Μελέτες καρδιαγγειακής ασφάλειας στο σακχαρώδη διαβήτη

Μελέτες καρδιαγγειακής ασφάλειας στο σακχαρώδη διαβήτη Nίκη Κατσίκη MD, MSc, PhD, FRSPH IASO/EASO Scope Member EASD Diabetes & Cardiovascular Disease Group Member Ειδική Παθολόγος, Επιστηµονική συνεργάτης Β Προπ. Παθολογικής Κλινικής Α.Π.Θ.

Large CV outcome studies in diabetes Glycemic control focused studies using multiple treatment modalities to achieve glycemic targets United Kingdom Prospective Diabetes Study (UKPDS) Action to Control Cardiovascular Risk in Diabetes (ACCORD) Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Veterans Affairs Diabetes Trial (VADT) Slide Source: Lipids Online Slide Library www.lipidsonline.org

UK Prospective Diabetes Study (UKPDS) 20-year Interventional Trial from 1977 to 1997 5,102 patients with newly-diagnosed type 2 diabetes recruited between 1977 and 1991 Median follow-up 10.0 years, range 6 to 20 years Results presented at the 1998 EASD Barcelona meeting 10-year Post-Trial Monitoring from 1997 to 2007 Annual follow-up of the survivor cohort Clinic-based for first five years Questionnaire-based for last five years Median overall follow-up 17.0 years, range 16 to 30 years UKPDS 80. N Eng J Med 2008; 359:

Glucose Interventional Trial Dietary Run-in Randomisation 1977-1991 Trial end 1997 744 Diet failure FPG >15 mmol/l 2,729 Intensive with sulfonylurea/insulin Intensive P 5,102 Newly-diagnosed type 2 diabetes 4209 1,138 (411 overweight) Conventional with diet Conventional P 149 Diet satisfactory FPG <6 mmol/l Mean age 54 years (IQR 48 60) UKPDS 80. N Eng J Med 2008; 359: 342 (all overweight) Intensive with metformin Intensive

UKPDS 80. N Eng J Med 2008; 359:

ACCORD and ADVANCE Studies: main findings ACCORD 10,251 participants Mean age: 62 years Median duration of diabetes mellitus: 10 years Mean A1C at entry: 8.3% Known heart disease or at least 2 risk factors ADVANCE 11,140 participants Mean age: 66 years Mean duration of diabetes mellitus: 8 years Mean A1C at entry: 7.48% History of major CV event or at least 1 risk factor Standard Intensive Standard Intensive A1C 7.0% 7.9% A1C <6.0% A1C usual care A1C 6.5% CONCLUSION: Intensive glucoselowering did not significantly reduce CVD events (primary outcome) may cause harm in high-risk patients with type 2 diabetes (increased mortality). ACCORD Study Group. N Engl J Med. 2008;358:2545-2559 ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. CONCLUSION: Intensive glucoselowering did not significantly reduce CVD events (primary outcome) reduces renal complications in high-risk patients by 21% (95% CI, 7 34%) and did not increase mortality Slide Source: Lipids Online Slide Library www.lipidsonline.org

Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS!! "! "! DCCT / EDIC*!! "! " " ACCORD! " # ADVANCE! " " VADT! " " Kendall DM, Bergenstal RM. International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med. 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med. 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358:2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129. (erratum: Moritz T. N Engl J Med 2009;361:1024) Initial Trial Long Term Follow-up * in T1DM

HbA1c levels Glucose arm HbA1c level (%) Mean±SD Standard Intensive Pre-randomisation 7.5±1.5 7.5±1.6 Last randomised visit 7.2±1.1 6.5±0.8 First ADVANCE-ON visit 7.3±1.3 7.3±1.4 Final ADVANCE-ON visit 7.4±1.3 7.2±1.2 Any effect observed during ADVANCE-ON is attributable to the glycaemic difference achieved during ADVANCE

Mortality (overall in-trial and post-trial follow-up)

Major Vascular events (overall in-trial and post-trial follow-up)

Microvascular events (overall in-trial and post-trial follow-up)

PROactive: Time to Primary Composite Endpoint: Pioglitazone vs. Placebo Kaplan-Meier Event Rate 0.25 0.20 0.15 0.10 0.05 Placebo Pioglitazone What if this was a 6-month trial? N events: 572 / 2633 514 / 2605 Pioglitazone vs. placebo 3-Year Estimate: 23.5% 21.0% HR 95% CI p value 0.90 0.80 1.02 0.095 10% RRR 0.0 0 6 12 18 24 30 36 No. at Risk: 5238 5018 4786 4619 4433 4268 693 Time from Randomization (Months) CI = confidence interval; HR = hazard ratio Reprinted from Dormandy JA, et al. Lancet. 2005;366: 1279 1289, with permission from Elsevier. Slide Source: Lipids Online Slide Library www.lipidsonline.org

PROactive Trial: Significant Reduction in Secondary Outcome All-cause mortality, nonfatal MI*, stroke 25 *Excluding silent myocardial infarction (MI) Events, % 20 15 10 5 16% RRR HR 0.84 (0.72 0.98) P = 0.027 Placebo 358 events Pioglitazone 301 events 0 0 6 12 18 24 30 36 Time from randomization (months) Reprinted from Dormandy JA, et al. Lancet. 2005;366: 1279 1289, with permission from Elsevier Limited. Slide Source: Lipids Online Slide Library www.lipidsonline.org

The AVANDIA (rosiglitazone) controversy

Balance of Evidence: Is Rosiglitazone Associated With Cardiovascular Risk? MI = myocardial infarction MET = metformin SU = sulfonylurea PIO = pioglitazone FDA Analysis MI signal with insulin and nitrates GSK ICT analysis MI signal Nissen et al. MI signal ACCORD Mortality not linked to any specific diabetes drug ADOPT No significant risk Comparable to MET, SU Lago et al. Lancet. No significant risk Comparable to PIO RECORD No significant risk Comparable to MET, SU McAfee et al. No significant risk Comparable to MET/SU Rosen et al. No significant risk Comparable to PIO [W]e believe that only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the controversy about its safety. Diamond et al., 2007 Diamond GA, et al. Ann Intern Med. 2007;147:578 581 Home PD. N Engl J Med. 2007;357:28 38 Krall RL. Lancet. 2007;369:1995 1996. Lago RM, et al. Lancet. 2007;370:1129 1136 McAfee AT, et al. Pharmacoepidemiol Drug Saf. 2007; 16:711 725 Nissen SE, et al. N Engl J Med. 2007;356:2457 2471 Rosen CJ. N Engl J Med. 2007;357:844 846.

The Jury: FDA July 2007 The Verdict: The panel voted 20 vs 3 that the available data suggest a conclusion that Rosiglitazone increases cardiac ischemic risk in T2DM but 22 vs 1 voted to continue its marketing

October 2010 More data needed

FDA: Dec 2008 guidelines (1) Concerns about CV risk should be more thoroughly addressed during antidiabetes drug development Evaluation of new antidiabetic drugs: 1. An upper bound of the 95% CI for the risk ratio of important CV events of <1.3 should be used as a key criterion for excluding unacceptable CV risk for new treatments of type 2 diabetes 2. Study patients must include those with relatively advanced disease, elderly patients, and patients with some degree of renal impairment 3. A minimum of 2 years CV safety data must be provided

FDA: Dec 2008 guidelines (2) All phase 2 and 3 studies should include a prospective, independent adjudication of CV events. Adjudicated events should include CV mortality, myocardial infarction (MI), and stroke and can include hospitalization for acute coronary syndrome, urgent revascularization procedures, and possibly other end points For satisfaction of the new statistical guidelines, the analysis of CV events may include a meta-analysis of all placebo-controlled trials, add-on trials (i.e., drug vs. placebo, each added to standard therapy), and active-controlled trials or an additional single large safety trial may be conducted that alone, or added to other trials, would be able to satisfy this upper bound before New Drug Application/Biologic License Application submission

Ολοκληρωµένες και συνεχιζόµενες µελέτες καρδιαγγειακών εκβάσεων των αναστολέων DPP-4 µετά την κυκλοφορία στην αγορά Μελέτη (χορηγός) Φάρµακα της µελέτης Πρωτεύον καταληκτικό σηµείο & σχεδιασµός N Καταλληλότητα Ηµεροµηνία ολοκλήρωσης ΕΧΑΜΙΝΕ (Takeda) Αλογλιπτίνη 6.25 25mg άπαξ ηµερησίως MACE Μη-κατωτερότητα 5380 >18έτη + ΟΣΣ 15 90 ηµέρες πριν από την τυχαιοποίηση Πλήρης SAVOR-TIMI 53 (Astra-Zeneca) Σαξαγλιπτίνη 2.0 2.5mg άπαξ ηµερησίως MACE Μη-κατωτερότητα και ανωτερότητα* 16.492 >40έτη + µε εγκατεστηµένη CVD και/ή πολλαπλούς παράγοντες κινδύνου Πλήρης TECOS (Merck) Σιταγλιπτίνη 50 100mg άπαξ ηµερησίως MACE + ασταθή στηθάγχη Μη-κατωτερότητα ~14.700 >50έτη + αγγειακή νόσο στις στεφανιαίες, εγκεφαλικές ή περιφερικές αρτηρίες Πλήρης CAROLINA (Boehringer Ingelheim) Λιναγλιπτίνη 5mg έν. γλιµεπιρίδης 1 4mg άπαξ ηµερησίως MACE + ασταθή στηθάγχη Μη-κατωτερότητα ~6000 40-85έτη + εγκατεστηµένη CVD ή ειδική για διαβήτη βλάβη τελικού οργάνου Σεπτ 2018 CARMELINA (Boehringer Ingelheim) Λιναγλιπτίνη 5mg άπαξ ηµερησίως MACE + ασταθή στηθάγχη, + νεφρική έκβαση Μη-κατωτερότητα ~8000 >18έτη + προϋπάρχουσες CV επιπλοκές και αλβουµινουρία (UACR 30mg/g) και/ή µικρο-αγγειακή βλάβη τελικού οργάνου (egfr 15 200mg/g) 2018 ACS: οξύ στεφανιαίο σύνδροµο; CVD: καρδιαγγειακή νόσος; MACE: µείζονα ανεπιθύµητα καρδιακά συµβάντα, OD: άπαξ ηµερησίως, UACR: λόγος αλβουµίνης/κρεατινίνης ούρων,egfr: εκτιµώµενος ρυθµός σπειραµατικής διήθησης. *Σχεδιάστηκε για να αξιολογήσει τη µη κατωτερότητα για την ασφάλεια, εφόσον καταδειχθεί η µη-κατωτερότητα, η µελέτη διεξάγεται για να ελέγξει την ανωτερότητα ως προς την αποτελεσµατικότητα 1 White WB et al. N Engl J Med. 2013;369:1327 1335. 2 Scirica BM et al. N Engl J Med. 2013;369:1317 1326. 3 Green JB et al. Am Heart J. 2013;166:983 989. 4 Rosenstock J et al. Diabet Vasc Dis Res. 2013;10:289 301. 5 Δελτίο τύπου 2013. Διαθέσιµο από: www.boehringer-ingelheim.com/ news/news_releases/press_releases/ 2013/31_july_2013_diabetes.html [Accessed Feb 2014]

Κίνδυνος, κατά την Έναρξη, των Πληθυσµών Ασθενών που Εντάχθηκαν σε Μελέτες ΚΑ Εκβάσεων των DPP-4 Αναστολέων Παράγοντες Κινδύνου Σταθερή ΣΝ-ΚΑΝ-ΠΑΝ Σαξαγλιπτίνη SAVOR-TIMI (N=16.492) 2 Προϋπάρχουσα ΚΑΝ ή πολλαπλοί παράγοντες κινδύνου για ΚΑΝ Σιταγλιπτίνη TECOS (N=~14.000) 3 Προϋπάρχουσα ΚΑΝ Ασθενείς µετά ΟΣΣ Αλογλιπτίνη EXAMINE (N=5380) 1 ΟΣΣ εντός15 90 ηµερών Παρουσιάστηκε Σεπ 2013 Παρουσιάστηκε Σεπ 2013 Ολοκλήρωση Μάρτιος 2015 Λιναγλιπτίνη CARMELINA (N=8300) 4 Προϋπάρχουσα ΚΑΝ + λευκωµατινουρία ή έκπτωση νεφρικής λειτουργίας Ολοκλήρωση Ιαν 2018 Δεν υπάρχει εξελισσόµενη µελέτη ΚΑ εκβάσεων για τη βιλνταγλιπτίνη ΚΑ = καρδιαγγειακός, DPP-4 = διπεπτιδυλική πεπτιδάση-4, ΣΝ = στεφανιαία νόσος, ΚΑΝ = καρδιαγγειακή νόσος, ΠΑΝ = περιφερική αρτηριακή νόσος, ΟΣΣ = οξύ στεφανιαίο σύνδροµο, EXAMINE = Examination of Cardiovascular Outcomes: Alogliptin vs Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome, SAVOR-TIMI = Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Trial- Thrombolysis in Myocardial Infarction, TECOS = Trial Evaluating Cardiovascular Outcomes With Sitagliptin, CARMELINA = Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in Patients With Type 2 Diabetes Mellitus at High Vascular Risk. 1. White W et al. N Engl J Med. 2013;369:1327 1335. 2. Scirica BM et al. N Engl J Med. 2013;369:1317 1326. 3. Green JB et al. Am Heart J 2013;166:983 989.e7. 4. CARMELINA: Cardiovascular and renal microvascular outcome study with linagliptin in patients with type 2 diabetes mellitus at high vascular risk. ClinicalTrials.gov web site. http://clinicaltrials.gov/ct2/show/ NCT01703298. Accessed September 12, 2014.

Πιθανές αιτίες για τα διαφορετικά ευρήµατα των µελετών SAVOR-TIMI 53, EXAMINE και TECOS: Διαφορές στα χαρακτηριστικά των ασθενών που συµπεριλήφθησαν. Διαφορές στην φαρµακευτική αγωγή που ελάµβαναν οι ασθενείς κατά την ένταξη. Διαφορές στην καταγραφή και τον ορισµό των επεισοδίων Καρδιακής Ανεπάρκειας, ανάµεσα στις µελέτες. Εγγενείς φαρµακολογικές διαφορές ανάµεσα στους διαφορετικούς αναστολείς DPP-4. Τυχαίο γεγονός.

GLP-1R agonists Trulicity Approved 18 Sep 2014 Approved Nov 2014 #

Marso SP et al N Engl J Med 2016 Sep 15 Epub ahead of print

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Antihyperglycemic Therapy in Type 2 Diabetes American Diabetes Association Standards of Medical Care in Diabetes. Approaches to Glycemic Treatment. Diabetes Care 2016; 39 (Suppl. 1)

Positive CV outcome trials UKPDS (follow-up) VADT (follow-up) PROACTIVE EMPA-REG LEADER SUSTAIN-6 Neutral CV outcome trials ADVANCE ORIGIN ELIXA SAVOR-TIMI EXAMINE TECOS

Beware of false knowledge; it is more dangerous than ignorance George Bernard Shaw (1856-1950)