic defects </li></ul><ul><ul><ul><li>MODY </li></ul></ul></ul><ul><ul><ul><li>Insulin receptor mutations or post receptor defects </li></ul></ul></ul><ul><ul><ul><li>Glycogen synthase deficiency </li></ul></ul></ul><ul><ul><ul><li>Many others </li></ul></ul></ul><ul><li>Gestational diabetes (GDM) </li></ul><ul><ul><ul><li>Onset of glucose intolerance usually in the 2 nd or 3 rd trimester </li></ul></ul></ul><ul><ul><ul><li>50% chance of ultimately developing to type 2 DM </li></ul></ul></ul>
  8. 8. Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG) <ul><li>Not diagnostic of DM </li></ul><ul><li>Risk factors for DM and CVD </li></ul>1 Give 75 g of glucose dissolved in 300 mL of water after an overnight fast in subjects who have been receiving at least 150-200 g of carbohydrate daily for 3 days before the test. 2 A fasting plasma glucose ≥ 126 mg/dL is diagnostic of diabetes if confirmed on a subsequent day. ≥ 200 ≥ 140 but < 200 < 140 Two hours after glucose load (mg/dL) ≥ 126 110-125 < 110 Fasting plasma glucose (mg/dL) Diabetes Mellitus 2 Impaired Glucose Tolerance Normal Glucose Tolerance   Table 27-5. The Diabetes Expert Committee criteria for evaluating the standard oral glucose tolerance test. 1
  9. 9. Pathophysiology of Type 1 DM <ul><li>Immune-mediated destruction of pancreatic β -cells </li></ul><ul><li>Certain antibodies detected in blood </li></ul><ul><ul><ul><li>Islet cell antibody (ICA) </li></ul></ul></ul><ul><ul><ul><li>Glutamic acid decarboxylase (GAD65) antibody </li></ul></ul></ul><ul><ul><ul><li>Insulin autoantibody (IAA) </li></ul></ul></ul><ul><li>HLA-DR3 and HLA-DR4 as well as DQA and DQB genes are strongly associated with type 1 DM </li></ul>
  10. 10. Pathophysiology of Type 1 DM <ul><li>Environmental triggers </li></ul><ul><ul><ul><li>Viral infections (mumps, influenza) </li></ul></ul></ul><ul><ul><ul><li>Early exposure to cow milk (BSA, bovine serum albumin) </li></ul></ul></ul><ul><ul><ul><li>Environmental toxins </li></ul></ul></ul><ul><ul><ul><li>Puberty </li></ul></ul></ul><ul><li>“ Honeymoon” phase ->transient remission </li></ul><ul><li>Hyperglycemia occurs when 80%-90% of β -cells are destroyed </li></ul>
  11. 11. Pathophysiology of Type 2 DM <ul><li>Multifactorial pathogenesis </li></ul><ul><ul><ul><li>Genetic mutations </li></ul></ul></ul><ul><ul><ul><li>Environmental factors </li></ul></ul></ul><ul><li>Genetically predisposed patients trigger onset of DM by leading a diabetogenic lifestyle </li></ul><ul><ul><ul><li>Over-eating -> obesity </li></ul></ul></ul><ul><ul><ul><li>Lack of exercise a.k.a. sedentary lifestyle </li></ul></ul></ul>
  12. 12. Pathophysiology of Type 2 DM <ul><li>Genetic predisposition </li></ul><ul><ul><ul><li>Many genes are responsible for causing both β -cell failure and insulin resistance </li></ul></ul></ul><ul><li>Family history </li></ul><ul><ul><ul><li>Increases risk by >2 times </li></ul></ul></ul><ul><ul><ul><li>One parent with type 2 DM: lifetime risk of developing DM is ~38% by age 80 </li></ul></ul></ul><ul><ul><ul><li>Both parents with DM: risk increases up to 60% by age 60% </li></ul></ul></ul>
  13. 13. Pathophysiology of Type 2 DM <ul><li>Other Risk Factors for developing type 2 DM </li></ul><ul><ul><ul><li>HTN ( ≥ 140/90 mmHg) </li></ul></ul></ul><ul><ul><ul><li>Hyperlipidemia (HDL ≤35 mg/dL, TGs ≥ 250mg/dL) </li></ul></ul></ul><ul><ul><ul><li>High risk ethnic groups: African Americans, Hispanics, Asians </li></ul></ul></ul><ul><ul><ul><li>W>M </li></ul></ul></ul>
  14. 14. Pathophysiology of Type 2 DM <ul><li>Typical physiological abnormalities in type 2 DM </li></ul><ul><ul><ul><li>Increased glucose production in the liver </li></ul></ul></ul><ul><ul><ul><li>Impaired insulin secretion </li></ul></ul></ul><ul><ul><ul><li>Insulin resistance </li></ul></ul></ul>
  15. 15. Pathophysiology of Type 2 DM <ul><li>Insulin Resistance </li></ul><ul><ul><ul><li>Strongly associated with obesity and physical inactivity </li></ul></ul></ul><ul><ul><ul><li>Due to defect in the expression of GLUT-4 receptor </li></ul></ul></ul><ul><ul><ul><li>Etiology both genetic and environmental </li></ul></ul></ul><ul><ul><ul><li>ß-cells produce more insulin to counteract the resistance resulting in hyperinsulinemia </li></ul></ul></ul><ul><ul><ul><li>Hyperinsulinemia is associated with HTN, dyslipidemia, and atherosclerotic vascular disease </li></ul></ul></ul>
  16. 16. <ul><li>Metabolic syndrome </li></ul><ul><ul><ul><li>A group of related conditions that increase the risk for CVD </li></ul></ul></ul><ul><ul><ul><li>Characterized by the presence of 3 or more conditions: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Abdominal obesity (waist >40in in men and >35in in women) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Elevated blood pressure ≥130/≥85 mmHg </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Insulin resistance (FBG ≥100 mg/dL) </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Dyslipidemia (triglycerides ≥150 mg/dL, HDL <40mg/dL in men and <50mg/dL in women </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Proinflammatory state (elevated C-reactive protein, CRP) </li></ul></ul></ul></ul></ul><ul><ul><ul><li>~22% of American adults have this syndrome </li></ul></ul></ul>Pathophysiology of Type 2 DM
  17. 17. Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dl The symptoms of diabetes include polyuria, polydipsia, polyphagia, ketoacidosis, and unexplained weight loss. OR FPG ≥ 126 mg/dl OR 2-h plasma glucose ≥200 mg/dl after an OGTT (using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water). Criteria for the diagnosis of diabetes These criteria should be confirmed by repeat testing on a different day
  18. 18. Screening for Type 2 DM <ul><li>Criteria for testing for diabetes in asymptomatic adult individuals </li></ul><ul><li>1. Testing for diabetes should be considered in all individuals at age 45 years and above, particularly in those with a BMI ≥25 kg/m2* and, if normal, should be repeated at 3-year intervals. </li></ul><ul><li>2. Testing should be considered at a younger age or be carried out more frequently in individuals who are overweight (BMI ≥25 kg/m2*) and have additional risk factors, as follows: </li></ul><ul><li>• are habitually physically inactive </li></ul><ul><li>• have a first-degree relative with diabetes </li></ul><ul><li>• are members of a high-risk ethnic population (e.g., African American, Latino, Native American, Asian American, Pacific Islander) </li></ul><ul><li>• have delivered a baby weighing >9 lb or have been diagnosed with GDM </li></ul><ul><li>• are hypertensive (≥140/90 mmHg) </li></ul><ul><li>• have an HDL cholesterol level <35 mg/dl and/or a triglyceride level >250 mg/dl </li></ul><ul><li>• have PCOS </li></ul><ul><li>• on previous testing, had IGT or IFG </li></ul><ul><li>• have other clinical conditions associated with insulin resistance (acanthosis nigricans) </li></ul><ul><li>• have a history of vascular disease </li></ul>
  19. 19. Acanthosis Nigricans A skin disorder characterized by velvety, light-brown-to-black, markings usually on the neck, under the arms or in the groin. Acanthosis nigricans is most often associated with hyperinsulimea http://www.aocd.org/skin/dermatologic_diseases/acanthosis_nigrica.html http://dermatology.cdlib.org/DOJvol6num1/original/acanthosis/katz.html
  20. 20. Treatment <ul><li>Desired outcomes: </li></ul><ul><ul><ul><li>Reduce risk for microvascular and macrovascular complications </li></ul></ul></ul><ul><ul><ul><li>Reduce mortality </li></ul></ul></ul><ul><ul><ul><li>Achieve glycemic control </li></ul></ul></ul><ul><ul><ul><li>Improve quality of life </li></ul></ul></ul>
  21. 21. Specific Desired Endpoints http://guidelines.gov/summary/summary.aspx?doc_id=7212&nbr=004306&string=diabetes <ul><li>Key concepts in setting glycemic goals: </li></ul><ul><li>A1C is the primary target for glycemic control. </li></ul><ul><li>Goals should be individualized. </li></ul><ul><li>Certain populations (children, pregnant women, and elderly) require special considerations. </li></ul><ul><li>Less intensive glycemic goals may be indicated in patients with severe or frequent hypoglycemia. </li></ul><ul><li>More stringent glycemic goals (i.e., a normal A1C, <6%) may further reduce complications at the cost of increased risk of hypoglycemia (particularly in those with type 1 diabetes). </li></ul><ul><li>Postprandial glucose may be targeted if A1C goals are not met despite reaching preprandial glucose goals. </li></ul>>40 mg/dL (>1.1 mmol/L)**** High-density lipoprotein (HDL) <150 mg/dL (<1.7 mmol/L) Triglycerides <100 mg/dL (<2.6 mmol/L) Low-density lipoprotein (LDL) Lipids*** <130/80 mmHg Blood pressure <180 mg/dL (<10.0 mmol/L) Peak postprandial capillary plasma glucose** 90-130 mg/dL (5.0-7.2 mmol/L) Preprandial capillary plasma glucose <7.0%* Hemoglobin A 1C Glycemic Control
  22. 22. Non- pharmacological treatment <ul><li>Diet </li></ul><ul><ul><li>Medical nutrition therapy (MNT) is recommended for all patients with DM </li></ul></ul><ul><ul><li>The goal is to achieve a reasonable body weight, reduce postprandial hyperglycemia, reduce cholesterol and TGs, and achieve blood pressure goals </li></ul></ul><ul><ul><li>Moderate weight loss of approximately 5% of total body weight can improve FBG in most patients </li></ul></ul><ul><ul><li>These goals help reduce the chronic complications of diabetes </li></ul></ul>
  23. 23. Composition of diet <ul><li>Protein </li></ul><ul><ul><ul><li>15%-20% of total calories </li></ul></ul></ul><ul><ul><ul><li>If microalbuminuria is present: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>0.8-1.0 g/kg of protein </li></ul></ul></ul></ul></ul><ul><ul><ul><li>If macroalbuminuria is present: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>0.8 g/kg </li></ul></ul></ul></ul></ul>
  24. 24. Composition of diet <ul><li>Carbohydrates </li></ul><ul><ul><ul><li>Total amount of carbohydrates is more important than the source and type of starch or sugar </li></ul></ul></ul><ul><ul><ul><li>Whole grain products, fruits and vegetables should be included in the diet </li></ul></ul></ul><ul><ul><ul><li>Carbohydrates should be evenly spaced out throughout the day as smaller meals and snacks </li></ul></ul></ul>
  25. 25. Composition of diet <ul><li>Fat </li></ul><ul><ul><ul><li><30% of total calories </li></ul></ul></ul><ul><ul><ul><ul><ul><li><10% of calories from saturated fats </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li><10% of calories from polyunsaturated fats </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>10%-15% of calories from monounsaturated fats </li></ul></ul></ul></ul></ul><ul><li>Sodium </li></ul><ul><ul><ul><li>Sodium intake should be between 1,500-2,400 mg/day </li></ul></ul></ul>
  26. 26. Physical Activity <ul><li>Aerobic exercise of 20-60 minutes 3-5 times per week has been shown to improve glucose tolerance, improve circulation, lower insulin requirements, and help lose weight </li></ul><ul><li>Before any start of exercise program patients should first be evaluated for silent ischemia with a cardiac stress test </li></ul>
  27. 27. Pharmacologic Treatment of Type 1 DM <ul><li>The primary therapy for type 1 DM is insulin therapy </li></ul><ul><li>Function of insulin </li></ul><ul><ul><ul><li>Stimulates entry of amino acids into cells -> enhances protein synthesis </li></ul></ul></ul><ul><ul><ul><li>Enhances lipogenesis and inhibits lypolysis and ketogenesis </li></ul></ul></ul><ul><ul><ul><li>Inhibits hepatic gluconeogenesis </li></ul></ul></ul><ul><ul><ul><li>Promotes the storage of glucose as glycogen </li></ul></ul></ul><ul><ul><ul><li>Inhibits formation of glucose from amino acids </li></ul></ul></ul><ul><ul><ul><li>Promotes generation of NO in vascular endothelial cells </li></ul></ul></ul>
  28. 29. Pharmacologic Treatment of Type 1 DM <ul><li>Mechanism of action: </li></ul><ul><ul><ul><li>Cells take up glucose only by facilitated diffusion through a group of hexose receptors </li></ul></ul></ul><ul><ul><ul><li>In most tissues the major transporter is GLUT-4 which is present in cytoplasmic vesicles </li></ul></ul></ul><ul><ul><ul><li>When insulin binds to its receptor on the cell surface, it activates a cascade reaction that result in rapid fusion of GLUT-4 with the cell membrane -> glucose is taken into the cell </li></ul></ul></ul>
  29. 30. Pharmacologic Treatment of Type 1 DM <ul><li>Exogenous insulins are categorized according to their strength, onset and duration of effect, species source (animal or human), and purity </li></ul><ul><li>Three types of insulin available : </li></ul><ul><ul><ul><li>Beef: differs from human insulin by 3 aa </li></ul></ul></ul><ul><ul><ul><li>Pork: differs by 1 aa </li></ul></ul></ul><ul><ul><ul><li>Human: made from recombinant DNA </li></ul></ul></ul>
  30. 31. Pharmacologic Treatment of Type 1 DM <ul><li>Pharmacokinetics </li></ul><ul><ul><ul><li>Half-life of IV: 9 minutes </li></ul></ul></ul><ul><ul><ul><li>Steady state is reached in 45 minutes </li></ul></ul></ul><ul><ul><ul><li>Onset of action faster and duration of action shorter for IV >IM>SQ </li></ul></ul></ul><ul><ul><ul><li>Rate of absorption fastest from abdomen and slowest from thigh and buttocks </li></ul></ul></ul><ul><ul><ul><li>Metabolized in: </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Liver: up to 50% is deactivated in the first passage </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Kidney: 15%-20% </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Muscle </li></ul></ul></ul></ul></ul>
  31. 32. Types of Insulins http://www.clevelandclinic.org/health/health-info/docs/3300/3376.asp?index=11452 16-20 hrs 30 min.-2½hrs  15 min. Humalog mix 75/25 18-24 hours 2-5 hours 30 min. Humulin 50/50 Up to 24 1-4 hours 10-20 min. Novolog 70/30 Up to24 hours 2-12 hours 30 min. Novolin 70/30 14-24 hours 2-4 hours 30 min Humulin 70/30       Pre-Mixed* 20-24 hours No peak time; insulin is delivered at a steady level 1-1½ hour Lantus 20-36 hours 10-20 hours 30 min.-3 hours Ultralente (U)       Long Acting 18-24 hours 3-10 hours 1-2½ hours Lente (L) 18-24 hours 4-12 hours 1-2 hours NPH (N)       Intermediate Acting 5-8 hours 2-5 hours 30 min. -1 hour Regular (R)       Short Acting 3-5 hours 1-3 hours 10-20 min. Novolog 3-5 hours 30 min to 2½ hours 15-30 min. Humalog       Rapid Acting Duration Peak Onset Type of Insulin & Brand Names
  32. 33. Pharmacologic Treatment of Type 1 DM <ul><li>Problems with Insulin </li></ul><ul><ul><ul><li>Lipoatrophy: loss of fat at injection site due to antibody formation leading to breakdown of fat in the area of injection ( need to rotate sites!) </li></ul></ul></ul><ul><ul><ul><li>Hypertrophy: increase in fat mass at the site, the area is anesthetized, however leads to erratic insulin absorption </li></ul></ul></ul><ul><ul><ul><li>Resistance: require large amounts of insulin to get desired effect, due to antibody formation </li></ul></ul></ul>
  33. 34. Pharmacologic Treatment of Type 1 DM <ul><li>Problems with insulin </li></ul><ul><ul><li>Hypoglycemia: </li></ul></ul><ul><ul><ul><ul><ul><li>Blood glucose < 50mg/dl </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Symptoms: hunger, palpitations, sweating, fainting </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Risk factors: age >70, renal insufficiency, excessive alcohol use, malnutrition </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Drug interactions: probenicid, allopurinol, aspirin, sympatholytics </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Treatment: rule of 15 -> 15g of carbohydrates every 15 minutes until BG is greater than 70mg/dl, then follow with a simple meal </li></ul></ul></ul></ul></ul>
  34. 35. Pharmacologic Treatment of Type 1 DM <ul><li>Foods that will provide 10g of carbs </li></ul><ul><ul><ul><li>½ cup of orange juice or soda </li></ul></ul></ul><ul><ul><ul><li>Sugar: 2 teaspoons or 2 cubes </li></ul></ul></ul><ul><ul><ul><li>Glucose tablets: 2-4 tablets </li></ul></ul></ul><ul><ul><ul><li>Apple juice: 1/3 cup </li></ul></ul></ul><ul><li>Foods to avoid </li></ul><ul><ul><ul><li>Ice cream, candy bars, cookies, cakes </li></ul></ul></ul><ul><li>If unconscious: Glucagon 1mg SQ, IM, or IV and Dextrose 50% 50ml infusion </li></ul>
  35. 36. Diabetic Ketoacidosis (DKA) <ul><li>Diabetic ketoacidosis is usually precipitated by a stressful event such as trauma, infection, surgery or myocardial infarction because these events are usually characteristic of an increased release of cortisol, glucagon, and catecholamines (hormones that stimulate production of glucose and ketoacids). </li></ul><ul><li>DKA presents as hyperglycemia (glucose: 250-800mg/dl), volume depletion, high anion gap metabolic acidosis, hypokalemia, glucosuria, urine ketosis (ketones are another source of energy when the glucose pathway is impaired), and hyperosmolality on labs. Patients present with tachycardia, polydipsia, abdominal pain, nausea, vomiting and coma. </li></ul>
  36. 37. Diabetic Ketoacidosis (DKA) <ul><li>Treatment: </li></ul><ul><ul><li>Fluid replenishment with normal saline (2-3L over first 3 hours) </li></ul></ul><ul><ul><li>Insulin continuous infusion (0.1 units/kg) </li></ul></ul><ul><ul><li>If serum K+ < 4.5 mEq/L, administer Potassium chloride 10 mEq/h </li></ul></ul><ul><ul><li>Routine use of bicarbonate is not recommended but can be used in critical patients if their acidosis was not corrected with hydration and insulin </li></ul></ul><ul><ul><li>Asses the cause of DKA (trauma, infection, non-compliance with meds) </li></ul></ul><ul><ul><li>Patients should be monitored closely </li></ul></ul>
  37. 38. Pharmacologic Treatment of Type 2 DM <ul><li>When choosing therapy, the patient’s age, weight, renal and hepatic function should be assessed </li></ul>
  38. 39. Pharmacologic Treatment of Type 2 DM <ul><li>Sulfonylureas </li></ul><ul><ul><ul><li>Increase insulin production in pancreas </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Bind to the SU-receptor on cell membrane of pancreatic ß-cells that associated with ATP-dependent K+ channel ->depolarization and opening of calcium-dependent channels -> increase in calcium causes an increase in insulin secretion </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Decrease gluconeogenesis in the liver </li></ul></ul></ul><ul><ul><ul><li>Improve insulin sensitivity in peripheral tissues </li></ul></ul></ul>
  39. 40. Sulfonylureas <ul><li>First generation </li></ul><ul><ul><ul><li>Acetohexamide (Dymelor), chlorpropamide (Diabinese), tolazamide (Tolinase), tolbutamide (Orinase) </li></ul></ul></ul><ul><ul><ul><ul><li>Lower in potency than 2 nd generation SUs </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Have more side effects </li></ul></ul></ul></ul><ul><li>Second generation </li></ul><ul><ul><ul><li>Glimepiride (Amaryl), glipizide (Glucotrol, Glucotrol XL), and glyburide (Diabeta, Micronase, Glynase) </li></ul></ul></ul>
  40. 41. Sulfonylureas <ul><li>Who is a candidate: </li></ul><ul><ul><ul><li>Normal weight type 2 DM patients </li></ul></ul></ul><ul><ul><ul><li>Onset of DM after age 30 </li></ul></ul></ul><ul><ul><ul><li>Initial BG < 250mg/dl </li></ul></ul></ul><ul><ul><ul><li>Relatively normal renal and hepatic function </li></ul></ul></ul><ul><li>Who is not a candidate: </li></ul><ul><ul><ul><li>Pregnant and lactating women </li></ul></ul></ul><ul><ul><ul><li>Ketosis-prone patients </li></ul></ul></ul><ul><ul><ul><li>Elderly, debilitated, or malnourished </li></ul></ul></ul>
  41. 42. Sulfonylureas <ul><li>Pharmacokinetics </li></ul><ul><ul><ul><li>All SUs are metabolized by the liver </li></ul></ul></ul><ul><ul><ul><li>Renally eliminated, require dosage adjustments </li></ul></ul></ul><ul><li>Efficacy: </li></ul><ul><ul><ul><li>HgA1c ↓1.5%-2% </li></ul></ul></ul><ul><ul><ul><li>FBG ↓50-60mh/dl </li></ul></ul></ul><ul><ul><ul><li>Dose can be increased every 1-2 weeks for glycemic control </li></ul></ul></ul><ul><li>Adverse effects: hypoglycemia, weight gain, GI upset </li></ul>
  42. 43. Sulfonylureas <ul><li>Drug interactions: </li></ul><ul><ul><ul><li>Clofibrate, phenylbutazone, salicylates, sulfonamides -> displace SUs from protein binding </li></ul></ul></ul><ul><ul><ul><li>Chloramphenicol, MAOIs, phenylbutazone -> reduce hepatic SU metabolism </li></ul></ul></ul><ul><ul><ul><li>Allopurinol, probenecid ->decrease urinary excretion of SUs </li></ul></ul></ul>
  43. 44. Sulfonylureas <ul><li>Glyburide </li></ul><ul><ul><ul><li>dose: 1.25-10 mg single or divided doses </li></ul></ul></ul><ul><ul><ul><li>0.75-12mg (glynase) </li></ul></ul></ul><ul><ul><ul><li>Half-life: biphasic 3.2 +10 </li></ul></ul></ul><ul><ul><ul><li>Onset: 1.5 hr </li></ul></ul></ul><ul><ul><ul><li>Duration: 24hr </li></ul></ul></ul><ul><ul><ul><li>50-200 times more potent than other SUs </li></ul></ul></ul><ul><ul><ul><li>Causes more hypoglycemia than other agents </li></ul></ul></ul><ul><ul><ul><li>Take on an empty stomach </li></ul></ul></ul>
  44. 45. Sulfonylureas <ul><li>Glipizide </li></ul><ul><ul><ul><li>Dose: 2.5-20 mg QD-BID, max dose= 40mg, 20mg (XL) </li></ul></ul></ul><ul><ul><ul><li>Half-life:3.5-6 hr </li></ul></ul></ul><ul><ul><ul><li>Onset:1 hr </li></ul></ul></ul><ul><ul><ul><li>Duration:12-16 hr </li></ul></ul></ul><ul><ul><ul><li>Once daily dosing available </li></ul></ul></ul><ul><ul><ul><li>safer in mild renal impairment </li></ul></ul></ul><ul><ul><ul><li>Minimal weight gain </li></ul></ul></ul><ul><ul><ul><li>Food has no effect on absorption </li></ul></ul></ul>
  45. 46. Sulfonylureas <ul><li>Glimipiride </li></ul><ul><ul><ul><li>Dose: 1-8 mg/day, max=8mg </li></ul></ul></ul><ul><ul><ul><li>Half-life:~2.5 hr </li></ul></ul></ul><ul><ul><ul><li>Onset:2-3 hr </li></ul></ul></ul><ul><ul><ul><li>Duration: 24hr </li></ul></ul></ul><ul><ul><ul><li>Take with first main meal </li></ul></ul></ul><ul><ul><ul><li>Indicated for second-line therapy with insulin </li></ul></ul></ul><ul><li>Tolbutamide (Orinase) </li></ul><ul><ul><ul><li>Dose: .25-3.0g divided doses, max=2-3g/day </li></ul></ul></ul><ul><ul><ul><li>Half-life: 5hr </li></ul></ul></ul><ul><ul><ul><li>Onset: 1hr </li></ul></ul></ul><ul><ul><ul><li>Duration:6-12hr </li></ul></ul></ul><ul><ul><ul><li>Least potent, shortest half-life </li></ul></ul></ul><ul><ul><ul><li>Preferred in kidney disease </li></ul></ul></ul>
  46. 47. Sulfonylureas <ul><li>Acetohexamide (Dymelor) </li></ul><ul><ul><ul><li>Dose: 0.25-1.5g single or divided doses </li></ul></ul></ul><ul><ul><ul><li>Half-life: 5 hrs </li></ul></ul></ul><ul><ul><ul><li>Onset: 1hr </li></ul></ul></ul><ul><ul><ul><li>Duration: 10-14 hrs </li></ul></ul></ul><ul><ul><ul><li>No advantage over tolbutamide, but was seen to be effective in patients who failed on tolbutamide </li></ul></ul></ul><ul><li>Tolazamide (Tolinase) </li></ul><ul><ul><ul><li>Dose:0.1-1.0g single or divided, max=1g </li></ul></ul></ul><ul><ul><ul><li>Half-life:7 hr </li></ul></ul></ul><ul><ul><ul><li>Onset: 4-6 hr </li></ul></ul></ul><ul><ul><ul><li>Duration: 10-14 hr </li></ul></ul></ul>
  47. 48. Sulfonylureas <ul><li>Chlorpropamide (Diabinese) </li></ul><ul><ul><ul><li>Dose: 0.1-0.5g single dose, max=0.5g </li></ul></ul></ul><ul><ul><ul><li>Half-life: 35 hr </li></ul></ul></ul><ul><ul><ul><li>Onset:1 hr </li></ul></ul></ul><ul><ul><ul><li>Duration: 72 hr </li></ul></ul></ul><ul><ul><ul><li>Longest duration </li></ul></ul></ul><ul><ul><ul><li>Cholestatic jaundice and hepatocellular disease has occurred (rare) </li></ul></ul></ul><ul><ul><ul><li>Disulfiram syndrome occurred in few cases </li></ul></ul></ul>
  48. 49. Sulfonylureas <ul><li>Place in therapy </li></ul><ul><ul><ul><li>Monotherapy for type 2 DM (FBG 140-160mg/dl) </li></ul></ul></ul><ul><ul><ul><li>Combination therapy (FBG > 160 mg/dl) </li></ul></ul></ul>
  49. 50. Meglitinides <ul><li>Non-sulfonylurea insulin secretagogues </li></ul><ul><ul><ul><li>Require glucose to work </li></ul></ul></ul><ul><ul><ul><li>Also bind the ATP –dependent K= channel to release insulin </li></ul></ul></ul><ul><ul><ul><li>Used for management of meal-related glucose loads </li></ul></ul></ul><ul><ul><ul><li>Less hypoglycemia than with SUs </li></ul></ul></ul>
  50. 51. Meglitinides <ul><li>Repaglinide (Prandin) </li></ul><ul><ul><ul><li>Pharmacokinetics: </li></ul></ul></ul><ul><ul><ul><ul><li>Metabolized by Cyt P450 3A4 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Half-life: 1 hr </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Excreted in bile </li></ul></ul></ul></ul><ul><ul><ul><li>Dose: 0.5-4mg QID, max 16mg/day, taken 0-30min before meal, if meal is skipped skip the dose as well </li></ul></ul></ul><ul><ul><ul><li>Not contraindicated in renal and hepatic insufficiency </li></ul></ul></ul>
  51. 52. Meglitinides <ul><li>Nateglinide (Starlix) </li></ul><ul><ul><ul><li>Pharmacokinetics: </li></ul></ul></ul><ul><ul><ul><ul><li>Metabolized by P450 2C9 (70%) and 3A4 (30%), inhibitor of 2C9 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>98% albumin bound </li></ul></ul></ul></ul><ul><ul><ul><li>Dose: 120mg TID 1-30min before food, 60mg TID can be given to patients who are close to their HgA1c goal </li></ul></ul></ul><ul><ul><ul><li>Safe in hepatically impaired and renally impaired patients </li></ul></ul></ul><ul><ul><ul><li>Synergistic with metformin, decreases HgA1c by 1.5-2.5% </li></ul></ul></ul>
  52. 53. Meglitinides <ul><li>Efficacy: </li></ul><ul><ul><ul><li>HgA1c ↓ 0.6%-1% </li></ul></ul></ul><ul><li>Adverse reaction </li></ul><ul><ul><ul><li>Low incidence of hypoglycemia (0.3%) </li></ul></ul></ul><ul><ul><ul><li>Slight weight gain </li></ul></ul></ul><ul><li>Contraindications: </li></ul><ul><ul><ul><li>Pregnancy, DKA, severe infection, children </li></ul></ul></ul>
  53. 54. Alpha-Glucosidase Inhibitors <ul><li>Acarbose (Precose) and Miglitol (glyset) </li></ul><ul><ul><li>Interfere with hydrolysis of carbohydrates and delay absorption of glucose and monosaccharides in the brush border of small intestine </li></ul></ul><ul><ul><li>Efficacy: </li></ul></ul><ul><ul><ul><li>reduce post-prandial hyperglycemia by about 50mg/dl </li></ul></ul></ul><ul><ul><ul><li>Reduce FPG by 25-30mg/dl </li></ul></ul></ul><ul><ul><ul><li>Decrease HgA1c 0.5-1.0% </li></ul></ul></ul><ul><ul><ul><li>Additive effect with SUs </li></ul></ul></ul><ul><ul><ul><li>Does not stimulate insulin secretion and will not cause hypoglycemia if used as monotherapy </li></ul></ul></ul><ul><ul><ul><li>No weight gain </li></ul></ul></ul>
  54. 55. Alpha-Glucosidase Inhibitors <ul><li>Adverse effects </li></ul><ul><ul><ul><li>GI: flatulence, diarrhea, and abdominal pain </li></ul></ul></ul><ul><ul><ul><li>Elevation in AST and ALT values: dose related and associated with low weight <60kg </li></ul></ul></ul><ul><li>Contraindications </li></ul><ul><ul><ul><li>DKA </li></ul></ul></ul><ul><ul><ul><li>Liver cirrhosis </li></ul></ul></ul><ul><ul><ul><li>inflammatory bowel disease </li></ul></ul></ul><ul><ul><ul><li>Pregnancy </li></ul></ul></ul><ul><ul><ul><li>Bowel obstruction </li></ul></ul></ul><ul><ul><ul><li>SCr >2.0 mg/dl </li></ul></ul></ul>
  55. 56. Alpha-Glucosidase Inhibitors <ul><li>Can be used in combination with insulin, SU, and metformin </li></ul><ul><li>Dose: dose must be slowly titrated up to avoid GI disturbances </li></ul><ul><ul><ul><li>Week 1-2: 25mg PO QD </li></ul></ul></ul><ul><ul><ul><li>Week 3-4: 25mg BID </li></ul></ul></ul><ul><ul><ul><li>Week 5-6: 25mg TID </li></ul></ul></ul><ul><ul><ul><li>Maintenance dose: 50mg TID if patient<60kg, 100mg TID if >60kg </li></ul></ul></ul>
  56. 57. Biguanides <ul><li>Metformin (Glucophage) </li></ul><ul><ul><ul><li>Antihyperglycemic or insulin sensitizer: </li></ul></ul></ul><ul><ul><ul><ul><li>Does not stimulate insulin secretion </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Decreases hepatic production of glucose </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increases glucose utilization by muscle and adipose tissue (partially reversing insulin resistance) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>May also reduce intestinal glucose absorption </li></ul></ul></ul></ul>
  57. 58. Biguanides <ul><li>Efficacy </li></ul><ul><ul><ul><li>Reduces FPG by 60-70 mg/dl </li></ul></ul></ul><ul><ul><ul><li>Reduces HgA1c by 1.5-2.0% </li></ul></ul></ul><ul><ul><ul><li>Reduction in: TGs by 16%, LDL by 8%, and increases HDL by 2% </li></ul></ul></ul><ul><ul><ul><li>Weight loss of 2-5 kg </li></ul></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><ul><li>GI: bloating, nausea, diarrhea, cramping </li></ul></ul></ul><ul><ul><ul><li>Metallic taste in the mouth </li></ul></ul></ul><ul><ul><ul><li>Lactic acidosis </li></ul></ul></ul><ul><ul><ul><li>Hypoglycemia if used in combination with insulin or SU </li></ul></ul></ul><ul><ul><ul><li>Headache </li></ul></ul></ul>
  58. 59. Biguanides <ul><li>Contrindications </li></ul><ul><ul><ul><li>Renal impairment: SCr ≥ 1.5mg/dl for men and ≥1.4mg/dl for women </li></ul></ul></ul><ul><ul><ul><li>Cardiac or respiratory insufficiency </li></ul></ul></ul><ul><ul><ul><li>History of lactic acidosis </li></ul></ul></ul><ul><ul><ul><li>Severe infection </li></ul></ul></ul><ul><ul><ul><li>Liver disease with abnormal LFTs </li></ul></ul></ul><ul><ul><ul><li>Alcohol abuse </li></ul></ul></ul>
  59. 60. Biguanides <ul><li>Drug interactions: </li></ul><ul><ul><ul><li>Drugs that are eliminated through renal tubular secretion can potentially interact with metformin such as digoxin, morphine, procainamide, vancomycin, ranitidine </li></ul></ul></ul><ul><ul><ul><li>Furosemide and nifedipine can potentially increase metformin plasma concentrations </li></ul></ul></ul><ul><li>Dosing: </li></ul><ul><ul><ul><li>start with 500mg or 850mg QD or BID and titrate slowly up to the desired effect </li></ul></ul></ul><ul><ul><ul><li>Increases should be done every 7-14 days </li></ul></ul></ul><ul><ul><ul><li>Maximum daily dose =2550mg or 2000mg for XR formulation </li></ul></ul></ul><ul><ul><ul><li>Administer with meals to minimize GI side effects </li></ul></ul></ul>
  60. 61. Biguanides <ul><li>Metformin is indicated as monotherapy as well as in combination with glitazones, alpha glucosidase inhibitors, meglitinides or insulin </li></ul>
  61. 62. Thiazolidinediones <ul><li>Glitazones: Rosiglitazone (Avandia) and Poiglitazone (Actos) </li></ul><ul><li>Referred to as insulin sensitizers because they increase insulin sensitivity and glucose uptake in muscle and adipose tissue without stimulating insulin secretion </li></ul><ul><li>MOA: Glitazones bind to the PPAR gamma receptor in the cell nucleus which stimulates gene transcription responsible for making GLUT-4-R. the GLUT-4 receptor moves to the cell membrane allowing glucose to enter the cell. </li></ul><ul><ul><li>Other effects: inhibit hepatic gluconeogenesis and redistribution of fat </li></ul></ul>
  62. 63. Thiazolidinediones <ul><li>Efficacy </li></ul><ul><ul><ul><li>Takes 2-3 months to see full effect </li></ul></ul></ul><ul><li>Rosiglitazone (Avandia) </li></ul><ul><ul><ul><li>Decreases: FPG by 30-60mg/dl, HgA1c by 0.8-1.5%, TGs by 7-14% </li></ul></ul></ul><ul><ul><ul><li>Increases: LDL by 14-18% and HDL by 11-14% </li></ul></ul></ul><ul><li>Pioglitazone (Actos) </li></ul><ul><ul><ul><li>Decreases: FPG by 39-65mg/dl, HgA1c by 1.0-1.6%, TGs by 5-26% </li></ul></ul></ul><ul><ul><ul><li>Increases: HDL by 6-13% </li></ul></ul></ul>
  63. 64. Thiazolidinediones <ul><li>Adverse effects </li></ul><ul><ul><ul><li>Serum transaminase elevations: baseline LFTs should be obtained and repeated every other month for the first 12 months and periodically thereafter. Drugs should not be started if baseline AST or ALT levels are greater than 2.5 times the normal and they should be stopped if AST and ALT are greater than 3 times the norm or if signs and symptoms of liver injury are present </li></ul></ul></ul><ul><ul><ul><li>Fluid retention </li></ul></ul></ul><ul><ul><ul><li>Weight gain </li></ul></ul></ul><ul><ul><ul><li>Hypoglycemia if combined with other agents </li></ul></ul></ul>
  64. 65. Thiazolidinediones <ul><li>Drug interactions </li></ul><ul><ul><ul><ul><li>Rosiglitazone is metabolized by Cyp2C8 and 2C9 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Pioglitazone is metabolized by Cyp2C8 and 3A4 </li></ul></ul></ul></ul><ul><ul><ul><li>Pioglitazone induces 3A4: decreased plasma concentration of OCs </li></ul></ul></ul><ul><ul><ul><li>Inhibitors of 3A4 will increase pioglitazone concentrations </li></ul></ul></ul>
  65. 66. Thiazolidinediones <ul><li>Pioglitazone and rosiglitazone are both indicated for monotherapy and in combination with SU, meglitinide, metformin or insulin </li></ul><ul><li>Doses: </li></ul><ul><ul><ul><li>Rosiglitazone :4-8 mg/day as a single dose or two divided doses </li></ul></ul></ul><ul><ul><ul><li>Pioglitazone: 15-45mg/day as a single daily dose </li></ul></ul></ul>
  66. 67. Exenatide (Byetta) <ul><li>Approved as an alternative for starting insulin therapy in type 2 diabetics who were not adequately controlled with metformin, a sulfonylurea or both. </li></ul><ul><li>MOA: </li></ul><ul><ul><li>Amino acid sequence similar to human glucagon-like peptide-1(GLP-1) </li></ul></ul><ul><ul><li>Stimulates insulin secretion in the presence of glucose </li></ul></ul><ul><ul><li>Lowers serum glucagon concentrations </li></ul></ul><ul><ul><li>Slows gastric emptying </li></ul></ul><ul><ul><li>Increase satiety </li></ul></ul>
  67. 68. Exenatide (Byetta) <ul><li>Promotes weight loss </li></ul><ul><li>Improves HgA1c values (decrease in 1.1% from baseline) </li></ul><ul><li>Starting dose of exenatidine is 5mcg SC BID at any time before the morning and evening meals </li></ul>
  68. 69. Medications that all diabetic patients should be on <ul><li>Aspirin (81-325mg/day) </li></ul><ul><li>Statin </li></ul><ul><li>ACEI </li></ul><ul><li>Beta-blocker </li></ul><ul><li>Thiazide diuretic </li></ul>
  69. 70. Monitoring /Counseling <ul><li>Assess nutrition and physical activity regularly </li></ul><ul><li>Monitor HgA1c every 3-6 months </li></ul><ul><li>Lipid profile yearly </li></ul><ul><li>Blood pressure each visit </li></ul><ul><li>Alcohol and smoke cessation </li></ul><ul><li>Thorough annual physical exam </li></ul><ul><li>Self-Monitoring Blood Glucose </li></ul><ul><li>Foot care </li></ul><ul><li>Annual dilated eye examination </li></ul><ul><li>Renal assessment for microalbuminuria </li></ul><ul><li>Cardiovascular complications </li></ul><ul><li>Influenza vaccine yearly </li></ul><ul><li>Pneumococcal vaccine every 5 years </li></ul><ul><li>Assess for peripheral neuropathy and PVD </li></ul><ul><li>Retinopathy </li></ul>
  70. 71. Patient case <ul><li>AD is a 70 y/o white male who presented to the ER with worsening SOB on exertion </li></ul><ul><ul><li>PMH: HTN, Dyslipidemia ( 8/15/05 Tchol=166mg/dl, TGs=153mg/dl, HDL=29.3mg/dl, LDL=106mg/dl), BPH, Gout, type 2 DM (HgA1C=7.6mg/dl from 8/05) </li></ul></ul><ul><ul><li>SH: smokes 1 cigar/day. Used to smoke 8-9 cigars/day > 20 yrs, cut down several years ago. </li></ul></ul><ul><ul><ul><li>-- ETOH </li></ul></ul></ul><ul><ul><ul><li>-- IVDA </li></ul></ul></ul><ul><ul><li>FH: Mother and Father --> DM </li></ul></ul>
  71. 72. <ul><li>Vital Signs: </li></ul><ul><li>Pulse: 88bpm CrCl ~62ml/min </li></ul><ul><li>Respiration: 24bpm </li></ul><ul><li>Temperature: 98 F </li></ul><ul><li>Weight: 227 lb [103.2 kg] </li></ul><ul><li>Height: 71.5 in </li></ul><ul><li>BP: 148/64mmHg </li></ul><ul><li>Labs: GLUCOSE 193.0 H mg/dl </li></ul><ul><li>UREA NITROGEN 43.0 H mg/dl </li></ul><ul><li>CREATININE 1.2 mg/dl </li></ul><ul><li>SODIUM 134.1 L mmol/L </li></ul><ul><li>POTASSIUM 5.2 H mmol/L </li></ul><ul><li>PROTEIN, TOTAL 6.2 L gm/dl </li></ul><ul><li>ALBUMIN 3.9 gm/dl </li></ul><ul><li>TOT. BILIRUBIN 1.4 H mg/dl </li></ul><ul><li>ALKALINE PHOSPHATASE 39.0 L U/L </li></ul><ul><li>SGOT 31 IU/L </li></ul><ul><li>SGPT 20.0 U/L </li></ul><ul><li>FINGER STICK GLUCOSE 235 H mg/dl </li></ul><ul><ul><li>GLUCOSE 193.0 H mg/dl </li></ul></ul><ul><ul><li>GLUCOSE 240.0 H mg/dl </li></ul></ul>
  72. 73. <ul><li>Current medications: </li></ul><ul><li>ALLOPURINOL TAB 100MG PO QD </li></ul><ul><li>ASPIRIN (ENTERIC COATED) TAB,EC 81MG PO QD </li></ul><ul><li>ENOXAPARIN NA (LOVENOX) INJ 40MG/0.4ML SC QD </li></ul><ul><li>GEMFIBROZIL TAB,ORAL 600MG PO BID </li></ul><ul><li>NIFEdipine (ADALAT CC) TAB,SA 5MG PO QD </li></ul><ul><li>ROSIGLITAZONE (AVANDIA) TAB 4MG PO BID </li></ul><ul><li>SIMVASTATIN (zoCOR) TAB 20MG PO QHS </li></ul><ul><li>TERAZOSIN HCL (HYTRIN) CAP,ORAL 5MG PO HS </li></ul><ul><li>glyBURIDE 5MG + METFORMIN HCL 500MG TAB 1 TABLET PO BID </li></ul><ul><li>liSINOpril 20MG/HCTZ 12.5MG TAB 1 TABLET PO QD </li></ul>
  73. 74. <ul><li>Risk factors for type 2 DM: family history, HTN, dyslipidemia, smoker, age, HgA1c? </li></ul><ul><li>Recommendations for therapy: </li></ul><ul><ul><li>Assess if the spikes in glucose are post-prandial, if yes then can add on a meglitinide such as nateglinide (Starlix) 60mg po TID </li></ul></ul><ul><ul><li>Or can add on Insulin NPH at bedtime or glargine (Lantus) at bedtime </li></ul></ul><ul><ul><ul><ul><li>Can start at 0.1-0.2U/kg IBW and then titrate up </li></ul></ul></ul></ul><ul><ul><li>Optimize statin therapy to Zocor 20mg QHS </li></ul></ul>
  74. 75. <ul><li>Monitoring: </li></ul><ul><ul><ul><li>Renal function: CrCl, serum creatinine </li></ul></ul></ul><ul><ul><ul><li>Signs of jaundice or hepatic dysfunction </li></ul></ul></ul><ul><ul><ul><li>Hypoglycemia: finger stick glucose TID </li></ul></ul></ul><ul><ul><ul><li>Fluid retention, edema </li></ul></ul></ul><ul><ul><ul><li>Weight gain </li></ul></ul></ul>
  75. 76. References: <ul><li>Hardman Joel, Limbird lee, editors. Goodman&Gilman’s the pharmacological basis of therapeutics. New York: McGraw-hill companies,inc </li></ul><ul><li>Dipiro J, Talbert R, editors. Pharmacotherapy: A Pathophysiologic Approach. McGraw-Hill Companies, Inc. New York: 2002 </li></ul><ul><li>http://www.clevelandclinic.org/health/health-info/docs/3300/3376.asp?index=11452 </li></ul><ul><li>http://guidelines.gov/summary/summary.aspx?doc_id=7212&nbr=004306&string=diabetes </li></ul><ul><li>http://www.aocd.org/skin/dermatologic_diseases/acanthosis_nigrica.html </li></ul><ul><li>http://dermatology.cdlib.org/DOJvol6num1/original/acanthosis/katz.html </li></ul>
  76. 77. <ul><li>UptoDate. http:// uptodateonline.com/application/topic.asp?file =diabetes/25035 </li></ul><ul><li>http:// uptodateonline.com/application/topic.asp?file =diabetes/25035 </li></ul><ul><li>http://guidelines.gov/summary/summary.aspx?doc_id=7212&nbr=004306&string=diabetes </li></ul><ul><li>http:// online.statref.com/Document.aspx?FxID =27&DocID=344&QueryID=21476&SessionID=5541B0ANAKYVMKCH   </li></ul><ul><li>http://guidelines.gov/algorithm/3306/NGC3306_1.pdf </li></ul><ul><li>Harrison's Principles of Internal Medicine - 16th Ed. (2005) </li></ul><ul><li>http:// online.statref.com/Document.aspx?DocId =2184&FxId=55&SessionId=54DBF6HNEZUTEQVW&Scroll=1&Index=0 </li></ul><ul><li>Treatment Guidelines from The Medical Letter. Volume 3, Issue 36. August 2005 </li></ul>

×