Diabetes mellitus amol

Diabetes mellitus amol

• 1.
  Drug Management of Diabetes Mellitus Dr. Amol Diwan SKNMC, Pune
• 2.
  Diabetes Mellitus • Diabetesmellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. • The name 'diabetes mellitus' derives from: Greek: 'diabetes' – “siphon” or “to pass through” Latin: 'mellitus' – “honeyed” or “sweet”** • Two major types : Type 1 and Type 2 • There is either ABSOLUTE or RELATIVE deficiency of insulin
• 3.
  Classification • Type 1 diabetes • Type 2 diabetes • Other 1. Genetic defects of beta cell function 2. Genetic defects in insulin action 3. Diseases of the exocrine pancreas 4. Endocrinopathies 5. Drug/ chemical - induced 6. Infections 7. Uncommon forms of immune-mediated diabetes 8. Genetic syndromes sometimes associated with diabetes • Gestational diabetes mellitus
• 4.
  Criteria for thediagnosis of diabetes mellitus A. Random plasma glucose concentration ≥200 mg/dl (11.1 mmol/l), with or without classic symptoms Random is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, polyphagia and unexplained weight loss. OR B. Fasting Plasma Glucose is ≥ 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h. OR C. 2-h post glucose load is ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. Oral Glucose Tolerance Test should be performed as described by WHO, taking a glucose load of 75 g glucose dissolved in water Any of these criteria establishes the diagnosis but needs to be confirmed on a later day HbA1c • It measures the amount of glycosylated hemoglobin in blood • It is not useful for the diagnosis of diabetes mellitus • It is often used for monitoring long-term glycemic control and reflect glycemia for the previous 3 months • Its recommended level for a good glycemic is less than 6.5%.
• 5.
  Prediabetes: IFG, IGT,Increased A1C Categories of increased risk for diabetes (prediabetes)* FPG 100–125 mg/dL: IFG OR 2-h plasma glucose in the 75-g OGTT 140–199 mg/dL: IGT OR A1C 5.7–6.4% ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S13. Table 3.
• 6.
  Therapeutic aims • Glycemiccontrol • Treatment of conditions associated with DM – Obesity – Hypertension – Dyslipidemia – Ischemic heart disease • Detection / treatment of DM related complications – renal – cardiovascular – retinal and – neuropathic
• 7.
  Therapeutic strategies • Diabetesmanagement should begin with Medical Nutrition Therapy (MNT) (A typical day’s meals and snacks should provide 1,500–2,000 calories with 50% of the calories from carbohydrate, 20% from protein, and 30% from fat) • An exercise regimen to increase insulin sensitivity and promote weight loss should also be started. • If the patient’s glycemic target is not achieved after 3 to 4 weeks of MNT & exercise regimen, pharmacologic therapy is indicated.
• 8.
  Pharmacologic (DRUG) management •Pharmacologic management of for Type 1DM is only insulin • Pharmacologic management of Type 2 DM includes both oral glucose lowering agents or/ plus insulin (As Type 2 DM is a progressive disorder, it ultimately requires multiple therapeutic agents and often insulin)
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  Recap of Drugs
• 10.
  Oral Glucose LoweringAgents, also called Oral Hypoglycemic Agents (OHA) Based on their mechanisms of action, oral glucose lowering agents are subdivided into those: 1. Increase insulin secretion ( Insulin Secretagogues) 2. Reduce glucose production 3. Decrease glucose absorption from GIT 4. Increase insulin sensitivity
• 11.
  1.Insulin Secretagogues (hypoglycemicagents) Sulfonylureas Meglitinides 1st. Generation: Acetohexamide Chlorpropamide Rapaglinide (0.25 - 4 mg tid/ qid) Tolazamide Nateglinide Tolbutamide (rarely used now ) 2nd. Generation: Glibenclamide (Glyburide) Glipizide Glicazide Glimepiride
• 12.
  Second generation sulfonylurea Morepotent  have fewer adverse effects  have fewer drug interactions  has longer duration (24 h)  e.g. Glipizide, glyburide (Glibenclamide), glimepiride  Contraindicated in hepatic impairement or renal insufficiency
• 13.
  Second generation sulfonylurea Examples Starting dose Max. daily dose Glibenclamide 1.25 mg – 2.5 mg 15 mg (5 mg) Glipizide 2.5 mg – 5 mg 40 mg (5 mg) Gliclazide 20 mg – 40 mg 320 mg (80 mg) Glimepride 1 - 2 mg 6 – 8 mg
• 14.
  Unwanted Effects: • Hyperinsulinemia& Hypoglycemia: • More in chlorpropamide & glibenclamide • Less in tolbutamide. • More in elderly and patients with renal disease. • Weight gain due to increase in appetite • GIT upset. • Dilutional hyponatremia, water intoxication (Chlorpropamide) vasopressin effect. • Disulfiram-like reaction with alcohol (chlorpropamide). • Tachyphylaxis (secondary failure).
• 15.
  Drugs which decreasehypoglycemic effect: • Microsomal inducers. • Thiazide diuretics • Corticosteroids. • Diazoxide. CONTRAINDICATIONS: • Pregnancy (use insulin) • Hepatic or renal insufficiency • Type I diabetes
• 16.
  Insulin Secretagogues (Sulfonylureas) • Mechanism of action: These drugs stimulate insulin secretion by interacting with the ATP sensitive K+ channel on the beta cells of pancreas - must have functional beta cells - • 1st generation sulfonylureas have a longer plasma half-life which causes a greater incidence of hypoglycemia • 2nd generation sulfonylureas are generally preferred, because they cause much less hypoglycemia due to their shorter half-life
• 17.
  Sulfonylureas 1. ADRs: hypoglycemia, weight gain 2. Contraindications: Type 1 DM, liver or kidney disease, sulfa allergy, pregnancy 3. Clinical advantage: Lean patients with high blood glucose 3. Drug interactions Drugs which can increase hypoglycemic effects of sulfonylureas 1. NSAIDs, 2. Sulfonamides 3. Warfarin 4. Beta -blockers Drugs which can decrease hypoglycemic effects of sulfonylureas 1. Thiazides, 2. Hydantoins 3. Oral contraceptives 4. Corticosteroids
• 18.
  Oral Antidiabetic Agents • Insulin secretagogues Hypoglycemia, is a side effect common to almost ALL these drugs – Sulfonylureas – Meglitinides Almost ALL of them are • Biguanides: Metformin contraindicated in severe liver, renal • Thiazolidinediones andAlpha glucosidase inhibitors should be • cardiac disease and used with extreme caution in elderly
• 19.
  Insulin Secretagogues (Meglitinides) Repaglinide / Nateglinide • Mechanism of Action: also interact with the ATP-sensitive K+ - channel and increase insulin secretion from β-cell of pancreas. • They have – Fast onset of action (<1h.) – short half-lives (1h.) – short duration of action(4h.) • So these agents are taken immediately before each meal • Clinical advantage: Effective in reducing post prandial hyperglycemia and hypoglycemia is rare • Dose: 0.25 – 4.0 mg (repaglinide) & 60-120 mg (nateglinide) tid / qid • ADR: They should be cautiously used in hepatic & renal dysfunctions
• 20.
  Meglitinides • Examples • Rapaglinide- Starting dose 0.5 mg 3 times before meal • Max. daily dose 8 mg • Nateglinide - Starting dose 120 mg 3 times before meal • Max. daily dose 360 mg
• 21.
  Adverse effects ofMeglitinides • Less incidence than sulfonylureas • Hypoglycemia (if meal is delayed) • Weight gain • Drug interactions - Repaglinide has recently been contraindicated in patients taking gemfibrozil due to the risk of severe/prolonged hypoglycemia - Clarithromycin, itraconazole, ketoconazole, MAOIs - Due to CYP2C8 and CYP3A4 interactions Contraindications • Hepatic and renal impairment.
• 22.
  2. BIGUANIDES 1. Metformin is the only drug used 2. Mechanisms of action: – Reduced hepatic gluconeogenesis – Increased glycolysis in peripheral tissues – Reduced absorption of glucose from GIT – Decreased plasma glucagon level 3. The initial starting dose is 500 mg OD/ BID, upto 1000 mg BID 4. ADR: Metallic taste in the mouth, diarrhea, anorexia, nausea, and loss of appetite The major ADR of metformin is lactic acidosis 5. Clinical Advantage: No hypoglycemia and No weight gain Useful in OBESE diabetics with not very high Blood Glucose 6. Metformin is contraindicated in patients with – renal / liver diseases – Lactic acidosis-any form of acidosis – congestive heart failure – Use of contrast radiography (should be stopped 48 hrs. before) – Long term use interferes with B12 absorption – Pregnancy
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  BIGUANIDES • Metformin 500mg • Starting dose 500 mg 1-3 doses with meals • 1000 mg ER od • Maximum dose 3000 mg • Tablets to be taken with or just after meal.
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  3. α-GLOCUSIDASE INHIBITORS Examples:acarbose, miglitol and Voglibose M.O.A.: Reversible inhibitors of intestinal alpha- glucosidases in intestinal brush border responsible for degradation of oligosaccharides to monosaccharides. include sucrase, maltase, dextranase, glycoamylase. Dose: start with a low dose (25 mg of acarbose or miglitol) and may be increased over weeks to months ADRs: diarrhea, flatulence, abdominal distention Clinical advantage: Pre-diabetic, obese persons
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  α-GLOCUSIDASE INHIBITORS • Acarbose25/50 mg • Start with 25 – 50 mg 1 – 3 times with first bite of meal • Max dose - 300 mg in divided dose
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  Kinetics of α-glucosidase inhibitors • Acarbose • Given orally, poorly absorbed. • Metabolized by intestinal bacteria. • Excreted in stool and urine. • Miglitol • well absorbed, no systemic effects. • Excreted unchanged in urine. • 6 times more potent inhibitor for sucrase
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  Uses of alpha-glucosidase inhibitors • Type II diabetics inadequately controlled by diet with or without other agents ( SU, Metformin) alone or combined with insulin or sulfonylurea.
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  Contraindications of α-glucosidase inhibitors • Inflammatory bowel disorders (IBD). • Renal disease. • Hepatic disease (used with caution). • Intestinal obstruction.
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  4. THIAZOLIDINEDIONES (glitazones) Rosiglitazone and Pioglitazone (Tro / Ciglitazone) • These drugs bind to the PPAR–y (peroxisome proliferators-activated receptor-y) nuclear receptor in adipose tissues • They correct insulin resistance • The first drug of this group, troglitazone, was withdrawn due to hepatotoxicity • For rosiglitazone and pioglitazone, liver function tests are recommended before starting and at regular intervals • These drugs are contraindicated in patients with liver disease or congestive heart failure • The safety of thiazolidinediones in pregnancy is not established.
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  Glitazones • Rosiglitazone 4mg/ 8 mg • 4 mg once daily morning • Max Dose - 8 mg • - Pioglitazone 15 mg / 30 mg • 15 mg once daily morning • Max Dose - 45 mg
• 31.
  Adverse effects ofpioglitazone • Fluid retention (Edema). • Weight gain. • Headache. • Liver function tests for 1st year of therapy. • Failure of estrogen-containing oral contraceptives. • Clinical benefits are not observed until 6-12 weeks
• 32.
  Incretin -mimetic (Exenatide/ Liraglutide) • It mimicks the endogenous incretin, glucagon-like peptide-1 (GLP-1) and thus it stimulates glucose- dependent insulin release • As opposed to insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia • Patients may attain modest weight loss. • This drug requires twice daily injections and is more expensive than high-dose glitazone therapy. Pramlintide : Synthetic amylin that reduces glucagon secretion and delays gastric emptying [s/c] Useful in type 1 and type 2 DM
• 33.
  DPP- 4 inhibitors •The newest oral hypoglycemic agents is Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin • A dipeptidyl peptidase IV (DPP-4) inhibitor • DPP-4 degrades numerous biologically active peptides including the endogenous incretins, GLP-1 and glucose-dependent insulinotropic peptide (GIP). • They can be used as a monotherapy or in combination with metformin or the glitazones • It is given orally and once daily
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  Dipeptyl- peptidase inhibitors Sitagliptin Vildagliptin Saxagliptin Septagliptin Allogliptin
• 35.
  Sitagliptin Has a Weight Neutral Profile • Monotherapy studies – No increase in body weight from baseline with sitagliptin compared with a small decrease in the placebo group • Add-on to metformin – A similar decrease in body weight for both treatment groups • Add-on to pioglitazone – No significant difference in body weight between treatment groups • Noninferiority vs Sulfonylurea A significant reduction in body weight with sitagliptin versus weight gain with glipizide 46
• 36.
  Clinical uses • Type2 DM as an adjunct to diet & exercise as a monotherapy or in combination with other antidiabetic drugs. • Adverse effects: Nausea, abdominal pain, diarrhea • Nasopharyngitis
• 37.
  Indications for oralantidiabetics:  NIDDM not controlled by diet and exercise alone  Maturity onset diabetes > 40yrs age, duration <5yrs  BSL < 300mg%  Use Repaglinide or Nateginide for post-prandial hyperglycemia  In obese individuals prefer Metformin or Glyclazide a  One drug combine drugs from each class if inadequate response Add TZDs Switch over to insulin
• 38.
  Prevention, Prevention, Prevention! •Refer patients with IGT, IFG, or A1C 5.7–6.4% to ongoing support program – Target weight loss = 7% of total body weight – Minimum of 150 min/week of moderate physical activity • Follow-up counseling important for success • Based on cost-effectiveness of diabetes prevention, third-party payers should cover such programs • In those with pre-diabetes, monitor for development of diabetes annually ADA. IV. Prevention/Delay of Type 2 Diabetes. Diabetes Care 2012;35(suppl 1):S16
• 39.
  Prevention, Prevention, Prevention! •Medications shown to delay progression of IGT/IFG to T2DM – Metformin (US DPP, NEJM 2002) – Acarbose (STOP-NIDDM, Lancet 2002) – Piaglitazone (ACT NOW, presentation 2008) • Consider metformin for prevention of type 2 diabetes if IGT, IFG, or A1C 5.7–6.4% – Especially for those with BMI >35 kg/m 2, age <60 years, and women with prior GDM • None are FDA approved for Diabetes Prevention
• 40.
  Easy A1c Correlation •NOTE: This is an estimate only • (A1C -2) x 30 – i.e. A1C= 7%; (7-2) x30 = 150mg/dL
• 41.
  How to treatType 2 DM
• 42.
  Diagnostic Criteria Fasting Glucose 2-h OGTT Random Glucose A1c mg/dL mg/dL mg/dL Normal <100 <140 <200 <5.7% Prediabetes 100-125 140-199 5.7-6.4% (IFG) (IGT) Diabetes ≥ 126 ≥ 200 ≥ 200 ≥ 6.5% Note: In the absence of unequivocal hyperglycemia, result(s) should be confirmed by repeat testing. ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S12. Table 2.
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  Determinants of selectionof drugs for Type 2 DM Efficacy Safety Cost
• 44.
  Choice of InitialGlucose-Lowering Agent • The level of hyperglycemia should influence the initial choice of therapy. • mild to moderate hyperglycemia [FPG < (200–250 mg/dL)] often respond well to a single, oral glucose-lowering agent. • more severe hyperglycemia [FPG > (250 mg/dL)] -stepwise approach "Combination Therapy" • Insulin can be used as initial therapy in individuals with severe hyperglycemia [FPG > (250–300 mg/dL) • Insulin secretagogues, biguanides, -glucosidase inhibitors, thiazolidinediones, and insulin are approved for monotherapy of type 2 DM
• 45.
  What is therole of an ideal oral hypoglycaemic agent? Conserve islet cell function - delay the subsequent use of insulin. Improve patient compliance- single daily dosing. Reduce the incidence of hypoglycaemic events
• 46.
  Efficacy of OralHypoglycemic Agents • Sulfonylureas are not much helpful in patients with moderate glucose intolerance and pancreatic β -cell loss • Thiazolidinediones (glitazones) do not demonstrate much efficacy in patients who don’t have much insulin resistance
• 47.
  Side effects • Thebenefits of combination therapy must be weighed against the risk of side effects. • For sulfonylureas, the major side effect has been the frequency and severity of hypoglycemia. • However, for many patients, weight gain is also unacceptable • Renal disease • Hepatic disease Risk of lactic acidosis • Pregnancy – OHAs are contraindicated • Meglitinides are safe at higher levels of serum Cr than sulfonylureas • Drug interactions
• 48.
  Cost Metformin and 2ndGeneration Sulfonylureas are LESS EXPENSIVE Newer drugs are MORE EXPENSIVE
• 49.
  Initial Treatment ofType 2 Diabetes • Diet and exercise are the most effective treatments for type 2 diabetes ! • Diet for approx 12 weeks • Then if control is poor (HbA1C > 7%) – Overweight (BMI > 25) - metformin – If not controlled then sulphonylureas, metaglitinides, amino acid derivatives • Contraindicated in pregnancy and when breast feeding • Used in conjunction with diet and exercise
• 50.
  Spectrum of OralHypoglycaemic Agents •Biguanides •Metformin (Biguanides) •Sulphonylureas •Glybenclemide, Glicliazide Glipizide, Glimepiride ∀α-Glucosidase • Acarbose , Miglitol, Voglibos inhibitors • Repaglinide, Nateglinide •Meglitinide analogues • Rosiglitazone , Pioglitazone •Thiazolidinediones • Sitagliptin, Vildagliptin, DPPV-4 Inhibitors Saxagliptin
• 51.
  Combination therapy inthe treatment of Diabetes Mellitus 1. Suphonylurea + Biguanides 2. Sulphonylurea + Insulin 3. Insulin + Biguanides 4. Insulin + Biguanides + Sulphonylurea 5. Non-sulphonylurea + Biguanide + Glitazone 6. Sulphonylurea + Acarbose 7. Metformin + Acarbose 8. Acarbose + Insulin 9. Repaglinide + Pioglitazone/Rosiglitazone (FDA approved).
• 52.
  Guideline for combinationtherapy • Obese Type 2 DM - Start first with biguanides – if fails with maximum dose add Sulphonylurea or any insulin secretagogue or glitazone or acarbose • or minimum amount of insulin. • Normal weight Type 2 DM - Start with sulphonylurea if fails with moderate dose of OHA or • you may add biguanide/glitazone add insulin in moderate dose
• 53.
  Guideline for combinationtherapy • Under-weight Type 2 DM - Start with insulin then add minimum sulphonylurea • - Never use biguanides.
• 54.
  Determinants of OADusage 1)Body Mass Index : Metformin, Gliptins BMI> 22kg/m2 2)Presence of GI symptoms: Sulpho, Gliptins, Glitazones 3)Renal Dysfunction: Gliptins,Glitazones(+/-),Sulpho (variable) 4) Aging Meglitinides, Gliptins(?) 5) Hepatic Dysfunction Nateglinide, Saxagliptin(?) 6) Compliance Gliptins, Glitazones, 7) Cost Metformin, Sulphas, Glitazones
• 55.
  Glycemic Control Algorithmfor Type 2 Diabetes Mellitus Goals Hb A1C ≤ 6.0%, Fasting BG ≤100 mg/Dl, 2-hr PP BG ≤140 mg/dL Avoid hypoglycemia; i.e. glucose <60 mg/dL or <70 mg/dL if IHD Initial Intervention 1. Diabetes Education 2. Medical Nutrition, Weight Control, Exercise If NOT CONTROLLED 3. Consider Monotherapy (Metformin, if OBESE) Goals not met after 3 months Goals Achieved • Continue Therapy • A1C every 3-6 months • Add additional oral agent if A1C ~7% Goals not met after 3 Months • Add insulin (see Insulin Algorithm) • Consider referral to endocrinologist
• 56.
  Type 2 DiabetesRecommendations • Metformin + lifestyle changes at diagnosis providing no contraindication – Medications are ALWAYS to be used in combination with healthy meal planning and regular physical activity (150 minutes per week) • If marked elevation of A1c /blood glucose and/or symptomatic consider insulin (+ or – other agents) from the outset • If noninsulin monotherapy at maximal tolerated dose does not achieve /maintain the A1c goal over 3–6 months, add a second oral agent, a GLP-1 receptor agonist, or insulin ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S21
• 57.
  Non-Insulin Hypoglycemic Agents Oral Parenteral •Biguanides • Amylin analogs •Sulfonylureas • Incretin mimetics •Meglitinides •Thiazolidinediones •Alpha Glucosidase inhibitors •Incretin Enhancers •(DPP-IV inhibitors)
• 58.
  Pharmacology - Biguanides Class Biguanides Compound Metformin Mechanism Activates AMP-kinase Action(s) • Hepatic glucose production ↓ • Intestinal glucose absorption ↓ • Insulin action ↑ Glucose Lowering • Fasting Effect • Post Prandial Advantages • No weight gain • No hypoglycemia • Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages • Gastrointestinal side effects (diarrhea, abdominal cramping) • Lactic acidosis (rare) • Vitamin B12 deficiency • Contraindications: reduced kidney function Cost Low – free at Marsh ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University
• 59.
  Pharmacology - Sulfonylureas Class Sulfonylureas (2nd generation) Compound • Glibenclamide/Glyburide • Glipizide • Gliclazide • Glimepiride Mechanism Closes KATP channels on β-cell plasma membranes Action(s) ↑ Insulin secretion Advantages • Generally well tolerated • Reduction in cardiovascular events and mortality (UKPDS f/u) Disadvantages • Relatively glucose-independent stimulation of insulin secretion: Hypoglycemia, including episodes necessitating hospital admission and causing death • Weight gain • Primary and secondary failure Cost Low – free at Marsh ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.
• 60.
  Pharmacology – Meglitinides Class Meglitinides Compound • Repaglinide (Prandin®) • Nateglinide (Starlix®) Mechanism Closes KATP channels on β-cell plasma membranes Action(s) Insulin secretion ↑ Advantages Accentuated effects around meal ingestion Disadvantages • Hypoglycemia, weight gain • Dosing frequency Cost Medium ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.
• 61.
  Pharmacology – Thiazolidinediones (TZD) Class Thiazolidinediones (Glitazones) Compound Pioglitazone (Actos®) Mechanism Activates the nuclear transcription factor PPAR-γ Action(s) Peripheral insulin sensitivity ↑ Advantages • No hypoglycemia • HDL cholesterol ↑ • Triglycerides ↓ Disadvantages • Weight gain • Edema • Heart failure (CI with stage III and IV) • Bone fractures Cost High ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.
• 62.
  Pharmacology – Thiazolidinediones (TZD) Class Thiazolidinediones (Glitazones) Compound Rosiglitazone (Avandia®) Mechanism Activates the nuclear transcription factor PPAR-γ Action(s) Peripheral insulin sensitivity ↑ Advantages No hypoglycemia Disadvantages • LDL cholesterol ↑ • Weight gain • Edema • Heart failure (CI with stages III and IV) • Bone fractures • Increased cardiovascular events (mixed evidence) • FDA warnings on cardiovascular safety Cost High ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.
• 63.
  Pharmacology – Alpha- Glucosidase Inhibiters Class α-Glucosidase inhibitors Compound • Acarbose • Miglitol Mechanism Inhibits intestinal α-glucosidase Action(s) Intestinal carbohydrate digestion and absorption slowed Advantages • Nonsystemic medication • Postprandial glucose ↓ Disadvantages • Gastrointestinal side effects (gas, flatulence, diarrhea) • Dosing frequency Cost Medium ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S22. Adapted with permission from Silvio Inzucchi, Yale University.
• 64.
  Pharmacology – Incretin Enhancers Class DPP-4 inhibitors (incretin enhancers) Compound • Sitagliptin (Januvia®) • Vildagliptin (available in Europe) • Saxagliptin (Onglza®) • Linagliptin (Tradjenta®) Mechanism Inhibits DPP-4 activity, prolongs survival of endogenously released incretin hormones Action(s) • Active GLP-1 concentration ↑ • Insulin secretion ↑ • Glucagon secretion ↓ Advantages • No hypoglycemia • Weight “neutrality” Disadvantages • Occasional reports of urticaria/angioedema • Cases of pancreatitis observed • Long-term safety unknown (cancer ?) Cost High ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.
• 65.
  Pharmacology – IncretinMimetics Class GLP-1 receptor agonists (incretin mimetics) Compound • Exenatide (Byetta®) • Liraglutide (Victoza®) Mechanism Activates GLP-1 receptors (β-cells/endocrine pancreas; brain/autonomous nervous system Action(s) • Insulin secretion ↑ (glucose-dependent) • Glucagon secretion ↓ (glucose-dependent) • Slows gastric emptying • Satiety ↑ Advantages • Weight reduction • Potential for improved β-cell mass/function Disadvantages • Gastrointestinal side effects (nausea, vomiting, diarrhea) • Cases of acute pancreatitis observed • C-cell hyperplasia/medullary thyroid tumors in animals (liraglutide) • Injectable • Long-term safety unknown Cost High ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.
• 66.
  Pharmacology – AmylinAnalog Class Antihyperglycemic Synthetic Analog Compound • Pramlintide (Symilin®) Mechanism • Amylinomimetic Action(s) • Glucagon secretion ↓ (glucose-dependent) • Slows gastric emptying • Satiety ↑ Advantages • Potential weight loss Disadvantages • Meal time injections • Nausea • Hypoglycemia in combination with insulin Cost High Lexi-Drugs Online [Internet]. Hudson (OH) : Lexi-Comp, Inc. 1978-2012[cited 2012 August 1].
• 67.
  Pharmacology – BileAcid Sequestrants Class Bile acid sequestrants Compound Colesevelam (Welchol®) Mechanism Binds bile acids/cholesterol Action(s) Bile acids stimulate receptor on liver to produce glucose Results • Lowers fasting and post prandial glucose Advantages • No hypoglycemia • LDL cholesterol ↓ Disadvantages • Constipation • Triglycerides ↑ • May interfere with absorption of other medications Cost High ADA. V. Diabetes Care. Diabetes Care 2012;35(suppl 1):S23. Adapted with permission from Silvio Inzucchi, Yale University.
• 68.
  Typical A1c Reductions Monotherapy Route of Administration A1c (%) Reduction Sulfonylurea PO 1.5-2.0 Metformin PO 1.5 Glitazones PO 1.0-1.5 Meglitinides PO 0.5-2.0 α -glucosidase inhibitors PO 0.5-1.0 DPP-4 PO 0.5-0.7 GLP-1 agonists Injectable 0.8-1.5 Amylin analogs Injectable 0.6 Insulin Injectable Open to target Unger J et al. Postgrad Med 2010; 122: 145-57
• 69.
  Fasting vs. PostprandialEffect Mostly targets FASTING Mostly targets POSPRANDIAL hyperglycemia hyperglycemia Insulin (long and intermediate Insulin (regular, rapid-action) action) Colesevelam α-glucosidase inhibitors Sulfonylureas Meglitinides TZD Pramlinitide Metformin DPP-4 inhibitors GLP-1 agonist
• 70.
  Considerations When SelectingTherapy • How long has the patient had diabetes (duration of disease – preservation of β-cell function)? • Which blood glucose level is not at target (fasting, postprandial, or both)? • Patient preference for route of administration (oral, injection)? • The degree of A1c lowering effect required to achieve goal? • Side effect profile and the patients tolerability? • Co – existing conditions ( CVD, osteoporosis, obesity, etc)?
• 71.
  Drug Pearls Medication PRO CON Metformin Low cost, A1c lowering, + CV Renal or hepatic impairment effects, weight loss, PCOS Sulfonylurea Low cost, A1c lowering Hypoglycemia, treatment failure Meglitinides Erratic meals, renal insufficiency Hypoglycemia, treatment failure Pioglitazone Insulin resistance, decrease in Edema, wt gain, CI with HF adipose tissue, TG reduction class III and IV α -glucosidase inhibitors Patients with constipation Long duration of T2DM, patients with GI problems DPP-4 Well tolerated ? long term safety GLP-1 agonists Obese patients GI side effects Amylin analogs Poor PPG control despite GI side effects insulin therapy Insulin Flexible treatment (basal, basal Hypoglycemia, weight gain bolus, etc)
• 72.
  Dyslipidemic Agents • Statintherapy should be added to lifestyle therapy, regardless of baseline lipid levels – with overt CVD – without CVD >40 years who have one or more other CVD risk factors • For patients at lower risk (without overt CVD, <40 years, etc.) – Consider statin therapy in addition to lifestyle therapy if LDL cholesterol remains >100 mg/dL – In those with multiple CVD risk factors ADA. VI. Prevention, Management of Complications. Diabetes Care 2012;35(suppl 1):S30-31
• 73.
  Insulin Insulin is essentialfor patients with: • Type I Diabetes mellitus • Type II DM poorly controlled with OHA s • Some secondary diabetes • Diabetes associated with pregnancy • Surgery (Perioperative) • In some serious concurrent diseases, AMI • Ketoacidosis • Along with glucose to treat hyperkalemia
• 74.
  Chemistry of insulin: •Polypeptide hormone MW 5808. • Contains 51 amino acids arranged in • two chains A (21) & B (30) linked by two disulphide bridges. • B cells of pancreatic islets synthesize insulin from a precursor called proinsulin. • Proinsulin is hydrolyzed into insulin & C-peptide. • Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues. • Proinsulin might have mild hypoglycemic action but C- peptide is inactive. • One milligram contains 28 units.
• 75.
  Types of insulin •Rapid-acting: Insulin aspart,- lispro, - glulisine (1-2h. onset / 4-6h. duration of action) • Short-acting: Regular Insulin, inhaled insulin (2-4h. onset / 6-12h. duration of action) • Intermediate-acting: NPH Insulin, Lente insulin (3-8h. onset / 12-20h. duration of action) • Long-acting: Insulin glargine, Insulin detemir ( Myristoylated insulin ) (6-12 onset / 16-30h. duration of action) • Pre-mixed insulins: NPH 70%+ Insulin aspart 30%
• 76.
  Ultra-short rapid-acting insulins • Insulin lispro, insulin aspart, insulin glulisine (injection) • Do not aggregate or form complexes • Fast onset of action (5-15 min) • Short duration of action (3-5 h) • Reach peak level 30-90 min after injection.
• 77.
  Short acting insulins regular insulins • Regular huminsulin R • Recombinant DNA technology • Clear solutions at neutral pH. • Hexameric analogue. • Onset of action 30-45 min (s.c.). • Peak 2-4 h. • Duration 6-8 h.
• 78.
  Short acting insulins regular insulins • I.V. emergency. • – Management of ketoacidosis • – After surgery • – During acute infection •  2-3 times/day. •  Control postprandial hyperglycemia & • ketoacidosis. •  Pregnancy
• 79.
  Intermediate acting insulins •Isophane (NPH), a neutral protamine hagedorn in phosphate buffer is combination of protamine & crystalline zinc insulin (1: 6 molecules). proteolysis release insulin. • Turbid suspension at neutral pH • Given S.C. only • Onset of action 1-2 h. • Insulin mixtures 75/25 - 70/30 - 50/50 (NPH/regular)
• 80.
  Intermediate acting insulins •Lente insulin • Mixture of 30% semilente insulin (amorphous precipitate of insulin with zinc in acetate buffer) + 70% ultralente insulin (poorly soluble crystal of zinc insulin) • Turbid suspension at neutral pH • Given S.C. • onset of action (1-3 h) • Peak serum level 4-8 h. • Duration of action 13-20 h. • Lente and NPH insulins are equivalent in activity. • Lente and NPH are Not used in emergencies (diabetic ketoacidosis). • Require several hours to reach therapeutic levels
• 81.
  Long acting insulin Insulin glargine (lantus) • Slow onset of action 2 h. • Clear solution • Forms precipitate (depot) at injection site. • absorbed less rapidly than NPH & Lente insulin. • Given s.c.- Maximum effect after 4-5 h • produce broad plasma concentration plateau (low continous insulin level). • Prolonged duration of action (24 h)- suitable Once daily • Should not be mixed with other insulin • Advantages over intermediate-acting insulins: • Constant circulating insulin over 24 hr with no pronounced peak. • More safe than NPH & Lente insulins ( reduced risk of hypoglycemia).
• 82.
  ADRs of insulin • Hypoglycemia • Lypodystrophy at the site of injection (atrophy or hypertrophy) • Weight gain • Hypersensitivity reactions. • Insulin resistance • Hypokalemia How to dose insulin • Sliding Scale Insulin It is the most frequent insulin regimen in hospitalized patients Otherwise, use • Basal- bolus insulin
• 83.
  The Basal/Bolus InsulinConcept • Basal Insulin – Suppresses glucose production between meals and overnight – Nearly constant levels – 50% of daily needs • Bolus Insulin (Mealtime or Prandial) – Limits hyperglycemia after meals – Immediate rise and sharp peak at 1 hour – 10% to 20% of total daily insulin requirement at each meal Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific profile
• 84.
  Dosage • Usual TotalDaily dose is 0.5 i.u. per kg BW • Higher doses are needed for those who: – have concurrent disease, AMI – have very high blood glucose levels – have ketoacidosis – are taking corticosteroids
• 85.
  Dosage (basal-bolus) Calculate the total daily dose of insulin (0.5 iu/kg) 2/3 rd before 1/3 rd before BREAKFAST EVENING MEAL 2/3 rd as 1/3 rd as 2/3 rd as 1/3 rd as intermediate or short-acting intermediate or short-acting long-acting insulin Insulin long-acting insulin Insulin
• 86.
  Monitoring therapy 1. Finger prick blood glucose testing Reagent strips and measuring instrument – Before each meal, before bed – Before meal blood glucose should be 70 – 120 mg/dl – After food level should be <180 mg/dl 2. Urine glucose testing – Less accurate than blood glucose – Renal threshold may vary – Useful in stable patients – Useful in patients who can’t do finger-prick 3. HbA1C measurement – Useful for measure of the degree of glycemia in the past 4-6 weeks – Good control if < 6 %
• 87.
  Increasing the doseof insulin • Any dietary error to be excluded and then the dose of insulin should be increased by 2-4 units. • Examples: • If breakfast and pre-lunch BG and/or urine glucose is high- add short acting insulin before breakfast • If post lunch and pre-dinner BG or urine is high – then increase morning dose of intermediate acting insulin by 2-4 units • If post dinner and late night BG or urine sugar is high, add short acting insulin 2-4 units before dinner • If fasting BG or urine sugar is high then increase pre- dinner intermediate acting insulin.
• 88.
  • Self-monitoring ofblood glucose (individualized frequency) • HbAIC testing (2-4 times/year) • Medical nutrition therapy and education (annual) • Eye examination (annual) • Foot examination (1-2 times/year) • Screening for diabetic nephropathy (annual) • Blood pressure measurement (quarterly) • Lipid profile (annual)
• 89.
  Essential information forpatients • What is hypoglycemia and how to treat it • Carry a diabetic card with details of drugs and patient information • Carry glucose (dextrose) or simple sugar (sucrose) • Careful while driving cars and handling heavy machine
• 90.
  Diabetic management “pearls” •When mixing insulins, draw up the regular insulin first • Allow mild hyperglycemia for the patient undergoing surgery—treat with short acting insulins • For elective surgery, schedule patient early in day to avoid prolonged fasting
• 91.
  “Pearls” • Use U-100syringes for U-100 vials • In patients with insulin pumps, use regular insulin or insulin aspart. Generally will deliver one unit per hour w/bolus insulin before meals • Tight glycemic control can reduce the complications of diabetes. • Use ACE inhibitors to delay nephropathy • Limit dietary intake of protein
• 92.
  “Pearls” • Glitazones mustsuspect hepatotoxicity • Metformin cautiously with liver and renal impairment Concern that with hepatotoxicity, because risks of lactic acidosis are increased. • Rotate sites of injection of insulin to avoid development of lipodystrophy • Absorption of injected insulin in abdomen is not uniform with injections in arms or legs
• 93.
  Lypoatrophy and Hyperlypotrophy
• 94.
  Injection Sites .. .. Arms Stomach Buttocks Thighs Site rotation is essential
• 95.
  Storage of insulin • Before use Store in fridge (2-8oC) • In-use vials Out of fridge to max 25oC (4-6 weeks) • In-use pens and cartridges Out of fridge at max 25oC (4 weeks)
• 96.
  Thank You