Insulin and oral Insulin and oral hypoglycemic drugshypoglycemic drugs
Endogenous insulin is secreted from Endogenous insulin is secreted from cells in the pancreas cells in the pancreas
Islet of Langerhans Alpha cell: 20%, glucagonBeta cell: 75%, insulinDelta cell: 5%, somatostatinD1 cell: VIPPP cell: pancreatic polypeptide
Glucose metabolism aGlucose metabolism and the regulation by ind the regulation by insulin and glucogannsulin and glucogan
Diabetes mellitus:Diabetes mellitus:
Insulin Insulin or its or its responses responses
blood glucose blood glucose
Acute or chronic Acute or chronic symptomssymptoms
A group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both
100 million people worldwide 85-90% cases are Type II
Diabetes MellitusDiabetes Mellitus
CLASSIFICATION
TYPE 1 (IDDM,10%) Deficiency of insulin secretion Genetic predisposition and possible links to
viral infections and environmental factors Possible autoimmune process with destruct
ion of beta pancreatic cells Require insulin supplementation, prone to
develop DKA ( 酮症酸中毒)
CLASSIFICATION
TYPE 2 Resistance to action of insulin on target organs Decrease in insulin production Increased risk with obesity high fat, high caloric di
ets Stronger genetic predisposition Variety of initial presentations: HHNKS ( 高血糖高渗性非酮症综合征 ), nephropathy, retinopathy, neuropathies
Disease can be delayed or prevented with life style changes
Natural History of Type 2 Natural History of Type 2 DiabetesDiabetes
050
100
150200250
-10 -5 0 5 10 15 20 25 30
Years of DiabetesYears of Diabetes
Glucose(mg/dL)
Relative Function
(%)
Insulin Resistance
Insulin Level“Beta-cell failure”
*IGT = impaired glucose tolerance
50100150200250300350
Fasting Glucose
Post-meal Glucose
Adapted from International Diabetes Center (IDC)Minneapolis, Minnesota
Obesity IGT Diabetes Uncontrolled hyperglycemiaObesity IGT Diabetes Uncontrolled hyperglycemia
CLASSIFICATION
SECONDARY CAUSES Exocrine pancreas disease: pancreatitis Genetic syndromes: Downs, Turners Infections: CMV, Congenital rubella Drugs: Glucocorticoids, Dilantin, beta
agonists Endocrinopathies: Cushing's, Acromegaly
Classification
Gestational Presents only during pregnancy 135,000 cases annually Increased risk of developing diabetes post
partum Tight glycemic control required to prevent
macrosomia, fetal cardiac and CNS abnormalities
CLINICAL FEATURES
PolyuriaPolydipsiaPolyphagiaWeight loss
TYPE 1 DM-- acute, severeTYPE 2 DM-- chronic, less severe
正常人正常人 糖尿病糖尿病 尿崩症尿崩症
Complications of diabetes mellitusComplications of diabetes mellitus
Acute complicationsAcute complications Diabetic ketoacidosis Diabetic ketoacidosis Hyperosmotic nonketotic comaHyperosmotic nonketotic coma Chronic complicationsChronic complications Cardiovascular diseasesCardiovascular diseases Renal damageRenal damage Retinal damageRetinal damage Nerve degenerationNerve degeneration Myopathy Myopathy Infection Infection
Rhinocerebral Mucormycosis
Therapy of Diabetes Mellitus
DietDietExerciseExerciseInsulin and its enhancers Insulin and its enhancers Oral hypoglycemic drugsOral hypoglycemic drugs
Insulin and its enhancersInsulin and its enhancers
Structure of insulinStructure of insulin
Insulin and its enhancersInsulin and its enhancers
InsulinInsulin1. 1. Pharmacological effectsPharmacological effects(1)(1) Carbohydrate metabolism:Carbohydrate metabolism: reducing blood glucose levels by glycogenreducing blood glucose levels by glycogen
olysis olysis , glycogen synthesis , glycogen synthesis , gluconeogenesis , gluconeogenesis (ketone badies (ketone badies ))
(2) Lipid metabolism: (2) Lipid metabolism: fat synthesis fat synthesis , lipolysis , lipolysis , plasma free fatty acids , plasma free fatty acids
(3) Protein metabolism: (3) Protein metabolism: active transport of amino acids active transport of amino acids , incorporation of , incorporation of amino acids into protein amino acids into protein , protein catabolism , protein catabolism
(4)(4) HR HR ,, myocardial contractility, renal blood flowmyocardial contractility, renal blood flow
Mechanism of insulin actionsMechanism of insulin actions Interacting with insulin receptorInteracting with insulin receptor
Insulin promotes glucose utilizationInsulin promotes glucose utilization
Insulin and its enhancersInsulin and its enhancers
InsulinInsulin1. 1. Pharmacological effectsPharmacological effects(1)(1) Carbohydrate metabolism:Carbohydrate metabolism: reducing blood glucose levels by glycogenreducing blood glucose levels by glycogen
olysis olysis , glycogen synthesis , glycogen synthesis , gluconeogenesis , gluconeogenesis (ketone badies (ketone badies ))
(2) Lipid metabolism:(2) Lipid metabolism: fat synthesis fat synthesis , lipolysis , lipolysis , plasma free fatty acids , plasma free fatty acids
(3) Protein metabolism: (3) Protein metabolism: active transport of amino acids active transport of amino acids , incorporation of , incorporation of amino acids into protein amino acids into protein , protein catabolism , protein catabolism
(4)(4) HR HR ,, myocardial contractility, renal blood flowmyocardial contractility, renal blood flow
Mechanism of insulin actionsMechanism of insulin actions Interacting with insulin receptorInteracting with insulin receptor
Insulin and its enhancersInsulin and its enhancers
InsulinInsulin1. 1. Pharmacological effectsPharmacological effects(1)(1) Carbohydrate metabolism:Carbohydrate metabolism: reducing blood glucose levels by glycogenreducing blood glucose levels by glycogen
olysis olysis , glycogen synthesis , glycogen synthesis , gluconeogenesis , gluconeogenesis (ketone badies (ketone badies ))
(2) Lipid metabolism:(2) Lipid metabolism: fat synthesis fat synthesis , lipolysis , lipolysis , plasma free fatty acids , plasma free fatty acids
(3) Protein metabolism:(3) Protein metabolism: active transport of amino acids active transport of amino acids , incorporation of , incorporation of amino acids into protein amino acids into protein , protein catabolism , protein catabolism
(4)(4) HR HR ,, myocardial contractility, renal blood flowmyocardial contractility, renal blood flow
Mechanism of insulin actionsMechanism of insulin actions Interacting with insulin receptorInteracting with insulin receptor
Interaction betwInteraction between insulin and iteen insulin and its receptors receptorIRS:IRS: insulin receptor insulin receptorsubstrate substrate
tyr:tyr: tyrosine tyrosine
P:P: phosphate phosphate
Insulin promotes the Insulin promotes the translocation of glucose translocation of glucose transporters into the transporters into the membranemembrane
2.2. Clinical uses Clinical uses(1)(1) Insulin-dependent patients with diabetes mellitInsulin-dependent patients with diabetes mellit
us us (type 1 diabetes mellitus) (type 1 diabetes mellitus)
(2) Insulin-independent patients:(2) Insulin-independent patients: failure to other drugsfailure to other drugs
(3) Diabetic complications:(3) Diabetic complications: diabetic ketoacidosis (diabetic ketoacidosis ( 酮症酮症酸中毒酸中毒 ), hyperosmotic nonketotic coma), hyperosmotic nonketotic coma ((高渗性非酮症性昏高渗性非酮症性昏迷迷))
(4) Critical situations of diabetic patients:(4) Critical situations of diabetic patients: fever, sevfever, severe infection, pregnancy, trauma, operationere infection, pregnancy, trauma, operation
(5) Others:(5) Others: promotion of Kpromotion of K++ uptake into the cells, pshychia uptake into the cells, pshychiatric disorders tric disorders
Insulin and its enhancersInsulin and its enhancers
3.3. Preparations Preparations
PropertiesProperties PreparationsPreparations OnsetOnset PeakPeak DurationDuration
Fast-actingFast-acting Regular insulinRegular insulin 0.5-1 0.5-1 hh
2-3 h2-3 h 6-8 h6-8 h
Intermmediate-aIntermmediate-actingcting
Neutral protamine hagNeutral protamine hagedornedorn
2-4 h2-4 h 6-10 h6-10 h 12-18 h12-18 h
Long-actingLong-acting Protamine zinc insulin Protamine zinc insulin suspensionsuspension
3-6 h3-6 h 6-10 h6-10 h 24-36 h24-36 h
Hirsch IB NEJM 352:174, 2005
Rapid Acting Insulin AnaloguesRapid Acting Insulin Analogues Current agents include lispro, aspart, and glulisine.Current agents include lispro, aspart, and glulisine. Remain monomeric after injection, resulting in rapid absorption, Remain monomeric after injection, resulting in rapid absorption,
and relatively rapid onset and offset.and relatively rapid onset and offset. Onset of action is 5-15 minutes, with peak action at 60-90 Onset of action is 5-15 minutes, with peak action at 60-90
minutes and duration of ~3-5 hours.minutes and duration of ~3-5 hours. Advantages include: Advantages include:
increased convenience- can take just prior to meal.increased convenience- can take just prior to meal. better postprandial glycemic control. better postprandial glycemic control.
Disadvantages include: Disadvantages include: short duration of action- can be problematic in Type 1 diabetic short duration of action- can be problematic in Type 1 diabetic
without basal insulinization, as with bedtime NPH.without basal insulinization, as with bedtime NPH. more expensive than regular insulin (~double the cost).more expensive than regular insulin (~double the cost).
Holleman and Hoekstra, NEJM, 337:176-83, 1997Holleman and Hoekstra, NEJM, 337:176-83, 1997Hirsch, NEJM, 352:174-83, 2005 Hirsch, NEJM, 352:174-83, 2005
Actions of different insulin preparationsActions of different insulin preparations
4.4. Adverse effects Adverse effects
(1) Hypersensitivity: (1) Hypersensitivity: treated with Htreated with H11 receptor antagonist, receptor antagonist,
glucocorticoids glucocorticoids
(2) Hypoglycemia:(2) Hypoglycemia: adrenaline secretion (sweating, hungeadrenaline secretion (sweating, hunger, weakenss, tachycardia, blurred vision, headache, r, weakenss, tachycardia, blurred vision, headache, etc.etc.), tre), treated with 50% glucoseated with 50% glucose
(3) Lipoatrophy: (3) Lipoatrophy: localized in injection siteslocalized in injection sites
(4) Insulin resistance: (4) Insulin resistance: Acute: stress induced, need large dose of insulinAcute: stress induced, need large dose of insulinChronic: need >200U/d and no complicationChronic: need >200U/d and no complication
Insulin and its enhancersInsulin and its enhancers
Insulin action enhancersInsulin action enhancers
Thiazolidinediones (TDs) Thiazolidinediones (TDs) 噻唑烷酮类化合物噻唑烷酮类化合物
Rosiglitazone Rosiglitazone 罗格列酮罗格列酮
Pioglitazone Pioglitazone 吡格列酮吡格列酮
Troglitazone Troglitazone 曲格列酮曲格列酮
Insulin and its enhancersInsulin and its enhancers
Rosiglitazone Rosiglitazone 罗格列酮罗格列酮
Insulin and its enhancersInsulin and its enhancers
Pioglitazone Pioglitazone 吡格列酮吡格列酮
Insulin action enhancersInsulin action enhancers
1.1. Pharmacological effects Pharmacological effects
Selective agonists for nuclear peroxisome proliferatoSelective agonists for nuclear peroxisome proliferator-activated receptor-r-activated receptor- ( (PPARPPAR, , 过氧化物酶增殖体激活受体过氧化物酶增殖体激活受体 ).).
(1) Lowering insulin resistance(1) Lowering insulin resistance(2) Lipid metabolism regulation: (2) Lipid metabolism regulation: TG, free fatty acid TG, free fatty acid (3) Antihypertensive effects(3) Antihypertensive effects(4) Effect on vascular complications in type 2 patients(4) Effect on vascular complications in type 2 patients
Insulin and its enhancersInsulin and its enhancers
2.2. Clinical uses Clinical uses
Used for treatment of insulin-resistant diUsed for treatment of insulin-resistant diabetic patients or type 2 patientsabetic patients or type 2 patients
3.3. Adverse effects Adverse effects
Edema, headache, myalgia, GI reactions, heEdema, headache, myalgia, GI reactions, hepatic damage (troglitazone)patic damage (troglitazone)
Insulin and its enhancersInsulin and its enhancers
Oral hypoglycemic Oral hypoglycemic drugs drugs
SulfonylureasSulfonylureas (磺酰脲类)(磺酰脲类)
BiguanidesBiguanides (双胍类)(双胍类)
-Glucosidase inhibitors-Glucosidase inhibitors ((葡萄糖苷酶抑制药)葡萄糖苷酶抑制药)
OthersOthers
Oral hypoglycemic drugs Oral hypoglycemic drugs
SulfonylureasSulfonylureas (磺酰脲类)(磺酰脲类)
Tolbutamide Tolbutamide (D860)(D860) 甲磺丁脲甲磺丁脲Chlorpropamide Chlorpropamide 氯磺丙脲氯磺丙脲Glibenclamide Glibenclamide 格列本脲 格列本脲 (( 优降优降糖糖 )) Glipizide Glipizide 格列吡嗪格列吡嗪Gliclazide Gliclazide 格列齐特 格列齐特 (( 达美康达美康 ))
SulfonylureasSulfonylureas
1.1. Pharmacological effects Pharmacological effects
(1)(1)Hypoglycemic effect:Hypoglycemic effect: blocking ATP-sensitive Kblocking ATP-sensitive K++ channel: Ca channel: Ca2+2+ inflow inflow , ins, ins
ulin release ulin release , stimulating insulin secretion, stimulating insulin secretion increasing insulin sensitivity (long-term use)increasing insulin sensitivity (long-term use) inhibit glucagon releaseinhibit glucagon release
(2) Antidiuretic effect(2) Antidiuretic effect
(3) Effect on coagulation function (3) Effect on coagulation function
Action of sulfonylureasAction of sulfonylureas
SulfonylureasSulfonylureas
1.1. Pharmacological effects Pharmacological effects
(1)(1)Hypoglycemic effect:Hypoglycemic effect: blocking Kblocking K++ channel: Ca channel: Ca2+2+ inflow inflow , insulin release , insulin release , ,
stimulating insulin secretionstimulating insulin secretion increasing insulin sensitivity (long-term use)increasing insulin sensitivity (long-term use) inhibit glucagon releaseinhibit glucagon release
(2) Antidiuretic effect(2) Antidiuretic effect
(3) Effect on coagulation function (Gliclazide)(3) Effect on coagulation function (Gliclazide)
2.2. Clinical uses Clinical uses
(1) Insulin-indenpedent diabetic patients (type 2): (1) Insulin-indenpedent diabetic patients (type 2): aloalone or combined with insulinne or combined with insulin
(2) Diabetes insipidus (2) Diabetes insipidus (( 尿崩症尿崩症 )): : Chlorpropamide (Chlorpropamide ( 氯磺丙脲氯磺丙脲 ): antiuretic hormone (ADH) ): antiuretic hormone (ADH)
SulfonylureasSulfonylureas
3.3. Adverse effects Adverse effects
(1) GI reactions(1) GI reactions
(2) CNS reactions(2) CNS reactions
(3) Hypoglycemia:(3) Hypoglycemia: especially in elderly, hepatic or reespecially in elderly, hepatic or renal insufficiencies nal insufficiencies
(4) Others:(4) Others: cholestatic jaundice, hepatic damage (Chlocholestatic jaundice, hepatic damage (Chlorpropamide),rpropamide), leukopenia.leukopenia.
SulfonylureasSulfonylureas
4.4. Drug interactions Drug interactions
(1) Potentiation of hypoglycemic effects(1) Potentiation of hypoglycemic effects replacement in plasma protein binding:replacement in plasma protein binding: salicylic acid, sulfates, isalicylic acid, sulfates, indomethacin, penicillin, warfarin, ndomethacin, penicillin, warfarin, etc.etc. inhibition of hepatic microsomal enzymes:inhibition of hepatic microsomal enzymes: chloramphenicol, w chloramphenicol, warfarinarfarin
(2) Attenuation of hypoglycemic effects(2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes:induction of hepatic microsomal enzymes: phenytoin, phenoba phenytoin, phenobarbital, rbital, etc.etc.
interactions in pharmacodynamics:interactions in pharmacodynamics: glucagon, thiazides, glucagon, thiazides, etc.etc.
SulfonylureasSulfonylureas
Oral hypoglycemic drugs Oral hypoglycemic drugs
BiguanidesBiguanides (双胍类)(双胍类)
Metformin Metformin 二甲双胍(甲福明)二甲双胍(甲福明) Phenformin Phenformin 苯乙双胍(苯乙福明)苯乙双胍(苯乙福明)
BiguanidesBiguanides
1.1. Pharmacilogical effects Pharmacilogical effects increasing glucose uptake in fat tissues and increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles anaerobic glycolysis in skeletal muscles decreasing glucose absorption in gut and gludecreasing glucose absorption in gut and glucagon releasecagon release
2.2. Clinical uses Clinical uses mild insulin-independent patients with obesitymild insulin-independent patients with obesity
3.3. Adverse effects Adverse effects severe lactic acidosissevere lactic acidosis ( (less for metforminless for metformin), m), m
alabsorption of vitamin Balabsorption of vitamin B1212 and folic acid and folic acid
Oral hypoglycemic drugs Oral hypoglycemic drugs
-Glucosidase inhibitors-Glucosidase inhibitors ((葡萄糖苷酶抑制葡萄糖苷酶抑制药)药)
AcarboseAcarbose 阿卡波糖阿卡波糖
Reducing intestinal absorption of starch (Reducing intestinal absorption of starch ( 淀粉淀粉 ), ), dextrin (dextrin ( 糊精糊精 ), and disaccharides (), and disaccharides ( 二糖二糖 ) by inhib) by inhibiting the action of intestinal brush border iting the action of intestinal brush border -glu-glucosidasecosidase
Oral hypoglycemic drugs Oral hypoglycemic drugs
OthersOthers
RepaglinideRepaglinide 瑞格列奈瑞格列奈
Oral insulin secretagogueOral insulin secretagogue
Pharmacological effectsPharmacological effects Repaglinide lowers blood glucose by stimulating the r
elease of insulin from the pancreas. It achieves this by closing ATP-dependent potassium
channels in the membrane of the beta cells. This depolarizes the beta cells, opening the cells' calcium channels, and the resulting calcium influx induces insulin secretion
Clinical usesClinical uses Type2 DM, diabetic nephropathy, elder DM patient
Repaglinide Repaglinide (( 餐时血糖调节剂餐时血糖调节剂 ))
Incretin MimeticsIncretin Mimetics
Mechanism of Action:Mechanism of Action: Act as an incretinAct as an incretin enhance insulin secretion in response enhance insulin secretion in response
to an oral glucose load.to an oral glucose load. Suppress post-prandial glucagon secretion in a glucose-dSuppress post-prandial glucagon secretion in a glucose-d
ependent mannerependent manner Delay gastric emptyingDelay gastric emptying Centrally suppress appetiteCentrally suppress appetite Preserve beta cell mass by reducing apoptosis and increaPreserve beta cell mass by reducing apoptosis and increa
sed neogenesis (animal models).sed neogenesis (animal models).
Keating, Drugs. 65(12):1681-92, 2005.Keating, Drugs. 65(12):1681-92, 2005.Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.
Incretin MimeticsIncretin Mimetics Exenatide (Byetta) is first Exenatide (Byetta) is first incretin mimetic on market. incretin mimetic on market. Synthetic version of salivary protein found in the Gila monsterSynthetic version of salivary protein found in the Gila monster53% o53% o
verlap with human GLP-1.verlap with human GLP-1.
Must be taken as a BID injection w/in 60 mins prior to mealMust be taken as a BID injection w/in 60 mins prior to meal Major side effects: nausea, vomiting, diarrhea. Increases the risk of AcMajor side effects: nausea, vomiting, diarrhea. Increases the risk of Ac
ute pancreatitis. ute pancreatitis. Use not recommended in severe renal impairment. Use not recommended in severe renal impairment. Not recommended as monotherapyNot recommended as monotherapy
To be used as add on therapy with SU, metformin, or TZD’sTo be used as add on therapy with SU, metformin, or TZD’s Increases the risk of Hypoglycemia when added to SU treatment.Increases the risk of Hypoglycemia when added to SU treatment.
Major advantage is weight loss (~5 kg) as well as maintained effect (?Major advantage is weight loss (~5 kg) as well as maintained effect (?preserved beta cell function).preserved beta cell function).
Efficacy: decreases A1C ~1.0%.Efficacy: decreases A1C ~1.0%.
Keating, Drugs 2005 65(12):1681-92Keating, Drugs 2005 65(12):1681-92
Site of DPP-IV Inactivation
Exenatide
A SYL GQ AKE RVKAH G F VEA T TSD S SY LE GQAA KE F I AW LVKGR -NH2GLP-1Human
Dipeptidylpeptidase IV (DPP-IV) InhibitorsDipeptidylpeptidase IV (DPP-IV) Inhibitors Mechanism of Action:Mechanism of Action:
Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal Acts to prevent breakdown of intrinsic GLP-1, thereby increasing portal GLP-1 levelsGLP-1 levels
Acts as an incretinActs as an incretin enhances insulin secretion in response to an oral enhances insulin secretion in response to an oral glucose load.glucose load.
Suppresses post-prandial glucagon secretion in a glucose-dependent Suppresses post-prandial glucagon secretion in a glucose-dependent mannermanner
Preserves beta cell mass by reducing apoptosis and increased Preserves beta cell mass by reducing apoptosis and increased neogenesis (animal models).neogenesis (animal models).
Sitagliptin (Januvia) is first DPP-IV inhibitor on market.Sitagliptin (Januvia) is first DPP-IV inhibitor on market. Effective as monotherapy or when used in conjunction with Effective as monotherapy or when used in conjunction with
metformin or a thiazolidinedione.metformin or a thiazolidinedione. Appears to maintain efficacy (?preserved beta cell fxn).Appears to maintain efficacy (?preserved beta cell fxn). Efficacy: decreases A1C ~0.8%.Efficacy: decreases A1C ~0.8%.
Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.Riddle and Drucker. Diabetes Care 2006; 29:435-49.
Case 150y/o, Chinese Male, CC: Hyperglycemia found ×2 mPE: BMI 29 Kg/m2 WC: 102cmLab Findings: FBG 155mg/dl, 2hPG:
276mg/dl, HbA1c: 7.5%Which DRUG or DRUGS will we order?
Treatment Strategies Beyond LifestyleTreatment Strategies Beyond Lifestyle
In general, try to initiate pharmacotherapy with an oraIn general, try to initiate pharmacotherapy with an oral agent in newly diagnosed type 2 diabetics unless:l agent in newly diagnosed type 2 diabetics unless:
Fasting plasma glucose is >300 mg/dl with ketonemia or ketFasting plasma glucose is >300 mg/dl with ketonemia or ketonuriaonuria
Markedly symptomaticMarkedly symptomatic
In patients who need insulin initially, often can be switIn patients who need insulin initially, often can be switched to oral agents after 6-8 weeks when glucose toxched to oral agents after 6-8 weeks when glucose toxicity resolvesicity resolves
Answer to Case 1 ( A newly diagnosed type 2 DM patient with obesity)
Lifestyle interventionMetformin 500mg q.d.-t.i.d
““Failure” of a Single Oral AgentFailure” of a Single Oral Agent Type 2 diabetes is a Type 2 diabetes is a
progressive disease, with progressive disease, with ’d ’d loss of beta cell function over loss of beta cell function over time. time.
Need to progress to multi-drug Need to progress to multi-drug therapy or add insulin in order to therapy or add insulin in order to maintain a similar level of maintain a similar level of glycemic control. glycemic control.
If glycemic goals are not met If glycemic goals are not met with agent in one class, we must with agent in one class, we must add second agent with different add second agent with different mechanism of action or add mechanism of action or add insulininsulin
22Nathan et al. Diabetes Care. 29:1963-1972, 2006.Nathan et al. Diabetes Care. 29:1963-1972, 2006.
• ADA consensus algorithm recommends addition of a ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C.not effective in getting patients to goal A1C.22
• ADA consensus algorithm recommends addition of a ADA consensus algorithm recommends addition of a SU, thiazolidinedione, or insulin if metformin therapy is SU, thiazolidinedione, or insulin if metformin therapy is not effective in getting patients to goal A1C.not effective in getting patients to goal A1C.22
11Kahn et al. N Engl J Med, 355:2427, 2006Kahn et al. N Engl J Med, 355:2427, 200611Kahn et al. N Engl J Med, 355:2427, 2006Kahn et al. N Engl J Med, 355:2427, 2006
Algorithm for the management of T2DMAlgorithm for the management of T2DM
From: China Guideline for Type 2 Diabetes (CDS,2007)From: China Guideline for Type 2 Diabetes (CDS,2007) From: China Guideline for Type 2 Diabetes (CDS,2007)From: China Guideline for Type 2 Diabetes (CDS,2007)
Add insulin
Add one or several agents below: Sulfonylurea or Meglitinide (one of the two), Glitazones , Alp
ha-Glucosidase Inhibitor
Diet,exercise,weight loss
+Metformin
3 month later HbA1c 6.5% ﹥
3 month later HbA1c > 6.5%
Overweight orobese patients
(BMI >=24Kg/m2)
Algorithm for the management of T2DM (Cont’)Algorithm for the management of T2DM (Cont’)
Non-obese Patients(BMI 24kg/m﹤ 2)
Diet, exercise, weight loss +One or several agents below: Metformin, Sulfonylurea or Meglitinide (one of the two), Thiazolidinedione,
Alpha-Glucosidase Inhibitor
Add insulin
3 month later HbA1c > 6.5%
From: China Guideline for Type 2 Diabetes From: China Guideline for Type 2 Diabetes (CDS,2007)(CDS,2007)From: China Guideline for Type 2 Diabetes From: China Guideline for Type 2 Diabetes (CDS,2007)(CDS,2007)
Use of Oral Agents to Optimize Glycemic Use of Oral Agents to Optimize Glycemic Control: ConclusionsControl: Conclusions
Choice of oral agents needs to be matched with patient Choice of oral agents needs to be matched with patient characteristics (thin vs. obese) as well as concurrent characteristics (thin vs. obese) as well as concurrent medical issues (renal, hepatic, cardiopulmonary status).medical issues (renal, hepatic, cardiopulmonary status).
Diabetes is a progressive disease, and will require an Diabetes is a progressive disease, and will require an increasing number of agents and/ or addition of insulin as increasing number of agents and/ or addition of insulin as the duration of diabetes increases.the duration of diabetes increases.
Each oral agent can only improve A1C a maximum of 2%, Each oral agent can only improve A1C a maximum of 2%, so if poor control persists on multiple agents, insulin is so if poor control persists on multiple agents, insulin is needed.needed.
Use Of Insulin In Type 2 DiabetesUse Of Insulin In Type 2 Diabetes
Indications Indications When glycemic control deteriorates despite combiWhen glycemic control deteriorates despite combi
nation oral agents. nation oral agents. Surgery in patients with type 2 DM (transient)Surgery in patients with type 2 DM (transient) PregnancyPregnancy
Method:Method: Start with bedtime intermediate (NPH) or long actiStart with bedtime intermediate (NPH) or long acti
ng (glargine, detemir) insulin in addition to oral ageng (glargine, detemir) insulin in addition to oral agents.nts.
If doesn’t work, switch to basal-bolus therapy as uIf doesn’t work, switch to basal-bolus therapy as used in conventional type 1 DM treatmentsed in conventional type 1 DM treatment
• Can continue metformin.Can continue metformin.• Stop insulin secretagogues.Stop insulin secretagogues.
4:004:00
2525
5050
7575
16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
Pla
sma
Insu
lin
P
lasm
a In
suli
n µµ
U/m
l)
U/m
l)
Basal/Bolus Insulin Absorption Pattern w/Basal/Bolus Insulin Absorption Pattern w/Standard Insulin PreparationsStandard Insulin Preparations
8:008:0012:0012:008:008:00
TimeTime
REG REGREG
NPH
4:004:00 16:0016:00 20:00 20:00 24:0024:00 4:004:00
BreakfastBreakfast LunchLunch DinnerDinner
8:008:0012:0012:008:008:00
TimeTime
Glargine
Basal-Bolus Treatment withBasal-Bolus Treatment withRapid and Long Acting AnaloguesRapid and Long Acting Analogues
Pla
sma
Insu
lin
Pla
sma
Insu
lin Lispro Lispro Lispro
or or or
Aspart Aspart Aspart
or oror
Glulisine Glulisine GlulisineGlulisine Glulisine Glulisine
Insulin Pump and Glucose Monitoring
Insulin Pump – “Open Loop”Patient sets basal infusion rate and w/ superimposedboluses
Continuous Glucose Monitor
“Closed Loop” insulin pump system is ultimate goal… infusion rate adjusted based on input from continuous glucose monitor.
Case 2
64y/o, Chinese Male.CC:polydipsia,polyuria,polyphagia × 12y lower limb edema × 3 mMetformin 500mg bid + Glipizide 80mg tidPE: BMI 22kg/m2, WC 78cm, decreased sensati
on and medium pitting edema in both lower limbs
Lab Findings: UA: PRO 3+,GLU 2+ ; FBG 188mg/dl, 2hPG 266 mg/dl HbA1c 8.3%;
Case2 (Cont’)
Liver function tests: nl transaminase, Alb 28g/l
SCr:1.5mg/dl, CCr: 52ml/minWhich DRUG or DRUGS should we Pre
scribe?
Answer to case 2 (long diabetes history with diabetic Nephropathy and Chronic renal insufficiency )
Should start with insulin treatment Regimen:
1. Regular insulin or rapid acting insulin analogs tid pre-meal + NPH or long acting insulin analog at bedtime
2. Insulin Pump