Insulin and Post Prandial

Transcription

1 Insulin and Post Prandial Pr Luc Martinez PCDE Meeting Barcelona 2016

2 Conflicts of interest disclosure Advis consultant f Amgen Inc.; AstraZeneca Pharmaceuticals LP; GlaxoSmithKline; Ipsen; Lilly; Mayoly Spindler; MSD; Menarini; Novo Ndisk; Pfizer Inc; Sanofi; Servier.

3 Is a chronic disease Type 2 Diabetes Caracterised by Increasing insulin resistance And decreased endogenous insulin production Resulting in chronic hyperglycaemia and po glycaemic control Increasing the risk of developing microvascular complications (retinopathy, neuropathy, nephropathy) and macrovascular complications (conary insufficiency, peripheral arteriopathy, vascular cerebral arteiopathy).

4 Nmal Daily Insulin Profile Insulin ( U/mL) B L D Time of Day Abbreviations: B, breakfast; L, lunch; D, dinner. Polonsky KS, et al. N Engl J Med. 1988;318:

5 Glucose and insulin over the day mg/dl 144 aaa :00

6 Notion of Post-meal Glucose Peaks in type 2 diabetes Glycaemia (mg/dl) 400 Type 2 diabetes Healthy subject Post-meal Glucose Peaks :00 12:00 16:00 20:00 24:00 04:00 08:00 Time Blood glucose nadir: 2 to 4 in the mning Cusi, Diabetes Care 1995;18:

7 The respective contributions of the different components of glucose exposure L. Monnier, C. Colette. Diabetes & Metabolism, Volume 41, Issue 6, Supplement 1, 2015, 6S9 6S15

8 Add-on therapies accding to the relative contributions of basal and postprandial Hyperglycemia L. Monnier, C. Colette. Diabetes & Metabolism, Volume 41, Issue 6, Supplement 1, 2015, 6S9 6S15

9 Contributions of Basal and Postprandial Hyperglycemia to overall Dysglycemia Baseline A1c categy (%) Total hyperglycemia (%) Basal hyperglycemia Postprandial hyperglycemia < M RIDDLE Diabetes Care 34: ,

10 Monotherapy Efficacy * Hypo risk Weight Side effects Costs Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin high low risk neutral/loss GI / lactic acidosis low If HbA1c target not achieved after ~3 months of monotherapy, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Metfmin Sulfonylurea high moderate risk gain hypoglycemia low Metfmin Thiazolidinedione high low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare high Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration high Metfmin GLP-1 recept agonist high low risk loss GI high Metfmin Insulin (basal) highest high risk gain hypoglycemia variable Triple therapy Metfmin Sulfonylurea If HbA1c target not achieved after ~3 months of dual therapy, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): TZD Metfmin Thiazolidinedione SU Metfmin DPP-4 Inhibit SU Metfmin SGLT-2 Inhibit SU Metfmin GLP-1 recept agonist SU Metfmin Insulin (basal) TZD DPP-4-i DPP-4-i TZD TZD TZD DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i Insulin SGLT2-i GLP-1-RA GLP-1-RA Insulin Insulin GLP-1-RA Insulin Insulin PCDE Combination Barcelona, 2016 injectable therapy If HbA1c target not achieved after ~3 months of triple therapy and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add GLP-1-RA mealtime insulin. In refracty patients consider adding TZD SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38: ; Diabetologia 2015;58:

11 Triggers to initiate insulin in Primary Care Patients uncontrolled under triple therapy Patients with long-standing diabetes and poly controlled Any patient not at HbA1c target despite intensive treatment

12 Aim of Basal Insulin Therapy Glycaemia (mg/dl) 400 Failure with ADOs ADOs Insulin bed time Post-meal Glucose Peaks :00 12:00 16:00 20:00 24:00 04:00 08:00 Time Basal Insulin Blood glucose nadir: 2 to 4 in the mning Cusi, Diabetes Care 1995;18:

13 Notion of Well Titrated Insulin Therapy Glycaemia (mg/dl) 400 Post Prandial Glycaemia are not nmalized, but are at an acceptable level ADOs insulin bed time Time HbA1c around 7% Crect dosage of Basal Insulin Cusi, Diabetes Care 1995;18:

14 In Praise of Simplicity Everything should be made as simple as possible, but not simpler. Albert Einstein

15 The Basal Insulin Therapy Advantages One Insulin Once daily injection 1 Glucose Target (FPG/HbA1c) Easy dose titration (FPG) Low dose Small gain weight Hypoglycemia unfrequent Education limited (pencils) Good acceptability Limits Beta cell function requested Selection of patients Risk f nocturnal hypoglycemia if combined with Sulfonylurea Need f intensification and addition of bolus over time

16 BASAL Insulin Therapy: what option? Intensification Optimisation 16

17 Optimisation: when, why, how? WHEN? WHY? HOW? FPG Not at target Basal Insulin Optimisation 1 HbA 1c Not at target FPG at target PPG not at target: Intensification 2 HbA 1c at target But frequent Hypocglycemia 17

18 Conceptual model of action profiles with once-daily dosing of Basal Insulin Duration 24 h Duration > 24 h Adapted Haahr H, Heise T Clinical Pharmacokinetics. 2014;53(9):

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20 Insulin Glargine U300

21 # Injections 1 Intensification Basal Insulin (usually with metfmin /- other non-insulin agent) Complexity low Start: 10U/day U/kg/day Adjust: 10-15% 2-4 U once-twice weekly to reach FBG target. F hypo: Determine & address cause; dose by 4 units 10-20%. 2 Add 1 rapid insulin* injections befe largest meal If not controlled after FBG target is reached ( if dose > 0.5 U/kg/day), treat PPG excursions with meal-time insulin. (Consider initial GLP-1-RA trial.) Change to premixed insulin* twice daily mod. Start: 4U, 0.1 U/kg, 10% basal dose. If A1c<8%, consider basal by same amount. Adjust: dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20%. Start: Divide current basal dose into 2/3 AM, 1/3 PM 1/2 AM, 1/2 PM. Adjust: dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20%. 3 If not controlled, consider basalbolus. Add 2 rapid insulin* injections befe meals ('basal-bolus ) If not controlled, consider basalbolus. high Start: 4U, 0.1 U/kg, 10% basal dose/meal. If A1c<8%, consider basal by same amount. Adjust: dose by 1-2 U 10-15% once-twice weekly to achieve SMBG target. F hypo: Determine and address cause; cresponding dose by 2-4 U 10-20%. Diabetes Care 2015;38: ; Diabetologia 2015;58: Flexibility me flexible less flexible

22 Insulin and GLP1 RA in combination Patient Chatacteristics High fasting glucose High postprandial glucose Susceptibility to GI disders Need f simple treatment approach Sht-acting GLP1-RA Long-acting GLP1-RA Choice of GLP-1 Long-acting GLP1-RA Sht-acting GLP1-RA Long-acting GLP1-RA Long-acting GLP1-RA Exenatide, lixisenatide Liraglutide, dulaglutide, exenatide LAR

23 Combination of Basal Insulin GLP-1 RA: Complementary actions Basal insulin reduces FBG GLP1-RA ameliates PPG Potential benefits Improvement in HbA1c Weight loss Less hypoglycemia episodes

24 Conclusion Fasting Plasma Glucose accounts f the highest part of hyperglycemia in patients poly controlled To focuse primarily on it in patients treated with basal insulin therapy Long-acting GLP1-RA If necessary, treat Post Prandial Glucose excursions with rapid insulin GLP1-RA