FoodSteps Navorming T2DM Anti-hyperglycemic Therapy: General Recommendations Gezonde leefstijl: voeding en beweging

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1 FoodSteps Navorming -- Insuline-therapie Insuline-therapie in type diabetes C. Mathieu Endocrinologie, UZ Leuven C. Mathieu Endocrinologie, UZ Leuven Thuis heb ik nog een ansichtkaart Waarop een kerk een kar met paard Een slagerij J. van der Ven Een kroeg, een juffrouw op de fiets Het zegt u hoogstwaarschijnlijk niets Maar het is waar ik geboren ben Dit dorp, ik weet nog hoe het was De boerenkind'ren in de klas Een kar die ratelt op de keien Het raadhuis met een pomp ervoor Een zandweg tussen koren door Het vee, de boerderijen En langs het tuinpad van m'n vader Zag ik de hoge bomen staan Ik was een kind en wist niet beter Dan dat 't nooit voorbij zou gaan Basic Steps in the Management of Type Diabetes Insuline starten voor huisartsen, C. Mathieu TDM Anti-hyperglycemic Therapy: General Recommendations Gezonde leefstijl: voeding en beweging SU Glinide DPP- inhibitoren GLP-R agonisten Insuline Metformine TZD Inzucchi et al. Diabetes Care, Diabetologia. LMN Zuid-West-Vlaanderen

2 FoodSteps Navorming -- Beta-cell function (%, HOMA) Subjects (%) Type diabetes is a complex disease Insulin resistance Waarom is er in type diabetes insuline nodig? Er is toch hyperinsulinisme? Unhealthy lifestyle and environmental factors + Healthy beta-cell Metabolic syndrome Increased risk of cardiovascular disease Type diabetes is a complex disease Type diabetes is a complex disease Unhealthy lifestyle and environmental factors + Genes Environment Inflammation FFA Glucose Unhealthy lifestyle and environmental factors + Insulin resistance Metabolic syndrome Increased risk of cardiovascular disease Hyperglycemia Failing beta-cell Hyperglycemia Type diabetes Type diabetes UKPDS HOMA-B: beta-cell function progressively declines Until we can stop the deterioration Diabetes diagnosis of functional betacell mass, most 8 type diabetic patients will eventually need insulin to maintain glucose control Extrapolation of beta-cell function prior to diagnosis 8 8 Years from diagnosis Clinical inertia: Failure to advance therapy when required Percentage of subjects advancing when HbA C > 8% 8 At insulin initiation, the average patient had: years with HbA C > 8% years with HbA C > %.% Diet.%.% 8.% Sulphonylurea Metformin Combination UKPDS. Diabetes 99; :9 8 Brown et al. Diabetes Care ;: LMN Zuid-West-Vlaanderen

3 Mean HbA c % FoodSteps Navorming -- Poor HbA c levels reflected in clinical practice Mean HbA c by country 8 Before intensification After intensification 9, 9, 8, 8, 9,9 8, UK & Ireland 8.8% Belgium.9% Finland 8.% Sweden.% Germany.% France 8.% Denmark 8.% Italy.88% OHD OHD Insulin Spain.% Calvert et al. Br J Gen Pract ;: Coninck et al. J Diabetes ;:8 9 TDM Anti-hyperglycemic Therapy: General Recommendations TDM Anti-hyperglycemic Therapy: General Recommendations Biggest hurdle? Biggest hurdle? Inzucchi et al. Diabetes Care, Diabetologia. Inzucchi et al. Diabetes Care, Diabetologia. Physician barriers to initiating insulin Patient barriers Time constraints Perceived patient incompetence Reliance on lifestyle changes Insufficient infrastructure Attitudes among patients willing or unwilling to accept insulin therapy Perceptions of insulin therapy among treatmentnaïve/experienced patients Desire to avoid unpleasant confrontation Concerns about outcomes and hypoglycaemia Potential for weight gain Can never stop insulin Patient s care not good enough Willing Unwilling Seen as sick Insulin experienced Insulin naïve Lack of confidence in insulin clinical data Impact on patient QoL and employment Fear of seeming incompetent to colleagues Not confident with therapy Problematic hypoglycaemia Anticipated pain (injecting) Weight gain Injection fear Lack of fairness Unsure when to initiate insulin Unsure when and how to intensify therapy Believe barriers reside mainly with patients Life will be restricted My diabetes will be more serious Insulin causes problems like blindness Less flexibility Diabetes worse % % % % % % % % 8%. Polonsky et al. Diabetes Care ;8: ;. Snoek et al. Health Qual Life Outcomes ;:9 Kunt and Snoek. Int J Clin Pract 9;(Suppl. ): LMN Zuid-West-Vlaanderen

4 FoodSteps Navorming -- Severe hypoglycaemic events Change in weight from baseline (kg) Severe hypoglycaemic events Severe hypoglycaemic events Change in weight (kg) Increased incidence of severe hypoglycaemia with intensive therapy in ACCORD, ADVANCE and VADT ACCORD ADVANCE Per patients per year.... Per patients per year Per patients per year VADT. Weight gain by treatment in UKPDS... Insulin Conventional Chlorpropamide Glibenclamide Metformin Weight gain by treatment Standard Intensive p<. Standard Intensive p<. Standard Intensive p<. -. Years from randomization. ACCORD Study Group. N Engl J Med 8;8: 9;. ADVANCE Collaborative Group. N Engl J Med 8;8: ;. Duckworth et al. N Engl J Med 9;:9 9 UKPDS Group (). Lancet 998; :8 8. Weight change in treat-to-target trials.... Riddle * p <. Hermansen weeks * p =. Detemir pm Detemir twice daily NPH pm NPH twice daily Glargine pm Philis-Tsimikas weeks weeks Outcome Reduction with an Initial Glargine INtervention NEJM June Summary of Findings Compared to standard glycemic care of people with early diabetes, IGT &/or IFG using once daily basal insulin glargine to target a FPG < 9 mg/dl (. mmol/l) for a median of. years... Maintains near-normal glycemic control Has a neutral effect on CV outcomes & on cancers Slows progression of dysglycemia Modestly increases hypoglycemia Modestly increases weight Hypoglycemia & Weight ( - years) Glargine (N=) Standard (N=) % /py % /py Any Non-severe or more episodes <. Severe or more episodes.. <. Weight Change Since Randomized Glargine Standard P. kg (. lbs) -. kg ( lb) <. P LMN Zuid-West-Vlaanderen

5 FoodSteps Navorming -- % patients with diabetes reaching targets Higher proportion of patients intensified by specialists (9) vs PCPs (9) Methods of overcoming clinical inertia p=.9 Adherence to medications Developing quality measures Education (CME) p=ns p=ns p<. Effective use of information system Motivating and supporting patients on selfmanagement PCP, primary care physician Shah et al. Diabetes Care ;8: Guidelines Zafar et al. Primary Care Diabetes ;: Personal feedback to HCP Recommendations Patient-adjusted dosing algorithm vs physician standard of care: -week RCT Insulin detemir was started once daily as add-on therapy to any other glucose-lowering regimens or as a replacement for prestudy basal insulin Insulin dose adjustments* algorithm sites: patients to adjust dose every days based on mean FPG values, n=8 FPG (mg/dl) Basal dose adjustment <8 Reduce detemir dose by U 8 No change > Increase detemir dose by U Summary There are many issues contributing to inertia, and consequently many potential solutions Inertia surrounding insulin initiation and intensification is apparent from clinical trials and real-life practice Improving education of physicians and patients may address current barriers Standard-of-care sites: physician to adjust dose based on standard of care, n=8 * Insulin detemir dose titration was not enforced in either group Meneghini et al. Diabetes Obes Metab ;9:9 Kunt, Snoek. Int J Clin Pract 9;(Suppl. ): Proportion of patients reaching HbA c targets is low 8 Praktisch insuline starten C. Mathieu Total cholesterol < mg/dl LDL cholesterol < mg/dl Blood pressure </8 mmhg HbAc <% Grant et al. Diabetes Care ;8: LDL, low-density lipoprotein LMN Zuid-West-Vlaanderen

6 FoodSteps Navorming -- Serum insulin Insulin (mu/l) Praktisch De challenge van subcutane toediening van insuline Welke insuline? Wanneer? Wie titreert? Hoe titreren? Normal free insulin levels (Mean) Meals 9 8 Time of day Breakfast Adapted from Polonsky et al. 988 Lunch Dinner Bedtime Wat doet de beta-cel? Insuline kristallen Molecular Size Determines the Rate of Subcutaneous Absorption Molecular size Subcutaneous tissue kda kda kda (mu/l) Effect subcutaan regular insulin (pmol/l) Actrapid, Humuline Regular, Insuman Rapid Human Actrapid (. U/kg) Insulin Zn + Zn + Absorption Zn + Capillary membrane Slow Absorption Rapid Absorption Werkingsduur: minuten-uren Time (minutes) Heinemann L et al. Diabetes Med 99;:8 LMN Zuid-West-Vlaanderen

7 FoodSteps Navorming -- GIR (mg/kg/min) GIR (mg/kg/min) GIR (mg/kg/min) Probleem subcutaan regular insulin Om basaal profiel te dekken: Molecular Size Determines the Rate of Subcutaneous Absorption Te kortwerkend Piekwerking Om maaltijden te dekken: Molecular size Insulin > kda High molecular weight forms Subcutaneous tissue kda Zn + Zn + kda kda Zn + Te trage start Te lange duur Absorption Capillary membrane Slow Absorption Rapid Absorption Humand insuline trager maken: Fysisch: eiwit (of Zn) toevoegen Humand insuline trager maken: Fysisch: eiwit (of Zn) toevoegen NPH insuline: protamine Humuline NPH, Insulatard, Insuman Retard NPH insuline: protamine Humuline NPH, Insulatard, Insuman Retard Humand insuline trager maken: GIR profiles following four identical NPH insulin injections Noodzaak tot mengen Subject no: Subject no: Subject no: Subject no: Subject no: Subject no: Clamp Clamp Clamp Clamp Dose at each injection: NPH Insulin. U/kg, thigh NPH insuline: protamine Humuline NPH, Insulatard, Insuman Retard Subject no: Subject no: Subject no: Elapsed time (hours) Elapsed time (hours) Elapsed time (hours) T. Heise et al. Diabetes ; :- NN- LMN Zuid-West-Vlaanderen

8 FoodSteps Navorming -- Plasma Insulin Levels Probleem fysisch vertraagde insuline Om basaal profiel te dekken: Te kortwerkend Piekwerking Variabiliteit +++ Insuline analogen: gewenste eigenschappen Basale insuline analogen : Trage en stabiele absorptie Lange werkingsduur Weinig fluctuatie in actieprofiel van dag tot dag Oplossing vertraging insuline Lantus Insulin Glargine Mechanism of Action The mechanics of sustained release Injection of an acidic solution (ph.) Microprecipitation of insulin glargine in subcutaneous tissue (ph.) Slow dissolution of free insulin glargine hexamers from microprecipitates (stabilised aggregates) Protracted action Adapted from Kaarsholm & Ludvigsen. Receptor 99;: 8. Lantus (insulin glargine) EMEA Summary of Product Characteristics... McKeage K et al. Drugs. ;:99-.. Kramer W. Exp Clin Endocrinol Diabetes. 999;(suppl ):S-S. Insulin Profiles Oplossing vertraging insuline Levemir Regular ( 8 hr) NPH ( hr) Glargine (~ hr) 8 8 Hours Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type Diabetes.. Ch. :-. Albuminbinding moeity A Myristic acid Gly Ile Val Glu Gln Thr Lys Cys Cys Lys Thr Pro B9 Ser B Thr Ile Phe Tyr A Cys Val Phe Asn Ser Asn Phe Cys Leu Gln Gly Tyr Tyr Asn Arg Glu Leu Gln His Leu Glu Cys Gly Gly Cys Ser Val Leu His Tyr Leu Ala Glu Val Leu LMN Zuid-West-Vlaanderen 8

9 FoodSteps Navorming -- GIR mg/(kg/min) Oplossing vertraging insuline Levemir Myristic acid binding sites Albumine Subcutaneous depot Potential sites of protraction Delayed absorption through self-association and albumin binding Myristic acid binding sites Myristic acid binding site Circulation Interstitial fluid Delayed delivery to target tissues due to retention by albumin binding (Delayed arrival at insulin receptors due to albumin binding) Curry S et al. Nature Structural Biology 998:: Variability in time-action profile of basal insulins* 8% 8% % NPH insulin 8. Insulin glargine 8. Insulin detemir 8 Time (hours)... 8 Time (hours)... 8 Time (hours) Insuline analogen: gewenste eigenschappen Basale insuline analogen : Trage en stabiele absorptie Lange werkingsduur Weinig fluctuatie in actieprofiel van dag tot dag Maaltijd-gerelateerde analogen : Snelle absorptie Piek actie die samenvalt met de piek van KH absorptie T. Heise, et al. Diabetes. *.U/kg Oplossing snellere insulines Humalog, Novorapid, Apidra (Lispro, Aspart, Glulisine) Molecular Size Determines the Rate of Subcutaneous Absorption Subcutaneous tissue Molecular size > kda kda kda kda Insulin High molecular weight forms Zn + Zn + Zn + Absorption Capillary membrane Slow Absorption Rapid Absorption Adapted from Kaarsholm & Ludvigsen. Receptor 99;: 8 LMN Zuid-West-Vlaanderen 9

10 FoodSteps Navorming -- Serum insulin Plasma Insulin Levels Serum glucose (mmol/l) Advancements Plasma Glucose (mg/dl) Blood glucose (mmol/l) Insulin profiles and glycemic excursions after a test meal in patients with type diabetes (pmol/l) NovoRapid, t = min Soluble human insulin, t = min Soluble human insulin, t = min (. U/kg) Bottom line: comparable glucose control- less hypoglycemia NovoRapid Soluble human insulin (. U/kg) 9 p<. p<. 8 Time (hours) Time (hours) Pre Post Pre Post Pre Post Breakfast Lunch Dinner Bedtime a.m. Adapted from Lindholm et al. 999 Adapted from Home et al. 998 Insulin Profiles Continuous development in insulin therapy 8 Aspart, Lispro, Glulisine (- hr) Regular ( 8 hr) NPH ( hr) Basal insulin analogues Next generation insulin Glargine (~ hr) Detemir (~- hr) Biphasic insulin analogues Rapid-acting insulin Recombinant analogues Neutral human Isolation protamine insulin of insulin Hagedorn (Banting & Best) (NPH) insulin 99s s 8 8 Hours Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type Diabetes.. Ch. : Time TDM Anti-hyperglycemic Therapy: General Recommendations Correcting Fasting Hyperglycemia Is Usually the First Task! Uncontrolled AC ~9% Controlled AC <% Normal AC % % Inzucchi et al. Diabetes Care, Diabetologia Time of Day LMN Zuid-West-Vlaanderen

11 FoodSteps Navorming -- Plasma Insulin Levels Plasma Glucose (mg/dl) Plasma Insulin Levels Plasma Insulin Levels Current pure insulin preparations and their pharmacokinetics following s.c. injection Insulin Profiles Aspart, Lispro, Glulisin ( hr) Insulin Onset of action Peak of action Duration of action Soluble - minutes - hours -8 hours Lispro/Aspart Glulisine NPH - minutes - hours - hours - hours - hours -8 hours Glargine (~ hr) Levemir (~- hr) Glargine - hours peakless > hours Levemir - hours -8 hours 8- hours 8 8 Hours Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type Diabetes.. Adapted from Burge and Schade. 99 Ch. :-. Insulin Profiles Insulin Profiles Regular ( 8 hr) NPH ( hr) Humuline / Novomix 8 8 Hours Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type Diabetes.. Ch. : Hours Based on Rosenstock J, Wyne K. In: Goldstein BJ, Muller-Wieland D, eds. Textbook of Type Diabetes.. Ch. :-. Starten met Basale Insuline Start ZTJ- zorg voor educatie en zelfmonitoring Hou de orale medicatie als is- als je start met laag HbAc (<8%), eventueel SU verminderen- Stop TZD, DPPi, GLPRa Voeg NPH toe bedtime:.u/kg Correcting Fasting Hyperglycemia Is Usually the First Task! Uncontrolled AC ~9% Controlled AC <% Evalueer nuchtere glycemie na paar dagen Verhoog minstens wekelijks de dosis > - mg/dl: verhoog dosis met E > mg/dl: verhoog dosis met E > 8 mg/dl: verhoog dosis met E > mg/dl: verhoog dosis met 8 E Treat to Target (< mg/dl) Verminder insuline als nuchter < mg/dl of hypoglycemie s nachtsverminder SU als hypoglycemie overdag Normal AC % % Time of Day then Treat Postprandial Hyperglycemia with a Short-Acting Analog at Main Meal if AC still >%! LMN Zuid-West-Vlaanderen

12 FoodSteps Navorming -- Wat als basale insuline onvoldoende is? Premixes = als HbAc >% en NPH kan niet verder opgedreven worden owv hypoglycemie = tussenoplossing die +/- regeling toelaat Humane: % Regular/NPH Switch naar Lantus, dose for dose Bij goed ochtendglycemie, maar vooral overdag oplopen glycemie: voeg maaltijdinsuline toe: -Snelle insuline bij maaltijden (basaal bolus) -Pre-mix insulines Analoog: Novomix : % Aspart Dosis zoeken = Rekenen Dit zijn ongenuanceerde casussen bedoeld om te leren spelen met insuline De casussen zijn allemaal statine en bloeddruk gecontroleerd jaar, vrouw, ex-verpleegster Huidige therapie: HbAc 9% Dagprofiel: Amarylle Co Glucophage x8mg Dagprofiel Wat is uw therapie suggestie als u weet dat patiënt volgende therapie heeft en een HbAc van 8% Dagprofiel Wat is uw therapie suggestie als u weet dat patiënt volgende therapie heeft en een HbAc van 8% - E Insulatard - Gliclazide x Co - Glucophage x 8mg - E Lantus LMN Zuid-West-Vlaanderen

13 FoodSteps Navorming -- Plasma Insulin Levels Dagprofiel jaar, man, ex-lasser Wat is uw therapie suggestie als u weet dat patiënt volgende therapie heeft en een HbAc van 8% - E Novomix ---- E Novomix ---- Glucophage x8mg Huidige therapie: HbAc 8% Diamicron xco Novonorm xmg Glucophage x8mg E Insulatard voor slapen Dagprofiel: jaar, vrouw, huisvrouw Huidige therapie: HbAc 8% Dagprofiel: Januvia mg Glucophage x8mg Erik S., jaar Diabetes type, behandeld met Metformine x8mg en s morgens E Humuline / en s avonds E Humuline / Hij wordt lid van een wielerclub maar durft er niet aan beginnen- uw advies? Insulin Profiles Empowerment through motivation E Humuline / E Humuline / LMN Zuid-West-Vlaanderen

14 FoodSteps Navorming -- Primary Care Endocrino logist Cardiol ogist Podologists Patient Ophtalmo logists Nurse educators. Dieticians LMN Zuid-West-Vlaanderen