Actualités en diabétologie Quoi de neuf en 2016? S. Aouiche Service de diabétologie CHU Mustapha Alger.Pr BOUDIBA

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1 Actualités en diabétologie Quoi de neuf en 2016? S. Aouiche Service de diabétologie CHU Mustapha Alger.Pr BOUDIBA

2 Deux médicaments valent mieux qu un dans le traitement du patient diabétique Jochen.SEUFERT Division of Endocrinology and Diabetology. University hospital of Freiburg. Germany

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14 PRE-DIABETES R. Holman (UK) J. Tuomelehto (Finland)

15 Rationale for «pre-diabetes» screening «Pre-diabetes» and diabetes are conditions in which early detection is appropriate, because: Duration of hyperglycemia is a predictor of adverse outcomes There are effective interventions to prevent disease progression and to reduce the risk of complications People often have unrecognised T2DM for several years before being disgnosed by the time of diagnosis as many as one in two can have clinically evident complications of diabetes Preventing the onset of diabetes, or treating the disease process at an earlier stage, should help to reduce the burden of T2DM We need to identify those asymptomatic individuals who are at risk of developing T2DM and determine which therapies can most effectively halt or delay disease progression Failure to identify IGT means a missed opportunity to prevent development of diabetes and, potentially, its attendant consequences

16 Natural history of IGT IGT after 10 years IGT 25% Normal 25% T2DM 50%

17 ADA guideline: Prevention/ delay of Type 2 Diabetes IDF framework for action on sugar Patients with IGT, IFG, or an A 1c % should be referred to an effective ongoing support program targeting weight loss of 7% of body weight and increasing physical activity to at least 150 min/week of moderate activity such as walking Metformin therapy for prevention of type 2 diabetes may be considered in those with IGT, IFG, or an A1c % especially for those with BMI > 35 kg/m 2, aged < 60 years, and women with prior GDM Screening for and treatment of modifiable risk fatcors for CVD is suggested A strong association between consumption of sugar in general, and sugar- sweetened beverages (including fruit juice) in particular, and increasing risk of type 2 diabetes has been suggested by a number of recent studies. In response to the growing prevalence of obesity and related health issues, the WHO has produced guidelines that recommend the daily intake of free sugar in adults and children be less than 10% of total energy intake Diabetes care 2014: 37 (suppl 1)

18 Lifestyle modifications and exercise Intervention Duration (years) Number of people Risk reduction (%) Daqing (China) 1 Lifestyle Diabetes Prevention Program (DPP; USA) 2 Lifestyle Diabetes Prevention Study (DPS; Finland) 3 Lifestyle Zensharen Study (japon) 4 Lifestyle ) Pan XR, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997, 20: ) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346: ) Tuomilehto J, et al. Prevention of type 2 diatetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N Engl J Med, 2001, 344: ) Saito T. Arch Intern Med Aug 8;171(15): doi: /archinternmed

19 Pharmacological treatment in pre-diabetes Intervention Duration (years) Number of people Risk Reduction (%) Diabetes Prevention Program (DPP; USA) 1 Metformine Fasting Hyperglycaemia Study (FHS) 2 Gliclazide 320mg (NS) Chinese IGT Study 3 STOP- NIDDM 4 Acarbose 50mgX2 Acarbose 100mgX2 Xendos Sudy 5 Orlistat (IGT 21%) Total : - 37 IGT : - 45 NAVIGATOR Study 6 Dream Study 7 Nateglinide (NS) Valsartan Rosiglitazone Ramipril (NS) ACT NOW Study 8 Pioglitazone 2, ) Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 5) Torgerson JS et al., Diabetes Care : diabetes with lifestyle intervention or metformin. N Engl J Med, 2002, 346: ) Saloranta C et al., Diabetes Care 2002;25: ) Herlihy OM et al., Diabetologia 2000; 43: suppl1:a73 3) Wenying et al., Chinese Journal of Endocrinology. N 3 issue,2001 7) DREAM Trial Investigators. Diabetologia. 2004;47: ) Chiasson et al., Lancet : ) Defenzo et al., N engl J Med 2011;364:

20 Pharmacotherapy for «pre-diabetes» Good evidence for alphaglucosidase inhibitors (acarbose) Good evidence for metformin Neutral outcomes sulfonylureas (FHS, gliclazide) Neutral outcomes for meglitinides (NAVIGATOR? Nateglinide) Good evidence for thiazolidinediones, but there are safety concerns Some evidence for basal insulin (ORIGIN? Glargine) Large-scale study data lacking on newer agents, such as: GLP-1 receptor agonists DPP-4 inhibitors SGLT2 inhibitors

21 Trial design : SCALE Obesity and prediabetes Liraglutide 3.0mg in weight management (160 weeks) EASD ADA. Diabetes Care 2010;33 (suppl 1) :

22 Type 2 diabetes diagnosis : weeks While on treatment, 26 participants in the liraglutide 3.0 mg group and 46 in the placebo group were diagnosed with T2DM over 3 years, equivalent to a cumulative probability of a TZDM diagnosis of 3%» versus 11% when taking censoring into account At week 160, the estimated time to onset of T2DM was 2.7 times longer with liraglutide 3.0 mg vs. placebo while on treatment [95% CI, 1.9 to 3.9], corresponding to a hazard ratio of 0.2 (p<0.0001)

23 Metformine dans le diabète type 1: caractéristiques et méthodologie de l étude REMOVAL John.Petrie Institute of Cardiovascular and Medical Sciences. University of Glascow

24 Hypothèse: - Les MCV sont une cause majeure d'une réduction de l'espérance de vie du patient DT1. - Une insulinothérapie intensive provoque des hypoglycémies et comporte un risque de prise de poids associé à l augmentation du LDL cholestérol - Dans le DT1, l association avec la metformine réduit les doses d insuline, la stabilisation du poids et abaisse le LDL cholestérol Metformine pourrait diminuer la progression de l'athérosclérose.

25 429 participants Australia, Canada, Denmark, the Netherlands, UK and USA

26 Le modèle saisonnier dans le diagnostic du diabète sucré gestationnel dans le sud de la Suède Anastasia.Katsarou Department of Clinical Sciences, Lund University,

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30 Résultats de l étude LEADER Pr. John B. Buse Professor of medecine, chief of the division of endocrinology and excutive associate Dean for clinical research, university of North Carolina School of medecine

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33 LEADER : primary and secondary CV outcomes *3 point MACE consisting of CV death, nonfatal MI or nonfatal stroke + CV death, nonfatal MI, nonfatal stroke, coronary revascularization or hospitalization for UA or HF Marso SP et al. N Engl J Med. 2016;375:

34 LEADER : primary outcome subgroup analyses Marso SP et al. N Engl J Med. 2016;375:

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38 Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes : Résultats SUSTAIN 6 Steven P. Marso The University of Texas Southwestern Medical School

39 Trial design Randomisation (1:1:1:1) Semaglutide 1.0 mg 3297 subjects with T2D Semaglutide 0.5 mg Placebo 1.0 mg Placebo 0.5 mg Trial information Randomised, double-blind, placebo-controlled, four-armed parallel-group trial Additional glucose-lowering medication could be added to achieve glycaemic control at the discretion of investigator Dose escalation * 4 8 weeks Treatment maintenance weeks Treatment duration 104 weeks Follow-up 5 weeks Inclusion criteria HbA 1c 7.0% Previously on 0 2 OADs, basal or pre-mix insulin ± 0 2 OADs Age 50 years with established CVD (prior cardio-, cerebro- or peripheral vascular disease, chronic heart failure [NYHA class II III]), or CKD stage 3 or worse or Age 60 years with at least one cardiovascular risk factor Key endpoints Primary: time to first occurrence of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke Secondary: time to first occurrence of revascularisation, unstable angina requiring hospitalisation, hospitalisation for heart failure, all-cause death, non-fatal MI or non-fatal stroke; time to each individual component *Dose escalation from a starting dose of 0.25 mg, dose doubled each step until trial dose achieved. (NCT ). Novo Nordisk, Data on file. CKD, chronic kidney disease; CVD, cardiovascular disease; MI, myocardial infarction; NYHA, New York Heart Association; OAD, oral antidiabetic drug. Marso et al. NEJM [in press]

40 Subjects with an event (%) 41 Primary outcome TIME TO FIRST OCCURRENCE OF CV DEATH OR NON-FATAL MI OR NON-FATAL STROKE HR, 0.74 (95% CI, 0.58; 0.95) Events: 108 semaglutide; 146 placebo P<0.001 for non-inferiority P=0.02 for superiority Placebo, 8.9% 5 Semaglutide, 6.6% Time since randomisation (weeks) Number of subjects at risk Semaglutide Placebo Figure 1A. Kaplan Meier plot for first event adjudication committee-confirmed CV death, non-fatal MI and non-fatal stroke using in-trial data from subjects in the full analysis set. *Not prespecified. CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Marso et al. NEJM [in press]

41 Summary of cardiovascular outcome Primary outcome CV death Non-fatal MI Non-fatal stroke All cause death, non fatal stroke All cause death Expanded CV outcome Unstable angina requiring hospitalisation Hospitalisation for heart failure Revascularisation Favours semaglutide 0. 5 Favours placebo 1. 0 HR (Semaglutide: placebo) 0.74* [0.58; 0.95] [0.65; 1.48] 0.74 [0.51; 1.08] 0.61* [0.38; 0.97] 0.77 [0.61; 0.97] 1.05 [0.74; 1.50] 0.74* [0.62; 0.89] 0.82 [0.47; 1.44] 1.11 [0.77; 1.61] 0.65* [0.50; 0.86] *Indicates significance (p-value <0.05). Values are estimated HRs with 95% CIs from a Cox proportional hazards model using «in-trial» data from subjects in the full analysis set. Marso et al. NEJM [in press] CI: confidence interval; CV: cardiovascular; HR, hazard ratio, MI, myocardial infarction

42 Overview of completed and future CV safety trials: more to come CARMELINA (n=8300) 4P-MACE + renal DECLARE-TIMI 58 (n=17,150) 3P-MACE: 1390 SAVOR-TIMI 53 (n=16.492) 3P-MACE: TECOS (n=14.724) 4P-MACE: 1300 EMPA-REG OUTCOME (n=7020) 3P-MACE: 691 SUSTAIN-6 (n=3297) 3P-MACE OMNEON (n=4000) 4P-MACE CAROLINA (n=6000) 4P-MACE: 631 Ertugliflozin CVOT (n=3900) 3P-MACE EXAMINE (n=5380) 3P-MACE: 621 ELIXA (n=6068) 4P-MACE: 844 LEADER (n=9340) 3P-MACE: 611 CANVAS (n=5700) albuminuria EXSCEL (n=14,000) 3P-MACE: 1591 REWIND (n=9622) 3P-MACE: 1067 Trial name (Number of participants) Primary endpoint: number of events recorded/required DPP-4i CVOTs GLP-1RA CVOTs SGLT-2i CVOTs CANVAS (n=4365) 3P-MACE: 420 Timing represents availibility of results for the primary endpoint, or estimated completion dates from ClinicalTrials.gov. CV, cardiovascular; CVOT, cardiovascular outcomes trial; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist. MACE, major adverse event; 3P-/4P-/5P-MACE, three-point/four-point MACE endpoint; SGLT-2i, sodium-glucose cotransporter-2 inhibitor. Adapted from Johansen, World J Diabetes 2015;6: ITCA CVOT (n=4000) 4P-MACE CREDENCE (n=3700) Renal + 5P- MACE HARMONY outcomes (n=9400) 3P-MACE

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