Presentation on theme: "Insulin Glargine in the Management of Hyperglycemia in Type 2 Diabetes"— Presentation transcript:
1Insulin Glargine in the Management of Hyperglycemia in Type 2 Diabetes 林志慶 醫師 M.D. Ph.D.國立陽明大學醫學院內科學系 台北榮民總醫院內科部腎臟科
2Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease3. Insulin therapy in Patients with Advanced Kidney Disease
3Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease3. Insulin therapy in Patients with Advanced Kidney Disease
4UKPDS: Improving HbA1c Control Reduced Diabetes-Related Complications EVERY 1%reduction in HbA1cREDUCED RISK (P<0.0001)1%Diabetes-relateddeathsMyocardial infarctionsMicrovascular complicationsAmputations or deaths from peripheral vascular disorders21%14%37%43%Relative RiskN=3642UKPDS=United Kingdom Prospective Diabetes Study.Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years.Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.4
52007 AJKD guidelinesTarget HbA1c for people with diabetes should be < 7.0%, irrespective of the presence or absence of CKD. (A)Lowering HbA1c levels to approximately 7.0% reduces the development of microalbuminuria. (Strong)5
62007 AJKD guidelinesLowering HbA1c levels to approximately 7.0% reduces the development of macroalbuminuria. (Moderate)Lowering HbA1c levels to approximately 7.0% reduces the rate of decrease in GFR.(Weak)6
7Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease3. Insulin therapy in Patients with Advanced Kidney Disease
9Major Targeted Sites of Oral Drug Classes M:\MWP-DPP-E43627_Core Platform_R5.ppt二○一七年四月十四日Major Targeted Sites of Oral Drug ClassesGlucose absorptionHepatic glucose overproductionImpaired insulinsecretionInsulin resistancePancreas↓Glucose levelMuscle and fatLiverBiguanidesTZDsSulfonylureasMeglitinidesα-Glucosidase inhibitorsGutDPP-4 inhibitorsPurpose:To provide a broad overview of the key mechanisms and targeted sites of available anti-hyperglycaemic drug classes.Take-away:Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve HbA1c control.DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.15Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287: ; Porte D et al. Clin Invest Med. 1995;18:247–254.References1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303.2. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.3. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:4. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254.5. Data on file, MSD.6. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619.15
16M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日BiguanideMetformin作用機轉 (1)降低肝臟中的葡萄糖合成作用(gluconeogenesis) (2)降低或延遲腸道的葡萄糖吸收，減少飯後血糖上升 (3)增加週邊組織的胰島素敏感性副作用 常見初期腸胃不適(噁心嘔吐、食慾不振) 腎功能不全者罕見的乳酸中毒報告上市產品DrugDose(mg)Daily dose and Frequency (mg)Glucophage(metformin)5001000~2550mg/day bid or tid
20α-Glucosidase Inhibitor M:\MWP-DPP-E43627_Core Platform_R5.ppt二○一七年四月十四日α-Glucosidase Inhibitor作用機轉 抑制腸內α-glucosidase的作用(分解碳水化合物的一群酵素)，使碳水化合物在腸道被分解為單糖和吸收延遲; 可降低糖尿病患者飯後的血糖濃度副作用 腸胃副作用(腹痛、腹瀉、脹氣)上市產品DrugDose(mg)Daily dose and Frequency (mg)Glucobay(acarbose)5050~100 mg tid
21α-Glucosidase抑制劑: acarbose M:\MWP-DPP-E43627_Core Platform_R5.pptα-Glucosidase抑制劑: acarbose二○一七年四月十四日NameDuration(hrs)代謝Acarbose2-6不被吸收MiglitolAlpha-Glucosidase inhibitors act by suppressing the enzyme responsible for metabolizing complex carbohydrates in the small intestine. They slow or block the breakdown and absorption of carbohydrates and certain sugars thereby delaying entry of glucose into liver and muscle tissue. Side Effects include flatulence, diarrhea and abdominal pain. Hypoglycemia may result if taken with a secretagogue or insulin. The use of alpha-Glucosidase inhibitors is contra-indicated in patients with renal dysfunction, inflammatory bowel disease, colonic ulceration or cirrhosis. They should not be used in patients with serum creatinine levels >2.0 mg/dL. This class of medications is not used much in US. Generic and brand names for common Alpha-Glucosidase inhibitors include Precose for acarbose and Glyset for miglitol.Information about the long-term use of acarbose in patients with reduced kidney function is sparse and its use in patients with later stage 3 and stages 4 and 5 CKDis not recommended.
22Definition of Incretins 二○一七年四月十四日Definition of Incretins“Intestine-derived factors that increaseglucose-stimulated secretion of insulin ”In ● cre ● tinIntestine Secretion InsulinCreutzfeldt. Diabetologia. 1985;28:565.
23Incretin Hormones Regulate Insulin and Glucagon Levels PancreasGutNutrient signals● GlucoseHormonal signalsGLP-1GIPGlucagon(GLP-1)Insulin(GLP-1,GIP)Neural signals cells cellsPurpose:To provide a high level overview of the incretin axis.Take-away:In response to the oral ingestion of glucose, the gut releases incretin hormones, which in turn stimulate insulin from the pancreatic β cells and suppress glucagon release from α cells.GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptideAdapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes CarAdapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. e. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744.References1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999; 20:876–913.2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91.3. D’Alessio DA, Vahl TP. Glucagon-like peptide 1: Evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab. 2004;286:E882–E890.4. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242.5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372.6. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.
25M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日DPP-4 Inhibition作用機轉上市產品釋出活性IncretinGLP-1與GIP進食腸胃道DPP-4 酵素無活性GLP-1XSitagliptin（DPP-4 抑制劑）胰臟GIPβ細胞α細胞DrugDose(mg)Daily dose and Frequency (mg)JANUVIA (sitagliptin)100100mg QDONGLYZA (saxagliptin)2.5-5mg2.5-5mg QD
26M:\MWP-DPP-E43627_Core Platform_R5.ppt DPP-4 InhibitionM:\MWP-DPP-E43627_Core Platform_R5.ppt二○一七年四月十四日NameDuration(hrs)代謝JANUVIA (Sitagliptin)12-24hrs70-80%腎臟排出，無法被透析排出ONGLYZA (Saxagliptin)24hrs全由肝臟代謝成無或弱活性產物，後從腎臟排出，可以被透析洗出1#QD # QD # QDOnglyza:Moderate or severe CKD, or ESRD under hemodialysis: 2.5mg QD(post-H/D)PD: no data
27M:\MWP-DPP-E43627_Core Platform_R5.ppt GLP-1 AnaloguesM:\MWP-DPP-E43627_Core Platform_R5.ppt二○一七年四月十四日作用機轉 產生類似GLP-1的作用副作用 對照性臨床研究中，不論單一或合併療法，表現出良好耐受性，出現臨床不良反應而停藥者與安慰劑相當上市產品DrugDose(mg)Daily dose and Frequency (mg)BYETTA (exenatide)5-10mcgBID
28M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日GLP-1 AnaloguesBYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min)caution in patients with renal transplantation.Moderate renal impairment (30-50 mL/min): caution should be applied when initiating or increasing doses of Byetta from 5 mcg to 10 mcgREFERENCE: U.S. Food and Drug Administration?
29Renal Side Effects of Exenatide 11/02/2009 FDA:From April 2005 through October 2008, FDA received 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. (total number: 6.6 million)
30Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease3. Insulin therapy in Patients with Advanced Kidney Disease
31Insulin Action: Comparison of New Insulin Analogs Rapid (Lispro, Aspart)RegularIntermediate (NPH)LongInsulin Level (U/ml)Hours
32Action Profiles Preparations Onset(h) Peak(h) Duration(h) Lispro/Aspart <RegularNPHUltralente < 20Glargine > 24A variety of human insulins that can be incorporated into a basal-bolus regimen that mimicks natural islet cell function are available1Genetically engineered short-acting human insulin preparations generally show a rapid onset of action and duration of action ranging from 3 to 4 hours1Lantus® (insulin glargine) activity is peakless and has an onset of action beginning 1 to 2 hours after subcutaneous injection1Lantus has demonstrated a duration of activity that is almost twice as long as that of NPH2The absorption of Lantus, which has a 24-hour duration of action, is prolonged without unwanted peaks3 and thus mimicks physiologic basal insulin more closely than does NPHModified after Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.1. Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.2. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:3. Lantus® (insulin glargine) US Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.
34Insulin therapy in renal disease BiesenbachG, Raml A, Schmekal B, Eichbauer-SturmG:Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. DiabetMed 20:642–645, 2003
35Insulin therapy in renal disease The American College of Physicians recommended:GFR (mL/min)Insulin50-10 mL/min25% decrease<10 mL/min50% decreaseHaemodialysisrequire less exogenousinsulin ( peripheral insulin resistance ↓)
36Insulin therapy in renal disease OBJECTIVE— Type 2 diabetic patients with end-stage renal disease (ESRD) on maintenance hemodialysis.CONCLUSIONS— The present study has demonstrated a significant25% reduction in basal insulin requirementsNo significant change in bolusesOverall the reduction of total insulin requirements was 15%
37Insulin therapy in renal disease ↓GFR:RI (rapid-acting insulin analogs): ↑ half-life and maximal serum concentrationsNPH (Caution!): long-acting ‘‘basal’’ insulin like glargineInsulin detemir : binding to serum albumin after injection so less predictable in patients with nephrotic syndrome and hypoalbuminema
38The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin 38
39ADA-EASD Guidelines Achievement of normal glycemic goals Initial therapy with lifestyle intervention and metforminEarly addition of insulin therapy in patients who do not meet target goalsRapid addition of and transition to new regimens, when glycemic goals are not achieved
40Management of Type 2 Diabetes ADA-EASD Check HbA1c every 3 months until < 7% and then at least every 6 monthsInsulin regimens under lifestyle and diet controlInitiation and intensification of insulin due to effectiveness and low expense although 3 oral agents can be used
41New ADA/EASD algorithm for T2DM: Basal insulin is recommended for insulin initiation At diagnosis:Lifestyle + Metformin+ Basal insulin+ Sulfonylureas+ Intensive insulinTier 1: well-validated therapiesSTEP 1STEP 2STEP 3Tier 2: Less well validated therapies+ PioglitazoneNo hypoglycaemiaOedema/CHFBone lossLifestyle + metformin+ GLP-1 agonistWeight lossNausea/vomiting+ SulfonylureaNathan et al. Diabetes Care 2008.Nathan DM, et al. Diabetologia 2009;52:17−30
42ADA-EASD Consensus Key messages on insulin - Insulin is the most effective drug in lowering BG- Insulin should be started with basal insulin- Basal Insulin is proposed as early as after Metformin- Then consider stepwise addition of bolus insulin starting with one shot at selected meal- Premixes are not recommended as first line insulin therapyThe following three-step approach to achieving and maintaining glycemic control is recommended. This graphic shows the relative glucose-lowering potential of all commonly used antidiabetes agents.Step 1 – initial therapy should be a combination of lifestyle intervention and metformin therapy. Metformin is the first-choice pharmacological intervention because of its efficacy, absence of weight gain and hypoglycemia, high level of acceptance, and low cost.Step 2 – additional therapy within 2–3 months of the initiation therapy or whenever HbA1c goal is not achieved. Basal insulin therapy should be considered for patients with HbA1c levels > 8.5% because insulin is the most effective glucose-lowering agent and can achieve reductions of up to 2.5%. Hospitalisation is not required to initiate insulin or adjust therapy. The patient is the key player and should be trained and empowered with the guidance of healthcare professionals.Step 3 – further adjustments to achieve glycemic targets. This involves initiation of basal insulin if not previously used or intensification of insulin therapy using prandial insulin to control postprandial glucose excursions. In some cases another oral agent may be added but this is often ineffective and can be relatively expensive.Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711–21.
43Normal Insulin Secretion: The Basal-Bolus Insulin Concept The basal–bolus insulin regimenBreakfastLunchDinnerPhysiological insulinPrandial insulin45Basal insulin30Insulin (mU/L)1506:0012:0018:0024:0006:00TimeFigure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21
44Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile 40020T2DM30015Plasma glucose (mg/dl)200Hyperglycaemia due to an increase in fasting glucosePlasma glucose (mmol/l)101005NormalIn patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentrations.Specifically targeting fasting hyperglycaemia will therefore lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy.Hirsch I, et al. Clin Diabetes 2005;23:78–86.MealMealMeal06.0010.0014.0018.0022.0002.0006.00Time of day (hours)Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86.
45Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile 4002030015Plasma glucose (mg/dl)200T2DMHyperglycaemia due to an increase in fasting glucosePlasma glucose (mmol/l)101005NormalLong-acting basal insulinIn patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentrations.Specifically targeting fasting hyperglycaemia will therefore lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy.Hirsch I, et al. Clin Diabetes 2005;23:78–86.MealMealMeal06.0010.0014.0018.0022.0002.0006.00Time of day (hours)Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86.
46ADA/EASD Consensus Algorithm for Type 2 Diabetes Mellitus Initiation of Basal Insulin:Start with bedtime intermediate-acting insulin, or bedtime or morning long-acting insulinCan initiate with 10 units or 0.2 units per kg↑ 2 units every 3 days, if 180> FBS >130 mg/dl↑ 4 units every 3 days if FBS >180 mg/dlIf hypoglycaemia or FBS <70 mg/dl, ↓ bedtime dose by 4 units, or 10% if dose >60 unitsNathan D, et al. Diabetologia 2006;49:1711−21.
47Insulin Therapy forType 2 Diabetes: Rescue, Augmentation, and Replacement of Beta-Cell Function
48Type 2 Diabetes Phase III Destiny of Type 2 Diabetes Pancreatic -Cell Decline Over Time in UKPDS100Insulin therapy75Rescue-Cell function (%)Augmentation50Replacement25Postprandial Hyper-glycemiaType 2 Diabetes Phase IType 2 Diabetes Phase IIType 2 Diabetes Phase IIIIGT–12–10–6–2261014Years from diagnosisAdapted from Lebovitz H. Diabetes Rev 1999;7:
49Augmentation therapy Rescue therapy May reverse glucose toxicity Using replacement regimens for several weeksMay reverse glucose toxicityAugmentation therapyWith basal insulinIf some β- cell function remainsStarting dose: u/kg/d orunits of insulin/d = FBS (mmol) = FBS/18 (mg/dl)e.g. FPG 180mg/dl 10 unitsFPG 270mg/dl 15 units
50Early Aggressive Insulin Therapy Study in Taiwan 60 newly diagnosed type 2 diabetic patients hospitalized patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for days.50 patients randomized to insulin therapy and oral antidiabetic drugs after discharge for 6 months and a follow-up for further 6 monthsHbA1c and Beta-cell function were measured.Chen HS, et al. Diabetes Care 2008; 31:
51Effect of Insulin vs. OADs on HbA1c in Newly Diagnosed T2DM Insulin groupOral antidiabetic drug group14P=0.002P=0.0091210HbA1c (%)8642Before therapy months monthsChen HS, et al. Diabetes Care 2008; 31:
52Significantly Improved β-cell Function with Basal Insulin Assessed by OGTT 14012010080604020#*Time (minutes)Plasma insulin (mU/mL)OAD group, after 6-month treatmentOAD group, at baselineInsulin group, after 6-month treatmentInsulin group, at baselineInsulin groupOAD group*P<0.05 between groups#P<0.05 baseline vs. after treatmentChen HS, et al. Diabetes Care 2008; 31:
53Replacement therapy Required for β- cell exhaustion With basal - bolus insulin (MDI)Required for β- cell exhaustionStarting dose : 0.5u/kg/dBasal % TDDBolus % TDD(% of estimated calories for each meal)Fasting Preprandial PostprandialAdjustment
54When to Consider Prandial Insulin A1C Versus FPG 240IncreaseBasal210180Fasting plasma glucose (mg/dL)StartPrandial150BiphasicBasal plusBasal/bolusTarget120678910A1C (%)
55Early Insulin Replacement in Type 2 DM May Preserve Beta-cell Function Glucose output“ Beta-cell rest ”? +Early insulinreplacementReduced strain ?Reduced toxicity ?-> Sustained insulinsecretion-glucosidase inhibitors (e.g. acarbose) – delay digestion and absorption of carbohydrates in the gastrointestinal tract.1,2Sulfonylureas and meglitinides – stimulate insulin secretion from the pancreas.1,2Biguanides (e.g. metformin) – suppress liver glucose output, enhance insulin sensitivity in the liver and stimulate insulin-mediated glucose disposal. They do not stimulate insulin secretion.1,2Thiazolidinediones – decrease insulin resistance in fat, muscle and liver. In addition, they improve estimates of -cell function.1,21Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.Glucose uptake Insulin resistance LipolysisAfter Gerstein & Rosenstock
57Insulin Glargine Structure SubstitutionExtensionA chainB chain11510520Asn30GlyArg1925Asparagine at position A21 replaced by glycineProvides stabilityAddition of 2 arginines at the C-terminus of the B chainSoluble at slightly acidic pHLantus® (insulin glargine) EMEA Summary of Product CharacteristicsMcKeage K et al. Drugs. 2001;61:
58Insulin Glargine vs NPH clear solution vs suspension NPH Glargine NPH NPH
59Injection of an acidic solution (pH 4.0) Mechanism of ActionInjection of an acidic solution (pH 4.0) Microprecipitation of insulin glargine in sub-cutaneous tissue (pH 7.4)Slow dissolution of free insulin glargine hexamers from microprecipitates (stabilised aggregates) Protracted actionKramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.
60Time-Action Profile of Lantus vs. NPH Plasma glucoseLepore et al. Diabetes 2000; 49:
61LEAD STUDY Lantus Evaluation in Asian type 2 Diabetics Inclusion criteria:Asian men and women with type 2 DM, insulin-naiveAged > 40 and 80 yearsTreatment with OADs for at least 3 monthsAny sulfonylurea, as monotherapy or in combination with metformin or acarbosePrevious sulfonylurea dose glimepiride 3 mgHbA1c between 7.5% and 10.5%FBG >120 mg/dL (6.7 mmol/L)BMI kg/m2Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:
63LEAD - Primary variable : change in HbA1c Insulin glargine(n=220)NPH insulin(n=223)-1.2-1-0.8-0.6-0.4-0.2Reduction in mean HbA1c (%)- 0.77- 0.99p=0.0319Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:
64LEAD: change in mean daily blood glucose (FAS) p=0.0018- 94- 80BaselineEndpoint50100150200250300276269189182Mean daily blood glucose (mg/dL)Insulin glargine(214)NPH insulin(219)Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:
65LEAD: Mean Basal Insulin Dose Mean initial doseMean basalof basal insulin*insulin dose atendpoint(IU/day)(IU/day)Insulin glargine9.632.1NPH insulin9.832.8* Start dose recommended by protocol: 0.15 U/kg/dayNo difference between PP and FAS populationPan C-Y et al. Diabetes Res Clin Pract 2007; 76:
66LEAD: Hypoglycemic Events 20040060080010001200p<0.004p<0.0003p<0.001Number of hypoglycemic episodesp<0.03All Symptomatic Severe NocturnalInsulin glargine NPH insulinPan C-Y et al. Diabetes Res Clin Pract 2007; 76:
67Follow-up assessments LACE: prospective, randomized real-life study of glargine + glulisine vs premixesAge 18 yearsHbA1c 7%Type 2 diabetesBMI ≥ 26Excluded if already taking exenatide or pramlintideGLAR + GLU ± orals or ± other (as naturally occurring)n = 197Premix ± orals or ± other (as naturally occurring)RandomizationInitial assessment3 month6 month9 monthFollow-up assessmentsNote: Inclusion – All patients eligible for BOTH insulin regimensDebit cards for all participants to cover additional, initial GLU copay sopatients will have equal financial access to both treatment armsLee et al. Poster presentation PS 085. Abstract EASD 2008Wednesday 12.30, Poster session
68Glargine + glulisine (n=106) LACE: glargine + glulisine vs premixes improved glycemic control with similar safetyGlargine + glulisine (n=106)Premixes (n=91)pBaseline HbA1c (%)9.25–Final adjusted HbA1c (%)6.937.520.009Change in HbA1c (%)–2.27–1.68Patients with hypoglycemia (last month)36%43%NSTotal insulin dose/day (U)74850.267Cost per day (all meds)10.82 (USD)12.06 (USD)0.209Total cost (6 months)(USD)(USD)Cost difference–225 (USD)Insulin pre-treated patients with T2DM (n=197)Lee et al. Poster presentation PS 085. Abstract EASD 2008
69Case of DMN: Insulin as Initial therapy Mr. King, 81 y/o male, diabetic nephropathy since 2008/102008/10/14, initiating Lantus 24 units qd FBS 130~160 mg/dl2008/12/3, adding Novonorm 1.5# tid FBS 100~120 mg/dl2009/11/27, maintaining Lantus 26 units qd + Novonorm 1.5# tidBefore Lantus (2008/10/9)After Lantus (2009/11/26)FBS (mg/dl) / HbA1c (%)237 / 13.2103 / 5.9BUN/Creatinine (mg/dl)38 / 2.4229 / 2.45eGFR (ml/min/1.73m2)27.727Urine Protein/Cr ratio1.31.49Cholesterol/TG (mg/dl)148/323125/111HDL/LDL (mg/dl)26/7628/80Na/K (mEq/L)139/3.9137/4P (mg/dl)3.03.6Albumin (g/dl)3.54
70The Basal / Basal Plus strategy for T2DM Stepwise intensification of treatment for continuity of controlFBG at targetHbA1c above targetFBG at targetHbA1c above targetBasal bolusBasal + three prandialFBG above targetHbA1c above targetBasal PlusAdd prandial insulin at main mealHbA1c above targetBasalAdd basal insulin and titrateOHA monotherapy and combinationsLifestyle changesProgressive deterioration of ß-cell functionOHA=oral hypoglycemic agentAdapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257−64
71Expected HbA1c Reduction in CKD Interventions Expected decrease in HbA1cLifestyle – 2 %Insulin – 3.5 %Sulfonylureas (glurenorm) – 2 %Glinides – 1.5 %Sitagliptin – 0.8 %a-glucosidase inhibitors – 0.8 %Pioglitazones – 1.4 %ADA: Managing hyperglycemia in T2DMThis consensus approach to management of hyperglycemia is intended to offer guidance in choosing the most appropriate therapy for patients with T2DM.Lifestyle intervention to decrease weight and increase activity is the initial step in T2DM management and metformin is the initial medication used.An A1C ≥7% should serve as a call to rapid action to initiate or change therapy and intensify treatment to achieve and maintain glycemic levels as close to the nondiabetic range as possible.Combinations of 3 oral agents can be used, although early initiation and intensification of insulin therapy may be beneficial because of efficacy and cost.Choices of antihyperglycemic agents are based primarily on relative glucose-lowering efficacy, nonglycemic effects of medications that may reduce long-term complications, safety profiles, tolerability, and cost.(1)Agents not referred to in this algorithm (eg, DPP-IV inhibitors) are relatively less effective choices for lowering A1C.(2)Nathan DM, et al. Diabetologia 2009;52:17−301. Nathan DM et al. Diabetologia. 2006;49:2. Nathan DM. N Engl J Med. 2007;356:
72Summary: Treatment of DM in CKD Novel diabetic medications are available in past few years.Some require adjustment of dose or should be even avoided according to the patient’s renal function.Metformin, 1st line Tx in patients with normal renal function, is contraindicated in CKD with Cr>1.5 (M) or 1.4 (F) mg/dL.CKD stage 3/4: SU (glipizide, gliclazide, glimepiride), Glinides, TZD, DPP4i, α-glucosidase inhibitor, insulinCKD stage 5 or ESRD: SU (glipizide, gliclazide), Glinide (repaglinide, mitiglinide), TZD, DPP4i, insulinJudicious titration of medications and frequent monitoring of blood glucose to avoid severe adverse effects!
73Summary for Basal Insulin Therapy Tight glycemic control reduces risk of complications.Earlier initiation of insulin helps achieve target of glycemic control.Lantus, long-acting insulin analog, as a basal insulin therapy with:Once daily, peakless, 24 hours basal insulinConsistent efficacy in glycemic controlLess hypoglycemia than NPH insulin and premixed human insulinLess adverse reactions than TZD add-on to OADsEasy titration according to FPG to achieve target
76Expected HbA1c Reduction Interventions Expected decrease in HbA1cLifestyle – 2 %Insulin – 3.5 %Metformin – 2 %Sulfonylureas – 2 %Pioglitazones – 1.4 %a-glucosidase inhibitors – 0.8 %Exenatide – 1 %Glinides – 1.5 %Pramlintide – 1 %Sitagliptin – 0.8 %ADA: Managing hyperglycemia in T2DMThis consensus approach to management of hyperglycemia is intended to offer guidance in choosing the most appropriate therapy for patients with T2DM.Lifestyle intervention to decrease weight and increase activity is the initial step in T2DM management and metformin is the initial medication used.An A1C ≥7% should serve as a call to rapid action to initiate or change therapy and intensify treatment to achieve and maintain glycemic levels as close to the nondiabetic range as possible.Combinations of 3 oral agents can be used, although early initiation and intensification of insulin therapy may be beneficial because of efficacy and cost.Choices of antihyperglycemic agents are based primarily on relative glucose-lowering efficacy, nonglycemic effects of medications that may reduce long-term complications, safety profiles, tolerability, and cost.(1)Agents not referred to in this algorithm (eg, DPP-IV inhibitors) are relatively less effective choices for lowering A1C.(2)Nathan DM, et al. Diabetologia 2009;52:17−301. Nathan DM et al. Diabetologia. 2006;49:2. Nathan DM. N Engl J Med. 2007;356:
77Relative Contributions of Diabetic Pathophysiologies Over Time Both beta-cell dysfunction + insulin resistance start years before diagnosisBeta-cell dysfunction determines the onset of hyperglycemia, glucose levels and disease progression, not insulin resistanceThose who develop DM have lost ~50% of beta-cell functionHepatic glucose over-productionRelative Contributions of Diabetes Pathophysiologies Over TimeThis is a conceptual slide about the relative contributions of diabetic pathophysiologies, beta-cell dysfunction, insulin resistance, and hepatic glucose overproduction.Build 1-From UKPDS, at the time of diagnosis of type 2 diabetes and 6 years afterwards about 50% and 73% of beta-cell function has been lost, respectively.1 This and other data2,3 has led to the projection that beta-cell dysfunction begins in individuals with normal glucose tolerance (NGT) more than 10 years before diagnosis.1 Beta-cell dysfunction is progressive with time.3,4Build 2-Insulin resistance, like beta-cell dysfunction, begins years before diagnosis4Build 3-Insulin resistance develops rapidly. It has been shown that there is no significant difference between the level of insulin resistance found in individuals with impaired glucose tolerance (IGT) and that found in type 2 diabetes patients.3 Although insulin resistance is known to drive metabolic deterioration in the development of type 2 diabetes, beta-cell dysfunction ultimately determines the onset of hyperglycemia and is a major factor associated with progressively rising plasma glucose levels and disease progression.3,5Basal hepatic glucose output did not differ significantly between NGT and IGT groups.6 It has been shown that during type 2 diabetes increases in hepatic glucose production correlate with the increases in fasting glucose levels.7100%Beta-cell dysfunction100%Insulin resistanceNGTIGTT2D DiagnosisLate Stage T2DMNGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetesBell D. Treat Endocrinol 2006; 5: ; Butler AE et al. Diabetes 2003;52: ; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6:Gastaldelli A, et al Diabetologia 2004:47:31-39; Mitrakou A, et al. N Engl J Med 1992; 326:22-29; Halter JB, et al. Am J Med 1985;79S2B:6-12References:Bell DSH. The case for combination therapy as first-line treatment for type 2 diabetic patients. Treat Endocrinol 2006;5:131–137.Butler AE, Jansen J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110.Del Prato S and Marchetti P. Targeting insulin resistance and beta-cell dysfunction: The role of thiazolidinediones. Diabetes Tech Ther 2004;6:719–131.Gastaldelli A, Ferranninni E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance: Results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31–39.Rhodes CJ. Type 2 diabetes—A matter of β-cell life and death? Science 2005; 307:380–384.Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 1992;326:22–29.Halter JB, Ward WK, Porte D, et al. Glucose regulation in non-insulin-dependent diabetes mellitus: Interaction between pancreatic islets and the liver. Am J Med 1985;79S2B:6–12.
78Decline of -cell function determines the progressive nature of T2DM (UKPDS) 100Time of diagnosis?% of Normal by HOMA-cell function80- 5% per yr60Pancreatic function= 50% of normal4020Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function with T2DM over time.At the time of diagnosis, -cell function is already reduced by about 50% and continues to decline regardless of therapy.Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.UKPDS Group. Diabetes 1995;44:1249―58.―10―8―6―4―2246Time (years)HOMA= Homeostasis model assessment.UKPDS Group. Diabetes 1995;44:1249―58.Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.