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Prof. Kamlesh KhuntiUniversity of Leicester
SGLT2i in Management of Diabetes
© Leicester Diabetes Centre at University Hospitals of Leicester NHS Trust, 2015. Not to be reproduced in whole or in part without the permission of the copyright owner.
Disclosures
Consultant: AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Novo Nordisk and Sanofi, Roche.
Research Support: AstraZeneca, Boehringer Ingelheim, Lilly, MSD, Novartis, Novo Nordisk, Roche and Sanofi, Janssen
Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, MSD, Novartis, Novo Nordisk and Sanofi
Outline
• Update on the SGLT2 inhibitor class• Cardiovascular Outcomes trials in Diabetes• Real World Experience with SGLT2i
The idea that disease could be diagnosed goes back to writings of Gelen , a Greco‐Roman doctor
“Piss Prophets”
ADA/EASD: position statement for managing hyperglycaemia
Insulin (MDI)
Healthy eating, weight control, increased physical activity
Two-drug combinations
Three-drug combinations
Metformin
SU
TZD DPP-4i SGLT2i
GLP-1 RA Insulin
TZD
SU DPP-4i SGLT2i
GLP-1 RA Insulin
DPP-4i
SU TZD SGLT2iInsulin
GLP-1 RA Insulin
TZD DPP-4i SGLT2i
GLP-1 RA
SUTZD
Insulin
More complex strategies
Initial monotherapy
DPP-4i, dipeptidyl peptidase-4 inhibitor; SGLT2i, sodium-glucose cotransporter 2 inhibitor; GLP-1 RA, glucagon-like peptide-1 receptor agonist; MDI, multiple daily injection; SU, sulfonylurea; TZD, thiazolidinedione.
SGLT2i
SU TZDDPP-4i Insulin
Escalate therapy at 3 months if target not achieved.
Inzucchi SE, et al. Diabetes Care. 2015;38:140-9. Inzucchi SE, et al. Diabetologia. 2015;58:429-42. Standards of medical care in diabetes-2016. Diabetes Care 2016;39(Suppl. 1):S1–S2.
↓CV risk
Control of LDL-
cholesterol
Antiplatelet therapy
Glycaemic control
Weight loss and lifestyle intervention*
Antihypertensive therapy
Reducing CV risk in T2D requires a multifactorial approach
*Includes smoking cessation.Rydén L et al. Eur Heart J 2013;34:3035–87.
The Ominous Octet: Eight core defects T2DMultifactorial in origin, has a variable and progressive course, requires
attention to attendant risk factors and co-morbidities on long term basis.
Pancreas
Decreased insulinsecretion
Liver
Increased HGP
Brain
Neurotransmission Dysfunction
Muscle
Decreased glucose uptake
Increased insulin secretion
Islet-α cell
KidneyIncreased glucose reabsorption
Adipose tissue
Increased lypolysis
Hyperglycemia
Decreased incretin effect
Gastrointestinal tissues
.
Adapted from DeFronzo, R.A.. Diabetes. 2009; 58: 773–795
Remaining glucose is
reabsorbed by SGLT1 (10%)
Proximal tubule
Glucosefiltration
SGLT2 inhibitors inhibit SGLT2 by an insulin-independent mechanism to remove excess glucose in the urine1
FORXIGA may be used without dosing reduction in patients with mild renal impairment, but is not recommended for use in patients with moderate‐to‐severe renal impairment (eGFR <60 mL/min/1.73 m2 or CrCl <60 mL/min).1 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.1CrCl, creatinine clearance; eGFR, estimated glomerular filtration rate; SGLT, sodium‐glucose co‐transporter.1. FORXIGA. Summary of product characteristics, 2014.
Reduced glucose reabsorption SGLT2
Increased urinary excretion of excess glucose (~70 g/day,
corresponding to 280 kcal/day*)
SGLT2
Glucose
SGLT2i
SGLT2 inhibitor
• By inhibiting SGLT2, SGLT2 inhibitorsremoves excess glucose in the urine and lowers HbA1c1
SNS activity (?)
SGLT2 inhibitors modulate a range of factors related to CV risk
Based on clinical and mechanistic studies
Inzucchi SE et al. Diab Vasc Dis Res 2015;12:90‒100.
Weight Visceral adiposity
Weight Visceral adiposity
Blood pressure Arterial stiffness
Blood pressure Arterial stiffness
Glucose Insulin Glucose Insulin
Albuminuria Albuminuria
Uric Acid Uric Acid
Novel Pathways (?)
LDL-C HDL-C
Triglycerides
LDL-C HDL-C
Triglycerides Oxidative
stress Oxidative
stress
SNS activity (?)
Improved Beta Cell Function
Hyperglucagonemia
SGLT2 Inhibition addresses other important pathophysiologic process of T2DM
Effect of SGLT2i
↑ Fat Oxidation β↑ Glucose production?? Effect on
Insulin Resistance
?? GLP-1 Response
↑ Insulin Sensitivity↓ Tissue Glucose Disposal
Inhibit Glucosereabsorption
Inhibit Glucosereabsorption
SGLT2i : Sodium Glucose Co Transporter InhibitorsJP Wilding et al.Energy balance and metabolic changes with sodium‐glucose co‐transporter 2 inhibition. Diabetes Obes Metab. 2016 Feb;18(2):125‐34. doi: 10.1111/dom.12578. Epub 2015 Dec 10.
DapagliflozinChange in HbA1c from baseline at Week 24, core placebo-controlled phase 3 studies
Baseline mean HbA1c (%) 7.92 7.92 8.06 7.93 8.11 8.38 8.53
Patients, n 66 61 65 133 132 223 142 150 140 140 210 192
Statistically significant vs placebo; adjusted mean change from baseline using ANCOVA, excluding data after rescue (LOCF).MET, metformin; SU, sulfonylurea; TZD, thiazolidinediones;
Add-on combinations with:
EMDAC Background document. Available from: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm3
78079.pdf.
Low doseMonoTx MonoTx + MET
+ DPP4i(+ MET) + SU + TZD
+ INS(+ OAD)
HbA
1c
from
bas
elin
e (9
5% C
I)
DAPA 5 mg DAPA 10 mg
5mg
5mg
10mg
5mg
10mg
10mg
5mg
10mg
5mg
10mg
5mg
10mg
–1.60
–1.40
–1.20
–1.00
–0.80
–0.60
–0.40
–0.20
0.00
0.20
0.40
1.Hach T, et al; 3. Häring H-U, et al. 6. Rosenstock J, et al; 7. Barnett A, et al. Diabetes. 2013;(Suppl 1) (P69-LB, P1092, P1102, P1104, respectively).
2. Roden M, et al. Lancet Diabetes Endocrinol. 2013;3:208-19. 4. Kovacs C, et al. Diabetes Obes Metab. 2014;16:147-58.
5. Häring H-U, et al. Diabetes Care. 2013;36:3396-404.
Pooled data
Pooled1 Monotherapy2 MET3 PIO4 MET + SU5
Insulin78 week6 Mild RI7
Empagliflozin 10 mg q.d. Empagliflozin 25 mg q.d.
Patients, n 831 821 224 224 217 213 165 168 225 216 169 155 98 97
Baseline mean 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
–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
Adj
uste
d m
ean
(SE)
diff
eren
ce
vers
us p
lace
bo in
cha
nge
from
ba
selin
e H
bA1c
(%)
a All statistically significant unless otherwise marked. RI, renal impairment.
EmpagliflozinChange in HbA1c Phase 3 pooled efficacy placebo-corrected changea from baseline
–1.60
–1.40
–1.20
–1.00
–0.80
–0.60
–0.40
–0.20
0.00
0.20
0.40
CanagliflozinHbA1c change from baseline (LOCF)1-6
1. Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-82. 2.Lavelle-Gonzalez FJ, et al. Diabetologia. 2013;56:2582-92. 3. Cefalu WT, et al. Lancet. 2013,382;941-50. 4. Schernthaner G, et al. Diabetes Care. 2013;36;2508-15. 5. Forst T, et al. Poster presented at the 73rd
Scientific Sessions of the American Diabetes Association (ADA) 2013, 21-23 June. Chicago, Illinois, USA. 6. Matthews D, et al. Poster presented at the 48th Annual Meeting of the German Diabetes Association (DDG), 8-11 May 2013, Leipzig, Germany.
-0.77 -0.73-0.82
-0.98
-0.65
-1.03
-0.88-0.93
-1.03 -1.07
-0.73
–1.60
–1.40
–1.20
–1.00
–0.80
–0.60
–0.40
–0.20
0.00
0.20
0.40 MET + CANA vs MET + SITA2
MET + CANA vs MET + GLIM3
MET + SU + CANA vs SITA4
MET + PIO + CANA5 + CANA6
N 195 197 368 367 483 485 377 113 114 566 587BL mean HbA1c
(%) 8.1 8.0 7.9 7.8 8.1 8.0 7.9 8.3
LS m
ean
chan
ge in
HBA1c
(%
) (9
5%
CI)
Monotherapy1 Dual therapy Triple therapy Add-on to insulin
All at 52 weeks except monotherapy at 26 weeks and add-on to insulin at 18 weeks
CANA 100 mg CANA 300 mg
‐1,21‐1,30
‐0,38 ‐0,42
‐0,74
‐2,0
‐1,5
‐1,0
‐0,5
0,0
n 17 19 10 14 20Mean baseline 7.61 8.03 8.45 7.89 7.97
SE (0.15) (0.22) (0.34) (0.20) (0.21)
‐0.46p=0.051
‐0.82p=0.004Ad
justed
mean (SE) change from
baseline in HbA
1c (%
)
Change from baseline in HbA1c at week 24 by baseline BMI: add-on to metformin study
ANCOVA in FAS (LOCF). p=0.275 for treatment by baseline BMI interaction.
Subjects with BMI <25 kg/m2 at baseline Subjects with BMI ≥25 kg/m2 at baseline
‐1,19‐1,05
‐0,64 ‐0,69 ‐0,69
‐2,0
‐1,5
‐1,0
‐0,5
0,0
‐0.88p<0.001
‐0.55p=0.016
‐0.51p<0.001
‐0.56p<0.001
‐0.36p<0.001
‐0.36 p<0.001
Empa 25 mgEmpa 25 mg / lina 5 mg Empa 10 mg / lina 5 mg Empa 10 mg Lina 10 mg
117 116 130 123 1087.94 7.93 7.98 8.02 8.03(0.07) (0.07) (0.07) (0.09) (0.09)
Khunti K et al 98th Annual Meeting of the Endocrine Society (ENDO), Boston, MA; April 1‐4, 2016
‐1,17
‐0,95
‐0,51‐0,64 ‐0,67
‐2,0
‐1,5
‐1,0
‐0,5
0,0
n 72 77 78 68 65Mean baseline 7.81 7.79 8.06 8.03 7.96
SE (0.09) (0.08) (0.10) (0.12) (0.09)
‐0.50p<0.001
‐0.66p<0.001Ad
justed
mean (SE) change from
baseline in HbA
1c (%
)
Change from baseline in HbA1c at week 24 by baseline eGFR: add-on to metformin study
ANCOVA in FAS (LOCF). p=0.494 for treatment by baseline eGFR (MDRD) interaction.
Baseline eGFR 60 to <90 mL/min/1.73 m2 Baseline eGFR ≥90 mL/min/1.73 m2
‐1,24 ‐1,24
‐0,78 ‐0,72 ‐0,72
‐2,0
‐1,5
‐1,0
‐0,5
0,0
‐0.31p=0.011
‐0.28p=0.021
‐0.52p<0.001
‐0.47p<0.001
‐0.52p<0.001
‐0.51 p<0.001
Empa 25 mgEmpa 25 mg / lina 5 mg Empa 10 mg / lina 5 mg Empa 10 mg Lina 10 mg
58 57 60 64 577.96 8.14 7.96 7.99 8.10(0.11) (0.11) (0.10) (0.12) (0.15)
Khunti K et al 98th Annual Meeting of the Endocrine Society (ENDO), Boston, MA; April 1‐4, 2016
SGLT inhibitor as an add on to metformin versus SU:
Comparable HbA1c reductions sustained over 4 years1
Data are adjusted mean change from baseline derived from a longitudinal repeated measures mixed model. A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety profile of FORXIGA 10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone.1CI, confidence interval. 1. Del Prato S, et al. Diabetes Obes Metab 2015;17:581–90; 2. Nauck MA, et al. Diabetes Care 2011;34:2015–22.
At 52 weeks, reductions in HbA1c were statistically non-inferior to glipizide (–0.52% for both)2
Mentioned diagram is only for educational purpose. AstraZeneca is not responsible for data and copyrights
Sustained HbA1c
reduction
Dapagliflozin as add-on to metformin versus SU:
Weight loss sustained over 4 years1
Dapagliflozin is not indicated for the management of obesity.3 Weight change was a secondary endpoint in clinical trials.3,4
A Phase III, multicentre, randomised, double-blind, parallel-group, 52-week, glipizide-controlled, non-inferiority study with a double-blind extension to evaluate the efficacy and safety of dapagliflozin 10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone. Data are adjusted mean change from baseline derived from a longitudinal repeated-measures mixed model.1. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 21–25 June 2013. Abstract 62-LB;2. Nauck MA, et al. Diabetes Care 2011;34:2015–22; 3. Dapagliflozin. Summary of product characteristics, 2014; 4. Bailey CJ, et al. Lancet 2010;375:2223–33.
At 52 weeks, Dapagliflozin was associated with weight loss of –3.2 kg versus weight gain of +1.4 kg with glipizide (p<0.0001)2
Above diagram is only for educational purpose. AstraZeneca is not responsible for data and copyrights
Sustained Wt. Loss
-1,0
-0,8
-0,6
-0,4
-0,2
0,0
0,2
Cha
nge
in H
bA1c
(%)
Nauck et al.1
Lavalle-Gonzalez et al.3
–0.5 –0.5
–0.7 –0.7 –0.7–0.9
SGLT2i, sodium-glucose co-transporter 2 inhibitors; *Significant vs. all comparators; **p<0·0001 (non-inferiority); †p<0.0001 vs. placeboNR, not reported.
NR
Sulfonylurea Dapagliflozin 10 mg
Sitagliptin 100 mg Empagliflozin 25 mg
Canagliflozin 300 mg
1. Nauck et al. Diabetes Care 2011;34:2015–22; 2. Ridderstråle et al. Lancet Diabetes Endocrinol. 2014;2(9):691-700; 3. Lavalle-Gonzalez et al. Diabetologia 2013;56:2582-92; 4. Cefalu et al. Lancet 2013;382:941–950.
Ridderstråleet al.2
**
SGLT2 inhibitors as add-on to metformin: HbA1c reductions and hypoglycemia
AgentHypoglycemia (%)
SGLT2 SU
DAPA1
(10 mg) 4† 41
EMPA2
(25 mg) 2† 20
CANA4
(300 mg) 5† 34
1. Nauck et al. Diabetes Care 2011;34:2015–2022; 2. Ridderstråle et al. Lancet Diabetes Endocrinol2014;2(9):691–700; 3. Lavalle-Gonzalez et al. Diabetologia 2013;56:2582–2592.
SGLT2is, sodium-glucose co-transporter 2 inhibitors; *Significant vs. all comparators; NR, not reported.
SGLT2 inhibitors as add-on to metformin: body weight reductions
-4,5
-3,5
-2,5
-1,5
-0,5
0,5
1,5C
hang
e in
bod
y w
eigh
t (kg
)
NR
1.2
–3.2*
1.6
–3.2
–1.2
–3.7*
Nauck et al.1
Ridderstråleet al.2
Lavalle-Gonzalez et al.3
Sulfonylurea Dapagliflozin 10 mg
Sitagliptin 100 mg
Empagliflozin 25 mg
Canagliflozin 300 mg
20
Effect of Dapagliflozin on Fat Loss
DXA, dual‐energy X‐ray absorptiometry. Bolinder J, et al. J Clin Endocrinol Metab 2012;97:1020–31
Above diagram is only for educational purpose. AstraZeneca is not responsible for data and copyrights
Consistent BP Reductions with Dapagliflozin: 4‐5 mmHg systolic
Mean changes in systolic blood pressure (mmHg)W
eek
24or
48 m
ean
chan
gefro
mba
selin
e m
mH
g
Monotherapy1
-6
-5
-4
-3
-2
-1
0
1
2
Add-on to Met2 Add-on to SU3 48 week add-on to insulin4
43
1Ferrannini E, et al. Diabetes Care 2010;33:2217-2224;; 3Bailey CJ, et al. Lancet 2010;375:2223-33;3Strojek K, et al. Diabetes Obes Metab 2011;13:928-38 4Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21-A22 [Abstract 0078-OR].
-6
-5
-4
-3
-2
-1
0
1
2
-6
-5
-4
-3
-2
-1
0
1
2
-6
-5
-4
-3
-2
-1
0
1
2
Dapagliflozin (10 mg)
Placebo
–3.7
–.9
–5.9
–0.2
–4.9
–1.3
–5.2
–0.1
Dapagliflozin as add-on to Metformin:
Sustained Reductions in SBP are over 4 years1
• The primary endpoint was change from baseline to Week 208 in HbA1c, with SBP and weight change as secondary endpoints
FORXIGA is not indicated for the management of high blood pressure.A Phase III, multicentre, randomised, double‐blind, parallel‐group, 52‐week, glipizide‐controlled, non‐inferiority study with a double‐blind extension to evaluate the efficacy and safety profile of FORXIGA 10 mg + metformin (1500–2000 mg/day) versus glipizide + metformin (1500–2000 mg/day) in patients with inadequate glycaemic control (HbA1c >6.5% and ≤10%) on metformin alone.1CI, confidence interval, SBP, systolic blood pressure; SU, sulphonylurea.1. Del Prato S, et al. Diabetes Obes Metab 2015;17:581–90
At Week 208, Dapagliflozin + metformin reduced HbA1c by –0.10% versus an increase of +0.20% with SU + metformin
Above diagram is only for educational purpose. AstraZeneca is not responsible for data and copyrights
Sustained BP reduction
Dapagliflozin real‐world evidence: Data from routine clinical practice confirms efficacy seen in randomised clinical trials1–5
• Dapagliflozin delivers comparable reductions in HbA1c, weight and blood pressure* in real-world clinical practice as seen in randomised clinical trials
*Dapagliflozin is not indicated for the management of weight loss or blood pressure, and any changes were secondary endpoints in clinical trials. Study details are available in slide notes.MET, metformin; SBP, systolic blood pressure.1. Bailey CJ, et al. Lancet 2010;375:2223–33; 2. Wilding JPH, et al. Ann Intern Med 2012;156:405–15; 3. Scheerer M, et al. Diabetologie und Stoffwechsel 2015;10:98; 4. Scheerer M, et al. Diabetologie und Stoffwechsel 2015;10:99; 5. Wilding JPH, et al. Poster presented at the 51st European Association for the Study of Diabetes, Stockholm, Sweden. 14–18 September 2015; Abstract A-15-209.
Real‐world data§¶**3–5Clinical trial data†‡1,2
–0.80 to –1.16%3–5
–2.5 to –4.6 kg3,5
–2.3 mmHg3
As add-on to various agents including metformin and insulin over 6–12 months, Dapagliflozin delivers:
As add-on to metformin and insulin at 24 weeks, Dapagliflozin delivers:
HbA1cAdd-on to MET: –0.84%1
Add-on to insulin: –0.96%2
WeightAdd-on to MET:
–2.9 kg1Add-on to insulin:
–1.6 kg2
SBPAdd-on to MET:
–5.1 mmHg1Add-on to insulin: –6.7 mmHg2
HbA1c
Weight
SBP
UTIs and genital infections• SGLT2 inhibitors work by eliminating excess glucose through the kidney and is associated with a higher incidence of genital
infections and UTIs1
• Most genital infections* and UTIs were mild to moderate in intensity, rarely led to discontinuation of medication and were generally resolvable with a single course of standard treatment1
• Pyelonephritis was uncommon and occurred at a similar frequency to control1
*Genital infection includes the preferred terms: Vulvovaginal mycotic infection, vaginal infection, balanitis, genital infection fungal, vulvovaginal candidiasis, vulvovaginitis, balanitis candida, genital candidiasis, genital infection, genital infection male, penile infection, vulvitis, vaginitis bacterial and vulval abscess.UTI, urinary tract infection.1. Summary of product characteristics, 2014; 2. EMDAC background document. Available at: www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm378079.pdfLast accessed September 2015; 3. McGovern AP, et al. Br J Diabetes Vasc Dis 2014;14:138–43; 4. Hitke ZZ, et al. Diabetes Medicine 2015;32(Suppl 1):29 (Abstract P471); 5. Bellan Kannan RB. et al. Diabetic Medicine 2015;32(Suppl 1):29 (Abstract P470); 6. Down S, et al. Diabetes Medicine 2015;32(Suppl 1):29 (Abstract P246).
Events (%)
Placebo-controlled pool (short-term)2
FORXIGA 10 mg
(N=2360)Placebo(N=2295)
UTIs 110 (4.7) 81 (3.5)
Genital infections 130 (5.5) 14 (0.6)
A comparable safety profile was also seen in real-world observational studies3–6
25
Empa‐Reg Outcomes: 3P‐MACE
CV death, nonfatal MI, nonfatal stroke.Cumulative incidence function. MACE, Major Adverse Cardiovascular Event;HR, hazard ratio Cumulative incidence function. MACE=Major Adverse Cardiovascular Event; HR=hazard ratio.
* CV death, nonfatal MI, nonfatal stroke† Two sided tests for superiority were conducted (statistics of significance was indicated if P=0.0498)Zinamann et al. Results of the EMPA-REG OUTCOME study. EASD 2015 Stockholm
.
Patients with event/analysed
Empagliflozin Placebo HR (95% CI) p-value
3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382
CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001
Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189
Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638
Empa Reg CV death, MI and Stroke
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction*95.02% CI Zinamann et al. Results of the EMPA-REG OUTCOME study. EASD 2015 Stockholm
26
Favours empagliflozin Favours placebo
CV safety trials are being conducted for each compound within the Newer Classes
Timings represent estimated completion dates as per ClinicalTrials.gov.Adapted from Johansen OE. World J Diabetes 2015;6:1092–96. (references 1–19 expanded in slide notes)
CANVAS-R8
(n = 5700)Albuminuria
2013 2014 2015 2016 2017 2018 2019
SAVOR-TIMI 531
(n = 16,492)1,222 3P-MACE
EXAMINE2
(n = 5380)621 3P-MACE
TECOS4(n = 14,724)
≥ 1300 4P‐MACE
LEADER6
(n = 9340)≥ 611 3P‐MACE
SUSTAIN-67
(n = 3297)3P-MACE
DECLARE‐TIMI 5815(n = 17,150)
≥ 1390 3P‐MACE
EMPA‐REG OUTCOME®5(n = 7034)
≥ 691 3P‐MACE
CANVAS10(n = 4365)
≥ 420 3P‐MACE
CREDENCE17
(n = 3700)Renal + 5P-MACE
CAROLINA®11(n = 6000)
≥ 631 4P‐MACE
ITCA CVOT9
(n = 4000)4P-MACE
EXSCEL14(n = 14,000)
≥ 1591 3P‐MACE
DPP-4 inhibitor CVOTs
SGLT2 inhibitor CVOTs
GLP-1 CVOTs
OMNEON13
(n = 4000)4P-MACE
CARMELINA12
(n = 8300)4P-MACE + renal
REWIND16
(n = 9622)≥ 1067 3P‐MACE
2021
ELIXA3
(n = 6068)≥ 844 4P‐MACE
HARMONY Outcomes19
(n = 9400) 3P-MACE
‐11,8
‐13,4
‐18
‐16
‐14
‐12
‐10
‐8
‐6
‐4
‐2
0Dual Insulin
Δ HbA1c (mmol/mol)
‐6,3
‐3.2
‐8
‐7
‐6
‐5
‐4
‐3
‐2
‐1
0Dual Insulin
ΔWeight (kg)
Changes in HbA1c and weight in type 2 diabetes patients initiating dapagliflozin treatment in routine UK primary care
A retrospective study using data from the Clinical Practice Research Datalink, a subset of the ~40,000 UK patients receiving dapagliflozin
n = 10173.6a
mmol/mol(8.9%)
n = 5683.4a
mmol/mol(9.8%)
n = 52103.8kga
Change in HbA1c at >180 days Change in weight at > 180 days
n = 95107.4kga
Results from a subset of the 2401 patients prescribed dapagliflozin in CPRD (which represents ~9% of UK population).a Baseline values
Wilding JP et al (2015) Presented at: EASD meeting (Poster #737) Stockholm, Sweden
Real world data on canagliflozin :after 6 months
• Using retrospective claims data from the United States, patients with type 2 diabetes had clinically meaningful improvements in HbA1c during the 6 months following the first canagliflozin prescription
• HbA1c reductions with canagliflozin were larger in patients with higher baseline A1C, and more patients achieved HbA1c treatment targets during the 6‐month follow‐up period
Chow W, et al Poster presented at 75th the scientific session of American Diabetes Association, 5-9 June 2015, Boston, MA. P1337.
Cha
nge
in
HbA
1c (%
)
OverallN = 826
HbA1c > 7n = 715
HbA1c > 8n = 501
HbA1c > 9n = 270
-0.81%-0.97%
-1.30%
-1.81%
8.59% 8.92% 9.54% 10.51%Pre-CANA HbA1c
Diabetic Ketoacidosis & SGLT2i
AACE /ACE Scientific and Clinical Review
Concluded that the prevalence of DKA is infrequent and the risk‐benefit ratio overwhelmingly favors continued use of SGLT2 inhibitors with no changes in current recommendations
AACE recommendsConsider halting SGLT2 inhibitors for at least 24 hrs. prior to surgeries, planned invasive procedures, or anticipated difficult physical activities
For any extreme stress events such as emergency surgeries, the drug should be stopped immediately and appropriate clinical care should be provided
http://media.aace.com/press-release/leading-us-medical-associations-assembly-domestic-and-international-diabetes-experts-cAACE: American Association of Clinical Endocrinologists. Accessed on 9th March 2016 SGLT2i : Sodium Glucose Co Transporter Inhibitors
Risk Factors for EuDKAPoor Nutrition, Post‐operative period
Management is similar to DKA ( IV fluids, Insulin, K+ )JP Wilding et al.
Diabetes Obes Metab. 2016 Feb;18(2):125‐34. doi: 10.1111/dom.12578. Epub 2015 Dec 10.
Summary
• T2DM Progressive disease• Effective treatment of T2DM requires multiple drugs used
in combination to correct multiple pathophysiological defects
• Selective inhibition of SGLT2 directly removes excess glucose and associated calories, along with sodium, resulting in blood glucose, weight, and blood pressure reductions
• SLGT2 inhibitors have the potential to help control hyperglycaemia at all stages of diabetes and improve marcrovascular and microvascular outcomes
Thank you
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