Presentation on theme: "Pharmacological Management Of Type 2 Diabetes"— Presentation transcript:
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 KSACarbohydrate Metabolism.Risk factors for Type 2 DMDiagnostic criteria for Type 2 DMSigns and symptoms of Type 2 DMLifestyle modification.
3 OUTLINES , cont’d Pharmacotherapy in Type 2 DM. Currently available therapeutic optionsfor Type 2 DM.New medications for managementof 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.
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 INSAUDI ARABIA2000 Diabetics attending Diabetic Center KSU.
10 +ve FAMILY HISTORY in +ve FAMILY HISTORY in general population = 32% DM FAMILY HISTORYIN SAUDI ARABIA:+ve FAMILY HISTORY ingeneral population = 32%+ve FAMILY HISTORY indiabetic 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.RetinopathyNeuropathyNephropathyWHO report 2000.
13 CARBOHYDRATE METABOLISM Homeostatic mechanisms maintain plasmaglucose 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 provideadequate fuel for (CNS), which uses glucose as itsprimary energy source.CNS: Central Nervous System.
14 CARBOHYDRATE METABOLISM – Cont’d Blood glucose concentration exceed theRe-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 ofenergy, but these tissues require insulin forglucose 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 glucoseand its storage as glycogen.It also stimulate the uptake of amino acid and theirconversion to protein.In adipose tissue, glucose is converted to free fattyacids and stored as triglycerides.Insulin prevents a breakdown of thesetriglycerides to free fatty acids.The liver doesn't require insulin for glucosetransport, but insulin facilitates the conversion ofglucose to glycogen and free fatty acids.
16 Fasting Glucose Metabolism in Nondiabetic Individual As blood glucose concentrations drop towardnormal during the fasting state, insulin release isinhibited .A number of counter regulatory hormonesthat promote an increase in blood sugar arereleased (e.g., glucagon, epinephrine, growthhormone, glucocorticoides).Several processes maintain a minimum bloodglucose 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 toliver glucose.Uptake of glucose by insulin dependent tissuesis diminished to conserve glucose for thebrain.Triglycerides are broken down into free fattyacids, which are used as alternative fuelsources.
18 Pathogenesis (1) impaired Insulin secretion (6) HyperglycemiaStimulates the pancreasto produce more insulin(5) Excess glucose accumulationin the circulation(2) Resistance to action of insulin(4) Glucoseoutput(3) GlucoseutilizationHepaticPeripheral
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 earlierage (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 ORFasting Plasma Glucose (FPG)>126 mg/dl ORResults of a 2-hour 75-g Oral GlucoseTolerance Test (OGTT) > 200 mg/dlDiabetes can be made when one of the following criteria is present:
25 Flowchart For The Diagnosis Of Diabetes Mellitus No typical symptomsCasual plasma glucose >11.1 mmol/lORFasting plasma glucose >7.0 mmol/lTypical symptoms and/or acute metabolic decompensationUnequivocal hyperglycemiaCasual PG >11.1 mmol/lORFPG >7.0 mmol/lNOYESRepeat FPGGo tofigure 2FPG>7.0 mmol/lNOYESDM
26 Flowchart For Individuals Suspected To Have Diabetes But Whose FPG <7.0 Mmol/L Oral GlucoseTolerance Test2- hour post -challenge glucose6.1 ( 110 ) ( 124 ) ( 140 ) 11 ( 200 )<7.8mmol/lmmol/l>11.1mmol/lNormalFastingGlucoseImpairedFastingGlycaemiaImpairedGlucoseToleranceDiabetesMellitus
27 GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES NormalBIOCHEMICALINDEX<100( mg/dl )AverageFasting Plasma Glucose OR Pre-prandial Glucose< 180< 120Average 2-hoursPostprandial Plasma Glucose< 140(mg/dl)Average Bedtime Glucose< 7 % (2)4 - 6%A1C (%) - SUSTAINEDWhole blood glucose (mg/dL) = plasma glucose (mg/dL) x 30.85Adapted from Applied Therapeutics, 2005
28 GOALS OF GLYCEMIC CONTROL FOR PEOPLE WITH DIABETES – Cont’d Less than 130/80 mmHgBlood PressuremMol / LMg / dlINDEXLIPIDS< 2.6< 100LDL< 1.7< 150TG> 1.1> 40HDL - Men> 1.4> 50HDL - WomenAdapted from Applied Therapeutics, 2005LDL: Low Denisty LipoproteinHDL: High Denisty LipoproteinTG: 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 Test2 hr½,1,1½ HrFasting< 140(7.8)< 200(11)< 100(5.6)Normal(7.8-11)> 200 (11)< 126(7.0)Impaired Glucose Tolerance( )Impaired Fasting Glucose> 200> 126Diabetes(Non Pregnant Adult)
31 LIFESTYLE MODIFICATION Lifestyle modification is a cornerstone of diabetes management and comprises the following:Medical Nutrition Therapyphysical activity and exerciseavoidance of smoking and alcoholicbeverages.MNT and exercise prescription should be the initial therapy in:obese (BMI > 30.0) andoverweight (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 identifyMacro-vascular, Micro-vascular andneurological 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 orDislipidemic should be discouraged from CONSUMING ALCOHOL.
36 STEPPED-CARE APPROACH TO TREATING TYPE 2 DIABETES MELLITUS Insulin Plus Thiazolidinedione, Metformin, or SulfonylureaInsulinOral Therapy Plus InsulinCombination Oral TherapyAdapted from Applied Therapeutics, 2005Single Oral AgentLifestyle changes: Diet, Exercise, Smoking, Lipids
37 INITIAL TREATMENT STRATEGY Initial Presentation(Based on presentation of the items listed within each box)• Mild or NO symptomsAND• Negative ketones• No acute concurrent illness• FPG > 200OR• Random > 300ANDDoes not meet criteriafor mild or severe• Marked hyperglycemiaOR• Significant weight loss• Severe/significant symptoms OR• 2+ or greater ketonuria OR• DKA, hyperosmolar state OR• Severe intercurrent illness orsurgeryStart MNT &Physical ActivityStart OralAnti-diabeticTherapy6 - 8 weekstarget not metStart InsulinImmediately
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.
40 α-Glucosidase Inhibitor SITES OF ACTIONα-Glucosidase InhibitorMetforminIncreasedHGOGlucoseAbsorptionHYPERGLYCEMIAGlinidesSUTZD’sDecreasedGlucoseUptakeImpaired insulinsecretion
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 BIGUANIDESMECHANISM OF ACTION:Not stimulate insulin release.There is an evidence that Metformin can:FPG by the gluco-neo-genesis and byhepatic 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 acidosisAlcohol intake.Shock.Surgery.Aging.Tittered to minimum effective dose.Renal function to be monitored regularlyMonitor 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 neededAlcohol 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 needed500 – 850 mg TID with meals.Slowly dose by 500 mg once or twice dailyinitially 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 neededDecrease liver glucose output.Improve insulin resistance.Decrease plasma insulin concentrationImprove lipid profile.Increase weight loss.Rarely cause hypoglycemia when usedalone.
49 GlinidesHelp YourPancreas MakeExtra insulinG L I N I D E S
50 MEGLITINIDES ( GLINIDES ) Help YourPancreas MakeExtra insulinMECHANISM OF ACTION:Close ATP sensitive K+ channels in beta cellslead to membrane depolarizationCa +2 influxinsulin secretion.K: PotassiumCa: Calcium.
51 PHARMACOKINETICS NATEGLINIDE REPAGLINIDE Rapidly absorbed. Rapidly absorbed & excreted.Absorption1.5Hr.1 HrT ½Metabolizedby the liverCompletely metabolized by the liver to inactive products.Metabolism75% excreted inthe urine and 10% in the feces.90% is excreted in the feces and 8% is excreted in the urine.ExcretionHighly protein bound (98%).>98%.PPBGlinidesHelp YourPancreas MakeExtra insulinHr: Hour.
52 ADVERSE DRUG REACTIONS: Mild hypoglycemia if intake not followed by food inindividual with blood glucose within normal range.Weight gain KG.CONTRAINDICATIONS & PRECAUTIONS:Should not be given to people with type 1DRUG INTERACTIONS:Enzyme Inducers : Anti-TB , Anti-EpilepticsEnzyme inhibitors: Azoles, Anti-fungal, MacrolidesGlinidesHelp YourPancreas MakeExtra insulinAnti-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.GlinidesHelp YourPancreas MakeExtra insulinNETAGLINIDE: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.TITERThe dose with caution in patient withliver dysfunction.GlinidesHelp YourPancreas MakeExtra insulin
55 Pancreas Make Extra insulin HelpYourPancreas Make Extra insulinS 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 receptorsIncrease 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 thetime 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 Tolbutamide7 hrs1.3 H (Parent compound)5 Hs ( Active metabolites )36 Hr (urine)Acidification serumt ½ to 68.5 hAverage is 7 hrs( hr )GliclazideGlimepirideGlibenclamideGlipizide8 – 12 hrs9 hrs1.5 – 4 hrs2 – 4 hrsDURATION OF ACTIONInterm HrInterm HrLongest 24 – 72 HShortest HrInterm. Up to 24 HrINTERM: Intermediate .
59 METABOLISM Tolazamide Acetohexamide Chlorpropamide Tolbutamide Metabolized to many compounds.Principally metabolized to Active compoundFurther metabolism to inactive metabolites.80%metabolized liverRapid and completeGliclazideGlimepirideGlibenclamideGlipizideMetabolizedin the liverCompletely metabolizedby the liverExtensively metabolizedEXCRETIONAllexcreted in the urine50% of metabolitesExcreted.20% excreted unchanged ( 10-60%)urine alkalanization excretion 4 folds.MetabolitesExcreted in the urine60-80% in the urine20% in the fecesMetabolites excreted in both feces and urine.50% of metabolites excreted by kidneyAnd remaining via biliary tract.Eliminated by the kidney
60 Pancreas Make Extra insulin ADVERSE DRUG REACTIONSSUHelpYourPancreas Make Extra insulinHypoglycemia.Weight gain.GIT symptoms ( Nausea, Fullness, bloating).Rare:Allergic dermatologic reactions,Hepatotoxicity,
61 Pancreas Make Extra insulin HelpYourPancreas Make Extra insulinCONTRAINDICATIONS ANDPRECAUTIONS: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.SUHelpYourPancreas Make Extra insulin
63 TZD’sHelp bodyCells useInsulinbetterG 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 absorptionAbsorptionCompleteHrElem. T ½3 - 4 HrsMainly in the liver by CYP3C4 and CYP2C8MetabolismExtensively metabolized by CYP2c82 active metabolitesMetabolitesLess potent than Parent compound15-30% of the dose is recovered in the urine as metabolites.Reminder excreted in the bile( feces) either as unchanged or metabolites.Excretion2/3rd in urine 1/3rd feces as conjugated metabolites
66 ROSIGLITAZONE PIOGLITAZONE TZD’sHelp bodyCells useInsulinbetterROSIGLITAZONEPIOGLITAZONEOccurs weeksMaximum effect may not be seen for weeks.ONSETBecause mainly excreted via feces with small amounts excreted as metabolites in the urine no dose adjustments are required.RENAL FAILUREAll are extensively bound to serum albumin.PPB
67 ADVERSE DRUG REACTIONS: TZD’sHelp bodyCells useInsulinbetterHEMATOLOGY:Small decrease in Hgb and HctTransient in Neutrophil countsoccurred infrequently withinfirst weeks of therapy.HGB: Hemoglobin .HCT: Hematocrit.
68 ADVERSE DRUG REACTIONS – cont’d TZDsHelp bodyCells useInsulinbetterCARDIOVASCULAR:Increase In plasma volume reported.No CHF has been observedCaution is suggested when usingthis group in CHFMild to moderate edemain small number of patients.CHF: Congestive Heart Failure .
69 ADVERSE DRUG REACTIONS – cont’d TZD’sHelp bodyCells useInsulinbetterHEPATOTOXICITY:Reversible elevation in transaminase( ALT, AST) 3 times the normal values.Enzyme elevation typically peakedbetween the 3rd and 7th month of therapy.ALT: Alanine Aminotransferase .AST: Aspartate Aminotransferase .
70 LFT monitoring for (TZD’s): FDA Requirements forLFT 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’sHelp bodyCells useInsulinbetterType 1 DM.Preexisting hepatic Disease.Severe CHFHypersensitivity 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:CYCLOSPORINETACROLIMUS
73 DOSAGE AND CLINICAL USE: ROSIGLITAZONETZD’sHelp bodyCells useInsulinbetterGreater hypoglycemic effect has been observed whenit 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.PIOGLITAZONEDOSE:15mg QD - starting dose.Up to 45 mg.
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 andsucrose into absorbable monosaccharide ( Glucose ).Reduction occurs only when the agents are taken with meal containing acomplex 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 istransported to the ileum thus prolonging the intestinal digestion.CHO: Carbohydrate .
76 Normal absorption of CHO Duodenum30 cmJejunum120 cmIleum130 cmWithAcarboseAcarbose Blocks Proximal Absorption
77 DOSAGE AND CLINICAL USE: Slowthe digestionofstarchesDOSAGE 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 monthsto the maximum of 200mg TID( maximum response after 6 months ).NOT AFFECT WEIGHT, NOT AFFECT LIPID PROFILE.
78 GI Amylase To Inactive Metabolites PHARMACOKINETICS:MIGLITOLACARBOSEGIT GoodGITABSORPTIONAdvantage of lackingHepatotoxicityGI Amylase To Inactive MetabolitesMETABOLISM2 Hr2.8 HrT ½
79 ADVERSE DRUG REACTIONS: Slowthe digestionofstarchesGIT – MAINLY.Flatulence, diarrhea, abdominal pain.( Due to fermentation ofunabsorbed CHO in small intestine).HEPATOTOXICITY:Monitor LFT monthly in patientusing 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 druglimits the availability of disaccharides andsucrose.Note: hypoglycemia limited to patients withcombination therapy.Slowthe digestionofstarchesD/C: Discontinue .
83 Amylin Analog GLOSSARY INCRETIN: hormone produced by the gastrointestinal tract in response to food intake and necessary for glucose homeostasisINCRETIN 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 AnalogPramlintide (Symlin)®Synthetic analog of the beta-cell hormone Amylin.It is currently approved in the U.S. only as adjunctive therapy withinsulin.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% oftreated patients ( nausea).
85 Pramlintide (Symlin)® Amylin AnalogPramlintide (Symlin)®Symlin also associated with weight loss around 1 – 1.5 Kg over 6month.Dosage and Clinical Use:Empiric insulin dose reductions is necessary to reduce therisk of hypoglycemic episodes.60 mcg SC prior each meals , Max. 120 mcg in the abdomenor thigh, prior major meals.
87 Incretin Mimetics Exenatide (Byetta)® Mechanism of Action: Naturally occurring peptide produced by the L- Cells of the smallintestine.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 postprandialglucose 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 experiencingnausea, vomiting or diarrhea.
89 Incretin Mimetics Exenatide (Byetta)® Dosage and Clinical Use : Adjunctive therapy in Type 2 diabetes who are notadequately controlled despite therapy with Metformin orsulfonylurea or the combination of Metformin andsulfonylurea.5 mcg SC twice daily , within 60 min before the morningand evening meal.
90 Some Anti-diabetic Interventions Summary Other AdvantagesDisadvantagesWeightA1C TG 10-20% - TC 5-10%Not Expensive.Lactic acidosis 1.5%MetforminNot ExpensiveWeight gain Weight gain 2KgSulfonylureasShort DurationWeight gainRepaglinideNo effect on the body weightExpensive,3 times dose %AcarboseImprove lipid profile %TZD’sWeight lossInjections,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/dLEfficacy: alpha-Glucosidase(PPG) by 25 to 50 mg/dL(FPG) by 20 to 30 mg/dLA1c by 0.5% to 1%Efficacy - SU A1c by % FPG by mg/dLTZD’s Efficacy when combinedwith ;(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%.
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 thereforeLess 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 bestdetermined 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 AvoidConsiderPatient situationAcarboseMetforminAcetohexamideGlipizideGlimepirideTolazamideINSULINTZD’sRepaglinides Renal FunctionInsulinRepaglinideMiglitol Liver FunctionHyperlipidemiaSURepaglanideObesityLong acting SUHypoglycemia due to irregular eating patternsAdapted from Applied Therapeutics, 2005