Κριτική θεώρηση των θεραπευτικών αλγόριθμων για το σακχαρώδη διαβήτη

Κριτική θεώρηση των θεραπευτικών αλγόριθμων για το σακχαρώδη διαβήτη Ερυφίλη Χατζηαγγελάκη Αναπλ. Καθηγήτρια Παθολογίας- Σακχαρώδη διαβήτη Β Προπ. Παθολογική Κλινική & Μονάδα Έρευνας του Πανεπιστημίου Αθηνών Πανεπιστημιακό Γ.Ν Αττικόν

Multiple, Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA _? hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Multiple, Complex Pathophysiological Abnmalities in T2DM GLP-1R agonists incretin effect DPP-4 inhibits A G I s gut carbohydrate delivery & absption Metfmin Insulin Glinides S U s Amylin mimetics _ pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA SGLT-2 _ DA agonists T Z D s? hepatic glucose production renal glucose excretion peripheral glucose uptake Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Ποιά υπογλυκαιμικά Φάρμακα?

Glucose-lowering agents classified by risk of hypoglycaemia High risk Low risk Insulin Sulphonylureas Glinides Metfmin -glucosidase inhibits Thiazolidinediones GLP-1 recept agonists DPP-4 inhibits SGLT-2 inhibits

Unmet Needs in Diabetes Care Multiple Defects in Type 2 Diabetes Adverse Effects of Therapy Weight Management Type 2 Diabetes Hyperglycemia CVD Risk (Lipid and Hypertension Control) Adapted from 2005 International Diabetes Center, Minneapolis, MN. All rights reserved.

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets - HbA1c < 7.0% (mean PG 150-160 mg/dl ) - Pre-prandial PG <130 mg/dl - Post-prandial PG <180 mg/dl - Individualization is key: Tighter targets (6.0-6.5%) - younger, healthier Looser targets (7.5-8.0% ) - older, combidities, hypoglycemia prone, etc. - Avoidance of hypoglycemia Diabetes Care 2012;35:1364 1379; Diabetologia 2012;55:1577 1596

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Patients (%) PANORAMA: proption of patients in Europe not reaching glycaemic target Patients with HbA 1C 7% (not at target) 52.0 38.2 36.3 32.9 39.8 40.3 42.3 37.4 28.3 25.9 Belgium (659) Germany (808) Greece (375) Italy (752) The Netherlands (611) Spain (752) Turkey (600) UK (501) France (759) All countries (5,817) de Pablos-Velasco P, et al. Clin Endocrinol 2012

Η πρωιμότερη και ενδεδειγμένη παρέμβαση μπορεί να βελτιώσει τις πιθανότητες των ασθενών να επιτύχουν το στόχο Δίαιτα Μονοθεραπεία και άσκηση OAD Αύξηση δόσης OAD OAD πολλαπλές εγχύσεις ινσουλίνης ημερησίως Συνδυασμός OAD OAD βασική ινσουλίνη Στόχος HbA 1c Μέση HbA 1c ασθενών 9 8 7 6 10 Συμβατική προσέγγιση σταδιακής θεραπείας Διάρκεια διαβήτη Πιο πρώιμη και δυναμική προσέγγιση παρέμβασης OAD=από του στόματος αντιδιαβητικός παράγοντας. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345 1355. Copyright 2005. Adapted with permission of Blackwell Publishing Ltd.

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Γιατί Μετφορμίνη από την αρχή? Ελάχιστοι πετυχαίνουν και ΔΙΑΤΗΡΟΥΝ τον στόχο μόνο με αλλαγή του τρόπου ζωής Είναι φτηνή Συνοδεύεται από μικρή μείωση του ΣΒ (επιθυμητό) καθώς και από απουσία κινδύνου υπογλυκαιμιών (επιθυμητό) Η μετφορμίνη είναι ασφαλής και μειώνει τον κίνδυνο των εμφραγμάτων (UKPDS) Φαίνεται ότι μειώνει και την ολική θνητότητα ενώ έχει μάλλον ευνοϊκή δράση στην μείωση εμφάνισης καρκίνου

Μετφορμίνη: Μείωση των μακροαγγειακών επεισοδίων σε υποομάδα της UKPDS *p=0.002 *p=0.017 *p=0.011 *p=0.01 Μείωση *Σύγκριση με δίαιτα 32% Βλάβη σχετιζόμενη με Διαβήτη 42% Θνησιμότητα σχετιζόμενη με διαβήτη 36% Θνησιμότητα κάθε αιτιολογίας 39% Ο.Ε.Μ. ADA Diabetes Care 1999;22(Sup 1):S27-S31 UKPDS Group. Lancet 1998;352:854-865

Monotherapy Efficacy * Hypo risk Weight Side effects Me min Costs intolerance contraindica on HbA1c 9% Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i Uncontrolled hyperglycemia (catabolic features, BG 300-350 mg/dl, HbA1c 10-12%) Combination injectable therapy SGLT2-i GLP-1-RA SGLT2-i GLP-1-RA Basal Insulin SGLT2-i DPP-4-i SGLT2-i GLP-1-RA 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 SGL T2-i: Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Ποιο είναι το επόμενο βήμα?

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Sulphonylureas and glinides: similar modes of action Sulphonylureas and glinides increase endogenous insulin secretion by binding to pancreatic b-cells and triggering a cascade of intracellular events 1 3 Although the mechanisms of action are similar, stimulation of insulin secretion is me rapid and sht-lasting with glinides 1,2 Glucose uptake Glucokinase Glycolysis Respiration ATP ATP-sensitive potassium channel Sulphonylureas Glinides Insulin release Pancreatic b-cell ATP = ange. Ca 2 = light green. K = blue. Voltage-gated calcium channel Ca 2 1. Gallwitz B, Haring H-U. Diabetes Obes Metab 2010;12:1 11; 2. Schuit FC, et al. Diabetes 2001;50:1 11; 3. Krentz AJ, Bailey CJ. Drugs 2005;65:385 411.

Secretagogues: Sulfonylureas Agents in Class: Glipizide, Glyburide, and Glimepiride Mechanism of action: increase insulin secretion from pancreatic beta cells Efficacy: lower A1C by 1-2%; glucose-lowering effect usually plateaus at one half of the maximum recommended dose Adverse effect: Hypoglycemia, weight gain is common AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algithm f the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Secretagogues: Glinides Agents in Class: Nateglinide, Repaglinide Mechanism of action: stimulate a rapid but shtlived release of insulin that lasts f 1-2 hours, therefe should be used to target postprandial glucose levels Efficacy: similar to s f repaglinide; nateglinide is less efficacious in A1C lowering (0.5-0.8%) Nonglycemic effect: weight gain similar to Adverse effect: Much less hypoglycemia than AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007; 13 (suppl 1) 2007 Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algithm f the Initiation and Adjustment of Therapy: Diabetes Care, 31(12):10-11, 2008

Incidence of Hypoglycemia (%) Υπογλυκαιμία από Σουλφονυλουρίες 25 21.3% 20 15 15.3% 14% 11% 10 5 5% 2.9% * 0 Glyburide Chlpropamide Glibenclamide Glimepiride Gliclazide Glipizide Sulfonylureas *Hypoglycemia: fingerstick blood glucose measurement 50 mg/dl (2.75 mmol/l) 1. Glucovance [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2004. 2. UKPDS Group. Lancet 1998; 352: 837 853. 3. Draeger KE, et al. Hm Metab Res. 1996; 28: 419 425. 4. McGavin JK, et al. Drugs 2002; 62; 1357 1364. 5. Metaglip [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2002

Hypoglycaemia, events/patient/year* Current Treatments Increase Risk of Hypoglycemia Patients with hypoglycaemia** (%) 20 45 40 39 15 10 35 30 25 20 p<0.05 glibenclamide vs. rosiglitazone 5 15 10 10 12 5 0 0 Glargine NPH Rosiglitazone Metfmin Glibenclamide *All symptomatic hypoglycaemic events ** Patients self-repting (unconfirmed) hypoglycaemia Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:2427 43

Change in weight (kg) Weight (kg) Most therapies result in weight gain over time UKPDS: up to 8 kg in 12 years 8 100 ADOPT: up to 4.8 kg in 5 years 7 Insulin (n=409) 6 5 96 4 Glibenclamide 92 Glibenclamide 3 2 1 0 Metfmin (n=342) 0 3 6 9 12 Years from randomisation Conventional treatment (n=411); diet initially then sulphonylureas, insulin and/ metfmin if FPG >15 mmol/l 88 0 0 1 2 3 4 5 Rosiglitazone Metfmin Glibenclamide Years UKPDS 34. Lancet 1998:352:854 65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427 43

Change in HbA1c (%) Δεν διατηρείται ο γλυκαιμικός έλεγχος με τις σουλφονυλουρίες 1 0-1 x x Glimpepiride Glyburide GLY x Glyburide x x Gliclazide Glyburide Gliclazide x Glyburide Alvarsson (n=39) Alvarsson (n=48) RECORD (n=301) Hanefeld (n=250) Charbonnel (n=317) UKPDS (n=1,573) Chicago (n=232) ADOPT (n=1,456) Periscope (n=178) -2 Tan (n=249) 0 1 2 3 4 5 6 10 Χρόνος (έτη) DeFronzo (Diabetes 2009; 58:773-795)

Σουλφονυλουρίες Πλεονεκτήματα Ταχεία αποτελεσματικότητα Χαμηλό κόστος Μακροχρόνια εμπειρία Μειονεκτήματα Προοδευτική απώλεια γλυκαιμικής ρύθμισης Αυξημένος κίνδυνος υπογλυκαιμίας Αύξηση σωματικού βάρους

National Trends in Use of Different Therapeutic Drug Classes to Treat Diabetes, 1994-2007 Alexander, G. C. et al. Arch Intern Med 2008;168:2088-2094.

Το επόμενο βήμα..

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Μηχανισμός δράσης

Η ενεργοποίηση των PPAR υποδοχέων αυξάνει την ευαισθησία στην ινσουλίνη Αγωνιστής PPAR Ρετινοϊκό οξύ Αυξημένη ανταπόκριση στην ινσουλίνη - πρόσληψη γλυκόζης - απελευθέρωσης ΕΛΟ Σύνθεση πρωτεΐνης PPAR RXR Μεταγραφή γονιδίου mrna Arner P. Diabetes Obes Metab 2001; 3 (Suppl 1): S11-S19β

Επίδραση των s στην κατανομή του λίπους Hi TG Hi FFA Ενδομυικό λίπος Υποδόριο λίπος TG FFA Ενδοηπατικό λίπος Ενδοκοιλιακό λίπος

Pioglitazone: Clinical Overview Efficacy as a monotherapy HbA 1c FPG PPG *Efficacy depends on adequate ß cell function. From a single trial using a dose of 30 mg of pioglitazone. From a single trial using doses of 15, 30 and 45 mg of pioglitazone. Advantages No hypoglycaemia Durability Increased HDL-C Reduction in triglycerides Possible reduction in CVD events (ProACTIVE) Disadvantages Weight gain Oedema/heart failure Bone fractures Possible increased risk of bladder cancer 1. Krentz AJ, Bailey CJ. Drugs. 2005;65:385 411; 2. Hung Y. et al. J Med Sci 2006;26:19 24; 3. NCT00722371. Available: http://clinicaltrials.gov/ct2/show/results/nct00722371?sect=xb015; 4. Inzucchi SE, et al. Diabetes Care 2012;35:1364 79.

Κύριοι μηχανισμοί αντιυπεργλυκαιμικής δράσης Μετφορμίνης/ Πιογλιταζόνης Diabetes, Obesity and Metabolism, 7, 2005, 675 691

Πιογλιταζόνη Μετφορμίνη: Διαφορετικοί και προσθετικοί Μηχανισμοί Δράσης Πιογλιταζόνη Μετφορμίνη Στοχεύει άμεσα την αντίσταση στην ινσουλίνη Αυξάνει τη χρήση της γλυκόζης, κυρίως από τους μύες Improved blood glucose control Μειώνει κυρίως την παραγωγή γλυκόζης από το ήπαρ Ορισμένες ινσουλινοευαίσθητες επιδράσεις Inzucchi SE. JAMA 2002; 287:360 372.

Ποιά είναι η επόμενη επιλογή?

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

GLP-1: μια ινκρετίνη με πολλαπλές άμεσες δράσεις στην ανθρώπινη φυσιολογία β α Πάγκρεας Έντερο Εγκέφαλος κορεσμού β α Γλυκοζοεξαρτώμενη έκκριση ινσουλίνης Γλυκοζοεξαρτώμενη έκκριση γλυκαγόνης GLP-1 Στόμαχι Γαστρικής κένωσης Καρδιά Ήπαρ Καρδιοπροστασίας Παραγωγής γλυκόζης L-κύτταρα εκκρίνουν GLP-1 αποδομείται από τη DPP-4 Adapted from Baggio & Drucker. Gastroenterol 2007;132;2131 57

New avenues f the pharmacological management of type 2 diabetes: An update Th. Cuny, Annales d Endocrinologie 73, 2012: 459-468

GLP-1R-dependent intracellular signal transduction pathways in the cardiomyocyte Ενεργοποιούνται αντι-αποπτωτικές κινάσες Ussher J R, Drucker D J Endocrine Reviews 2012;33:187-215

GLP-1: Nmalization of Plasma Glucose in Type 2-Diabetes [mmol/l] [pmol/l] [mmol/l] Glucose [mg/dl] Insulin [mu/l] 250 200 150 100 50 Nauck & Meier Regul Pept 124 0 40 35 30 25 20 15 10 5 0 (Suppl.):135-148, 2005 p < 0.0001 GLP-1/Placebo * * 0 0 60 120 180 240 * 250 * * * * 200 * * * * 14 12 10 50 p < 0.0001 0 0 60 120 180 240 Time [min] * 8 6 4 2 150 100 Glucose [mg/dl] Glucagon [pmol/l] 300 250 200 150 100 50 0 20 15 10 5 0 GLP-1/Placebo 16 14 12 10 8 6 4 2 0 0 60 120 180 240 p < 0.0001 * * * 0 60 120 180 240 * Time [min] *

Δύο φαρμακολογικές προσεγγίσεις για την αυξανόμενη δράση του GLP-1 σε ασθενείς Αναστολείς της διπεπτιδυλικής πεπτιδάσης 4 (DPP-4) Αυξάνουν τα κυκλοφορούντα φυσικά παραγόμενα επίπεδα του GLP-1, αναστέλλοντας το ένζυμο DPP-4 Αγωνιστές του υποδοχέα του GLP-1 Δεσμεύουν & ενεργοποιούν τον υποδοχέα του GLP-1. Είναι ανθεκτικά κατά της διάσπασης από το ένζυμο DPP-4 DΡP-4 DΡP-4 Ανενεργό GLP-1 Ενεργό φυσικό GLP-1 Ανενεργός αγωνιστής Αγωνιστής του υποδοχέα του GLP-1 του GLP-1 Υποδοχέας GLP-1 Υποδοχέας GLP-1 Κυτταρική μεμβράνη Κυτταρική μεμβράνη Δράση του GLP-1 Δράση του GLP-1 DeFronzo RA et al.,. Curr Med Res Οpin. 2008, 24:2943-2952.

GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely sht half-life Μιμητικά ινκρετινών Add GLP-1 analogues with longer half-life: Exenatide Liraglutide Lixisenatide Exenatide LAR Injectables Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003 Ενισχυτικά της δράσης των ινκρετινών Block DPP-4, the enzyme that degrades GLP-1: Sitagliptin Vildagliptin Saxagliptin Linagliptin Alogliptin Oral agents

Ο FDC Σιταγλιπτίνης και Μετφορμίνης οδήγησε σε σημαντικές μειώσεις της HbA 1c στις 18 εβδομάδες ανεξάρτητα από την αρχική HbA1c Reasner C et al. Diabetes Obes Metab. 2011;13:644 652.

HbA1c (%) Metfmin Sitagliptin: HbA1c over 2 years 9.0 8.5 8.0 7.5 7.0 6.5 SITA 100 mg od (n = 50) MET 500 mg bd (n =64) MET 1000 mg bd (n = 87) SITA 50 mg MET 500 mg bd (n = 96) SITA 50 mg MET 1000 mg bd (n = 105) 6.0 SITA = sitagliptin; MET = metfmin 0 6 12 18 24 30 38 46 54 62 70 78 91 104 weeks Williams-Herman D et al. EASD 2008

BrdU-positive cells (%) Apotag-positive cells (%) b-cell mass (mg) Vildagliptin and b-cell Preservation and Regeneration (neonatal rat model) Insulin Vildagliptin 60 mg/kg, po x 21 days 120 100 80 60 40 20 Replication P<.001 Vehicle 2.5 2.0 1.5 1.0 0.5 Apoptosis P<.05 Vildagliptin 0.14 0.12 0.10 0.08 0.06 0.04 0.02 ß-cell mass P<.05 0 Vehicle Vildagliptin 0.0 Vehicle Vildagliptin 0.00 Vehicle Vildagliptin Day 7 Day 21 Adapted from Duttaroy A, et al. Diabetes 2005. 54 (suppl 1)

Improved glycaemic control with vildagliptin added to insulin, with without metfmin, in patients with type 2 diabetes mellitus W. kothny et, al., Diabetes, Obesity and Metabolism, 15 (3), 252-257, 2013

Exenatide Metfmin AMIGO 1: Efficacy Results Changes in A1C Changes in FPG Change From Baseline After 30 Weeks (%) 0,2 0-0,2-0,4-0,6-0,8-1 0,08-0,4 Placebo 5 mcg 10 mcg -0,78 Change From Baseline After 30 Weeks (mg/dl) 20 15 10 5 0-5 -10-15 14,4-7,2 Placebo 5 mcg 10 mcg -10,1 A1C values decreased f both groups treated with exenatide FPG levels decreased in the groups taking exenatide and Increased in the placebo group DeFronzo. Diabetes Care. 2005;28:1092.

Use of Twice-Daily Exenatide in Basal Insulin Treated Patients With Type 2 Diabetes: A Randomized, Controlled Trial Buse Jb, et, al., Ann Intern Med. 154 (2):103-112, 2011

Μεταβολή στη HbA 1c (%) Το πρόγραμμα LEAD: μειώσεις στη HbA 1c κατά την προσθήκη liraglutide HbA1c % 8.18 στην έναρξη 8.19 8.23 8.3 8.4 8.4 LEAD 3 μονοθεραπεία LEAD 2 Met συνδυασμός 0.0-0.2-0.4-0.6-0.8-1.0-1.2-1.4-1.6 58% 62% 31% 53% 66% 56% 51% 43% LEAD 1 συνδυασμός 57% LEAD 4 Met συνδυασμός 58% -1.1-1.5-0.7-1.3* -1.3* -1. 2-1.5 * -1.4* -0.8-1.5* -1.5* 8.5 8.5 8.4 56% 36% 8.48 8.56 8.3 8.1 54% 52% LEAD 5 Met συνδυασμός -1.3 * 44% -1.0 % επίτευξη του στόχου της ADA Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Rosiglitazone Glargine Στατιστικά σημαντικό *vs. placebo, vs. rosiglitazone, vs. glimepiride, vs. glargine Marre et al. Diabetic Medicine 2009; 10.1111/j.1464-5491.2009.02666.x (LEAD-1); Nauck et al. Diabetes Care 2009; 32; 84 90 (LEAD-2);Garber et al. Lancet 2009; 373 (9662): 473 81 (LEAD-3); Zinman et al. Diabetologia 2008; 51 (Suppl. 1): S359 (Abstract 898) (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD 5)

Η Λιξισενατίδη στη θεραπεία του Διαβήτη Τύπου 2 Δίαιτα και άσκηση GetGoal-Μono Μονοθεραπεία GetGoal-Mono Japan Μονοθεραπεία 1 από του στόματος χορηγούμενο αντιδιαβητικό δισκίο GetGoal-Μ Προσθήκη σε MET GetGοal-F1 Προσθήκη σε MET GetGoal-Χ Προσθήκη σε MET 2 από του στόματος χορηγούμενα αντιδιαβητικά δισκία GetGοal-S Προσθήκη σε ± MET GetGoal-Ρ Προσθήκη σε Πιογλιταζόνη ± MET GetGoal-Μ-Asia Προσθήκη σε MET± Βασική ινσουλίνη Από του στόματος χορηγούμενα αντιδιαβητικά δισκία GetGοal-L Προσθήκη σε Βασική Ινσουλίνη ± MET GetGoal-L-Asia Προσθήκη σε Βασική Ινσουλίνη ± GetGoal-Duο1 Προσθήκη σε Βασική Ινσουλίνη ± MET

Μέση HbA 1c (%) ±SE LS mean change in HbA 1c (%) GetGoal-L-Asia: Μεταβολή στα επίπεδα της HbA 1c από την αρχική επίσκεψη έως την εβδομάδα 24 Λιξισενατίδη βασική ινσουλίνη Placebo βασική ινσουλίνη 8.8 8.6 8.4 8.6% 0.2 0 0.1% 8.2 0.2 8.0 7.8 0.4 7.6 0.6 7.4 7.2 7.6% 0.8 0.8% 7.0 Baseline 4 8 12 16 20 24 Week Week 24 LOCF* 1.0 p<0.0001 Week 24 LOCF* LS mean difference vs placebo: 0.9% (95% CI: 1.1 to 0.7) Modified intent-to-treat (mitt) population; *LOCF (on treatment value available) analysis f least squared mean mean change at Week 24 Seino et al. Diabetes Obes Metab 2012

LS mean change (kg) GetGoal-L: Μεταβολή του Σωματικού Βάρους στην εβδομάδα 24 Λιξισενατίδη βασική ινσουλίνη Placebo βασική ινσουλίνη 0 0.5 1.0 1.5 2.0 p<0.0001 LS mean difference vs placebo: 1.3 kg (95% CI: 1.8 to 0.7) mitt population; LS Mean Change from baseline to Week 24 (LOCF) Riddle et al. Abstract 983-P; ADA 2012

Υπάρχουν 2 τύποι των Αγωνιστών του Υποδοχέα του GLP-1 που επηρεάζουν σε διαφορετικό βαθμό, την FPG και την PPG ΓΕΥΜΑΤΙΚΟΙ Αγωνιστές του Υποδοχέα του GLP-1 ΜΗ ΓΕΥΜΑΤΙΚΟΙ Αγωνιστές του Υποδοχέα του GLP-1 Επίδραση στην FPG Επίδραση στην ΡPG Επίδραση στην FPG Επίδραση στην ΡPG Adapted from: Fineman MS, et al. Diabetes Obes Metab. 2012.

Ένας Γευματικός Αγωνιστής του Υποδοχέα του GLP-1 συμπληρώνει τις δράσεις της Βασικής Ινσουλίνης Βασική ινσουλίνη* Γευματικός Αγωνιστής του Υποδοχέα του GLP-1** Επίδραση στην FPG Επίδραση στην PPG Επίδραση στο ΣΩΜΑΤΙΚΟ ΒΑΡΟΣ Επίδραση στην FPG Επίδραση στην PPG Επίδραση στο ΣΩΜΑΤΙΚΟ ΒΑΡΟΣ Το πρωτεύουν αποτέλεσμα ήταν η μεταβολή στην τιμή της A1C. Τα επίπεδα της A1C μειώθηκαν κατά 1,74% με την Εξενατίδη και 1,04% με το εικονικό φάρμακο (διαφορά μεταξύ των ομάδων -0,69%, P <0,001) JB Buse et al.,. Ann Intern Μed. 2011, 154:103-112

Επιλογές για πρόσθετο έλεγχο πέρα της βασικής ινσουλίνης Πλεονεκτήματα Γευματική ινσουλίνη Μειονεκτήματα Αποτελεσματική στον έλεγχο της PPG Αυξημένος κίνδυνος για υπογλυκαιμία Πρόσληψη βάρους Αγωνιστές του Υποδοχέα του GLP-1 Πλεονεκτήματα Μειονεκτήματα Χαμηλή συχνότητα υπογλυκαιμιών Απώλεια βάρους σε μερικούς ασθενείς Αποτελεσματικοί στον έλεγχο της PPG Πιθανώς λιγότερο αποτελεσματικοί σε προχωρημένου σταδίου ΣΔ καθώς μειώνεται η λειτουργία των β-κυττάρων

Όφελος για τον ασθενή Βασική ινσουλίνη Συμπληρωματικός μηχανισμός δράσης Γευματικός Αγωνιστής του Υποδοχέα του GLP-1 FPG > PPG HbA 1C PPG > FPG Κίνδυνος υπογλυκαιμιών Υπογλυκαιμίες Χαμηλός κίνδυνος υπογλυκαιμιών Πρόσληψη βάρους Μικρότερη πρόσληψη βάρους Απώλεια βάρους Απλός στην έναρξη και απλός στη χρήση Δόση ινσουλίνης QoL

Ποιά είναι η επόμενη επιλογή?

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Combination injectable therapy Figure 2. An -hyperglycemic therapy in T2DM: General recommenda ons 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Αναστολείς SGLT2 ( Γλιφλοζίνες)

Nmal renal glucose handling (180 L/day) (900 mg/l)=162 g/day Majity (90%) of glucose is reabsbed by SGLT2 SGLT2 Proximal tubule SGLT1 SGLT2 inhibit SGLT2 Remaining glucose is reabsbed by SGLT1 (10%) Minimal to no glucose excretion Glucose Glucose filtration Με ένα καθημερινό ρυθμό σπειραματικής διήθησης στα 180 L, περίπου 162 g γλυκόζης πρέπει να απορροφηθούν καθημερινά για να διατηρηθεί μια συγκέντρωση γλυκόζης πλάσματος στα 100 mg % Η επαναπορρόφηση της γλυκόζης γίνεται κυρίως στο εγγύς σωληνάριο με τη διαμεσολάβηση 2 πρωτεινικών μεταφορέων, των συν-μεταφορέων νατρίου -γλυκόζης,sglt1 και SGLT2. Η φιλτραρισμένη γλυκόζη επιστρέφει στην κυκλοφορία και τίποτα δεν απεκκρίνεται στο ούρα Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; Lee YJ, et al. Kidney Int Suppl 2007;72:S27 35; Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21.

Wright EM. Am J Physiol Renal Physiol 2001;280:F10 18; Lee YJ, et al. Kidney Int Suppl 2007;106:S27 35; Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14 21; Fxiga. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca, 2013. Accessed: 12 August, 2013. SGLT2 is a new target that can help lower blood glucose levels by inhibiting renal glucose reuptake Reduced glucose reabsption SGLT2 SGLT2 Proximal tubule SGLT1 SGLT2 inhibit SGLT2 Minimal to no glucose excretion Glucose Glucose filtration Η ποσότητα της γλυκόζης που απομακρύνεται από τους νεφρούς μέσω του ανωτέρω μηχανισμού, εξαρτάται από τη συγκέντρωση της γλυκόζης στο αίμα και το ρυθμό σπειραματικής διήθησης Increased urinary excretion of excess glucose (~70 g/day, cresponding to 280 kcal/day*)

Οφέλη από την αναστολή του SGLT2 Μηχανισμός δράσης ανεξάρτητος από την ινσουλίνη Μείωση των: FPG PPG HbA 1C Αποβολή θερμίδων στα ούρα & μείωση του βάρους Άμεση αποβολή γλυκόζης και οι σχετιζόμενες θερμίδες Γλυκοζουρία Whaley JM, et al. Diabetes Metab Syndr Obes 2012;5:135 48.

Αναστολείς SGLT2: Για ποιούς ασθενείς Εκείνοι που δεν ανέχονται τη μετφορμίνη Ασθενείς που δεν μπορούν να διατηρήσουν τον καλό γλυκαιμικό έλεγχο μόνο με τη μετφορμίνη Όσοι δεν πετυχαίνουν το στόχο τους μόνο με την ινσουλίνη και συνδυασμό άλλων δισκίων Άτομα που θέλουν να χάσουν βάρους Εκείνοι με καλή νεφρική λειτουργία Προσοχή σε ηλικιωμένους και εκείνους που βρίσκονται σε κίνδυνο για υπόταση

Primary endpoint f 24-week adjusted from baseline HbA1c (%) Consistant reduction of HbA1c from baseline at week 24 in all dapagliflozin studies Baseline HbA1c Monotherapy 1 Add-on to Met 2 Add-on to Glim 3 Add-on to Pio 4 Add-on to Ins 5 7.92 8.06 8.11 8.37 8.53 Dapa Met XR 6 9.05-0.23-0.3-0.13-0.42-0.3-0.89-0.84 * * -0.82 * -0.97-0.9 * * -1.44 *p <0.001 compared with placebo * 1 Ferrannini E, et al. Diabetes Care 2010;33:2217-24. 2 Bailey CJ, et al. Lancet 2010;375:2223-33. 3 Strojek K, et al. Diabetes Obes Metab 2011;13:928-38. 4 Rosenstock J, et al. 71 st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 0986-P 5 Wilding J, et al. Diabetes. 2010;59 (Suppl 1):A21-A22. Abstract 0078-OR 6 Henry R, et al. 71 st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR. -1.98

Dapagliflozin added on PIO PLB to Pioglitazone PIO DAPA 5 PIO DAPA 10 10 PIO PLB PIO DAPA 5 PIO DAPA 10 Rosenstock et al.diabetes Care, Vol.35, July, 2012

Empagliflozin as Add-On to Metfmin in Patients With Type 2 Diabetes Häring H-U., et al., Diabetes Care (37), 2014

Insulin dose HbA1c Rosenstock J., et al. Dia Care (37) 2014

Rosenstock J., et al. Dia Care (37) 2014 Body weight

Initial Combination of Empagliflozin and Linagliptin in Subjects With DM 2 Lewin A., et al., Diab Care, 2015

Η τελευταία επιλογή..

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Combination 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Insulin level ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulins Rapid (Lispro, Aspart, Glulisine) Sht (Regular) Hours Long (Detemir) (Degludec) Long (Glargine) 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection

Figure 3. Approach to star ng & adjus ng insulin in T2DM Basal Insulin (usually with metfmin /- other non-insulin agent) Start: 10U/day 0.1-0.2 U/kg/day Adjust: 10-15% 2-4 U once-twice weekly to reach FBG target. F hypo: Determine & address cause; ê dose by 4 units 10-20%. Diabetes Care 2015;38:140; Diabetologia 2015;10.1077/ s00125-014-3460-0

Figure 3. Approach to star ng & adjus ng insulin in T2DM Basal Insulin (usually with metfmin /- other non-insulin agent) Start: 10U/day 0.1-0.2 U/kg/day Adjust: 10-15% 2-4 U once-twice weekly to reach FBG target. F hypo: Determine & address cause; ê dose by 4 units 10-20%. 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 Start: 4U, 0.1 U/kg, 10% basal dose. If A1c<8%, consider ê basal by same amount. Adjust: ê dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; ê 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: ê dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; ê cresponding dose by 2-4 U 10-20%. If not controlled, consider basalbolus. Add 2 rapid insulin* injections befe meals ('basal-bolus ) Start: 4U, 0.1 U/kg, 10% basal dose/meal. If A1c<8%, consider ê basal by same amount. Adjust: ê dose by 1-2 U 10-15% once-twice weekly to achieve SMBG target. F hypo: Determine and address cause; ê cresponding dose by 2-4 U 10-20%. If not controlled, consider basalbolus. Diabetes Care 2015;38:140; Diabetologia 2015;10.1077/ s00125-014-3460-0

Figure 3. Approach to star ng & adjus ng insulin in T2DM # Injections 1 Basal Insulin (usually with metfmin /- other non-insulin agent) Start: 10U/day 0.1-0.2 U/kg/day Adjust: 10-15% 2-4 U once-twice weekly to reach FBG target. F hypo: Determine & address cause; ê dose by 4 units 10-20%. Complexity low 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 ê basal by same amount. Start: Divide current basal dose into 2/3 AM, 1/3 PM 1/2 AM, 1/2 PM. Adjust: ê dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. Adjust: ê dose by 1-2 U 10-15% oncetwice weekly until SMBG target reached. F hypo: Determine and address cause; ê cresponding dose by 2-4 U 10-20%. F hypo: Determine and address cause; ê 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. Start: 4U, 0.1 U/kg, 10% basal dose/meal. If A1c<8%, consider ê basal by same amount. Adjust: ê dose by 1-2 U 10-15% once-twice weekly to achieve SMBG target. F hypo: Determine and address cause; ê cresponding dose by 2-4 U 10-20%. Diabetes Care 2015;38:140; Diabetologia 2015;10.1077/ s00125-014-3460-0 Flexibility me flexible less flexible

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Figure 2A. An -hyperglycemic Combination therapy injectable in T2DM: Avoidance therapy of hypoglycemia 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Figure 2B. An -hyperglycemic Combination therapy injectable in T2DM: Avoidance therapy of weight gain 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate neutral rare Metfmin SGLT2 inhibit intermediate loss GU, dehydration Metfmin GLP-1 recept agonist loss GI Metfmin Insulin (basal) est 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): Metfmin Thiazolidinedione Metfmin DPP-4 Inhibit Metfmin SGLT-2 Inhibit Metfmin GLP-1 recept agonist Metfmin Insulin (basal) DPP-4-i DPP-4-i DPP-4-i SGLT2-i SGLT2-i SGLT2-i DPP-4-i SGLT2-i GLP-1-RA GLP-1-RA GLP-1-RA Figure 2C. An -hyperglycemic Combination therapy injectable in T2DM: Minimiza therapy on of costs 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 SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Figure 1. Modula on of the intensiveness of glucose lowering therapy in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with hypoglycemia and other drug adverse effects me stringent low Approach to the management of hyperglycemia HbA1c 7% less stringent Disease duration newly diagnosed long-standing Life expectancy long sht Usually not modifiable Imptant combidities absent few / mild severe Established vascular complications absent few / mild severe Patient attitude and expected treatment effts ly motivated, adherent, excellent self-care capacities less motivated, non-adherent, po self-care capacities Potentially modifiable Resources and suppt system Readily available limited Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077/s00125-014-3460-0

Διαφορετικοί ασθενείς Διαφορετικοί τρόποι ζωής Διαφορετική θεραπευτική αντιμετώπιση Ο διαβητικός χρειάζεται καλή γλυκαιμική ρύθμιση με τη σωστή αντιδιαβητική αγωγή

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