1-year After

Empa-Reg Outcome
 1-year After Empa Reg Outcome

Does Offloading Help?

• Acute / Chronic Metabolic Effects of Empagliflozin
• Pooled Safety Assessments

Empa Reg Outcome

• Further Assessments
• Corollary Developments
 Familial Renal Glycosuria
A Benign Condition of SGLT2-gene mutations

Glucose loss: Up to >150g per day, at normal plasma glucose

concentrations, in absence of tubular dysfunction
Benign Condition, NOT associated with:
• Hypoglycaemia
• Chronic Kidney Disease
• Urinary Tract Infections
Severe cases maybe associated with:
• Episodic dehydration
• Ketosis during starvation / pregnancy
• Hyponatremia associated volume-depletion
Bhimma R et al. http://emedicine.medscape.com/article/983678-overview
SGLT2 RNA SGLT2 Transporter Expressed Mainly in Kidneys

SGLT2 expression
is mainly in the kidney
SGLT1 RNA

SGLT1 expression is mainly

in the gastrointestinal tract,
skeletal muscle, heart and, to
a small degree, in the kidney

SGLT1, sodium glucose cotransporter 1; SGLT2, sodium glucose cotransporter 2.

Adapted from: Chen J, et al. Diabetes Ther. 2010;1:57–92.
 SGLT2-i: Antihyperglycemic Effect Independent of
β-cell Function and / or Insulin Resistance1–4

SGLT2 inhibition
Impaired β- directly targets
cell function glucose via urinary
glucose excretion

Persistent
Persistent
hyperglycaemia
hyperglycaemia

Insulin
resistance

SGLT2, sodium glucose cotransporter 2.

1. Adapted from: DeFronzo RA. Diabetes. 2009;58:773–795; 2. Adapted from: Poitout V and Robertson RP. Endocrinology. 2002;143:339–342;
3. Adapted from: DeFronzo RA. Diabetes Obes Metab. 2012;14:5–14; 4. Robertson RP, et al. Diabetes. 2003;52:581–587.
 SGLT2-i as the Robin Hood
Does Offloading Help?

Calorie Restriction Volume Metabolic

Mimicry Offload Efficiency

FPG ↓ Hemo- Substrate ↓ Metabolic

HbA1c ↓ BP ↓
PPG ↓ concentration Switch Stress
 Metabolic Effects of SGLT2-i
Glycaemia, Insulin sensitivity, β-cell function

Hyperglycaemia

SGLT2 inhibition Kidney

Lowered
Plasma Glucose Renal glucose
excretion

Peripheral Tissues Liver Pancreas

Weight Loss

Metabolic Adaptations Improved

Enhanced Insulin Hyperinsulinemia
Weight Loss
Sensitivity
Del Prato S. Diabet Medicine. 2009;26:1185–1192.
Clinical Medicine Insights: Therapeutics 2011
Ferrannini E, et al. J Clin Invest 2014;124:499–508
 Biochemical Effects of Empagliflozin
Plasma Glucose
Baseline
Acute dosing (Day 1)
14 Chronic dosing (Day 28)

12
Plasma glucose
(mmol/L)

10

6
Fasting
4
-180 -120 -60 0 60 120 180 240 300

Drug Time (min)

Ferrannini E, et al. J Clin Invest 2014;124:499–508

Biochemical Effects of Empagliflozin
Improved Insulin Secretion
Baseline
Acute dosing (Day 1)
Chronic dosing (Day 28)

Ferrannini E, et al. J Clin Invest 2014;124:499–508.

 Biochemical Effects of Empagliflozin
Improved Insulin Resistance
HOMA IR
0.6 Change from Baseline at 12 weeks 0.48

0.3 0.23

-0.3

-0.6 -0.52

-0.9

-1.2 -1.04
Placebo Empagliflozin 10 Empagliflozin Sitagliptin
mg 25mg 100mg

US-NIH. https://clinicaltrials.gov/ct2/show/NCT00749190. Accessed Oct 4, 2016.

 Glycemic Control Over 4 years
Empagliflozin or Glimepiride as Add-on to Metformin
HbA1c Reduction
Glimepiride 1–4 mg Empagliflozin 25 mg
8.5
Adjusted mean (SE) HbA1c (%)*

Empagliflozin vs glimepiride change

8.3
from baseline at week 208:* -0.18%
8.1 (95% CI -0.33 to -0.03)
7.9 p=0.0172
7.7
7.5
7.3
7.1
6.9
6.7
6.5
0 4 12 28 40 52 65 78 91 104 117 130 143 156 169 182 195 208
Week
Glimepiride 761 758 738 699 660 609 561 522 493 457 338 329 314 297 284 268 259 243
Empagliflozin 759 751 734 702 672 645 621 589 564 545 453 433 427 413 403 391 384 365

*MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and off-
treatment values). †ANCOVA in the FAS using a LOCF approach to impute values missing at week 208 or measured after
the use of rescue therapy.
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
 Hypoglycemic Events (%) Over 4 years
Empagliflozin vs. Glimepiride as Add-on to Metformin
Adjusted RR 0.112
(95% CI 0.074, 0.169)
p<0.0001

30 27.9
Percentage of patients with confirmed
hypoglycemic adverse events*

25 Hypoglycemia requiring assistance:

20 • 5 (0.6%) patients on glimepiride.
15 • No patients on empagliflozin.
10

5 3.1

0
Glimepiride (n=780) Empagliflozin (n=765)

Cochran-Mantel-Haenszel test; treated set (patients who received ≥1 dose of study drug).
*Plasma glucose ≤70 mg/dL and/or requiring assistance. RR, risk ratio.
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
 SGLT2-i as Add-on to Metformin
No Significant Differences in Efficacy
Chances of Achieving HbA1c level of <7.0%

Network Meta-analysis results in black

Pairwise Meta-analysis results in gray
Adapted: Shyangdan DS et al. BMJ Open. 2016 Feb 24;6(2):e009417.
 Effect on Weight Over 4 years
Empagliflozin vs. Glimepiride as Add-on to Metformin
3 Glimepiride 1–4 mg Empagliflozin 25 mg
Adjusted mean (SE) change from

2
baseline in weight (kg)

-1 Difference: -4.9 kg
(95% CI -5.5 to -4.3)
-2 p<0.0001

-3

-4

-5
0 12 28 52 78 104 130 156 182 208
Week
Glimepiride 745 743 703 610 524 458 331 301 269 248

Empagliflozin 739 737 706 642 590 551 443 420 395 368

MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and
off-treatment values).
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
 Change in Body Composition over 2 years therapy
Empagliflozin vs. Glimepiride as Add-on to Metformin
1.5

Mean (95% CI) change from baseline in 1.0

~ 40% mass
0.5 is fat
total body mass (kg)

0.0

-0.5

-1.0
>80% mass
-1.5
is fat
-2.0

-2.5

Glimepiride 1-4 mg† Emagliflozin 25 mg QD

(n = 38) (n = 46)
Mean total fat mass, 0.4 -1.9
kg (95% CI) (-0.5, 1.3) (-2.7, -1.1)
Mean total fat-free 0.5 -0.4
mass, kg (95% CI) (-0.2, 1.1) (-1.0, 0.2)
CI, confidence interval; EMPA, empagliflozin; H2H, head-to-head; QD, once daily, SD, standard deviation.
*Dedicated sub-study using dual energy X-ray absorptiometry; patient participation was optional.
†The mean (SD) highest dose of glimepiride over 104 weeks was 2.71 (1.24) mg; 40.1% of patients received the 4 mg dose.
Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700.
 Effect on Systolic BP Over 4 years
Empagliflozin vs. Glimepiride as Add-on to Metformin
4 Glimepiride 1–4 mg Empagliflozin 25 mg

3
Adjusted mean (SE) change from

2
baseline in SBP (mmHg)

1
0
Difference: -6.2 mmHg
-1 (95% CI -8.5 to -4.0)
p<0.0001
-2
-3
-4
-5
-6
0 4 8 12 16 28 40 52 65 78 91 104 117 130 143 156 169 182 195 208
Week
Glimepiride* 739 677 650 612 554 490 438 394 358 327 238 224 207 191 177 165 161 146

Empagliflozin† 735 669 649 618 579 537 510 475 446 427 361 336 331 314 302 289 284 266

MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
 eGFR Over 4 years
Empagliflozin vs Glimepiride as Add-on to Metformin
Glimepiride 1–4 mg Empagliflozin 25 mg
93
Mean (SE) eGFR (mL/min/1.73m2)

91 Difference 5.1;
(95% CI 3.5 to 6.8)
89 p<0.0001

87

85

83

81
0 12 28 52 78 104 130 156 182 208 LVOT FU*
Week
Glimepiride 757 751 726 707 677 657 503 492 478 459 588 573

Empagliflozin 742 740 713 690 679 651 537 525 520 510 579 570

Baseline: mean (SE) in the treated set; weeks 12–208: adjusted mean (SE) from MMRM in the treated set; LVOT and FU:
adjusted mean (SE) from ANCOVA in patients from the FAS who had a measurement at follow-up. *FU was 4 weeks after
termination of study medication. FU, follow up; LVOT, last value on treatment.
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA
 Change in HbA1c and Insulin Dose over 52 weeks
Empagliflozin as Add-on to MDI Insulin
HbA1c Insulin daily dose

9 Placebo (n = 185) 110 Placebo (n = 175)

Empagliflozin 10 mg (n = 184) Empagliflozin 10 mg (n = 171)
105
Adjusted mean (SE) HbA1c (%)

8.5 Empagliflozin 25 mg (n = 185) Empagliflozin 25 mg (n = 178)

Adjusted mean (SE) insulin

100

daily dose (IU/day)

8 95
90
7.5
85
7 80
75
6.5
70
6 65
0 4 8 12 16 20 24 28 32 36 40 44 48 52 0 4 8 12 16 20 24 28 32 36 40 44 48 52
Week Week
N BL 4 8 12 18 24 32 40 46 52 N BL 18 24 32
Week 40 46 52
PBO 185 184 177 178 169 171 168 159 153 152 PBO 175 169 169 166 154 151 147
10 mg 184 183 179 181 168 170 163 158 153 153 10 mg 171 175 166 169 167 169 161 166 154 154150 151150 147
25 mg 185 185 179 176 168 174 165 166 161 160 25 mg 178 168 169 164 164 158 159
171 166 167 161 154 150 150
MMRM. FAS (OC−52). MMRM. FAS (OC−52).
178 168 169 164 164 158 159

BL, baseline; HbA1c, glycosylated haemoglobin; IU, international unit; MDI, multiple daily injections; PBO, placebo; SE, standard error.
MMRM, FAS, observed cases (OC). The FAS included patients treated with ≥ 1 dose of study drug who had a baseline HbA1c value; some patient data for
insulin dose at baseline were missing.
Rosenstock J, et al. Diabetes Care. 2014; manuscript in preparation.
 Safety and Tolerability –
Pooled Phase III Analysis
Empagliflozin Comparators
Number of patients 1652 1048

Hepatic injury1 1.1% 1.9%

Volume depletion2 0.3% 0.3%

Serum creatinine increase3 0.1% 0.1%

Urinary tract infection4 8.4% 7.5%

Genital infection4 3.9% 0.8%

Hypoglycaemia5 4.6% 2.4%

Hypoglycaemia5 without 1.2% 0.7%
SU background therapy*
AESI, adverse event of special interest; SU, sulphonylurea.
1. Selected hepatic events (narrow SMQ); 2. Based on BICMQ, including hypotension, syncope, dehydration and orthostatic hypotension;
3. Creatinine ≥ 2 × baseline and > 1 × ULN; 4. Based on BICMQ; 5. Confirmed hypoglycaemic events (all hypoglycaemic events that had a glucose value ≤ 70 mL/dL or where
assistance was required).
*Data from SAF-2 with n = 1211 and 823 for total number of patients in ‘all randomized empagliflozin’ and ‘all comparators’, respectively.
TS. Data on file.
 Electrolyte Changes

Empagliflozin Empagliflozin
Placebo
10 mg 25 mg

SERUM Change Change Change

Baseline Baseline Baseline
ELECTROLYTES from BL* from BL* from BL*

Sodium, mmol/L 141 (2) 0 (2) 141 (2) 0 (2) 141 (2) 0 (2)

Potassium, mmol/L 4.1 (0.3) 0 (0.3) 4.2 (0.3) 0 (0.3) 4.1 (0.3) 0 (0.3)

Calcium, mmol/L 2.4 (0.1) 0 (0.1) 2.4 (0.1) 0 (0.1) 2.4 (0.1) 0 (0.1)

Magnesium, mmol/L 0.9 (0.1) 0 (0.1) 0.9 (0.1) 0 (0.1) 0.9 (0.1) 0.1 (0.1)

Phosphate, mmol/L 1.2 (0.1) 0 (0.1) 1.2 (0.1) 0 (0.1) 1.2 (0.1) 0 (0.1)

BL, baseline; eGFR, estimated glomerular filtration rate.

Data are mean (SD) unless otherwise indicated.
*Changes from baseline at last value on treatment, except for eGFR, which is change from baseline at Week 24 in the treated set. †Normalised to a
standard reference range. ‡Haematocrit: n = 772 for placebo, n = 800 for empagliflozin 10 mg, n = 785 for empagliflozin 25 mg; uric acid and electrolytes: n
= 776 for placebo, n = 802 for empagliflozin 10 mg, n = 785 for empagliflozin 25 mg; serum creatinine: n = 776 for placebo, n = 802 for empagliflozin 10 mg,
n = 787 for empagliflozin 25 mg.
Data on file.
 Risk of Bone-fractures with Empagliflozin
ADA
2016
Pooled† safety and tolerability analysis (>12,000 patients)
EMPAGLIFLOZIN
Comparator 10 mg QD 25 mg QD
N, (%) (n = 4203) (n = 4221) (n = 4196)
123 119 105
Bone fractures
(2.9%) (2.5%) (2.8%)

No clinically relevant changes in

 Bone mineral density over 2 years
 Serum 25-OH Vit. D and PTH levels
 Urine Telopeptide/creatinine ratio
AE, adverse event; QD, once daily.
*Investigator-defined based on 8 prospectively
defined preferred terms: blood pressure (BP) decreased, BP ambulatory decreased, BP systolic decreased, dehydration, hypotension, orthostatic
hypotension, hypovolemia and syncope.
†Data were pooled from 3 Phase I trials, 5 dose-finding Phase II trials and 13 Phase IIb/III trials (including extension trials) that investigated
JARDIANCE® 10 mg and JARDIANCE® 25 mg compared with placebo in patients with T2D. Analyses were descriptive in nature and performed in
the treated set (all patients treated with ≥ 1 dose of randomized trial medication);
Lund S. et al. 127 LB. ADA 2016, New Orleans, USA.
 DKA events in Empagliflozin and Comparator arms
ADA
2016

Pooled† safety and tolerability analysis (>15,000 patients)

EMPAGLIFLOZIN
Comparator 10 mg QD 25 mg QD
N, (%) (n = 5599) (n = 4558) (n = 5520)
5 5 2
DKA
(0.1%) (0.1%) (< 0.1%)

AE, adverse event; QD, once daily.

*Investigator-defined based on 8 prospectively
defined preferred terms: blood pressure (BP) decreased, BP ambulatory decreased, BP systolic decreased, dehydration, hypotension, orthostatic
hypotension, hypovolemia and syncope.
†Data were pooled from 3 Phase I trials, 5 dose-finding Phase II trials and 13 Phase IIb/III trials (including extension trials) that investigated
JARDIANCE® 10 mg
®
and JARDIANCE 25 mg compared with placebo in patients with T2D. Analyses were descriptive in nature and performed in the
treated set (all patients treated with ≥ 1 dose of randomized trial medication);
Lund S. et al. 127 LB. ADA 2016, New Orleans, USA.
Mechanism of Ketogenesis with SGLT2-i
 SGLT2-i are not approved for use in Type-1 DM; may predispose to DKA

 Down-titration in insulin dose maybe done gradually rather than rapidly

 Adequate Carbohydrate consumption and Hydration should be ensured

 Reassuring Long-term Renal Safety of Empagliflozin
Lesser events of Acute Renal Failure / Acute Kidney Injury

Kaplan-Meier estimates in patients treated with ≥1 dose of study drugbased on events that occurred during treatment or ≤7 days after the last intake of study drug.
Post-hoc analyses.
Acute renal failure: narrow standardized MedDRA query “decreased renal function”.
Acute kidney injury: MedDRA preferred term.
MedDRA, Medical Dictionary for Regulatory Activities.
Wanner C et al. N Engl J Med. 2016 Jul 28;375(4):323-34.
 CVD in T2D: Some Stats!

CVD in patients of T2D:

• Atherosclerotic CVD occurs 14.6 years earlier

• 2/3rd deaths attributable to CVD

• Risk of HF is 2.5 - 5 fold higher

• HF is the second commonest manifestation of CVD

• Risk of MI in T2DM = Risk of MI in patients of prior MI

Low Wang CC et al. Circulation. 2016 Jun 14;133(24):2459-502.

 Empa Reg Outcome Study
The Watershed in the Management of T2DM

11,531 >97 % >99 %

completed vital status
pts screened
trial available
7020 pts
randomized

163
Indians
Asia
North America, Australia,
New Zealand
Latin America
Europe 42 Nations
Africa 590 sites
 Trial design
Stable background Background glucose-lowering therapy adjustment
glucose-lowering therapy allowed to achieve glycaemic equipoise

Placebo
(n=2333)

Randomised Empagliflozin 10 mg
Screening
and treated
(n=11,531) (n=2345)
(n=7020)
Pooled
Empagliflozin 25 mg
(n=2342)

• Study medication in addition to standard of care

– Glucose-lowering therapy was to remain unchanged for first 12 weeks

• At least 691 events required

Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

30
 Key Baseline Characteristics
• >50% patients had T2D of >10 years duration
• >25% patients had eGFR <60 ml/min/1.73 m2
• ≈39% patients had albuminuria (Micro- or Macro-albuminuria)

≈99% patients had pre-existing CVD

• >75% patients had Coronary artery disease (CAD)
• >46% patients had a history of MI
• ≈10% patients had Cardiac failure

Background ‘Standard of Care’ therapy:

• >48% patients were receiving insulin
• >80% were on ACE-i/ARB
• >76% were on statins
• ≈89% were receiving Anti-platelet agents
Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720
 38% RRR
CV Mortality In CV Death

Empagliflozin vs. Placebo, On Top of Standard of Care

HR 0.62
(95% CI 0.49, 0.77)
p<0.0001

Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

 “In patients with long-standing suboptimally controlled type 2
diabetes and established atherosclerotic cardiovascular disease,
empagliflozin or liraglutide should be considered as they have
been shown to reduce cardiovascular and all-cause mortality
when added to standard care.

Ongoing studies are investigating the cardiovascular benefits of

other agents in these drug classes.” B
 AACE/ACE Consensus Statement
Comprehensive Type 2 Diabetes Management Algorithm - 2017
Executive Summary

In the only SGLT-2 inhibitor cardiovascular outcomes trial

reported to date, empagliflozin was associated with significantly
lower rates of all-cause and cardiovascular death and lower risk
of hospitalization for heart failure. Heart failure-related
endpoints appeared to account for most of the observed
benefits in this study.

Empagliflozin has recently received FDA approval for indication

of reduction in cardiac mortality.

AACE / ACE. In Press. https://www.aace.com/sites/all/files/diabetes-algorithm-executive-summary.pdf. Accessed Jan 11, 2017.

 Hospitalizations for Heart Failure 35% RRR
In HHF
Empagliflozin vs. Placebo, On Top of Standard of Care

HR 0.65
(95% CI 0.50, 0.85)
p=0.0017

Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

 Consistent CV Mortality Benefit
Regardless of HF Burden

Placebo Empagliflozin HR CV deaths Absolute

(95% CI) (%) mortality
reduction
Overall 137/2333 172/4687 0.62 100% 2.2%
population (5.9%) (3.7%) (0.49, 0.77)

HF Burden 54/353 63/605 0.67 37.9% 4.9%

(HFH, HFBL, (15.3%) (10.4%) (0.47, 0.97)
HFAE)
No HF Burden 83/1980 109/4082 0.63 62.1% 1.4%
(4.1%) (2.7%) (0.48, 0.84)

HFH: HF hospitalization
HFBL: HF at baseline
HFAE: HF as an investigator-reported adverse event
Fitchett D et al. Presented at ESC, 2016.
 32% RRR
All-cause Mortality In Death due
to any cause
Empagliflozin vs. Placebo, On top of Standard of Care

HR 0.68
(95% CI 0.57, 0.82)
p<0.0001

Zinman B et al. N Engl J Med 2015;doi:10.1056/NEJMoa1504720

Mortality Benefit with Newer Antidiabetic Interventions
On Top of Current Standard of Care1,2
Number Needed to Treat to Prevent 1 Additional Death
On Top of the Current Standard of Care
EMPA REG OUTCOME LEADER
Empagliflozin Liraglutide
for 3 years1 for 3 years2

This is not a
head to head
comparison
T2DM with high CV risk T2DM with high CV risk
92% hypertension >92% hypertension

On Top of On top of
>80% ACEi/ARB >80% ACEi/ARB
>75% statin >72% statin
1. Zinman B et al. N Engl J Med. 2015 Nov 26;373(22):2117-28.
2. Marso SP et al. N Engl J Med. 2016 Jul 28;375(4):311-22.
 Empagliflozin 39%
RRR
Reduced New Onset or Worsening Nephropathy

Kaplan-Meier estimate. Patients treated with at least one dose of study drug. Hazard ratios are based on Cox regression analyses. HR, hazard ratio; CI, confidence
interval.
Wanner C et al. N Engl J Med. 2016 Jul 28;375(4):323-34.
 Sustained Reductions in eGFR with Empagliflozin1
Validated Primary Endpoints for Renal Protection2,3

1. Wanner C. Microvascular and renal outcomes: an update. In: Empa-Reg Outcome: One Year Later. Oral Presentation #S44.3.
Presented at 52nd annual conference of EASD, Munich, 2016 Sep 16.
http://www.easdvirtualmeeting.org/resources/microvascular-and-renal-outcomes-an-update. Accessed Oct 24, 2016.
2. Levey AS et al. Am J Kidney Dis. 2014 Dec;64(6):821-35.
3. Lambers Heerspink HJ et al. Am J Kidney Dis. 2014 Dec;64(6):860-6.
Wanner C. Microvascular and renal outcomes: an update. In: Empa-Reg Outcome: One Year Later. Oral Presentation #S44.3. Presented at
52nd annual conference of EASD, Munich, 2016 Sep 16. http://www.easdvirtualmeeting.org/resources/microvascular-and-renal-outcomes-
an-update. Accessed Oct 24, 2016.
Meta-analysis of 8 RCT :CV Risk

• 8 RCTs; n = 11,292
– Placebo (n): 3845; Exposure: 7448.3 patient-years
– Empagliflozin (n): 7457; Exposure: 15482.1 patient-years
• Primary endpoint: 4P-MACE
• Secondary endpoint: 3P-MACE

Salsali A et al. Diabetes Obes Metab 2016, 18, 1034-40.

 CV Death
Empagliflozin (pooled) vs Placebo

Salsali A et al. Diabetes Obes Metab 2016, 18, 1034-40.

 All Cause Mortality
Empagliflozin (pooled) vs Placebo

Salsali A et al. Diabetes Obes Metab 2016, 18, 1034-40.

 Differing Features of SGLT-2 Inhibitors
Empagliflozin Dapagliflozin Canagliflozin

SGLT2 : SGLT1
selectivity@
>2,5001 >1,2001 >2501

Non-specific*
Lowest2 Intermediate2 Highest2
Tissue Distribution

Higher in patients
Risk of
No imbalance$3 No imbalance$4 with moderate
Hyperkalemia
renal impairment$5

Risk of Bone
No imbalance3,6 No imbalance4,7 Increased risk5,8
fractures

Risk of Imbalance observed for

No imbalance3,6 No imbalance5,8
Malignancy bladder cancer#4,7

CV Risk Reduction
Cardiovascular Study ongoing Study ongoing
demonstrated
Outcome Trial (DECLARE-TIMI 58)10 (CANVAS)11
(EMPA-REG OUTCOME)9

Long-term renal safety Risk of Acute Kidney Risk of Acute Kidney

Renal Safety
demonstrated12 Injury increased13 Injury increased13
Early Intervention for CV Protection in T2D
or Treat-to-fail Step-ladder?
Q of the family :
• Insulin-independent action
• Decreases FPG, PPG, A1c
• Weight loss
• Blood pressure
• Low risk of hypoglycemia
• Effective at all stages (when renal function
adequate)
Q Unique to empa
• CV Benefits (Empagliflozin)
• Mortality Benefit
 SGLT2-inhibitors
Considerations for Clinical Use

Characteristics Considerations
• Insulin-independent action • Uro-genital infections

• Decreases FPG, PPG, A1c • Ineffective in renal impairment

• Weight loss • Monitoring of renal function,

volume and electrolyte status
• Blood pressure lowering
• Volume-depletion related AE’s in
• CV Benefits (Empagliflozin)
predisposed individuals
• Low risk of hypoglycemia
• Bone fractures (Canagliflozin)
• Effective at all stages (when
• Euglycemic Diabetic Ketoacidosis
renal function adequate)
(rare, preventable and mitigable)
 Appropriate Use of SGLT-2 Inhibitors

Do Not Use in:

• eGFR < 45 mL : Will not work

• Pregnant and breast-feeding women (Lack of data )
• Type 1 Diabetes/ Ketosis
• For weight loss in non-diabetic patients

58
Cautious Use in:
Be Cautious
• Elderly
• Dehydrated
• Drugs which predispose to E.I
• UTI
• GTI