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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