How to apply novel outcome data with GLP-1 RA to clinical practice - - PowerPoint PPT Presentation
Preventing Cardiovascular Disease in Patients with T2DM How to apply novel outcome data with GLP-1 RA to clinical practice Lars Rydn Department of Medicine K2 Karolinska Institutet Stockholm, Sweden Ljubljana April 19 , 2018 For internal
For internal Medical Affairs training only
Lars Rydén
Department of Medicine K2 Karolinska Institutet Stockholm, Sweden Ljubljana April 19, 2018
Preventing Cardiovascular Disease in Patients with T2DM
Two options
Effects Insulin secretion Glucagon secretion Beta-cell mass Insulin sensitivity Gastric emptying Satiety
Baggio LL & Drucker DJ. Gastroenterology 2007;132:2131–2157
Requires injection Mimics the effect of GLP-1 Reduces HbA1c by ≥1% Causes weight loss of 2–3 kg Low risk of hypoglycaemia when used with metformin Reduced risk of hypoglycaemia if combined with insulin
Broad approach
Drucker DJ. Cell Metab 2016;24:15–30
GLP-1 receptor agonists
Shortacting Longacting
Human analogues
Liraglutide QD Semaglutide QW Dulaglutide QW
Exendin-4 based
Exenatide BID Lixisenatide OD
Exendin-4 based
Exenatide LARQW ITCA 650 Meier JJ. Nat Rev Endocrinol 2012;8:728–742 Madsbad S et al. Diabetes Obes Metab 2011;13:394–407
Results from available outcome trials
Shortacting Longacting
Human analogues
Liraglutide QD Semaglutide QW Dulaglutide QW
Exendin-4 based
Exenatide BID Lixisenatide OD
Exendin-4 based
Exenatide LARQW ITCA 650
Lixisenatide Exenatide ITCA 650
ITCA 650 is an investigational product and not currently approved
Pfeffer MA et al. N Engl J Med 2015;373:2247–2257
Type 2 diabetes and recent ACS n=6,068 Treatment Lixisenatide Placebo Follow-up: 25 months (median) Impact on CV death or non-fatal MI, stroke
HbA1c at the end of study Lixisenatide 7.4% Placebo 7.6%
Holman RR et al. N Engl J Med 2017;377:1228–1239
Type 2 diabetes with (74%) or without CVD n=14,752 Treatment Exenatide (2 mg once weekly) Placebo Follow-up: 3.2 years (median) Impact on CV death or non-fatal MI or stroke
HbA1c at the end of study Exenatide 7.7% Placebo 7.9%
Results from available outcome trials
Shortacting Longacting
Human analogues
Liraglutide QD Semaglutide QW Dulaglutide QW
Exendin-4 based
Exenatide BID Lixisenatide OD
Exendin-4 based
Exenatide LARQW ITCA 650
Lixisenatide Liraglutide Semaglutide
Semaglutide is an investigational product and not currently approved
Marso SP et al. N Engl J Med 2016;375:311–322
Type 2 diabetes at high risk for CVD n=9,340 Treatment Liraglutide (1.8 mg once daily) Placebo Follow-up: 3.8 years (median) Impact on CV death or non-fatal MI or stroke
HbA1c at the end of study Liraglutide ~7.7% Placebo ~8.0%
Marso SP et al. N Engl J Med 2016;375:1834–1844
Type 2 diabetes at high risk for CVD n=3,297 Treatment Semaglutide (0.5 or 1.0 mg once daily) Placebo Follow-up: 3.8 years (median) Impact on CV death or non-fatal MI or stroke
HbA1c at the end of study Liraglutide ~7.3% Placebo ~8.3%
Semaglutide sc once-weekly
Semaglutide is an investigational product and not currently approved
Semaglutide is an investigational product and not currently approved
Marso SP et al. N Engl J Med 2016;375:311–322
Patient characteristics at study start
20 40 60 80 100 With previous CVD ( age ≥ 5 0 ) With CVD risk factors ( age ≥ 6 0 ) Percentage of patients
Variable
Male sex (%) 64 Age (years) 64 Diabetes duration (years) 13 HbA1c 8.7 BMI (kg/m2) 32.5 Blood pressure (mmHg) 136/77 Heart failure (%) 18
Liraglutide Placebo
Marso SP et al. N Engl J Med 2016;375:311–322
75.8 50.8 3.0 6.3 3.8 43.7 77.1 50.6 2.6 6.0 3.7 45.6 20 40 60 80 100
M e t f ormin Su lphony lure a s Alpha - glucosida se inhibit ors TZ Ds Glinide s I n sulinProportion of patients ( % ) SUs Metform in Alpha-glucosidase inhibitors TZDs Glinides I nsulin Liraglutide Placebo
Liraglutide Placebo
Background therapy at study start
Metformin SU AGI TZD Glinides Insulin
92.7 41.8 76.3 68.7 6.7 92.1 41.8 75.2 66.8 7.0 20 40 60 80 100
Antihypertensive therapy Diuretics Lipid-lowering drugs Platelet aggregation inhibitors Other anti-thrombotic medicationProportion of patients ( % ) Platelet aggregation inhibitors Antihypertensive therapy Diuretics Lipid-lowering drugs Other anti-throm botic m edication
BP-lowering Diuretics Lipid-lowering ASA Plat stab
Marso SP et al. N Engl J Med 2016;375:311–322
Treatment/guideline Blood glucose
Blood pressure
Lipids
Antiplatelet therapy
Treatment recommendations
Marso SP et al. N Engl J Med 2016;375:311–322
Hazard rat io ( 9 5 % CI ) Favours placebo Favours liraglut ide
Subgroup H azard ratio ( 95% CI ) p-value for interaction N o. of patients Prim ary analysis 0.87 ( 0.78 ; 0.97) 9340 Sex 0.84 Female 0.88 (0.72 ; 1.08) 3337 Male 0.86 (0.75 ; 0.98) 6003 Age 0.27 <60 years 0.78 (0.62 ; 0.97) 2321 ≥60 years 0.90 (0.79 ; 1.02) 7019 Geographic region 0.20 Europe 0.82 (0.68 ; 0.98) 3296 North America 1.01 (0.84 ; 1.22) 2847 Asia 0.62 (0.37 ; 1.04) 711 Rest of the world 0.83 (0.68 ; 1.03) 2486 Race 0.32 White 0.90 (0.80 ; 1.02) 7238 Black or African American 0.87 (0.59 ; 1.27) 777 Asian 0.70 (0.46 ; 1.04) 936 Other 0.61 (0.37 ; 1.00) 389 Ethnic group 0.30 Hispanic or Latino 0.74 (0.54 ; 1.02) 1134 Not Hispanic or Latino 0.89 (0.79 ; 1.00) 8206
0 .2 2 1
Subgroup H azard ( 95% Prim ary analysis 0.87 ( 0.78 H bA1c ≤8.3% 0.89 (0.76 ; >8.3% 0.84 (0.72 ; Duration of diabetes ≤11 years 0.82 (0.70 ; >11 years 0.90 (0.78 ; Risk of CVD Age ≥50 years and established CVD 0.83 (0.74 ; Age ≥60 years and risk factors for CVD 1.20 (0.86 ; Chronic heart failure Yes 0.94 (0.72 ; No 0.85 (0.76 ; Antidiabetic therapy 1 OAD 0.75 (0.58 ; >1 OAD 0.95 (0.78 ; Insulin with OAD(s) 0.89 (0.74 ; Insulin without OAD 0.86 (0.63 ; None 0.73 (0.42 ; Renal function <60 mL/min/1.73 m2 0.69 (0.57 ; ≥60 mL/min/1.73 m2 0.94 (0.83 ;
Favours liraglu t id e Favours placebo H azard rat io ( 9 5 % CI )
0 . 2 2 1
Consistency
p=0.04 p=0.01
Marso SP et al. N Engl J Med 2016;375:311–322
Primary endpoint Heart failure hospitalisation Cardiovascular death Non-fatal myocardial infarction Non-fatal stroke All-cause mortality
Presented at the American Diabetes Association 77th Scientific Sessions, Session 1-AC-SY13. 11 June 2017, San Diego, CA, USA
Primary outcome by insulin use at baseline
Favours placebo Favours liraglutide
Hazard ratio (95% CI)
Hazard ratio (95% CI) Liraglutide Placebo N % N %
Total number of patients 4668 4672 Primary outcome 0.87 (0.78 ; 0.97) 608 13.0 694 14.9 Insulin use at baseline (Y/N) Yes 0.88 (0.75 ; 1.03) 295 14.5 347 16.3 No 0.86 (0.74 ; 1.01) 313 11.9 347 13.7
0,5 0,75 1 1,25
Primary outcome in patients never treated with insulin during the trial
Hazard ratio (95% CI) Liraglutide Placebo N R N R
Total number of patients 4668 4672 Primary outcome 0.87 (0.78 ; 0.97) 608 3.4 694 3.9 Patients not on insulin at baseline 2630 2541 Primary outcome 0.82 (0.68 ; 0.98) 229 2.9 217 3.5
0,5 0,75 1 1,25
Favours placebo Favours liraglutide
Hazard ratio (95% CI)
Tim e from random isation ( m onths) Patients w ith an event ( % ) 54 2 6 8 10 Placebo Liraglutide 4 48 42 36 30 24 18 12 6
HR 0 .8 4 (95% CI 0.73 ; 0.97) p=0.02
Microvascular events
Event type Definition – one or m ore of the below
Microvascular even ts Renal
Eye
with intravitreal agents
*and eGFR ≤45 mL/min/1.73 m2 per MDRD Marso SP et al. N Engl J Med 2016;375:311–322 Time to first microvascular event
Liraglutide Placebo
ETD –0.40 (95% CI: –0.45 ; 0.34) p<0.001
2,019 500 1000 1500 2000 2500
Metformin Sulphonylureas Alpha-glucosidase inhibitors TZDs Glinides InsulinSUs Metformin Alpha-glucosidase inhibitors TZDs Glinides Insulin Number of patients Additional classes added Liraglutide Placebo DPP-4 inhibitors 149 170 GLP-1RAs 87 139 SGLT-2 inhibitors 100 130 Liraglutide Placebo
GLOD added
Glycaemic control
HbA1c
0,0
Baseline 8.7 8.7
30 35 40 45 50 55 60 65 70 75 5,0 5,5 6,0 6,5 7,0 7,5 8,0 8,5 9,0
3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 EOT63
Mean HbA1c (mmol/mol) Mean HbA1c (%) Time since randomisation (months)
EOT*
*EOT may be any time from Month 42 to Month 60 Marso SP et al. N Engl J Med 2016;375:311–322
Marso SP et al. N Engl J Med 2016;375:311–322
Treatment diff –0.4%
95% CI (–0.45 ; –0.34)
p<0.001 Treatment diff –2.3 kg
95% CI (–2.54 ; –1.99)
p<0.001 Small decrease TC LDL-C and TGs Small increase HDL-C Treatment diff –1.2 mmHg
95% CI (–1.9 ; –0.5)
p<0.001
HbA1c Body Weight SBP Lipids
Impact on HbA1c, weight, blood pressure and lipids
Severe hypoglycaemia
4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6 4 0 4 4 4 8 5 2 5 6 6 0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 54 8 12 16 20 24 28 32 36 40 48 52 56 60 44 40 35 30 25 20 15 10 5 45 50 55 60 65
Mean number of episodes per 1000 patients
Rate ratio: 0.69 95% CI: (0.51 ; 0.93) p=0.013
Time since randomisation (months)
Placebo Liraglutide Liraglutide Placebo Number of patients with severe hypoglycaemia (%) 114 (2.4) 153 (3.4)
Presented at the American Diabetes Association 77th Scientific Sessions, Session 1-AC-SY13. 11 June 2017, San Diego, CA, USA Marso SP et al. N Engl J Med 2016;375:311–322
Marso SP et al. N Engl J Med 2016;375:311–322
In summary
p=0.01
CV death
–22% p=0.04
All death
–15% p=0.02
Microvasc
–16% p=0.02
Renal
–22% p=0.003
Male sex (%) 64 Age (years) 64 Diabetes duration (years) 13 HbA1c 8.7 BMI (kg/m2) 32.5 Blood pressure (mmHg) 136/77 Heart failure (%) 18
Marso SP et al. N Engl J Med 2016;375:1834–1844
Semaglutide sc once-weekly
Patient characteristics at study start
Male sex (%) 61 Age (years) 65 Diabetes duration (years) 14 HbA1c 8.7 BMI (kg/m2) 32.8 Blood pressure (mmHg) 136/77 Heart failure (%) 24
Semaglutide is an investigational product and not currently approved
SUSTAIN 6
Semaglutide sc once-weekly
Marso SP et al. N Engl J Med 2016;375:1834–1844
Semaglutide sc once-weekly Primary endpoint Non-fatal myocardial infarction Cardiovascular death Non-fatal stroke
Semaglutide is an investigational product and not currently approved
Marso SP et al. N Engl J Med 2016;375:1834–1844
Semaglutide sc once-weekly
Favours semaglutide Favours placebo Semaglutide is an investigational product and not currently approved
Semaglutide sc once-weekly
Glycaemic control and Body weight
HbA1c Weight
Marso SP et al. N Engl J Med 2016;375:1834–1844 *p<0.0001
Semaglutide is an investigational product and not currently approved
Marso SP et al. N Engl J Med 2016;375:1834–1844
Semaglutide sc once-weekly
Retinopathy
1 2 3 4 5 6 7 8 8 16 24 32 40 48 56 64 72 80 88 96 104 Subjects with an event (%) Time since randomisation (weeks)
Semaglutide Placebo
HR 1.76 (1.11–2.78) p=0.02
Semaglutide is an investigational product and not currently approved
HR 1.15 (0.87–1.52) p=0.33
0.6 vs 0.5/100 patient-years
Marso SP et al. N Engl J Med 2016;375:1834–1844
In summary
p=0.001
CV death
–2% n.s.
All death
+5% n.s.
Stroke
–39% p=0.04
Renal
–36% p=0.05
Semaglutide sc once-weekly
Semaglutide is an investigational product and not currently approved
Semaglutide sc once-weekly
Semaglutide is an investigational product and not currently approved
Why different outcomes?
ELIXA in patients with T2DM and a recent ACS
Why different outcomes? Patient populations in different GLP-1RA trials
REWIND1 (N=9,901) ELIXA2 (N=6,068) EXSCEL3 (N=14,752) SUSTAIN 64 (N=3,297) LEADER5 (N=9,340) Drug tested Dulaglutide Lixisenatide Exenatide Semaglutide Liraglutide
Dosage 1.5 mg/week 20 μg*/day 2.0 mg/week 0.5 or 1 mg /week 1.2 or 1.8 mg /day Mean age (yrs) 66 60 63 65 64 Gender (% female) 46 31 38 39 36 Diabetes duration (yrs) 10.0 9.3 12 13.9 12.8 Prior CVD (%) 31 100 73 59 72 Mean BMI (kg/m2) 32 30 32 33 33 Mean HbA1c (%) 7.3 7.7 8.0 8.7 8.7
*Initial dose of 10 μg with down- or up-titration permitted to maximum of 20 μg/day
Why different outcomes?
ELIXA in patients with T2DM and a recent ACS
Why different outcomes?
ELIXA in patients with T2DM and a recent ACS
Exendin-4 vs. Human analogue GLP-1
Similarities and dissimilarities
Exenatide 2005 Liraglutide 2010 Lixisenatide 2013 Albiglutide 2014 Dulaglutide 2014 Semaglutide Under investigation
– – Lån ≥ –
Liraglutide Figur 3.3: GLP-1 strukt
– – Lån ≥ – GLP 1
– – Lån ≥ –
Lixisenatide
His Gly Thr ThrSer Phe GluGly Asp Leu Ser Lys Gln Met Glu Glu Ala Val Glu Arg Phe Leu Ile Glu TrpLeu Pro Lys Gly Gly Asp SerSerGly AlaProProProSerExenatide
His Aib Thr Thr Ser Phe Glu Gly Asp Val Ser Ser Tyr Leu Glu Gly Ala Ala Gln Lys Phe Glu Ile Ala Trp Leu Gly Val Gly Arg ArgSemaglutide GLP-1
Metab 2011;13:434–438; 5. Tanzeum. Prescribing information; 6. Marbury T et al. Diabetes 2014;63(Suppl. 1):A260(1010-P); 7. Kapitza C et al. J Clin Pharm 2015;55:497–504; 8. Fineman M et al. Clin Pharmacokinet 2011;50:65–74
Agent Half-life Tmax
Exenatide BID1 2.4 hours 2 hours Lixisenatide OD2 2.7–4.3 hours 1.25–2.25 hours Liraglutide OD3 13 hours 8–12 hours Dulaglutide OW4 90 hours (3.75 days) 24–48 hours (1–2 days) Albiglutide OW5 6–7 days 3–5 days Semaglutide OW6,7 155–184 hours (~7 days) 24–36 hours (1–1.5 days) Exenatide OW8 7–14 days 6–7 weeks
spacer C-18 fatty acidSemaglutide is an investigational product and not currently approved
Gaps in knowledge
REWIND of great interest
PIONEER 6 will provide insights
Of interest to study
Of interest to study
Impact on guidelines (January 2018)
CVOT, cardiovascular outcomes trial
Germ any USA I taly Norw ay Sw itzerland
2 0 1 6 2 0 1 7
Brazil Hungary
Slovenia
France Turkey Latvia Position Paper Slovakia Bosnia and Herzegovina Sw eden Denm ark – Cardio Bulgaria Canada Czech Republic Spain Catalonia, Andalucía Position Paper Greece Poland Scotland
Korea
Impact on guidelines (January 2018)
In patients with type 2 diabetes and established atherosclerotic cardiovascular disease begin with lifestyle management and metformin then choose an agent proven to reduce major adverse cardiovascular events and cardiovascular mortality (currently empagliflozin and liraglutide) after considering drug-specific and patient factors
Evidence level A: Supportive evidence from well conducted trials
ADA, American Diabetes Association; CVOT, cardiovascular outcomes trial American Diabetes Association. Diabetes Care 2018;41(Suppl 1):S73–S85
Rydén L et al. Clin Ther 2016;38:1279–1287; ClinicalTrials.gov (accessed 15/3 2018)
Completed and ongoing
GLP-1RA FREEDOM (ITCA 650, GLP-1RA in DUROS) n=4000; duration ~2 yrs Q2 2016 – RESULTS EXSCEL (Exenatide ER, QW GLP-1RA) n=14,752; follow-up ~3 yrs Q3 2017 – RESULTS PIONEER 6 (Oral semaglutide, GLP-1RA) n=3176; duration ~1.5 yrs Completion Q4 2018 LEADER (Liraglutide, GLP-1RA) n=9340; duration 3.5–5 yrs Q2 2016 – RESULTS HARMONY OUTCOMES (Albiglutide, QW GLP-1RA) n~9400; duration ~4 yrs Completion Q2 2018 ELIXA (Lixisenatide, GLP-1RA) n=6068; follow-up ~2 yrs Q1 2015 – RESULTS SUSTAIN 6 (Semaglutide, QW GLP-1RA) n=3297; duration ~2.8 yrs Q3 2016 – RESULTS REWIND (Dulaglutide, QW GLP-1RA) n=9622; duration ~6.5 yrs Completion Q3 2018
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