Place actuelle des sulfamides hypoglycémiants dans la prise en charge du diabète de type 2

Place actuelle des sulfamides hypoglycémiants dans la prise en charge du diabète de type 2 Eugène SOBNGWI MD, MPhil, PhD Professeur des Universités Praticien Hospitalier Hôpital Central de Yaoundé Faculté de Médecine et des Sciences Biomédicales et Labatoire de Médecine Moléculaire et Métabolismes, Centre de Biotechnologie Université de Yaoundé 1, Cameroun

Sulfamides hypoglycémiants et DT2 Objectifs de la Prise en Charge Efficacité des Sulfamides / Objectifs Les Sulfamides sont-ils comparables Conclusion

C O M PA R A I S O N E F F I C A C I T E O B J E C T I F S OBJECTIFS MAJEURS DE LA PRISE EN CHARGE DU DT2 Enjeux Objectifs

O B J E C T I F S Le diabète dans le monde 2014 2035

O B J E C T I F S Global diabetes prevalence

O B J E C T I F S Le coût du diabète Diabetes is a human and economic burden 4.9 million deaths per year 50% of deaths under 60 years of age Intersects with all dimensions of development US$612 billion 11% of wldwide healthcare expenditure

Hazard Ratio (95% CI) O B J E C T I F S Glycémie et risque cardiovasculaire 4.0 Total Stroke Total Ischemic Heart Disease CV Death 2.0 1.0 0.5 Risk: 21% (CI 18-24) rise per 1 mmol/l rise in glucose Risk: 23% (CI 19-27) rise per 1 mmol/l rise in glucose Risk: 19% (CI 15-22) rise per 1 mmol/l rise in glucose 4.5 5.0 5.5 6.0 6.5 7.0 7.5 4.5 5.0 5.5 6.0 6.5 7.0 7.5 4.5 5.0 5.5 6.0 6.5 7.0 7.5 Usual Fasting Glucose (mmol/l) Asia Pacific Coht Studies Collabation. Diabetes Care. 2004;27: 2836-2842.

O B J E C T I F S Contrôle glycémique et complications UKPDS A 1% Decrease in HbA 1c Is Associated with a Large Reduction in Complications HbA 1c 1% 37% 43% 21% 14% Microvascular complications Amputation fatal peripheral blood vessel disease Deaths related to diabetes Heart attack 12% Stroke Stratton IM, et al. BMJ. 2000;321(7258):405-412.

O B J E C T I F S Mtalité liée au diabète Nat Rev Nephrol. 2015 Nov 10. doi: 10.1038/nrneph.2015.188. Diabetes: Renal complications and excess mtality in type 2 diabetes mellitus. N Engl J Med. 2015 Oct 29;373(18):1720-32. doi: 10.1056/NEJMoa1504347. Excess Mtality among Persons with Type 2 Diabetes. Tancredi M 1, et al. Mtality among persons with type 2 diabetes, as compared with that in the general population, varied greatly, from substantial excess risks in large patient groups to lower risks of death depending on age, glycemic control, and renal complications.

O B J E C T I F S Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association (ADA) and the European Association f the Study of Diabetes (EASD) Inzucchi SE, Bergenstal RB, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR Diabetes Care 2015;38:140 149 Diabetologia 2015;58:429 442

Position de l'ada-easd : Prise en charge de l'hyperglycémie dans le DT2 OBJECTIFS GLYCÉMIQUES - HbA1c < 7,0 % (glycémie moyenne 150-160 mg/dl [8,3-8,9 mmol/l] - Glycémie pré-prandiale < 130 mg/dl (7,2 mmol/l) - Glycémie post-prandiale < 180 mg/dl (10,0 mmol/l) - La personnalisation est la clé : Cibles plus strictes (6,0-6,5 %) - patients plus jeunes, en meilleure santé Cibles moins strictes (7,5-8,0 % ) - sujets plus âgés, combidités, tendance à l'hypoglycémie, etc. - Éviter l'hypoglycémie Diabetes Care, Diabetologia. 19 Avril 2012 [publication électronique avant impression]

Approach to the Management of Hyperglycemia Risks potentially associated with hypoglycemia, other drug adverse effects me stringent Low HbA1c 7% less stringent High Figure 1. Modulation of the intensiveness of Diabetes Care 2012;35:1364 1379 glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia Diabetologia 2012;55:1577 1596 2015;58:429-442

ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables - Metfmin - Sulfonylureas - Thiazolidinediones - DPP-4 inhibits - SGLT-2 inhibits - Meglitinides - a-glucosidase inhibits - Colesevelam - Dopamine-2 agonists - Amylin mimetics - GLP-1 recept agonists Diabetes Care 2012;35:1364 1379; Diabetologia 2012;55:1577 1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

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

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk 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): 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 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 TZD SGL T2-i: Metfmin Figure 2. Anti-hyperglycemic therapy Basal Insulin Mealtime Insulin GLP-1-RA in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk 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): 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 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 TZD SGL T2-i: Metfmin Figure 2. Anti-hyperglycemic therapy Basal Insulin Mealtime Insulin GLP-1-RA in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk 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): 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 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 TZD SGL T2-i: Metfmin Figure 2. Anti-hyperglycemic therapy Basal Insulin Mealtime Insulin GLP-1-RA in T2DM: General recommendations Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

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 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk 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): 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 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 TZD SGL T2-i: Basal Insulin Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

Monotherapy Efficacy * Hypo risk Weight Side effects Metfmin Costs intolerance contraindication HbA1c 9% Dual therapy Efficacy * Hypo risk Weight Side effects Costs Healthy eating, weight control, increased physical activity & diabetes education Metfmin 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 moderate risk gain hypoglycemia low Metfmin Thiazolidinedione low risk gain edema, HF, fxs low Metfmin DPP-4 inhibit intermediate low risk neutral rare Metfmin SGLT2 inhibit intermediate low risk loss GU, dehydration Metfmin GLP-1 recept agonist low risk 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): 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 Uncontrolled hyperglycemia (catabolic features, BG 300-350 mg/dl, HbA1c 10-12%) Combination injectable therapy SGLT2-i GLP-1-RA Insulin SGLT2-i GLP-1-RA Insulin Basal Insulin SGLT2-i Insulin DPP-4-i Insulin Insulin 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 TZD SGL T2-i: Metfmin Mealtime Insulin GLP-1-RA Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

O B J E C T I F S OBJECTIFS Prévention microvasculaire Prévention macrovasculaire Optimisation glycémique PEC du DT2 Qualité de vie et coût

C O M PA R A I S O N E F F I C A C I T E O B J E C T I F S EFFICACITE DES SULFAMIDES ET OBJECTIFS THERAPEUTIQUE DU DT2 Efficacité glycémique Prévention des complications Effets secondaires et qualité de vie

E F F I C A C I T E Optimisation glycémique

E F F I C A C I T E Efficacy of Monotherapy with Oral Diabetes Agents Drug Fasting Plasma Glucose Reduction (mg/dl) A1C Reduction (%) Thiazolidinedione 35-40 0.5-1.0 Sulfonylurea 60-70 1.0-2.0 Biguanide 60-70 1.0-2.0 Meglitinide 60-70 1.0-2.0 Alpha-glucosidase inhibit DeFronzo Annals of Internal Medicine 1999;131:281-303 Nathan N Engl J Med 2002; 347:1342-1349 20-30 0.5-1.0

E F F I C A C I T E Evolution du taux d HbA1C durant la période de suivi Différences d HbA1C observées pendant la phase initiale de l étude perdue dès la 1ère année de suivi Holman RR. N Engl J Med 2008;359:577-89

E F F I C A C I T E Holman RR. N Engl J Med 2008;359:577-89

E F F I C A C I T E Effets bénéfiques du traitement intensif précoce maintenus, voire amplifiés dans le temps Holman RR. N Engl J Med 2008;359:577-89

E F F I C A C I T E Y a t-il intérêt à intensifier le traitement hypoglycémiant au cours du DT2 Y-a-t il un bénéfice microvasculaire à baisser l HbA1c 6,5% Y-a-t il un bénéfice macrovasculaire à baisser l HbA1c 6,5%

E F F I C A C I T E Clinical trials to prevent cardiovascular disease in patients with T2D

E F F I C A C I T E Essais cliniques d intensification du contrôle glycémique ACCORD 10000 patients ; âge moyen 62,2 ans DT2 ancien ( 10 ans d évolution) et compliqué (AVC = 35 %) Durée de suivi = 3,5 ans (arrêt de l étude) ADVANCE 11000 patients ; âge moyen 62,2 ans DT2 ancien (~8 ans) et compliqué (maladies CV=32 %) Durée de suivi = 5 ans VADT ~ 1800 patients, vétérans de l armée US ; âge moyen 60,4 ans DT2 ancien (~ 11,5 ans d évolution), déséquilibré (HbA1C=9,4 %) et compliqué (AVC=40 %, neuropathie=43 %, rétinopathie=62 %) Durée de suivi = 6 ans

E F F I C A C I T E Reduction of CV disease risk in type 2 diabetes: lessons learned from ACCORD and VADT trials ACCORD 1 VADT 2 Number 10,251 1,791 Primary CVD endpoint Mtality (overall) 10% (p=0.16) 22% (p=0.04) 13% (p=0.12) 6.5% (p=ns) CV mtality 39% (p=0.02) 25% (p=ns) 1. N Engl J Med. 358(2008)2545-59 2. N Engl J Med. 360(2009)129-39

E F F I C A C I T E ADVANCE study: Action in Diabetes and Vascular disease preterax and diamicron mr Controlled Evaluation 2x2 factial randomized trial (2 arms, 4 subgroups) Blood pressure-lowering arm: Perindopril-Indapamide placebo on top of current therapy, including other BP-lowering drugs. Glucose-lowering arm: Gliclazide MR-based intensive therapy targeting an HbA 1c 6.5% versus standard glucose control. 11 140 patients Intensive BP-control Perindopril-Indapamide Standard BP-control PLACEBO Intensive HbA 1c control with Gliclazide Standard HbA 1c control Intensive HbA 1c control with Gliclazide Standard HbA 1c control (same glycemic control) Rationale and design of the ADVANCE study. J Hypertens. 2001;19(suppl 4):S21-S28. ADVANCE-baseline characteristics. Diabet Med. 2005;22:1-7.

Mean HbA1c (%) What have we learned with ADVANCE trial? A 1c progressive and sustained reduction 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 Standard Intensive (Gliclazide MR) Δ 0.67% (95% CI 0.64 0.70); p<0.0001 0 6 12 18 24 30 36 42 48 54 60 66 Follow-up (Months) Mean HbA 1c at final visit 7.3 % 6.5% Gliclazide MR at the dose of 120 mg in 70% of patients ADVANCE collabative group. N Engl J Med 2008; 358:2560-72

E F F I C A C I T E ADVANCE: Protection rénale ESRD Intensive glucose control based on gliclazide MR improves kidney outcomes 65% Perkovic et al. Kidney Int 83(2013) 517 24

E F F I C A C I T E ADVANCE: Protection rénale ADVANCE results f different stages of renal disease in the intensive arm based on gliclazide MR. Perkovic V et al; ADVANCE Collabative Group. Kidney Int. 2013;83(3):517-523.

E F F I C A C I T E ADVANCE: positive trend f reducing cardiovascular death CONTROL Group; Turnbull FM, Abraira C, Anderson RJ, et al. Diabetologia. 2009;52:2288-2298.

What have we learned with ADVANCE trial? Interaction data Renal disease is reduced by 33% (p=0.005) Cardiovascular death is reduced by 24% (p=0.04) Zoungas Diabetes Care 2009

E F F I C A C I T E The Benefits of Early Intensive Control UKPDS 10-year Post-trial Follow-up Intensive vs Conventional Treatment 1* 10-year Post-trial Follow-up 2 1977-1991 Randomisation 1997 (20 years) Trial End (Noninterventional) 1 2007 (30 years) 12% 16% 9% 15% 25% 24% Any diabetes-related endpoint Microvascular disease Myocardial infarction *P<.05 f intensive vs conventional treatment. 1. UKPDS Study Group. Lancet. 1998;352(9131):837-853. 2. Holman RR, et al. N Engl J Med. 2008;359(15):1577-1589.

E F F I C A C I T E Cumulative incidence (%) End-stage kidney disease overall in-trial and post-trial follow-up Standard In-trial (5.0 yrs) Post-trial (5.4 yrs) Overall (9.9 years) Intensive Standard Intensive End-stage kidney disease HR (95%CI) 0.35 (0.15-0.83) 0.65 (0.38-1.11) 0.54 (0.34-0.85) Follow-up (years) Event no. (intensive vs standard) (7 vs 20) -13 (22 vs 33) -11 (29 vs 53) -24 Relative risk reduction 46% 95% CI: 15 to 66% p<0.01

E F F I C A C I T E Evolution de la connaissance

C O M PA R A I S O N E F F I C A C I T E O B J E C T I F S LES SULFAMIDES SONT ILS PAREILS? Efficacité glycémique Preuves microvasculaires Preuves macrovasculaires Effets secondaires

C O M PA R A I S O N Conary death rate accding to the insulin-secreting agents associated with metfmin in T2DM (Flence Register) Gliclazide/ Glimepiride OR 2.09 [1.07;4.11] Glibenclamide Monami M, et al. Diabetes Metab Res Rev 2006;2:477-82

C O M PA R A I S O N Incidence of conary events in T2DM accding to SUs treatment Gliclazide P 0.016 Glibenclamide (Monami M, et al. Diabet Metab Res Rev. 2007)

C O M PA R A I S O N Mtalité cardiovasculaire

C O M PA R A I S O N Hazard ratios (95% CI) f different endpoints in relation to monotherapies with different glucose-lowering agents accding to previous myocardial infarction. Tina Ken Schramm et al. Eur Heart J 2011;32:1900-1908 Published on behalf of the European Society of Cardiology. All rights reserved. The Auth 2011. F permissions please email: journals.permissions@oup.com

C O M PA R A I S O N

C O M PA R A I S O N Rate pf progression of retinopathy (per 100 patient years) Rate of severe hypoglycaemia (per 100 patient years) Le prix de l optimisation: L hypoglycémie 12 10 severe hypoglycaemia 120 8 6 4 2 0 risk of retinopathy 0 5.5 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5 HbA 1c (%) 60 0 Adapted from: N Engl J Med 1993;329:977 86

C O M PA R A I S O N ADVANCE trial shows the low risk of hypoglycemia 1. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, et al. N Engl J Med. 2008;358(24):2545-2559. 2. UKPDS Group (33). Lancet. 1998;352:837-853. 3. The ADVANCE Collabative Group; Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358(24):2560-2572.

ADVANCE intensive glucose control strategy No drug Other SUs Metfmin Initiation Switch Add-on Gliclazide MR Drug titration at physician s discretion based on HbA 1c and FBG levels HbA 1c target 6.5% 30 mg 60 mg 90 mg 120 mg Add other OADs Add insulin Progressively maximize the dose 70% of the patients

C O M PA R A I S O N Ramadan Risque d hypoglycémie Randomized trial 1 021 patients with T2D (Egypt, Israel, Jdan, Lebanon, Saudi Arabia and UAE) Sitagliptin vs. SU Primary end-point: symptomatic hypoglycemia Al Sifri S et al. Int J Clin Pract. 2011;65:1132-1140 Mbanya JC, et al. Diab Res Clin Pract 2015

C O M PA R A I S O N Ramadan Hypoglycemia in different clinical trials Gliclazide MR Gliclazide MR Al Sifri S et al. Int J Clin Pract. 2011;65(11):1132-1140. Aravind SR et al. Curr Med Res Opin. 2012;28:1289-1296.

C O M PA R A I S O N Prise de poids ADVANCE: Weight change The ADVANCE Collabative Group; Patel A, MacMahon S, Chalmers J, et al. N Engl J Med. 2008;358(24):2560-2572.

C O M PA R A I S O N Hypoglycémie GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. HbA1c decreased similarly in both groups from 8 4% to 7 2% on gliclazide MR and from 8 2% to 7 2% on glimepiride. Hypoglycaemia with blood glucose level < 3 mmol/l occurred significantly less frequently (P = 0 003) with gliclazide MR (3 7% of patients) compared with glimepiride (8 9% of patients). Schernthaner G et al. Eur J Clin Invest. 2004 Aug;34(8):535-42

C O M PA R A I S O N Hypoglycémie: Métaanalyse Octobre 2015

C O M PA R A I S O N Mécanisme: Variations in tissue selectivity amongst insulin secretagogues: a systematic review. Abdelmoneim AS et al. Diabetes Obes Metab. 2012 Feb;14(2):130-8. Data were extracted from 27 studies IC(50) values f SUR1 were below those f SUR2A/SUR2B f all insulin secretagogues The C(SS) f gliclazide, glipizide, mitiglinide and nateglinide lie between IC(50) values f SUR1 and SUR2A/SUR2B, suggesting that these drugs bind selectively to pancreatic recepts. The C(SS) f glimepiride and glyburide (glibenclamide) was above IC(50) values f all three isofms, suggesting these drugs are nonselective. Insulin secretagogues display different tissue selectivity characteristics at therapeutic doses. This may translate into different levels of cardiovascular risk.

C O M PA R A I S O N E F F I C A C I T E O B J E C T I F S Conclusion Enjeux et Objectifs Objectifs glycémiques Prévention des complications Efficacité des sulfamides Optimisation glycémique Efficacité microvasculaire Effets macrovasculaires variables Sont-ils tous pareils Efficacité glycémique comparable Moins d hypoglycémie sous Gliclazide Avantage cardiovasculaire au Gliclazide