52
Diabetes & cardiovascular outcome : focus on gliflozines Christophe De Block, MD PhD Diabetology-Endocrinology, Antwerp University Hospital, Belgium President Diabetes Liga
Diabetes & cardiovascular outcome : focus on gliflozines
Christophe De Block, MD PhD Diabetology-Endocrinology,
Antwerp University Hospital, Belgium President Diabetes Liga
Diabetes management anno 2016
Is glucose control important for prevention of CVD in DM2?
Glycemic targets: How low should we go?
Characteristics ACCORD ADVANCE VADT UKPDS
N 10,251 11,140 1,791 4,209 Mean age 62 66 60.4 53 Duration T2D 10 yrs 8 yrs 11.5 yrs 0 yrs History of CVD 35% 32% 40% 0 BMI 32 28 31 28 Baseline A1c 8.3% 7.5% 9.4% 8.0% End A1c 6.5% 6.4% 6.9% 7.1%
UKPDS group Lancet 1998; 352: 837–53-Gerstein HC et al. NEJM 2008; Patel A et al. NEJM 2008; VADT:Duckworth W et al. NEJM 2009
RCTs on Intensive Glycemic Control in T2DM: baseline data
The ACCORD Study Group. N Engl J Med. 2008;358(24):2545-2559. ADVANCE collaborative group. N Engl J Med 2008; 358:2560-72
Meta-analysis: non-fatal AMI
Ray KK et al. Lancet 2009
Pts with a short duration of DM, lower A1c at baseline, and without a history of CVD seemed to benefit more form more-intensive glucose-lowering strategies
Diabetes management anno 2016
which antidiabetic drugs have proven to be cardiovascular safe?
Myocardial infarction: metformin
Schramm TK et al. Eur Heart J 2011; 32 (15): 1900-‐8
Mortality and CV risk: insulin secretagogues vs me7ormin
Introductie • belangrijkste doodsoorzaak bij type 2 diabetes (in 50 tot
80%) is van cardiovasculaire oorsprong • door verbeterde glycemie-, lipiden- en bloeddrukcontrole
neemt de mortaliteit te wijten aan myocardinfarcten af en worden onze patiënten ouder.
• desgevolgend wordt het risico op de ontwikkeling van hartfalen proportioneel steeds groter. – het risico neemt toe met 15% per verhoging van de
HbA1c-waarde met 1%.
• omdat er veel vragen rezen met thiazolidinediones, eiste de FDA in 2008 dat alle nieuwe geneesmiddelen voor diabetes werden geëvalueerd op het vlak van cardiovasculaire veiligheid.
Scheen A. Nat Rev Cardiol 2013;10:73–84
Incretins & cardiovascular risk factors
Summary of CV outcomes trials with DPP4 inhibitors
SAVOR-TIMI 531 EXAMINE2 TECOS3 CAROLINA®4 CARMELINA®5 Intervention Saxagliptin/
placebo Alogliptin/ placebo
Sitagliptin/ placebo
Linagliptin/ glimepiride
Linagliptin/ placebo
Main inclusion criteria
History of or multiple risk
factors for CVD
ACS within 15–90 days before randomisation
CVD ≥ 2 specified traditional CV risk factors or manifest CVD
High risk of CV events (e.g. albuminuria, prior CVD)
No. of patients 16,492 5380 14,671 6041 8300 Primary outcome 3P-MACE 3P-MACE 4P-MACE 4P-MACE 4P-MACE
Key secondary outcome Expanded MACE 4P-MACE 3P-MACE 3P-MACE 3P-MACE; renal
composite
Target no. of events 10406 650 1300 631 6257
Estimated median follow-up (y) 2.1 1.5 3.0 6–7* 4*7
Estimated completion Completed Completed Completed 20188 2018
*Ongoing. 1. Scirica et al. N Engl J Med 2013;369:1317–26. 2. White et al. N Engl J Med 2013;369:1327–35. 3. Green et al. N Engl J Med 2015; DOI: 10.1056/NEJMoa1501352. 4. Marx et al. Diabetes Vasc Dis Res 2015;12:164–74. 5. NCT01897532. 6. Scirica et al. Am Heart J 2011;162:818–25.e6. 7. Data on file (BI trial no. 1218.22 trial protocol). 8. NCT01243424.
Cardiovascular safety trials with DPP4-inhibitors
Scirica BM, et al. N Engl J Med. 2013; White et al N Engl J Med 2013; Green JB et al. NEJM 2015
Primary end-point
SAVOR-TIMI EXAMINE
TECOS
SAVOR-TIMI 53: Increased risk of hospitalisation for heart failure in saxagliptin arm
0
8212 8280
180
8036 8064
Days
0
1
2
3
Hos
pita
lisat
ion
for h
eart
failu
re (%
)
4
360
7856 7867
720
4959 4978
540
7389 7375
Placebo Saxagliptin
HR 1.27 (1.07–1.51); p = 0.007
2.8%
3.5%
Placebo
Saxagliptin
12 Scirica et al. Circulation 2014;130:1579–88.
glycaemic effects
non-glycaemic effects
Reduced FPG & PPG
1.0 to 1.5 % HbA1C
2 to 3 kg weight Loss
Satiety, fullness,
gastric motlity
↑ natriuresis 3 to 5 mm Hg
BP
GLP1 receptor agonisten
↑ heart rate (2-5 bpm)
low risk of hypoglycaemia
Improved lipid profile
Summary of ELIXA findings
*1. Pfeffer et al. ADA, 8 Jun 2015, Boston, USA (oral presentation).
Randomisation 1 2 3 years of median follow-up
ELIXA1 ACS
HbA1c 5.5–10% n = 6068
Lixisenatide
Placebo 4P-MACE 1.02
(95% CI: 0.89–1.17)
• No difference in 4P-MACE with lixisenatide vs placebo − HR 0.1.02 (95% CI: 0.89–1.17)
• No difference in HHF with lixisenatide vs placebo − HR 0.96 (95% CI: 0.75–1.23)
• No difference in CV death + HHF with lixisenatide vs placebo − HR 0.97 (95% CI: 0.82–1.16)
2.1 year median follow-up
Glomerulus Proximal tubule S1 S2
S3 Collecting duct
Adapted from Bays H. Curr Med Res Opin 2009;25(3):671–681.
GLUCOSE REABSORPTION
GLUCOSE FILTRATION
The kidneys filter and reabsorb 180 g of glucose per day
Minimal glucose excetion
SGLT2 ~90%
SGLT1 ~10%
Special transporters in the kidneys are responsible for the reabsorption of glucose
(180-200 L/day) (900 mg/L) =162-180 g/day!
“MaladapBve” renal glucose reabsorpBon in paBents with poorly controlled diabetes1
SGLT1
SGLT2
In T2DM, SGLT2 is upregulated and glucose reabsorption is increased. An adaptive response to
conserve glucose (i.e., for energy needs) becomes maladaptive in diabetes
Glucose
1. Gerich JE. Diabetic Medicine 2010;27:136–142.
Urinary glucose excretion
SGLT2 Reduced glucose reabsorption
Increased urinary excretion of excess
glucose (~70 g/day,
corresponding to 280 kcal/day*)
Proximal tubule
Glucose filtration
*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.4
1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4.ForxigaSPC latest version.
SGLT2
Glucose
gliflozin
SGLT2inhib
Dapagliflozin selectively inhibits SGLT2 in the renal proximal tubule
Majority of glucose is reabsorbed by SGLT2
(90%)
In normal renal glucose handling, 90% of glucose is reabsorbed by SGLT21–4
SGLT2 inhibitors: efficacy data HbA1c, FPG, PPG
Pooled data
Empagliflozin: Placebo-‐corrected change* from baseline in HbA1c
-‐0.62
-‐0.74
-‐0.57 -‐0.48
-‐0.64
-‐0.46
-‐0.52 -‐0.68
-‐0.85
-‐0.64 -‐0.61 -‐0.59 -‐0.62 -‐0.68
-‐1.00
-‐0.90
-‐0.80
-‐0.70
-‐0.60
-‐0.50
-‐0.40
-‐0.30
-‐0.20
-‐0.10
0.00
Adjusted
mean (SE) differen
ce versus p
lacebo
in change from
baseline in HbA
1c (%
)
Pooled Monotherapy MET PIO MET+SU Insulin 78 week Mild RI
Empagliflozin 10 mg QD Empagliflozin 25 mg QD
PaBents, n 831 821 224 224 217 213 165 168 225 216 169 155 98 97
BL HbA1c, % 7.98 7.96 7.87 7.86 7.94 7.86 8.07 8.06 8.07 8.10 8.27 8.27 8.02 8.01
BL, baseline; MET, me\ormin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea. *All sta`s`cally significant unless otherwise marked. Hach T, et al., Häring H-‐U, et al., Rosenstock J, et al., Barnef A, et al. Diabetes 2013;(Suppl 1) (P69-‐LB, P1092, P1102, P1104, respec`vely); Kovacs C, et al. Diabetes Obes Metab 2013 Aug 1. doi: 10.1111/dom.12188 [Epub ahead of print]; Häring H-‐U, et al. Diabetes Care 2013 [Epub ahead of print].
6.8
7.0
7.2
7.4
7.6
7.8
8.0
8.2
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96 100 104 108
Adjusted
mean (95%
CI) Hb
A 1c (%)
Weeks
Glimepiride
Empagliflozin 25 mg QD
Jardiance® add-‐on to me7ormin versus SU (glimepiride) Change in HbA1c over Bme
0
CI, confidence interval; H2H, head-‐to-‐head; HbA1c, glycosylated haemoglobin; QD, once daily. MMRM. FAS (OC).
Sources: Adapted from Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700 , EMPA-‐REG H2H-‐SU.
Analysed pa`ents
Glimepiride 761 758 738 699 660 609 562 524 494 461
Empagliflozin 759 751 734 702 672 646 624 593 568 548
65 78 91 104
Difference in change from baseline at Week 104:
-‐0.11% (95% CI: -‐0.21, -‐0.01)
p = 0.026
BE/EMP/00048 05/2015
Jardiance® add-‐on to me7ormin versus SU (glimepiride) PaBents with confirmed hypoglycaemic AEs* over 104 weeks
24.2
2.5
0
5
10
15
20
25
30
Percen
tage of p
a`en
ts with
con
firmed
hypo
glycaemic AEs
Glimepiride (n = 780) Empagliflozin 25 mg QD (n = 765)
Adjusted RR 0.10 (95% CI: 0.07, 0.16)
p < 0.0001
AEs, adverse events; CI, confidence interval; H2H, head-‐to-‐head; QD, once daily; RR, rela`ve risk. *Plasma glucose ≤ 3.9 mmol/L (70 mg/dL) and/or assistance required. Cochran–Mantel–Haenszel test (treated set).
Sources: Adapted from Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700 , EMPA-‐REG H2H-‐SU. Data on file.
Events requiring assistance were reported in: • 2 (0.3%) pa`ents on glimepiride • No pa`ents on empagliflozin
BE/EMP/00048 05/2015
-‐1
-‐0.8
-‐0.6
-‐0.4
-‐0.2
0
0.2 0 6 12 18 24 30 36 42 48 54 60 66 72 78
Adjusted
mean (SE) change from
baseline in HbA
1c over `
me (%
)
Time (weeks)
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
MMRM. FAS (OC-‐78). Rosenstock J, et al. Diabetes 2013;(Suppl 1) (P1102); Data on file.
78-‐week study with empagliflozin as add-‐on to long-‐acBng insulin HbA1c change over Bme to Week 78
EMPA-‐REG
BASAL: study 1245.33
N/week BL 12 18 30 42 54 66 78 Placebo 156 129 141 132 119 113 105 98 10 mg 160 132 148 137 123 121 115 114 25 mg 137 120 123 114 110 107 98 96
–0.71
–0.43
Canagliflozin: triple therapy HbA1c Change from Baseline Over Time
Active (Sitagliptin)-controlled Add-on to Metformin + SU Study (DIA3015)
Based on ANCOVA model (LOCF)
CANA 300 mg SITA 100 mg
LS M
ean
Cha
nge
from
Bas
elin
e ±
SE
HbA
1c (
%)
BL 6 52 12 18 26 34 42 Time (weeks)
BL Mean HbA1c : 8.1% N = 755
-0.37 % (95% CI: -0.500; -0.250)
Schernthaner G, et al. Diabetes Care 2013;36(9):2508-15.
LS mean change
–1.03%
–0.66%
Pooled data
-‐1.80 -‐1.93
-‐1.63
-‐1.95 -‐1.76
-‐2.90
-‐1.43
-‐2.01 -‐2.15
-‐2.01 -‐1.81 -‐1.99
-‐2.80
-‐2.00
-‐3.50
-‐3.00
-‐2.50
-‐2.00
-‐1.50
-‐1.00
-‐0.50
0.00
Adjusted
mean (SE) differen
ce versus p
lacebo
in change from
baseline in bod
y weight (kg)
BL, baseline; BW, body weight; MET, me\ormin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea. *All sta`s`cally significant unless otherwise marked. Hach T, et al., Häring H-‐U, et al., Rosenstock J, et al., Barnef A, et al. Diabetes 2013;(Suppl 1) (P69-‐LB, P1092, P1102, P1104, respec`vely); Kovacs C, et al. Diabetes Obes Metab 2013 Aug 1. doi: 10.1111/dom.12188. [Epub ahead of print]; Häring H-‐U, et al. Diabetes Care 2013 [Epub ahead of print].
Empagliflozin: Placebo-‐corrected change* from baseline in body weight Pooled data from
4 pivotal Phase III trials
PaBents, n 831 821 224 224 217 213 165 168 225 216 169 155 98 97
BL BW (kg) 78.77 79.10 78.35 77.80 81.59 82.21 77.97 78.93 77.1 77.5 91.6 94.7 92.05 88.06
Pooled Monotherapy MET PIO MET+SU Insulin 78 week Mild RI
Empagliflozin 10 mg QD Empagliflozin 25 mg QD
17.7
-‐22.3 -40
-30
-20
-10
0
10
20
30
40
Mean (95%
CI) change from
baseline in
subcutaneo
us adipo
se `ssue
(cm
3 ) 11.2
-‐11.0 -25
-20
-15
-10
-5
0
5
10
15
20
25
Mean (95%
CI) change from
baseline in abd
ominal
visceral adipo
se `ssue
(cm
3 )
Jardiance® add-‐on to me7ormin versus SU (glimepiride) Change from baseline in visceral & subcutaneous fat at Week 104*
CI, confidence interval; EMPA, empagliflozin; H2H, head-‐to-‐head; QD, once daily. *Dedicated sub-‐study using magne`c resonance imaging; pa`ent par`cipa`on was op`onal.
Sources: Adapted from Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700 , EMPA-‐REG H2H-‐SU, appendix.
Glimepiride (n = 34)
Empagliflozin (n = 39)
Glimepiride EMPA 25 mg QD
Mean baseline (95% CI)
174.4 (143.3, 205.5)
156.7 (138.6, 174.8)
Glimepiride EMPA 25 mg QD
Mean baseline (95% CI)
337.0 (297.8, 376.2)
346.3 (312.5, 380.2)
Glimepiride (n = 34)
-‐22.2 cm3
(95% CI: -‐37.1, -‐7.4)
p = 0.0039
-‐40.0 cm3
(95% CI: -‐58.9, -‐21.1)
p < 0.0001
Empagliflozin (n = 39)
BE/EMP/00048 05/2015
Pooled data
-‐3.40
-‐2.60
-‐4.10 -‐3.86
-‐2.70
-‐4.00 -‐3.57
-‐3.80 -‐3.40
-‐4.80 -‐4.73
-‐2.10 -‐2.30
-‐5.12 -‐7.00
-‐6.00
-‐5.00
-‐4.00
-‐3.00
-‐2.00
-‐1.00
0.00
Adjusted
mean (SE) differen
ce versus p
lacebo
in change from
baseline in SBP
(mmHg
)
BL, baseline; MET, me\ormin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SBP, systolic blood pressure; SE, standard error; SU, sulphonylurea. *All sta`s`cally significant unless otherwise marked. †Not sta`s`cally significant. Hach T, et al., Häring H-‐U, et al., Rosenstock J, et al., Barnef A, et al. Diabetes 2013;(Suppl 1) (P69-‐LB, P1092, P1102, P1104, respec`vely); Kovacs C, et al. Diabetes Obes Metab 2013 Aug 1. doi: 10.1111/dom.12188 [Epub ahead of print]; Häring H-‐U, et al. Diabetes Care 2013 [Epub ahead of print].
Empagliflozin: Placebo-‐corrected change* from baseline in SBP Pooled data from
4 pivotal Phase III trials
PaBents, n 831 821 224 224 217 213 165 168 225 216 169 155 98 97
BL SBP (mmHg) 129.6 129 133 129.9 129.6 130 126.5 125.9 128.7 129.3 132.4 132.8 137.4 133.7
Pooled Monotherapy MET PIO MET+SU Insulin 78 week Mild RI
†
Empagliflozin 10 mg QD Empagliflozin 25 mg QD
Empagliflozin: Phase III pooled efficacy and cardiovascular risk factor analysis Change in lipids from baseline at Week 24
Pooled data from 4 pivotal Phase III trials
LDL-‐C HDL-‐C Triglyceride LDL/HDL-‐C raBo‡ Total cholesterol
Mean baseline 2.62 2.57 2.57 1.26 1.26 1.27 1.86 1.95 1.96 2.18 2.11 2.11 4.70 4.67 4.70
0.02 0.00
0.03
0.00
0.04
0.08 0.07
-‐0.11
-‐0.04
0.11 0.10
0.07
-‐0.02 -‐0.01
0.16
-‐0.20
-‐0.15
-‐0.10
-‐0.05
0.00
0.05
0.10
0.15
0.20
Adjusted
mean (SE) change, m
mol/l
Placebo (n = 825) Empagliflozin 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822)
**
***
** **
*
HDL-‐C, high-‐density lipoprotein cholesterol; LDL-‐C, low-‐density lipoprotein cholesterol; QD, once daily; SE, standard error. *p < 0.05 ; **p < 0.001; ***p = 0.008 versus placebo. ‡LDL/HDL-‐C ra`o does not have units. ANCOVA. Adapted from: Hach T, et al. Diabetes 2013;(Suppl 1) (P69-‐LB).
Male versus female pa`ents
Empagliflozin: Phase III pooled safety and tolerability analysis Events consistent with UTI
8.2
13.0
3.8
9.3
18.5
1.9
7.5
15.9
1.1 0.0
5.0
10.0
15.0
20.0
25.0
30.0
All pa`ents with events Female pa`ents Male pa`ents
Pa`e
nts w
ith events c
onsistent with
UTI (%
)
Placebo (n = 825) Empagliflozin 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822)
Pooled data from 4 pivotal Phase III trials
QD, once daily; UTI, urinary tract infec`on. Kim G, et al. Diabetes 2013;(Suppl 1) (P74-‐LB).
Male versus female pa`ents
Empagliflozin: Phase III pooled safety and tolerability analysis Events consistent with genital infecBon
0.7 1.0 0.5 4.2 6.3
2.6 3.6 7.0
1.1 0.0
10.0
20.0
30.0
40.0
50.0
60.0
All pa`ents with events Female pa`ents Male pa`ents
Pa`e
nts w
ith events c
onsistent
with
gen
ital infec`o
n (%
)
Placebo (n = 825) Empagliflozin 10 mg QD (n = 830) Empagliflozin 25 mg QD (n = 822)
Pooled data from 4 pivotal Phase III trials
QD, once daily. Kim G, et al. Diabetes 2013;(Suppl 1) (P74-‐LB).
Considerations for gliflozin dosage and administration
• The efficacy of gliflozins is dependent on renal funcBon – Dapagliflozin is not recommended for use in pa`ents with moderate to severe
renal impairment (CrCl <60 mL/min or eGFR* <60 mL/min/1.73 m2) – Canagliflozin ... start: CrCl > 60 ml/min, stop if CrCl < 45 ml/min – Empagliflozin ... start: CrCl > 60 ml/min ; stop if CrCl < 45 ml/min
• Gliflozins are not recommended in: – Pa`ents aged ≥75 years or <18 years – Pa`ents receiving loop diureBcs – Pa`ents who are volume depleted
• Cau`on should be exercised in pa`ents for whom a gliflozin-‐induced drop in blood pressure could pose a risk
*eGFR calculated with Modification of Diet in Renal Disease Formula. Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012.
SGLT2-inhibitors:
empagliflozin
cardiovascular safety ?
Patients 7034
Long-term CV safety of empagliflozin is being evaluated in a large, multicentre Phase III trial (EMPA-REG OUTCOME™)
Countries 42
592 Clinical sites Countries with study centres involved in the EMPA-REG OUTCOME™ trial
41%
19% Asia
Europe
North America /
Western Pacific
20%
15%
Latin America
4% Africa
*
*Cumulative percentage for North America, Australia and New Zealand. 1. Zinman et al. Cardiovasc Diabetol 2014;13:102. 2. NCT01131676.
EMPA-REG OUTCOME™: Study design
34
Placebo run-in
2 weeks
Empagliflozin 10 mg QD + usual care
Empagliflozin 25 mg QD + usual care
Placebo + usual care
Screening (n = 11,507)
Background therapy adjustment allowed after Week 12
12 weeks of stable background glucose-lowering therapy
Visit 1
Week 4 8 12 16 28 40 52 0 -2 -3
Visit 3 Visits 4–7 every 4 weeks
Visits 8–10 every 12 weeks
Visits every 14 weeks
Visit 2
Follo
w-u
p
R
End of study visit
+30 days
Aim Compound-specific To determine CV safety of empagliflozin vs placebo + usual care for glycaemic control and CV risk in patients with T2D and high CV risk
Zinman et al. Cardiovasc Diabetol 2014;13:102.
EMPA-REG OUTCOME™: Inclusion criteria
Adults with insufficient glycaemic control High risk of CV events (≥1 of the following)
• Age ≥ 18 years • HbA1c
o ≥ 7% and ≤ 10% if on background glucose-lowering therapy, or
o ≥ 7% and ≤ 9% if drug-naïve
• BMI ≤ 45 kg/m2
• History of MI (> 2 months prior to enrolment) • Evidence of single/multi-vessel CAD • Unstable angina > 2 months prior to consent
with evidence of single- or multi-vessel CAD • History of stroke (ischaemic or haemorrhagic)
> 2 months prior to consent • Occlusive peripheral artery disease
Zinman et al. Cardiovasc Diabetol 2014;13:102.
EMPA-REG OUTCOME™: Primary endpoint
• Target number of events: ≥ 691 • Non-inferiority and superiority of empagliflozin vs placebo will be
assessed (hierarchical testing)
– 90% power to demonstrate non-inferiority for the primary (3P-MACE) and key secondary (4P-MACE) outcome
– ≥ 80% power to detect hazard ratio of 0.785 for primary (3P-MACE) outcome
36
Primary endpoint: time to 1st occurrence of any of the following adjudicated components of the primary composite endpoint (3P-MACE) 1. CV death (including fatal stroke and fatal MI) 2. Non-fatal MI (excluding silent MI) 3. Non-fatal stroke
Zinman et al. Cardiovasc Diabetol 2014;13:102.
Glucose-lowering medication* Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9) Sulphonylurea 992 (42.5) 985 (42.0) 1029 (43.9) Thiazolidinedione 101 (4.3) 96 (4.1) 102 (4.4) Insulin 1135 (48.6) 1132 (48.3) 1120 (47.8)
Mean daily dose, U** 65 (50.6) 65 (47.9) 66 (48.9)
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342) HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84) Time since diagnosis of type 2 diabetes, years ≤5 423 (18.1) 406 (17.3) 434 (18.6) >5 to 10 571 (24.5) 585 (24.9) 590 (25.2) >10 1339 (57.4) 1354 (57.7) 1318 (56.3)
Baseline characteristics: type 2 diabetes
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug
*Medication taken alone or in combination **Placebo, n=1135; empagliflozin 10 mg, n=1132; empagliflozin 25 mg, n=1120
Systolic blood pressure, mmHg 135.8 (17.2) 134.9 (16.8) 135.6 (17.0) Diastolic blood pressure, mmHg 76.8 (10.1) 76.6 (9.8) 76.6 (9.7) Heart rate, bpm* 70.7 (0.2) 71.0 (0.2) 70.5 (0.2) LDL cholesterol, mg/dL 84.9 (35.3) 86.3 (36.7) 85.5 (35.2) HDL cholesterol, mg/dL 44.0 (11.3) 44.7 (12.0) 44.5 (11.8) eGFR, mL/min/1.73m2 (MDRD) 73.8 (21.1) 74.3 (21.8) 74.0 (21.4) ≥90 mL/min/1.73m2 488 (20.9%) 519 (22.1%) 531 (22.7%) 60 to <90 mL/min/1.73m2 1238 (53.1%) 1221 (52.1%) 1204 (51.4%) <60 mL/min/1.73m2 607 (26.0%) 605 (25.8%) 607 (25.9%)
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342) Body mass index, kg/m2 30.7 (5.2) 30.6 (5.2) 30.6 (5.3) Weight, kg 86.6 (19.1) 85.9 (18.8) 86.5 (19.0) Waist circumference, cm 105.0 (14.0) 104.7 (13.7) 104.8 (13.7)
Baseline characteristics: CV risk factors
Data are n (%) or mean (SD) in patients treated with ≥1 dose of study drug *Mean (SE). LDL, low density lipoprotein; HDL, high density lipoprotein; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease equation
Baseline characteristics: CV complications
Placebo (n=2333)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342) Any CV risk factor 2307 (98.9%) 2333 (99.5%) 2324 (99.2%)
Coronary artery disease 1763 (75.6%) 1782 (76.0%) 1763 (75.3%) Multi-vessel coronary artery disease
1100 (47.1%) 1078 (46.0%) 1101 (47.0%)
History of MI 1083 (46.4%) 1107 (47.2%) 1083 (46.2%) Coronary artery bypass graft 563 (24.1%) 594 (25.3%) 581 (24.8%) History of stroke 553 (23.7%) 535 (22.8%) 549 (23.4%) Peripheral artery disease 479 (20.5%) 465 (19.8%) 517 (22.1%) Single vessel coronary artery disease
238 (10.2%) 258 (11.0%) 240 (10.2%)
Cardiac failure* 244 (10.5%) 240 (10.2%) 222 (9.5%) Data are n (%) in patients treated with ≥1 dose of study drug
*Based on narrow standardised MedDRA query “cardiac failure”
EMPA-REG OUTCOME™: Background therapies
40 Zinman et al. Cardiovasc Diabetol 2014;13:102.
Treated set (n = 7034) Glucose-lowering therapy, n (%)
No therapy 128 (1.8) Monotherapy 2055 (29.2)
Metformin (% of monotherapy) 745 (36.3) Insulin (% of monotherapy) 954 (46.4)
Dual combination therapy 3188 (45.3) Metformin + sulphonylurea (% of dual combination therapy) 1383 (43.4) Metformin + insulin (% of dual combination therapy) 1420 (44.5)
Total metformin 5205 (74.0)* Total insulin 3446 (48.2)* Anti-hypertensive therapy, n (%) 6641 (94.4)
Blockers of the renin–angiotensin system 5651 (80.3) β-blockers 4537 (64.5) Any diuretic 3015 (42.9)* Calcium channel blockers 2114 (30.1)
Other therapies, n (%) Acetylsalicylic acid 5990 (85.2) Statins 5387 (76.6) Fibrates 630 (9.0)
HbA1c
6.0
6.5
7.0
7.5
8.0
8.5
9.0
Adj
uste
d m
ean
(SE
) HbA
1c (%
)
Week
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
2294 2296 2296
Placebo Empagliflozin 10 mg Empagliflozin 25 mg
2272 2272 2280
2188 2218 2212
2133 2150 2152
2113 2155 2150
2063 2108 2115
2008 2072 2080
1967 2058 2044
1741 1805 1842
1456 1520 1540
1241 1297 1327
1109 1164 1190
962 1006 1043
705 749 795
420 488 498
151 170 195
12 28 52 94 108 80 122 66 136 0 150 164 178 192 206 40
All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat)
Zinman B, NEJM 2015
Zinman B, NEJM 2015
Zinman B, NEJM 2015
EMPA-REG OUTCOME®: Therapeutic considerations
• Empagliflozin, as used in this trial, for 3 years in 1,000 patients with type 2 diabetes at high CV risk:
– 25 lives saved (82 vs 57 deaths)
• 22 fewer CV deaths (59 vs 37)
– 14 fewer hospitalisations for heart failure (42 vs 28)
– 53 additional genital infections (22 vs 75)
Observations and hypotheses
• Effects on mortality were more impressive than effects on MACE • Protective effect occurred early (3-6 months)
• Modest but significant effect on risk factors of atherosclerosis: – HbA1c (- 0.3%), weight, waist circumference, BP, HDL and uric acid – BP: - 4 mmHg
• Meta-analysis in T2DM : -10 mmHg : -12% AMI, -13% all-cause mortality, -27% stroke
• Favourable effects on markers of arterial stiffness and vascular resistance
• Increase in glucagon secretion: may exert a positive CV effect
• Osmotic diuretic effect (35% RR in hospitalisations for heart failure)
Observations and hypotheses • Osmotic diuretic effect (35% RR in hospitalisations for heart failure)
– Meta-analysis of 4 trials with hydrochlorothiazide or chlorthalidone in T2DM (HDFP, EWPHE, STOP-H, SHEP): -20% MACE, -15% acute coronary events, -36% strokes, no effect on CV mortality and all-cause mortality
– Recent meta-analysis of 3 trials (ALLHAT, ACCOMPLISH, INSIGHT): no benefits compared to other BP lowering drugs, except for -17% congestive heart failure
– All these diuretics: hypokalemia, hyperuricaemia, rise in heart rate; this was not seen in empagliflozin
– Eplerenone (EPHESUS trial): -17% composite endpoint of CV mortality/CV hospitalisations
– Benefits in EMPA-REG trial were more pronounced in patients already treated with diuretics (HR: 0.57)
– No reduction in stroke (even higher incidence of stroke within a month of treatment interruption)
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