Nowe terapie w cukrzycy typu 1. Edward Franek CSK MSWiA IMDiK PAN

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1 Nowe terapie w cukrzycy typu Edward Franek CSK MSWiA IMDiK PAN

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3 Insulina

4 Insulina Insulina

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7 Krótka historia leczenia w cukrzycy typu Początek komercyjnej produkcji insuliny Wprowadzenie intensywnej insulinoterapii Wprowadzenie na rynek ludzkiej rekombinowanej insuliny Analogi insuliny, pompy, CGMS Present day Odkrycie Bantinga i Besta Standaryzacja strzykawek i dawek insuliny Wprowadzenie glukometrów domowych DCCT DCCT, Diabetes Control and Complications Trial. 7

8 Subjects reaching goal HbAc (%) Tylko mały odsetek chorych na cukrzycę typu osiąga właściwe wyrównanie glikemii % 22% 7% 4% 30% 29% 0 <6 6 <3 3 <8 8 <26 26 <50 50 Age (years) Miller KM et al. Diabetes Care 205;38:97. 8

9 Mean HbAc (%) Postępy w insulinoterapii i monitorowaniu nie powodują normalizacji stężeń cukru Current Age (years)* * 2 years old and 80 years old are pooled. Participants required to be in both cohorts with 3 years diabetes duration in ; Foster N et al. ADA 208; 689-P 9

10 Mean HbAc (%) event in prior 2 months (%) event in the last 2 months (%) Wyrównanie cukrzycy i objawy niepożądane w praktyce klinicznej- wiele miejsca na poprawę!! TD Exchange Clinic Registry 67 endocrinology clinics (pediatric and adults) Total mean HbAc = 8.3% - Not achieving goals 7% reported a severe hypoglycemic event (seizure or coma) in the prior 2 months Struggling with insulin 8% reported a DKA in the prior 2 months Mean HbAc by age group month frequency of severe hypoglycemia 2* Total =.8% month frequency of DKA 2* Total = 4.8% Age (years) HbAc HbAc Beck RW et al. J Clin Endocrinol Metab 202;97: ; 2 Weinstock RS et al. J Clin Endocrinol Metab 203;98: ; *Cross-sectional analysis from the TD Exchange Clinical Registry that included 702 patients from 26 to 93 years of age; DKA=diabetic ketoacidosis; HbAc=glycated hemoglobin; TD=Type diabetes

11 Powikłania narządowe i układowe cukrzycy wynikają z hiperglikemii

12 Severe hypoglycemia (in 00 patients-years) Hipoglikemia a wyrównanie cukrzycy typu Conventional treatment Intensive treatment Retinopathy (in 00 patients-years) HbA c (%) DCCT Research Group. N Engl J Med 993; 329:

13 Wyrównywanie cukrzycy Hiperglikemia i jej powikłania Hipoglikemia i jej powikłania 3

14 Krótka historia leczenia w cukrzycy typu Początek komercyjnej produkcji insuliny Wprowadzenie intensywnej insulinoterapii Wprowadzenie na rynek ludzkiej rekombinowanej insuliny Analogi insuliny, pompy, CGMS Co dalej? Present day Odkrycie Bantinga i Besta Standaryzacja strzykawek i dawek insuliny Wprowadzenie glukometrów domowych DCCT DCCT, Diabetes Control and Complications Trial. 4

15 Diabetes, or the Pissing Evil Thomas Willis, 674 Mocz chorych jest zadziwiająco słodki, jak cukier lub miód Areteusz z Kapadocji, II wiek diabetes Awicenna, XI wiek John Rollo, XVIII wiek diabetes mellitus Sieradzki J: Cukrzyca, Via Medica 2005

16 Nerkowa reabsorpcja glukozy w stanie fizjologii Glukoza SGLT-2 ~90% SGLT- ~0%

17 Cukromocz naturalny mechanizm zmniejszający glikemię Glukoza Kiedy glikemia przekracza próg nerkowy = wyczerpanie pojemności transportera; pojawia się cukromocz SGLT-2 ~90% SGLT- ~0% Glikozuria

18 ~90% Glukoza STOP SGLT- ~0% To samo dzieje się, kiedy aktywność transportera zostaje zahamowana Inhibitory SGLT-2 naśladują naturalny SGLT-2 mechanizm obronny organizmu Glikozuria i natriuria

19 24 countries in total Both studies: Belgium, Canada, Germany, Sweden, UK and US DEPICT- only: Australia, Austria, Denmark, Finland, France, Hungary, Israel, Italy, Mexico, Romania, Spain DEPICT-2 only: Argentina, Chile, Japan, Netherlands, Poland, Russian Federation, Switzerland Badanie DEPICT Patients with HbAc 7.5 to 0.5% randomized :: (stratified by: current CGM use, method of insulin administration, and baseline HbAc) Dapagliflozin 5 mg + insulin Eligible patients with HbAc 7.7.0% Screening period Lead-in period R Dapagliflozin 0 mg + insulin Placebo + insulin Diet and Exercise Screening period ( 28 Days) Lead-in period (8 weeks) 24-week double-blind short-term treatment period 28-week participant and site-blinded long-term treatment period W 4 W W 2 W W 2 W 4 W 8 W 0 W 2 W 8 W 22 Week 8 Day Week 24 Week 52 Week 56 Visits at Weeks 4, 2, 0, and 22 could be conducted as phone visits W 32 W 40 W 48 End of longterm treatment period Dandona P et al. Lancet Diabetes Endocrinol 207;5: ; Mathieu C et al. Presented at ADA 208: 23-OR; Total daily insulin dose recommended to be reduced by up to 20% on Day, before attempting to titrate back to baseline levels taking into account self-monitored blood glucose, local guidance and individual circumstances; CGM=continuous glucose monitoring; HbAc=glycated hemoglobin 30-day posttreatment follow up

20 DEPICT-: Wpływ dapagliflozyny na wyrównanie DM Dandona P et al. Supplementary appendix. Lancet Diabetes Endocrinol 207;5: ; DAPA=dapagliflozin; HbAc=glycated hemoglobin; PBO=placebo; INS=insulin

21 Dandona P et al. Lancet Diabetes Endocrinol 207;5: ; 2 Dandona P et al. Presented at ADA 208: 9-LB; *Values at Week 56 are mean (standard deviation); BL=baseline; CI=confidence interval; DAPA=dapagliflozin; INS=insulin; PBO=placebo; SE=standard error DEPICT-: Wpływ dapagliflozyny na masę ciała Week 24 DAPA 5 mg + INS (N=259) Adjusted mean change from BL, % (SE): 2.84 (0.25) Difference vs. PBO + INS, % (95% CI): 2.96 ( 3.63, 2.28) p<0.000 DAPA 0 mg + INS (N=259) Adjusted mean change from BL, % (SE): 3.60 (0.25) Difference vs. PBO + INS, % (95% CI): 3.72 ( 4.38, 3.05) p<0.000 PBO + INS (N=260) Adjusted mean change from BL, % (SE): 0.2 (0.26) Week 52 2 DAPA 5 mg + INS Difference vs. PBO + INS, % (95% CI): 2.95 ( 3.83, 2.06) * DAPA 0 mg + INS Difference vs. PBO + INS, % (95% CI): 4.54 ( 5.40, 3.66) PBO + INS

22 DEPICT-: Wpływ dapagliflozyny na dawki insuliny Week 24 2 Mean change in TDD, % (SE) DAPA 5 mg + INS (N=259) Adjusted mean change from BL, % (SE): 7.74 (.49) Difference vs. PBO + INS, % (95% CI): 8.80 ( 2.56, 4.88) p<0.000 DAPA 0 mg + INS (N=259) Adjusted mean change from BL, % (SE): 2.6 (.43) Difference vs. PBO + INS, % (95% CI): 3.7 ( 6.75, 9.43) p<0.000 PBO + INS (N=260) Adjusted mean change from BL, % (SE):.6 (.66) Dandona P et al. Presented at ADA 208: 9-LB; 2 Dandona P et al. Lancet Diabetes Endocrinol 207;5: ; BL=baseline; CI=confidence interval; DAPA=dapagliflozin; INS=insulin; PBO=placebo; SE=standard error

23 Effect of TDD Reduction >20% and 20% on Fasting β-ohb Henry RR et al. Diabetes Obes Metab 207;9:84 82; The horizontal line represents the β-ohb level suggestive of DKA; β-ohb=β-hydroxybutyrate; DAPA=dapagliflozin; DKA=diabetic ketoacidosis; INS=insulin; TDD=total daily insulin dose

24 DEPICT-: Potwierdzona kwasica ketonowa DAPA 5 mg + INS (N=277) Over 24 weeks Over 52 weeks 2 DAPA 0 mg + INS (N=296) PBO + INS (N=260) DAPA 5 mg + INS (N=277) DAPA 0 mg + INS (N=296) PBO + INS (N=260) Patients with event sent for DKA adjudication, n (%) 6 (6) 9 (6) 6 (2) 24 (9) 28 (9) 9 (3) Events of definite DKA, n Patients with definite DKA, n (%) 4 () 5 (2) 3 () (4) 0 (3) 5 (2) IR/00 patient-years Severity of events, n Mild Moderate Severe 2 Number of events of euglycemic DKA, n NA NA NA Primary cause of definite events, n Insulin pump failure Missed insulin dose Not identified Other 2 0 Mean TDD change in week prior to event, % NA NA NA Mean TDD change at Week 24/52, % NA NA NA Dandona P et al. Lancet Diabetes Endocrinol 207;5: ; 2 Dandona P et al. Presented at ADA 208: 9-LB; DAPA=dapagliflozin; DKA=diabetic ketoacidosis; INS=insulin; IR=incidence rate; NA=not available; PBO=placebo; TDD=total daily insulin dose

25 Mean (SD) change from baseline at day 7 in UGE (g/24 h) Mean (SD) change from baseline at day 9 in UGE (g/24 h) Lekcja z badań fazy 2 (dopasowywanie dawki) empagliflozyny UGE in patients with TD UGE in patients with T2D 2 Empagliflozin [WART [WART 2.5 OŚĆ] OŚĆ] [WART mg OŚĆ] [WART OŚĆ] Placebo (n = 9) empagliflozin 2.5 mg (n = 9) empagliflozin 0 mg (n = 9) empagliflozin 25 mg (n = 8) [WART OŚĆ] Empagliflozin [WART [WART 0 mg OŚĆ] [WART OŚĆ] OŚĆ] [WART OŚĆ] Placebo (n = 2) empagliflozin 2.5 mg (n = 9) empagliflozin 0 mg (n = 9) empagliflozin 25 mg (n = 9) empagliflozin 00 mg (n = 9) Baseline mean Baseline mean SD, standard deviation; UGE, urinary glucose excretion. Pieber TR et al. Diabetes Obes Metab 205;7:928; 2. Heise T et al. Diabetes Ther 203;4:33. 25

26 Main safety Main efficacy Podobny efekt 0 x mniejszej dawki empagliflozyny w DM EASE-,2 J-EASE- 3 Placebo-corrected: 2.5 mg 0 mg 25 mg 2.5 mg 0 mg 25 mg HbAc at day 28 (%) -0.35* -0.36* -0.49* * Weight at day 28 (kg) * -.5* -.7 Time in range a, week 4 (hour/day) * * +4.0 General safety Comparable to T2D Comparable to T2D DKA No reported cases No reported cases Severe hypoglycaemia One case on placebo No reported cases Genital infections No reported cases Two cases on empagliflozin 2 Empagliflozin improved glycaemic control with weight loss and without increased hypoglycaemia in short-term Phase 2 trials *p<0.05; p<0.00.; a time in range defined as >70 to 80 mg/dl;. Pieber TR et al. Diabetes Obes Metab 205 ;7:928; 2. Famulla et al. Diabetes Technol Ther 207;9:49; 3. Shimada A et al. Diabetes Obes Metab 208;20:

27 Badani EASE-2 i EASE-3 EASE-2 26 weeks (primary endpoint) week 6 weeks 2 weeks 52 weeks 3 weeks Screening TD therapy intensification Placebo run-in R Placebo Empagliflozin 0 mg Empagliflozin 25 mg Follow-up CGM CGM CGM EASE-3 26 weeks 3 weeks Placebo Screening TD therapy intensification Placebo run-in R Empagliflozin 2.5 mg Empagliflozin 0 mg Follow-up Empagliflozin 25 mg CGM* CGM* CGM* *CGM performed as sub-study in ~20% patients; R, randomisation 27

28 Mean (SE) HbAc (%) 6-week intensification 2-week run-in EASE-3: Redukcja HbAc n with data at visit Placebo Empagliflozin 2.5 mg Empagliflozin 0 mg Empagliflozin 25 mg 7.5 Screening Placebo Empagliflozin 2.5 mg Empagliflozin 0 mg Week Empagliflozin 25 mg * (95% CI:-0.42, -0.5) p< * (95% CI:-0.42, -0.5) -0.52* -0.45* p<0.000 (95% CI:-0.66, CI:-0.58, -0.39) -0.32) p< * (95% CI:-0.66, -0.39) p<0.000 HbAc reduced with all three doses versus placebo *Adjusted mean change from baseline vs placebo; Screening and week 0: descriptive data in full analysis set. Week 4 26: adjusted data based on mixed model repeated measures in full analysis set (observed cases). 28

29 Adjusted mean (95% CI) difference vs placebo in change from baseline in HbAc at week 26 (%) Redukcja HbAc w zależności od wartości wyjściowej Highest HbAc reduction observed in subgroup of patients with HbAc 8% at baseline 0,2 HbAc <8.0% at baseline 0,2 HbAc 8.0% at baseline ~60% of patients 0,0 0,0-0,2-0,2-0,4-0,6-0,8 -,0-0,8-0,35 Empagliflozin 2.5 mg (n=0) Empagliflozin 0 mg (n=06) Empagliflozin 25 mg (n=98) -0,39-0,4-0,6-0,8 -,0-0,35-0,53-0,62 Empagliflozin 2.5 mg (n=36) Empagliflozin 0 mg (n=38) Empagliflozin 25 mg (n=44) Mixed model repeated measures in full analysis set (observed cases). p<0.00; p<0.000 for difference vs placebo. 29

30 Adjusted mean (SE) change from baseline in weight (kg).0 EASE-3: Redukcja masy ciała Placebo Empagliflozin 2.5 mg Empagliflozin 0 mg Empagliflozin 25 mg * (95% CI:-2.3, -.2) p< * (95% CI:-2.3, -3.4* -3.0* -3.0* -.2) (95% p<0.000 CI:-3.6, CI:-4.0, -2.5) (95% CI:-3.6, -2.9) -2.5) p<0.000 p<0.000 All three doses significantly reduced body weight * (95% CI:-4.0, -2.9) p< n analysed Placebo Empa 2.5 mg Empa 0 mg Empa 25 mg Week *Adjusted mean change from baseline vs placebo; Screening and week 0: descriptive data in full analysis set. Week 4 26: adjusted data based on mixed model repeated measures in full analysis set (observed cases). 30

31 Adjusted mean (SE) change from baseline in total daily insulin dose (U/kg) 0.02 EASE-3: Redukcja dawki insuliny (Half the reduction in basal dose and half in bolus dose) Placebo Empagliflozin 2.5 mg Empagliflozin 0 mg Empagliflozin 25 mg * (-6%) (95% CI:-0.07, -0.03) p< * (-6%) (95%-0.09* -0.07* CI:-0.07, (-3%) (-0%) -0.03) (95% p<0.000 CI:-0., CI:-0.09, -0.07) -0.05) p< * (-3%) (95% CI:-0., -0.07) p<0.000 Reduction in total daily insulin dose with all doses n analysed Placebo Empa 2.5 mg Empa 0 mg Empa 25 mg Week Adjusted mean change from baseline vs placebo. Screening and week 0: descriptive data in full analysis set. Week 4 26: adjusted data based on mixed model repeated measures in full analysis set (observed cases). 3

32 Adjudication results: Certain DKA Pooled* placebo (n=484) Pooled* empagliflozin 0 mg (n=49) Pooled* empagliflozin 25 mg (n=489) EASE-3 placebo (n=24) EASE-3 empagliflozin 2.5 mg (n=24) Patients with certain DKA, n (%) 6 (.2) 2 (4.3) 6 (3.3) 3 (.2) 2 (0.8) Certain DKA events, n Incidence rate per 00 patient-years Events by severity, n Severe Moderate Mild Outcome of event Fatal *Consists of EASE-2 and EASE-3 data up to 52 weeks; Treated set. On-treatment analysis. 32

33 Podsumowanie W leczeniu cukrzycy typu przez prawie sto lat podstawowym lekiem jest insulina Leczenie to uratowało życie milionów ludzi, ale nie jest doskonałe Wciąż poszukuje się rozwiązań, które umożliwią uzyskanie prawidłowych stężeń cukru bez niedocukrzeń Jednym z takich rozwiązań mogą być flozyny 33

34 Dziękuję za uwagę 34

35 Potential explanations for increased UGE in TD vs T2D Glucose ( variability/load) + Organ performance ( hyperfiltration) + SGLT2 inhibitor 2,3 ( expression/activity) = Urinary glucose excretion ( in TD vs T2D) TD T2D. Cherney DZ, Perkins BA, Soleymanlou N, et al. Circulation 204;29:587; 2. Farber SJ, Berger EY, Earle DP. J Clin Invest 95;30:25; 3.Ghezzi C, Wright EM. Am J Physiol Cell Physiol 202;303:C