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Pharmacological Management Of Type 2 Diabetes

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1 Pharmacological Management Of Type 2 Diabetes
Manal Hassan Bashihab, Pharmacy Practice Resident First Year

2 OUTLINES Introduction to Type 2 DM
Screening of asymptomatic individuals. Prevalence of Type 2 DM in KSA Carbohydrate Metabolism. Risk factors for Type 2 DM Diagnostic criteria for Type 2 DM Signs and symptoms of Type 2 DM Lifestyle modification.

3 OUTLINES , cont’d Pharmacotherapy in Type 2 DM.
Currently available therapeutic options for Type 2 DM. New medications for management of type 2 DM. Diabetic complications and their preventive measures. Measurement of quality Indicators

4 TYPE 2 DM - AN INTRODUCTION
Disorders of insulin action and secretion. It is characterized by symptomatic glucose intolerance as well as alterations in lipid and protein metabolism. Type 2 diabetes is the most common form of diabetes.

5 TYPE 2 DM – AN INTRODUCTION - Cont’d
Type 2 diabetes is frequently undiagnosed for many years because hyperglycemia develops gradually and at earlier stages. It is often not severe enough for the patient to notice any of the classic symptoms of diabetes. Nevertheless, such patients are at increased risk of developing Macro-vascular and Micro-vascular complications.

6 PREVALENCE OF TYPE 2 DM IN KSA

7 Diseases Distribution In (KSA ) With The Year 2000
Diabetes is the leading disease that put a great pressure on the health system. 2000 Diabetics attending Diabetic Center KSU.

8 70 % GENERAL MORTALITY IN SAUDI DIABETICS 2000 Saudi diabetics
2000 Diabetics attending Diabetic Center KSU.

9 OBESITY IN SAUDI ARABIA 2000 Diabetics attending Diabetic Center KSU.

10 +ve FAMILY HISTORY in +ve FAMILY HISTORY in general population = 32%
DM FAMILY HISTORY IN SAUDI ARABIA: +ve FAMILY HISTORY in general population = 32% +ve FAMILY HISTORY in diabetic population = 38%

11 WHO report 2000. Prevalence of Microvascular complications:
Comparing data from Arab countries with data of the highest & lowest prevalence world wide in the year 2000. Retinopathy Neuropathy Nephropathy WHO report 2000.

12 Carbohydrate Metabolism

13 CARBOHYDRATE METABOLISM
Homeostatic mechanisms maintain plasma glucose concentration between mg/dL (3.1 to 7.8 mmol/L). A minimum concentration of mg/dL (2.2 to 3.3 mmol/L) is required to provide adequate fuel for (CNS), which uses glucose as its primary energy source. CNS: Central Nervous System.

14 CARBOHYDRATE METABOLISM – Cont’d
Blood glucose concentration exceed the Re-absorptive capacity of the kidneys( 180 mg/dL ), glucose spills into the urine resulting in a loss of calories and water. Muscle and fat use glucose as major source of energy, but these tissues require insulin for glucose uptake. If glucose is unavailable, these tissues are able to use amino acids and fatty acids for fuel.

15 Postprandial Glucose Metabolism in the Nondiabetic Individual
In muscle, insulin promotes the uptake of glucose and its storage as glycogen. It also stimulate the uptake of amino acid and their conversion to protein. In adipose tissue, glucose is converted to free fatty acids and stored as triglycerides. Insulin prevents a breakdown of these triglycerides to free fatty acids. The liver doesn't require insulin for glucose transport, but insulin facilitates the conversion of glucose to glycogen and free fatty acids.

16 Fasting Glucose Metabolism in Nondiabetic Individual
As blood glucose concentrations drop toward normal during the fasting state, insulin release is inhibited . A number of counter regulatory hormones that promote an increase in blood sugar are released (e.g., glucagon, epinephrine, growth hormone, glucocorticoides). Several processes maintain a minimum blood glucose concentration for the CNS. CNS: Central Nervous System.

17 Fasting Glucose Metabolism in Nondiabetic Individual – Cont’d
Glycogen in the liver  glucose. Amino acids are transported from muscle to liver  glucose. Uptake of glucose by insulin dependent tissues is diminished to conserve glucose for the brain. Triglycerides are broken down into free fatty acids, which are used as alternative fuel sources.

18 Pathogenesis (1) impaired Insulin secretion
(6) Hyperglycemia Stimulates the pancreas to produce more insulin (5) Excess glucose accumulation in the circulation (2) Resistance to action of insulin (4) Glucose output (3)  Glucose utilization Hepatic Peripheral

19 Insulin Resistance Syndrome

20 RISK FACTORS FOR DIABETES INCLUDE:
Overweight/Obesity - Inactivity. Hypertension. A first degree relative with DM Previous Gestational DM Coronary Heart Disease Dyslipidemia Previously identified impaired fasting glucose (IFG) OR impaired glucose tolerance (IGT).

21 DIAGNOSIS

22 CLINICAL PRESENTATION OF HYPERGLYCEMIA

23 SCREENING OF ASYMPTOMATIC INDIVIDUALS.
Screening of asymptomatic individuals at high risk for Type 2 DM should be carried out on an opportunistic basis. Screening should begin at age 40 years, and be considered at an earlier age (e.g. 30 years) if risk factors for diabetes are present. Screening should be carried out every 3 years for those with normal glucose tolerance and annually for those with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).

24 DIAGNOSTIC CRITERIA OF TYPE 2 DM
(Non-Pregnant Adults) Casual plasma glucose > 200 mg/dl and symptoms of diabetes OR Fasting Plasma Glucose (FPG) >126 mg/dl OR Results of a 2-hour 75-g Oral Glucose Tolerance Test (OGTT) > 200 mg/dl Diabetes can be made when one of the following criteria is present:

25 Flowchart For The Diagnosis Of Diabetes Mellitus
No typical symptoms Casual plasma glucose >11.1 mmol/l OR Fasting plasma glucose >7.0 mmol/l Typical symptoms and/or acute metabolic decompensation Unequivocal hyperglycemia Casual PG >11.1 mmol/l OR FPG >7.0 mmol/l NO YES Repeat FPG Go to figure 2 FPG >7.0 mmol/l NO YES DM

26 Flowchart For Individuals Suspected To Have Diabetes But Whose FPG <7.0 Mmol/L
Oral Glucose Tolerance Test 2- hour post - challenge glucose 6.1 ( 110 ) ( 124 ) ( 140 ) 11 ( 200 ) <7.8 mmol/l mmol/l >11.1 mmol/l Normal Fasting Glucose Impaired Fasting Glycaemia Impaired Glucose Tolerance Diabetes Mellitus

27 GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES
Normal BIOCHEMICAL INDEX <100 ( mg/dl ) Average Fasting Plasma Glucose OR Pre-prandial Glucose < 180 < 120 Average 2-hours Postprandial Plasma Glucose < 140 (mg/dl) Average Bedtime Glucose < 7 % (2) 4 - 6% A1C (%) - SUSTAINED Whole blood glucose (mg/dL) = plasma glucose (mg/dL) x 30.85 Adapted from Applied Therapeutics, 2005

28 GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES – Cont’d
Less than 130/80 mmHg Blood Pressure mMol / L Mg / dl INDEX LIPIDS < 2.6 < 100 LDL < 1.7 < 150 TG > 1.1 > 40 HDL - Men > 1.4 > 50 HDL - Women Adapted from Applied Therapeutics, 2005 LDL: Low Denisty Lipoprotein HDL: High Denisty Lipoprotein TG: Triglycerides.

29 The American Diabetes Association Diagnostic Criteria for DM
Normal and Diabetic Plasma Glucose Levels in mg/dL (mmol/L) for the Oral glucose Tolerance Test 2 hr ½,1,1½ Hr Fasting < 140 (7.8) < 200 (11) < 100 (5.6) Normal (7.8-11) > 200 (11) < 126 (7.0) Impaired Glucose Tolerance ( ) Impaired Fasting Glucose > 200 > 126 Diabetes (Non Pregnant Adult)

30 LIFESTYLE MODIFICATION

31 LIFESTYLE MODIFICATION
Lifestyle modification is a cornerstone of diabetes management and comprises the following: Medical Nutrition Therapy physical activity and exercise avoidance of smoking and alcoholic beverages. MNT and exercise prescription should be the initial therapy in: obese (BMI > 30.0) and overweight (BMI > 25.0) type 2 diabetic patients UNLESS they are SYMPTOMATIC or SEVERELY HYPERGLYCEMIC.

32 MNT should be individualized.
Saturated fat intake should not exceed 10%, with carbohydrates 50-60% and Proteins 15-20% of total calorie intake. Diet should include foods from each of the basic food groups. An EXERCISE PROGRAM TAILORED to suit the individual’s age, fitness, aptitude and interest should be prescribed. A PRE-EXERCISE EVALUATION to identify Macro-vascular, Micro-vascular and neurological complications is recommended.

33 Individuals with diabetes, especially those on insulin treatment, should receive specific
EDUCATION on the prevention of exercise-induced hypoglycemia. Individuals with diabetic neuropathy should avoid exercises associated with REPETITIVE FOOT TRAUMA. Individuals with severe diabetic Proliferative Retinopathy should avoid activities that dramatically elevate blood pressure.

34 Individuals with diabetes should be discouraged
from SMOKING. Diabetic patients with poor glycemic control or Dislipidemic should be discouraged from CONSUMING ALCOHOL.

35 PHARMACOLOGICAL MANAGEMENT OF TYPE 2 DM

36 STEPPED-CARE APPROACH TO TREATING TYPE 2 DIABETES MELLITUS
Insulin Plus Thiazolidinedione, Metformin, or Sulfonylurea Insulin Oral Therapy Plus Insulin Combination Oral Therapy Adapted from Applied Therapeutics, 2005 Single Oral Agent Lifestyle changes: Diet, Exercise, Smoking, Lipids

37 INITIAL TREATMENT STRATEGY
Initial Presentation (Based on presentation of the items listed within each box) • Mild or NO symptoms AND • Negative ketones • No acute concurrent illness • FPG > 200 OR • Random > 300 AND Does not meet criteria for mild or severe • Marked hyperglycemia OR • Significant weight loss • Severe/significant symptoms OR • 2+ or greater ketonuria OR • DKA, hyperosmolar state OR • Severe intercurrent illness or surgery Start MNT & Physical Activity Start Oral Anti-diabetic Therapy 6 - 8 weeks target not met Start Insulin Immediately

38 Considerations For Selecting Initial Oral hypoglycemic Therapy
A combination of two drugs of different classes may be used as initial pharmacotherapy when there is marked hyperglycemia or when MNT & physical activity alone have not resulted in an A1C of < 8.0% . MNT: Medical Nutrition Therapy.

39 ORAL HYPOGLYCEMIC AGENTS
BIGUANIDES GLINIDES SULFONYLUREAS THIAZOLIDINEDIONE -GLUCOSADASE INHIBITORS:

40 α-Glucosidase Inhibitor
SITES OF ACTION α-Glucosidase Inhibitor Metformin Increased HGO Glucose Absorption HYPERGLYCEMIA Glinides SU TZD’s Decreased Glucose Uptake Impaired insulin secretion

41 Stop the liver from making extra sugar when it is not needed
B I G U A N I E S

42 Stop the liver from making extra sugar when it is not needed
BIGUANIDES MECHANISM OF ACTION: Not stimulate insulin release. There is an evidence that Metformin can: FPG by the gluco-neo-genesis and by hepatic glucose production. It seems to improve peripheral sensitivity to insulin: enhanced glucose disposal and clearance. decreased plasma insulin concentration. TG ( %) by long term therapy.  Total cholesterol ( 5-10 % ) HDL by small increments. Weight loss more likely to occur. Stop the liver from making extra sugar when it is not needed

43 Stop the liver from making extra sugar when it is not needed
PHARMACOKINETICS: ABSORPTION: From small intestine ( 50 – 60 %) ELIMINATION: Kidney as un-metabolized medication. PLASMA T ½: 6.2 Hrs. PLASMA PROTEIN BINDING: Not bound to plasma protein. Stop the liver from making extra sugar when it is not needed

44 Stop the liver from making extra sugar when it is not needed
ADVERSE DRUG REACTIONS: Diarrhea, GI Disturbances, Abdominal Discomfort, Metallic Taste. Lactic Acidosis. Stop the liver from making extra sugar when it is not needed

45 Stop the liver from making extra sugar when it is not needed
CONTRAINDICATIONS AND PRECAUTIONS: Renal impairment ( may accumulate GFR less than 60 ml/min ) Hepatic disease. CHF. History of lactic acidosis Alcohol intake. Shock. Surgery. Aging. Tittered to minimum effective dose. Renal function to be monitored regularly Monitor CrCl in patients over 80 years. Stop the liver from making extra sugar when it is not needed

46 Stop the liver from making extra sugar when it is not needed
DRUG INTERACTIONS: Stop the liver from making extra sugar when it is not needed Alcohol potentiates the effect of Metformin on lactate metabolism. Parenteral contrast studies (e.g., angiography) that use iodinated materials.

47 Stop the liver from making extra sugar when it is not needed
Dosage & Clinical Use: Stop the liver from making extra sugar when it is not needed 500 – 850 mg TID with meals. Slowly  dose by 500 mg once or twice daily initially followed by  weekly increments of 500 mg daily. Not used in patients over 80 Y.O. unless normal Renal function. (CrCl is  60 ml/min). CrCl : Creatinine Clearance.

48 Stop the liver from making extra sugar when it is not needed
METFORMIN HAS POTENTIAL ADVANTAGES: Stop the liver from making extra sugar when it is not needed Decrease liver glucose output. Improve insulin resistance. Decrease plasma insulin concentration Improve lipid profile. Increase weight loss. Rarely cause hypoglycemia when used alone.

49 Glinides Help Your Pancreas Make Extra insulin G L I N I D E S

50 MEGLITINIDES ( GLINIDES )
Help Your Pancreas Make Extra insulin MECHANISM OF ACTION: Close ATP sensitive K+ channels in beta cells lead to membrane depolarization Ca +2 influx insulin secretion. K: Potassium Ca: Calcium.

51 PHARMACOKINETICS NATEGLINIDE REPAGLINIDE Rapidly absorbed.
Rapidly absorbed & excreted. Absorption 1.5Hr. 1 Hr T ½ Metabolized by the liver Completely metabolized by the liver to  inactive products. Metabolism 75% excreted in the urine and 10% in the feces. 90% is excreted in the feces and 8% is excreted in the urine. Excretion Highly protein bound (98%). >98%. PPB Glinides Help Your Pancreas Make Extra insulin Hr: Hour.

52 ADVERSE DRUG REACTIONS:
Mild hypoglycemia if intake not followed by food in individual with blood glucose within normal range. Weight gain KG. CONTRAINDICATIONS & PRECAUTIONS: Should not be given to people with type 1 DRUG INTERACTIONS: Enzyme Inducers : Anti-TB , Anti-Epileptics Enzyme inhibitors: Azoles, Anti-fungal, Macrolides Glinides Help Your Pancreas Make Extra insulin Anti-TB: Anti Tuberculosis.

53 DOSAGE AND CLINICAL USE:
REPAGLINIDE: If A1C  8% starting dose = 0.5 mg with each meal. If A1C  8% starting dose = 1-2 mg. Weekly tittered the dose by 1 mg Per Each Meal. Maximum Dose: 4 mg per dose or 16 mg per day. Glinides Help Your Pancreas Make Extra insulin NETAGLINIDE: 60 or 120 mg TID

54 ROLE: OMMITT ADD TITER The dose if you skipped the meal.
The dose if you add an extra meal. TITER The dose with caution in patient with liver dysfunction. Glinides Help Your Pancreas Make Extra insulin

55 Pancreas Make Extra insulin
Help Your Pancreas Make Extra insulin S U L F O N Y L U R E A S

56 SULFONYLUREAS FIRST GENERATION: SECOND GENERATION:
Acetohexamide, chlorpropamide, tolazamide, and tolbutamide. SECOND GENERATION: Glipizide, Gliburide, Gliclazide, and Glimepiride. MECHANISM OF ACTION: (A) - Stimulate insulin release from pancreas beta cells specific receptors Increase beta cell sensitivity to glucose. (B) Extra-pancreatic effect ( Sulfonylureas can): NORMALIZE hepatic glucose production, REVERSE insulin resistance in peripheral tissues in type 2 DM. BUT failure of this effect in type 1 DM.

57 PHARMACOKINETICS OF ORAL SULONYLUREAS
All are highly protein binding 90 – 100%. Food does not impair the extent of absorption but may delay the time to peak. TOLBUTAMIDE & GLIPIZIDE: More effectively when given 30 min before meal, rather than with meal. GLIBINCLAMIDE: Unlike Glipizide Food does NOT delay the rate or extent of absorption.

58 Pharmacokinetics: HALF LIFE : Tolazamide Acetohexamide Chlorpropamide
Tolbutamide 7 hrs 1.3 H (Parent compound) 5 Hs ( Active metabolites ) 36 Hr (urine) Acidification  serum t ½ to 68.5 h Average is 7 hrs ( hr ) Gliclazide Glimepiride Glibenclamide Glipizide 8 – 12 hrs 9 hrs 1.5 – 4 hrs 2 – 4 hrs DURATION OF ACTION Interm Hr Interm Hr Longest 24 – 72 H Shortest Hr Interm. Up to 24 Hr INTERM: Intermediate .

59 METABOLISM Tolazamide Acetohexamide Chlorpropamide Tolbutamide
Metabolized to many compounds. Principally metabolized to Active compound Further metabolism to inactive metabolites. 80% metabolized liver Rapid and complete Gliclazide Glimepiride Glibenclamide Glipizide Metabolized in the liver Completely metabolized by the liver Extensively metabolized EXCRETION All excreted in the urine 50% of metabolites Excreted. 20% excreted unchanged ( 10-60%) urine alkalanization excretion 4 folds. Metabolites Excreted in the urine 60-80% in the urine 20% in the feces Metabolites excreted in both feces and urine. 50% of metabolites excreted by kidney And remaining via biliary tract. Eliminated by the kidney

60 Pancreas Make Extra insulin
ADVERSE DRUG REACTIONS SU Help Your Pancreas Make Extra insulin Hypoglycemia. Weight gain. GIT symptoms ( Nausea, Fullness, bloating). Rare: Allergic dermatologic reactions, Hepatotoxicity,

61 Pancreas Make Extra insulin
Help Your Pancreas Make Extra insulin CONTRAINDICATIONS AND PRECAUTIONS: Type 1 DM. Pregnancy and lactation. Severe hepatic or renal dysfunction. Severe acute intercurrent illness or stress.

62 Pancreas Make Extra insulin
DRUG INTERACTIONS: Antacids:  Glyburide absorption due to  gastric PH. Chloramphenicol: Tolbutamide hepatic metabolism and t½ 2-3 fold. Salicylates: may  sulfonylurea activity through protein binding displacement or inhibition of active renal tubular secretion. Rifampin:  Tolbutamide and Glyburide metabolism. SU Help Your Pancreas Make Extra insulin

63 TZD’s Help body Cells use Insulin better G L I T A Z O N E S

64 THIAZOLIDINEDIONE MECHANISM OF ACTION:
These drugs  insulin resistance In MUSCLE and LIVER, which enhances glucose utilization and  hepatic glucose output. Because this group enhance the effect of insulin, insulin must be present for them to exert their clinical effect. They bind to and activate a nuclear receptor (PPAR-γ ) That is present in many insulin sensitive tissues to regulates the transcription of insulin responsive- genes that influence glucose and lipid metabolism. PPAR-γ: Peroximase Proliferator Activated Receptor Gamma .

65 Pharmacokinetics: PIOGLITAZONE ROSIGLITAZONE PKa Absorption Elem. T ½
Food does not alter absorption Absorption Complete Hr Elem. T ½ 3 - 4 Hrs Mainly in the liver by CYP3C4 and CYP2C8 Metabolism Extensively metabolized by CYP2c8 2 active metabolites Metabolites Less potent than Parent compound 15-30% of the dose is recovered in the urine as metabolites. Reminder excreted in the bile ( feces) either as unchanged or metabolites. Excretion 2/3rd in urine 1/3rd feces as conjugated metabolites

66 ROSIGLITAZONE PIOGLITAZONE
TZD’s Help body Cells use Insulin better ROSIGLITAZONE PIOGLITAZONE Occurs weeks Maximum effect may not be seen for weeks. ONSET Because mainly excreted via feces with small amounts excreted as metabolites in the urine no dose adjustments are required. RENAL FAILURE All are extensively bound to serum albumin. PPB

67 ADVERSE DRUG REACTIONS:
TZD’s Help body Cells use Insulin better HEMATOLOGY: Small decrease in Hgb and Hct Transient  in Neutrophil counts occurred infrequently within first weeks of therapy. HGB: Hemoglobin . HCT: Hematocrit.

68 ADVERSE DRUG REACTIONS – cont’d
TZDs Help body Cells use Insulin better CARDIOVASCULAR: Increase In plasma volume reported. No CHF has been observed Caution is suggested when using this group in CHF Mild to moderate edema in small number of patients. CHF: Congestive Heart Failure .

69 ADVERSE DRUG REACTIONS – cont’d
TZD’s Help body Cells use Insulin better HEPATOTOXICITY: Reversible elevation in transaminase ( ALT, AST)  3 times the normal values. Enzyme elevation typically peaked between the 3rd and 7th month of therapy. ALT: Alanine Aminotransferase . AST: Aspartate Aminotransferase .

70 LFT monitoring for (TZD’s):
FDA Requirements for LFT monitoring for (TZD’s): • If initial ALT is > 2.5 times normal, do not start this medication • Once TZD is started, monitor ALT periodically thereafter according to clinical judgment. • If ALT is > 2.5 times normal during treatment, check weekly. If rise persists or becomes 3 times > normal, discontinue TZD

71 CONTRAINDICATIONS AND PRECAUTIONS
TZD’s Help body Cells use Insulin better Type 1 DM. Preexisting hepatic Disease. Severe CHF Hypersensitivity to this group. Drugs metabolized by CYP3A4

72 HEPATIC MICROSOMAL ENZYME:
DRUG INTERACTIONS: HEPATIC MICROSOMAL ENZYME: Pioglitazone induce hepatic microsomal enzyme (CYP3A4) Rosiglitazone does not appear to inhibit any of the major CYP enzymes. And this is the underlying mechanism for their interactions with ESTROGEN and TERFENADINE (  level by %) , and should be alert about other medications metabolized by this enzyme: CYCLOSPORINE TACROLIMUS

73 DOSAGE AND CLINICAL USE:
ROSIGLITAZONE TZD’s Help body Cells use Insulin better Greater hypoglycemic effect has been observed when it is given as 2 divided doses rather than as single dose. Typical dose is 4 mg QD or 2 mg BID, regardless of meal. Dose can be titrated up to 8 mg BID. PIOGLITAZONE DOSE:15mg QD - starting dose. Up to 45 mg.

74 Alpha Glucosidase Inhibitors
Slow the digestion of starches Alpha Glucosidase Inhibitors

75 ALPHA GLUCOSIDASE INHIBITORS:
MECHANISM OF ACTION: Reversibly inhibits variety of enzymes ( GLUCOSIDASES ) present in the BRUSH BORDER of mucosa of small intestine  that are responsible for breakdown of complex poly saccharides and sucrose into absorbable monosaccharide ( Glucose ). Reduction occurs only when the agents are taken with meal containing a complex CHO. Slow the absorption of glucose into blood. Diminish the rise in postprandial blood glucose. The portion of CHO that remains undigested in the jejunum is transported to the ileum  thus prolonging the intestinal digestion. CHO: Carbohydrate .

76 Normal absorption of CHO
Duodenum 30 cm Jejunum 120 cm Ileum 130 cm With Acarbose Acarbose Blocks Proximal Absorption

77 DOSAGE AND CLINICAL USE:
Slow the digestion of starches DOSAGE AND CLINICAL USE: DOSE: 50 mg TID if the patient is less than 60 KG. 100 mg TID over 60 KG. Increase by 25 mg per meal every 1-2 months to the maximum of 200mg TID ( maximum response after 6 months ). NOT AFFECT WEIGHT, NOT AFFECT LIPID PROFILE.

78 GI Amylase To Inactive Metabolites
PHARMACOKINETICS: MIGLITOL ACARBOSE GIT Good GIT ABSORPTION Advantage of lacking Hepatotoxicity GI Amylase To Inactive Metabolites METABOLISM 2 Hr 2.8 Hr T ½

79 ADVERSE DRUG REACTIONS:
Slow the digestion of starches GIT – MAINLY. Flatulence, diarrhea, abdominal pain. ( Due to fermentation of unabsorbed CHO in small intestine). HEPATOTOXICITY: Monitor LFT monthly in patient using more than 150 mg / day

80 CONTRAINDICATIONS & PRECAUTIONS:
GIT CONDITIONS: Malabsorption, IBS, intestinal obstruction. LIVER DISEASE: Monitor Monthly, D/C If increased. HYPOGLYCEMIA: Should be titrated by glucose because the drug limits the availability of disaccharides and sucrose. Note: hypoglycemia limited to patients with combination therapy. Slow the digestion of starches D/C: Discontinue .

81 DRUG INTERACTIONS: Absorption diminished by: CHARCOAL,
Slow the digestion of starches DRUG INTERACTIONS: Absorption diminished by: CHARCOAL, DIGESTIVE Enzyme Preparations.

82 NON-INSULIN SYNTHETIC ANALOGS
(B) INCRETIN MIMETICS AND NON-INSULIN SYNTHETIC ANALOGS

83 Amylin Analog GLOSSARY INCRETIN:
hormone produced by the gastrointestinal tract in response to food intake and necessary for glucose homeostasis INCRETIN MIMETICS: a class of agents used for managing type 2 diabetes that mimics the enhancement of glucose-dependent insulin secretion and other gluco-regulatory actions of naturally occurring Incretins

84 Pramlintide (Symlin)®
Amylin Analog Pramlintide (Symlin)® Synthetic analog of the beta-cell hormone Amylin. It is currently approved in the U.S. only as adjunctive therapy with insulin. Mechanism of Action: It is administered SC before meals and slows gastric emptying. Preventing an increase of Serum Glucagon after meal. Increasing the feeling of satiety, promote weight loss. It decreases the A1C by 0.5 – 0.7 %. The major clinical side effects are GIT, approximately in 30% of treated patients ( nausea).

85 Pramlintide (Symlin)®
Amylin Analog Pramlintide (Symlin)® Symlin also associated with weight loss around 1 – 1.5 Kg over 6 month. Dosage and Clinical Use: Empiric insulin dose reductions is necessary to reduce the risk of hypoglycemic episodes. 60 mcg SC prior each meals , Max. 120 mcg in the abdomen or thigh, prior major meals.

86 Incretin Mimetics

87 Incretin Mimetics Exenatide (Byetta)® Mechanism of Action:
Naturally occurring peptide produced by the L- Cells of the small intestine. Exenatide is synthetic Exendin -4 was approved for use in the U.S. in 2005. Mechanism of Action: Stimulation GLP-1 receptor in the pancreatic beta cell. Stimulation of the production of insulin . Inhibition of the release of glucagon after meals. Slowing the rate of gastric emptying . Appetite suppression and weight loss . GLP-1: Glucagon - Like Peptide 1 Receptor Agonist.

88 Incretin Mimetics Exenatide (Byetta)®
It lowers A1C by 0.5 – 1 % mainly by lowering postprandial glucose levels. Associated with an around 2-3 Kg weight loss over 6 month. Associated with hypoglycemia. Majority of side effects 30-45% of treated patients experiencing nausea, vomiting or diarrhea.

89 Incretin Mimetics Exenatide (Byetta)® Dosage and Clinical Use :
Adjunctive therapy in Type 2 diabetes who are not adequately controlled despite therapy with Metformin or sulfonylurea or the combination of Metformin and sulfonylurea. 5 mcg SC twice daily , within 60 min before the morning and evening meal.

90 Some Anti-diabetic Interventions Summary
Other Advantages Disadvantages Weight A1C  TG 10-20% -  TC 5-10% Not Expensive. Lactic acidosis  1.5% Metformin Not Expensive Weight gain Weight gain  2Kg Sulfonylureas Short Duration Weight gain Repaglinide No effect on the body weight Expensive, 3 times dose  % Acarbose Improve lipid profile  % TZD’s Weight loss Injections, Little experience  2-3 Kg  0.5 – 1 % Exenatide  1-1.5Kg  0.5 – 0.7 % Pramlintide

91  FBG to 61 mg/dL.  PPG to 48 mg/dL.  A1c by 1.7%.
Metformin Efficacy:  A1c by 1.5% to 1.7%  FPG by mg/dL Efficacy: alpha-Glucosidase (PPG) by 25 to 50 mg/dL (FPG) by 20 to 30 mg/dL A1c by 0.5% to 1% Efficacy - SU  A1c by %  FPG by mg/dL TZD’s Efficacy when combined with ; (SU) A1c = 0.9% - 1.3% (Metformin) A1c = 0.8% -1.2% (Insulin) A1c = 0.6% - 1.0% Efficacy of Repaglinide  FBG to 61 mg/dL.  PPG to 48 mg/dL.  A1c by 1.7%.

92 COMBINATION THERAPY

93 SUGGESTED WELL-STUDIED COMBINATION THERAPY:
• Insulin Secretagogue + Metformin** • Sulfonylurea + Alpha-Glucosidase Inhibitor • Thiazolidinediones + Sulfonylurea** • Thiazolidinediones + Metformin** • Thiazolidinediones + Repaglinide • Sulfonylurea + Exenatide • Metformin + Exenatide

94 Glipizide / Metformin (Metaglib)®
2.5/250 mg, 2.5/500 mg, 5/500 mg. Glyburide / Metformin (Glucovance)® 1.25/500 mg, 2.5/500mg, Metformin / Rosiglitazone (Avandamet) ® 500/1mg, 500/2 mg, 500/4 mg

95 COMBINATION THERAPY OF INSULIN WITH ORAL AGENTS

96 COMBINATION THERAPY OF INSULIN WITH ORAL AGENTS
In type 2 diabetes, management using oral agents should be combined, or replaced, with insulin therapy depending on disease progression and development of secondary failure of oral agents. Decisions to introduce insulin therapy to type 2 diabetic patients are often predicated on their inability to achieve target HbA1c levels after a duration of about 6 months or so, despite good compliance with optimal oral anti-diabetic regimens coupled with weight control and exercise programs.

97 COMBINATION THERAPY OF INSULIN WITH ORAL AGENTS
This may be initiated as a bedtime dose of intermediate or long acting or insulin with maintenance of oral agents during the day, an approach frequently termed bedtime insulin and daytime sulfonylurea or BIDS for short. In patients with satisfactory fasting and pre-meal blood glucose levels but elevated post-dinner or bedtime readings,using premixed regular and intermediate-acting insulin pre-dinner may prove more effective than intermediate-acting insulin at bedtime. Introduction of insulin should not be delayed if metabolic control becomes suboptimal.

98 THE ADVANTAGES OF BIDS INCLUDE:
Improved glycemic control with a smaller dose of insulin and therefore Less weight gain than pure insulin therapy.

99 When glycemic control is not achieved despite BIDS regimen,
discontinuing Sulfonylurea and switching to basal-bolus insulin regimen becomes necessary. However, Metformin and Thiazolidinediones or α- Glucosidase inhibitors may still be used in conjunction with exogenous insulin to attenuate the insulin dose. Fine-tuning of insulin doses is best determined by home blood glucose monitoring.

100 Type 2 diabetes subjects who are switched to insulin temporarily during episodes of acute stress, such as sepsis, may be put back on oral agents when their glycemic control improves with declining insulin resistance and gluco-toxicity.

101 Treating Type 2 Diabetes Under Special Situations
Avoid Consider Patient situation Acarbose Metformin Acetohexamide Glipizide Glimepiride Tolazamide INSULIN TZD’s Repaglinides  Renal Function Insulin Repaglinide Miglitol  Liver Function Hyperlipidemia SU Repaglanide Obesity Long acting SU Hypoglycemia due to irregular eating patterns Adapted from Applied Therapeutics, 2005

102 CHRONIC DIABETIC COMPLICATIONS

103 The Risk Of Serious Complications Is Increased
Dramatically In Diabetes Mellitus Relative Risk Complication 20 X Blindness 25 X End-stage Renal disease 40 X Amputation 2 - 5 % Myocardial Myocardial 2 - 3 % Stroke

104 Biology of Microvascular Complications:
Eye Kidney Nerves Retinopathy Cataract Glaucoma Nephropathy Microalbuminuria Gross albuminuria Neuropathy Peripheral Autonomic Blindness Kidney Failure Amputation Death OR Diasbility

105 Biology of Macrovascular Complications:
Heart Brain Extremities Coronary Artery Disease Cerebrovascular Disease Peripheral Vascular Disease Ulceration Gangrene Amputation Heart attacks Heart Failure Stroke Cognitive impairment

106 MEASUREMENT OF QUALITY INDICATORS

107 Measurement of quality Indicators
Recommended Frequency Quality Indicator High risk: 3-4 month At risk: 6 monthly HbA1c High risk: as clinically indicated At risk: annual Eye assessment Foot assessment Nephropathy assessment At risk: 3-4 month Blood pressure Weight and BMI Lipid profile At risk: as clinically indicated Cardiac assessment Self-management education

108 SUMMARY Diabetes is more than a glucose issue!
Empower the person with diabetes Think PREVENTION! Screen early Treat aggressively

109 Willing is not enough We must DO!
Knowing is not enough we must APPLY !


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