Dr.

Vishal Gupta
Professor, Department of General Medicine,
SMS Medical College and attached Hospital, Jaipur
International Diabetes Federation

9.3% 8.9%
Prevalence Prevalence
77 mn
Diabetes
463 mn Diabetes Population
Population

Global Scenario

India : The capital of diabetes

IDF Diabetes Atlas 9th edition, 2019
UKPDS : Intensive Glycemic Control Is Essential To Improve
Micro-Vascular & Macro-Vascular Outcomes
Every 1% HbA1c
Reduction

Death due to Diabetes -21%

Heart Attack -14%

Microvascular Complication
-37%

Peripheral Vascular Disorders

-43%

BMJ 2000;321:405-412 UKPDS : UK Prospective Diabetes Study; HbA1c: Glycosylated Hemoglobin

 Pathogenesis of T2DM : The ominous octet

4 DeFronzo RA. Diabetes. 2009 Apr 1;58(4):773-95.

 SGLT RECEPTORS
 Two sodium glucose transporters, cause glucose reabsorption: SGLT-1 and SGLT-2.

 SGLT-2 is found in the proximal tubule of the kidney, accounts for 90% of the re-absorption of glucose.

 SGLT-1 is found in the gut and other tissues, account for glucose absorption
Glucose

SGLT2
~90%

SGLT1
~10%

Urinary
Adapted from Bays H. Curr Med Res Opin. 2009;25(3):671-681.
glucose excretion
 Empagliflozin - SGLT2 Inhibition Reduces Renal Glucose
Reabsorption and Increases Urinary Glucose Excretion

Glomerulus Proximal Convoluted Tubule Early Distal Tubules

Glucose in
urine

Decreased glucose reabsorption into

systemic circulation

Glucose SGLT2 SGLT2 inhibitor SGLT1

 SGLT2 inhibition lowers the elevated renal
threshold for glucose in type 2 diabetes1
Glomerulus Proximal tubule Distal tubule Collecting duct

Glucose filtration
SGLT2 SGLT1

SGLT2
Glucose inhibitor
reabsorption Marked
Loop of increase in
• Plasma glucose concentration: 10 mmol/L Henle glucose
• Plasma filtered: 180 L/day
• Glucose filtered: ~320 g/day excretion
• Glucose excreted: ~70–119 g/day (equivalent to ~280–476 kcal/day)2-4

SGLT: sodium–glucose co-transporter.

Figure adapted from: Bailey CJ. Trends Pharmacol Sci. 2011;32:63–71.
1. DeFronzo RA et al. Diabetes Obes Metab. 2012;14:5–14; 2. Invokana (canagliflozin). Summary of Product Characteristics; 3. Jardiance (empagliflozin). Summary of Product Characteristics;
4. Forxiga (dapagliflozin). Summary of Product Characteristics. All SmPCs available at: https://www.medicines.org.uk/emc/ (accessed April 2018).
 SGLT2i Lowers Renal Threshold for Glucose Excretion
125
Type 2 diabetes Non-diabetic Type 2 diabetes
+ Empagliflozin (180 mg/dL) (240 mg/dL)
100
(70-90 mg/dL)

75
Excretion
Glucose

RTG RTG RTG

Urinary

(g/d)

50
EMPA-gliflozin
25

50 100 150 200 250 300

Plasma Glucose (mg/dL)
Adapted with permission from Abdul-Ghani MA, DeFronzo RA.
RTG = renal threshold for glucose excretion.
1. Cowart SL, Stachura ME. In: Walker HK et al, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston, MA:
Butterworths; 1990:653-657. 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14(6):782-790. 3. Nair S, Wilding JP. J Clin Endocrinol Metab.
2010;95(1):34-42. 4. INVOKANA® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2013. 5. Rave K et al. Nephrol Dial Transplant.
2006;21(8):2166-2171. 6. Oku A et al. Diabetes. 1999;48(9):1794-1800.
 Metabolic Adaptations following SGLT2-i Therapy
Improved Glycaemia, Insulin sensitivity, β-cell function
Hyperglycaemia

SGLT2 inhibition Kidney

Lowered
Plasma Glucose Renal glucose
excretion

Peripheral Tissues Liver Pancreas Weight Loss

Metabolic Switch Improved

Weight Loss Enhanced Insulin Hyperinsulinemia
Sensitivity
Kalra S, Ved J, Baruah M. IJEM. 2017;21(3):482-3.
Del Prato S. Diabet Medicine. 2009;26:1185–1192. Ferrannini E,
et al. J Clin Invest. 2014;124:499–508
 Multiple mechanisms may contribute to CV benefits with SGLT2 inhibitors

SGL2
inhibitors

Na+/H+
Glycosuria1 Natriuresis1
exchanger2

Reduced Reduced Reduced Tubuloglo- Increased

Reduced Increased
total plasma blood merular mitochondrial
HbA1c uricosuria
body fat volume pressure feedback calcium

Reduced Reduce Reduced Reduced

Ketone oxidative Increased Reduced
glucotoxicity arterial renal
utilisation stress haematocrit preload
& inflammation stiffness damage

Increased Reduced
oxygen myocardial
delivery wall stretch

Additional CV benefits
SGLT2 inhibitors modulate a range of factors related to
CV risk: Based on clinical and mechanistic studies
Novel
Pathways (?)
 Blood pressure
 Arterial
stiffness  Albuminuria

 SNS  SNS  Uric Acid

activityactivity
(?) (?)  Glucose
 Insulin

 Weight  LDL-C
 Visceral  HDL-C
adiposity  Triglycerides
 Oxidative
stress

SGLT 2 inhibitors exerts multiple role beside glycemic control

 Known knowns or known unknowns: possible mechanisms
responsible for the benefits of SGLT2 inhibition

• On top of glycaemic lowering, SGLT2 inhibitors demonstrates additional clinical

benefits versus placebo:
– Blood pressure lowering
– Weight loss
– Reduction in major cardiovascular events in patients with established
cardiovascular disease1

• The mechanisms responsible for the cardiovascular effects are currently unknown
– May be a combination of natriuresis, glycosuria (dual inhibition) and/or Na+/H+
exchange
– Ongoing mechanistic studies may provide answers
 Dapagliflozin : Ideal Patient Profile
In DM with
• Patients not achieving targeted HbA1c
• Overweight & Obese patients
• CVD & CKD patients with eGFR>45
Ideal Profile
• High risk of hypoglycemia (v/s Insulin / SUs)

Curr Opin Endocrinol Diabetes Obes. 2017 Feb; 24(1): 73–79; DM: Diabetes Mellitus; HbA1c: Glycosylated Hemoglobin; CVD: Cardio Vascular Disease CKD: Chronic Kidney Disease; eGFR: Estimated Glumerular Filteration Rate; SUs: Sulfonyl Ureas
 SGLT2 inhibitors
Points Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin Sotagliflozin
FDA
March 29, 2013 January 8, 2014 August 1, 2014 December 2017 May 26, 2023
approval

Dose range 100-300 mg/day 10-25 mg/day 5 mg-10 mg/day 200 - 400 mg/day
Half-life (h) 12-15 17 10-19 12-18 21 - 35

At any time of In the morning In the morning In the morning

Administrati Before the first
the day with or with or without with or without with or without
on meal of the day
without food food food food
 SGLT2 Inhibitors: Do They All Work the Same Way?
Volume of
Half-life Oral Plasma Metabolism and SGLT2 selectivity
Drug (dose) distribution
(hours) bioavailability (%) protein elimination (vs SGLT1)
(L)
binding (%)

Hepatic
Canagliflozin 10.6–
65 83.5 98 conjugated ~ 250 fold
(100–300 mg OD) 13.1
Renal excretion

Hepatic
Dapagliflozin
12.9 78 118 91 conjugated ~ 1200 fold
(5–10 mg OD)
Renal excretion

Hepatic
Empagliflozin
12.4 60 73.8 86.2 conjugated ~ 2500 fold
(10–25 mg OD)
Renal excretion

Diabetes Therapy volume 12, pages55–70 (2021); SGLT: Sodium–Glucose Co-Transporter; OD: Once Daily
Empagliflozin vs. Glimepiride as Add-on to Metformin 89% Lower
Risk of Hypoglycemic Events
Adjusted RR 0.112
(95% CI 0.074, 0.169) p<0.0001

Hypoglycemia requiring assistance:

• 5 (0.6%) patients on glimepiride.

• No patients on empagliflozin.

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
 Glycemic Efficacy-Fasting Plasma Glucose
FPG (mg/dL) reduction in pivotal trials - 24 week
Monotherapy Add-on to Add-on to Add-on to Add on
MET PIO MET+SU Basal insulin
224 224 217 213 165 168 225 216 169 155
N value 138 146
152.79 152.61 154.59 149.37 151.92 151.74 150.84 156.42
Baseline FPG 0
Adjusted mean
(SE) difference -10
vs Placebo in
change from
baseline in FPG
-20
(mg/dL)
-30 -23.40
-26.49 -28.65 -28.44* -28.20 -29.50
-31.20 -23.4 -28.44
-40 * * *
* -36.20 * *
* Empagliflozin 10
Empagliflozin 25 mg QD
mg QD

2014;16:147–158 P: < 0.05

BL, baseline; MET, Metformin; PIO, pioglitazone; QD, once daily; RI, renal impairment; SE, standard error; SU, sulphonylurea. * All data are
Placebo-corrected and statistically significant unless otherwise marked. 1. Hach T, et al. Diabetes.
2013;62(suppl 1A);A21 (P69-LB); 2. Roden M, et al. Lancet Diabetes Endocrinol. 2013;1(3):208–219; 3. Häring H-U, et al. Diabetes Care.
1 8
2014 (in press); 4. Kovacs C, et al. Diabetes Obes Metab. 2014;16(2):147–158; 5. Häring H-U, et al. D ia betes
Care. 2013;36(11):3396–404; 6. Rosenstock J, et al. Diabetologia. 2013;56(suppl 1);S372 (P931); 7. Barnett A, et al, Lancet Diabetes
Endocrinol. 2014; doi:10.1016/S2213-8587(13)70208-0.
 Glycemic Efficacy-Post prandial Plasma Glucose
EMPA-REG METTM in Type 2 Diabetes

1245.23
EMPA-REG MET: study
Change in 2-h PPG* at Week 24
Placebo 10 mg QD Empagliflozin Comparison with Placebo
(n = 57) (n = 52) 25 mg QD
20 (n = 58)
6.0
Adjusted mean (SE)

10
baseline in 2-h PPG
change from

0 -51.9 (95% CI: -50.5 (95% CI:

(mg/dL)

-69.2, -34.6) -67.4, -33.5)

-10 P<0.0001 P<0.0001
-20
-30
-46-.0 -44.5
-40
Placebo EMPA 10 mg EMPA 25 mg
-50
Mean baseline 2-h PPG
264.5 254.6 252.1
(mg/dL)
-60
CI, confidence interval; EMPA, Empagliflozin; PPG, post-prandial glucose; QD, once daily; SE, standard error.
*2-h PPG was evaluated in a subset of 167 randomised patients who had a valid MTT (MTT set).
ANCOVA, MTT (LOCF).
Häring HU, et al. Diabetes Care. 2014;37:1650–1659.
 Empagliflozin vs. Glimepiride as Add-on to Metformin Systolic BP
Reduction Maintained Over 4 years
baseline in SBP
Adjusted mean (SE)
change from

Difference: -6.2 mmHg

(95% CI -8.5 to -4.0)
(mmHg)

p<0.0001

4 81216 28 40 52 65 78 91 104 117 130 143 156 169 182 195

Week
Glimepiride* 739 677 650 612 554 490 438 394 358 238 224 207 191 177 165 161 146
327
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
 Empagliflozin vs. Glimepiride as Add-on to Metformin
Weight-loss Maintained Over 4 years
baseline in weight
Adjusted mean (SE)
change from

Difference: -4.9 kg
(95% CI -5.5 to -4.3)
(kg)

p<0.0001

12 28 52 78 104 130 156 182

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
Empagliflozin Improves UACR Outcomes in Patients with
Albuminuria

Empagliflozin Empagliflozin
33% Lower Odds of Deterioration in UACR 61% Higher Odds of Improvement in UACR
Status Status
Wanner C et al. FR-PO805, American Society of Nephrology Kidney Week, 15–20 November 2016, Chicago, IL, USA.
 SGLT2-i agent Effect Loop Diuretic Effect

Day Day

Day Day
• SGLT2-i agent ↓ses IF volume by 2-fold greater than blood volume
• Loop diuretic ↓ses IF volume by only 78% of reduction in blood volume
Hallow KM et al. Diabetes Obes Metab. 2017 Oct 12. doi: 10.1111/dom.13126.
Pharmacological properties of available SGLT2 inhibitors
Empagliflozin Dapagliflozin Canagliflozin
Therapeutic dose (mg/day) 10–25 5–10 100–300
Starting dose 10 10 100
Administration QD QD QD
With or without food With or without food Before first meal
Peak plasma concentration (hours
post-dose) 1.5 Within 2 1–2
Absorption
≥ 60% ~ 78% ~ 65%
(mean oral bioavailability)
Metabolism  Primarily glucuronidation - no active metabolite 
Elimination Hepatic:renal 43:57 Hepatic:renal 22:78 Hepatic:renal 67:33
(half-life, hours) [12.4] [12.9] [13.1]*
Selectivity over SGLT1 1:5000 > 1:1400 > 1:1601
Glucose excretion with higher dose
78 ~ 70 119
(g/day)

Empagliflozin primarily excreted from kidney and liver

with lowest affection for SGLT1 receptors.
Quick Snapshot: Dapagliflozin Landmark Trials
Hazard
Ratio

Reduces cardio-renal risks in patients with/without DM

https://www.grepmed.com/images/12169/ebm-table-inhibitors-cvd-visualabstract CV: Cardio Vascular; HHF: Hospitalization due to Heart Failure; MACE: Major Adverse Cardiac Event; T2DM: Type 2 Diabetes Mellitus; ASCVD: Athero Sclerotic Cardio
Vascular Disease; CKD: Chronic Kidney Disease, eGFR: Estimated Glomerular Filteration Rate; ESKD: End Stage Kidney Disease; GDMT: Guideline Directed Medical Therapy; HFrEF: Heart Failure reduced Ejection Fraction; DM: Diabetes Mellitus
Dapagliflozin : Glucose Lowering Effect

Sugar flowsout of the urine thus offering glycemic control

1- Diabetes Care, Volume 33, Number 10, October 2010; 2- Ther Adv Drug Saf. 2014 Dec; 5(6): 242-254; 3- Diabetes Care, Volume 38, March 2015; 4- Diabetes, Obesity & Metabolism 17:616-621, 2015; 5-Sci Rep. 2019; 9:6864; HbA1c:
Glycosylated Hemoglobin; SUs: Sulfonylureas; Met: Metformin DPP4i: Dipeptidyl Peptidase 4 inhibitor; OADs: Oral Anti Diabetics
 Dapagliflozin : Low Incidences of Hypoglycemia

SGLT2i action becomes negligible when the plasma glucose concentration

drops below 90 mg/dL

1- Diabetes Care, Volume 33, Number 10, October 2010; 2- Bailey et al. BMC Medicine 2013, 11:43; 3- Diabetes Care, Volume 38, March 2015; 4- Diabetes, Obesity & Metabolism 17:616-621, 2015; 5- Sci Rep. 2019; 9:6864; SGLT2i: Sodium Glucose
Co-Transporter 2 Inhibitor; SUs: Sulfonylureas; Met: Metformin; DPP4i: Dipeptidyl Peptidase 4 inhibitor
 Dapagliflozin : Body Weight Change

Dapagliflozin induces 200-300 calorie loss/day as sugar flows out of the

urine, thus resulting in weight reduction

1- Diabetes Care, Volume 33, Number 10, October 2010; 2- Ther Adv Drug Saf. 2014 Dec; 5(6): 242-254; 3- Diabetes Care, Volume 38, March 2015; 4- Diabetes, Obesity & Metabolism 17:616-621, 2015; 5- Indian Journal Of Endocrinology &
Metabolism, Vol 22, Issue 6, November-December 2018; SUs: Sulfonylureas; DPP4i: Dipeptidyl Peptidase 4 inhibitor; Met: Metformin ; OADs: Oral Anti Diabetics
 Dapagliflozin : Favorable Lipid Profile
Placebo Dapagliflozin 10 mg
10
Mean change from baseline (%)

8
6.0
6

4 2.9 2.7 2.5

2
0.0
0

-2 -1.0 -0.7

-2.7
-4

LDL-C HDL-C Triglycerides Total cholesterol

Positive effect on lipid triads

SPC]. AstraZeneca UK Limited. 2015; LDL: Low Density Lipoprotein; HDL: High Density Lipoprotein
Dapagliflozin Add-on treatment: Significantly Reduced UACR

UACR Absolute UACR Absolute

change : -3.7 mg/g change : 0.82 mg/g

53.3% patients showed improved urine

albumin-to-creatinine ratio (UACR)
https://www.jocmr.org/tables/jocmr3419wt.htm; UACR: Urine Albumin Creatinine Ratio; SGLT2i: Sodium Glucose Co-Transporter 2 Inhibitor;
Dapagliflozin : Stable Insulin Dose Over 2 Years in T2DM

0.8% reduction in HbA1c, -0.9-1.4 kg weight reduction &

reduced hypoglycemia in T2DMs inadequately
controlled with high dose of Insulin

Diabetes, Obesity & Metabolism 16:124-136,2014; HbA1c: Glycosylated Hemoglobin; T2DM: Type 2 Diabetes Mellitus;
Dapagliflozin : Excellent Glycemic Control With Insulin Dose
Reduction in T1DM (52 Weeks Study)

8% - 14% insulin dose reduction

Drugs (2019) 79:1877–1884; T1DM: Type 1 Diabetes Mellitus

Steps to prevent genital infections in patients on SGLT2i

Proper Personal Hygiene to avoid any Drink 2 glasses of water half an hour
UTI/fungal infections before taking the dose

UTI: Urinary Tract Infection

 US FDA & EMA have given approval for Dapagliflozin Propanediol
Monohydrate NOT TO DAPAGLIFLOZIN. All international studies are
conducted with Dapagliflozin Propanediol Monohydrate

• NOT WITH DAPAGLIFLOZIN

• DAP exhibits high hygroscopicity and it uptakes 7.4% water at 95% RH at
250C
• In contrast, DAP-PDO-H2O uptakes 2% water at 95% RH at 250C

• As compared to the amorphous DAP,

• DAP-PDO-H2O has a multi-component crystal structure leading to improved
solubility leading to better BA

European Journal of Pharmaceutical Sciences 104 (2017) 255–261; DAP: Dapagliflozin; BA: Bio Availability; RH: Relative Humidity; USFDA: United States Food and Drug Administration; EMA: European Medical Association
 Cardio-Reno protective benefits : Confirmed by 3 major landmark studies

T2DMs : Effective glycemic control as a monotherapy / add-on therapy

SGLT2 inh T1DMs : Reduces insulin dose & offers additional glycemic control

High safety profile: Least hypoglycemic incidences with reduction in

weight & SBP

Dapagliflozin Propanediol Monohydrate: Proven stable formulation with

3 years stability data

Drugs 2019 79:1135-1146; T2DM: Type 2 Diabetes Mellitus; T1DM: Type 1 Diabetes Mellitus; SBP: Systolic Blood Pressure
Comparison of key pharmacological differences between SGLT 2 INHIBITORS

Empaglifloazin have highest selectivity for SGLT2 receptor

 Heart failure outcome with SGLT2 inhibitors
Hospitalisation for heart failure EMPA-REG OUTCOME study1
Adults with type 2 diabetes and established CV disease
CV death, non-fatal MI, or non-fatal stroke

Patients with event (%)

20
HR 0.86
(95.02% CI: 0.74, 0.99) Placebo
15
p<0.001 for non-inferiority
p=0.04 for superiority
10

HR 0.65 5 Empagliflozin
(95% CI 0.50, 0.85);
p=0.002*
0
0 6 12 18 24 30 36 42 48
Patients at risk: Months
Empagliflozin 4687 4580 4455 4328 3851 2821 2359 1534 370
Placebo 2333 2256 2194 2112 1875 1380 1161 741 166
RRR for HHF is 35%; rates of HHF: 2.7% (empagliflozin) vs 4.1% (placebo); ARR for HHF is 1.4%
*Nominal p-value. Cumulative incidence function
ARR, absolute risk reduction; CV, cardiovascular; HHF, hospitalisation for heart failure; RRR, relative risk reduction
Zinman B et al. N Engl J Med 2015;373:2117 1. Zinman B et al. N Engl J Med. 2015;37:2117–2128. 2. Neal B et al. N Engl J Med. 2017;377:644-657.

Hospitalization for heart failure and other adverse events were significantly
reduced in patients with empagliflozin as compared to placebo group.
 Summary of CV outcome trials with SGLT2 inhibitors
EMPA-REG DECLARE-
CANVAS2 CANVAS-R3 CREDENCE4 Ertugliflozin CVOT6
OUTCOME®1 TIMI 585
Interventions Empagliflozin/ Canagliflozin/ Canagliflozin/ Canagliflozin/ Dapagliflozin/ Ertugliflozin/
placebo placebo placebo placebo placebo placebo
Main inclusion Est. vascular Est. vascular Est. vascular Stage 2 or 3 CKD + High risk for CV Est. vascular
criteria complications complications or ≥ complications or ≥ macroalbuminuria events complications
2 CV risk factors 2 CV risk factors

No. of patients 7034 4339 5700 3627 17,150 3900

Primary outcome 3P-MACE 3P-MACE Progression of ESKD, 3P-MACE 3P-MACE

albuminuria S-creatinine
doubling, renal/CV
death
Key secondary 4P-MACE Fasting insulin Regression of 4P-MACE + HHF 4P-MACE + HHF + 4P-MACE
outcome secretion, albuminuria, revascularisation
progression of change in eGFR
albuminuria
Target no. 691 ≥ 420 TBD TBD 1390 TBD
of events
Estimated ~3 years 6–7 years 3 years ~4 years
Adapted from Inzucchi et al. Diabetes Vasc Dis Res 2015;12:90‒100. 1. Zinman et al. Cardiovasc 4–5 years
Diabetol 5–7 years
median FU
2014;13:102.
38
Estimated 2. NCT01032629.
20153. NCT01989754.
Apr 4.
2017
NCT02065791. 5.2017 2019
NCT01730534. 6. NCT01986881. 2019 2021
completion
 Empagliflozin pooled Phase III placebo-corrected change from
baseline in HbA1c*
Pooled data Empagliflozin 10 mg QD Empagliflozin 25 mg QD
Insulin
Pooled1 Monotherapy2 MET3 PIO4 MET + SU5 Mild RI7
0.0 78-week6
Adjusted mean (SE) difference vs

in change from baseline in HbA1c

-0.2

-0.4

-0.6
-0.48 -0.46
placebo

-0.57 -0.52
-0.8 -0.62 -0.64 -0.61 -0.64 -0.59 -0.62
(%)

-0.68 -0.68
†
-1.0 -0.74
†
† -0.85
-1.2 †

Patients, 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 7.96

Reduction in the HbA1c level by empagliflozin was significantly higher as

compared to placebo and glycemic control proportional to dose of empagliflozin.
 Empagliflozin versus glimepiride: Change from baseline in visceral and
subcutaneous fat at Week 104*
abdominal visceral adipose tissue (cm2)
Mean (95% CI) change from baseline in

Mean (95% CI) change from baseline in

Glimepiride Glimepiride

subcutaneous adipose tissue (cm2)

(n=34) Empagliflozin (n=34) Empagliflozin
30 (n=39) 40 17.7 (n=39)
11.2
20 30
20
10 10
-22.2 cm2 -40.0 cm2
0 (95% CI: -37.1, -7.4) 0 (95% CI: -58.9, -21.1)
p=0.0039 p<0.0001
-10 -10
-20
-20 -30
-30 -11.0 -40 -22.3
Mean baseline (95% CI) Mean baseline (95% CI)
174.4 156.7 337.0 346.3
(143.3, 205.5) (138.6, 174.8) (297.8, 376.1) (312.5, 380.2)
CI, confidence interval; EMPA, empagliflozin; H2H, head-to-head
*Dedicated sub-study using magnetic resonance imaging; patient participation was optional.
Ridderstråle M, et al. Lancet Diabetes Endocrinol. 2014;2:691‒700. Supplementary appendix.
 Empagliflozin pooled safety and tolerability data: Summary of
adverse events
Empagliflozin
Placebo 10 mg QD 25 mg QD
n (%) (n = 3695) (n = 3806) (n = 4782)
Patients with any AE 2621 (70.9) 2686 (70.6) 3499 (73.2)
Patients with AE(s) leading to discontinuation
208 (5.6) 191 (5.0) 255 (5.3)
of trial drug
Patients with serious AE(s) 494 (13.4) 393 (10.3) 573 (12.0)
One or more severe AE(s) 324 (8.8) 258 (6.8) 373 (7.8)
Deaths 29 (0.8) 19 (0.5) 26 (0.5)
250 215.1
Rate per 100 patient-

200 176.3 167.1 Placebo (n = 3695)

150 Empagliflozin 10 mg QD (n = 3806)
Empagliflozin 25 mg QD (n = 4782)
100
years

50 6.4 5.0 4.5 16.4 10.7 10.8

0
Patients with any AE Patients with serious AE

Overall adverse events was lowest with Empagliflozin 25 mg

followed by Empa 10 mg and placebo in increasing order.
Empagliflozin significantly reduces the incidence of nephropathy, prevent
progression to microalbuminuria, and prevent composite renal failure
HbA1c reduction, weight loss, SBP reduction was significantly higher with Empa
25 mg, followed by Empa 10 mg and placebo in decreasing order
A study published by Elsevier
suggest that after 52 weeks of
follow-up empagliflozin and
dapagliflozin both groups showed
significant reductions in HbA1c and
FPG, but the reduction was greater
in the empagliflozin group (P <
0.001). Hence, empagliflozin was
more effective in reducing
HbA1c and improving other
cardiometabolic parameters than
dapagliflozin
 Take home message
 SGLT2 inhibitors are a new strategy for the treatment of T2DM.
 Their action is based on the blockage of SGLT2 of renal tubular cells which as a result has glycosuria and excess
calories' loss.
 The accompanying beneficial effects of this phenomenon are :
 Regulation of fasting and postprandial blood glucose levels
 HbA1c reduction
 Body weight loss
 Reduction of SBP and cardiovascular benefit
 However it is associated with genital and urinary tract infections.

 SGLT2 inhibitor can be combined with the existing treatments for T2DM and can be an effective weapon for
the management of uncontrolled diabetes.
Thank you