SGLT2 inhibitors - Beyond

Glycemic control
 Holy Grail
• In medieval legend- the cup or platter used by
Christ at the Last Supper, and in which Joseph of
Arimathea received Christ's blood at the Cross.
• Holy Grail rests inside the Basilica of San Isidoro
in the northern Spanish city of León.

• Often used to denote an elusive object or goal

that is sought after for its great significance.
 From the triumvirate to the ominous octet: a
new paradigm for the treatment of T2D Decreased
incretin effect

Increased
Decreased lipolysis
insulin secretion

Increased Islet α-cell Increased

glucagon Hyperglycaemia glucose
secretion re-absorption

Increased Decreased
hepatic glucose
glucose uptake
production

Neurotransmitter
dysfunction
T2D, Type 2 Diabetes.
1. Adapted from: DeFronzo RA. Diabetes. 2009;58:773–795; 2. Adapted from: Tahrani AA, et al. Lancet. 2011;378:182–197.
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 SGLT2 expression is mainly in the kidney

SGLT2 expression
SGLT2 RNA

is mainly in the kidney

SGLT1 expression is mainly

SGLT1 RNA

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.
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 SGLT 1,2

• SGLTs transfer glucose and sodium from the lumen into the cytoplasm of tubular cells through
a secondary active transport mechanism
• At the basolateral membrane GLUT2 transfers the intracellular glucose to the interstitium
and plasma by a facilitated transport process (via a Na+/K+ ATPase)

GLUT2, glucose transporter 2; SGLT, sodium glucose cotransporter.

1. Adapted from: Wright EM, et al. Physiology 2004;19:370–76; 2. Bakris GL, et al. Kidney Int 2009;75;1272–1277.
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Glucose re-absorption is up regulated in diabetes via SGLT2

SGLT2 mRNA1 TmG increases in T2D2

Chart pTitle
< 0.05
440
423.9
5 * 420

400 398.1
4

Tm (mg/min)
380
Fold increase

3
360
2
340
1
320

0 300
Control T2D Control subjects Patients with T2D
(n = 9) (n = 12)

T1D, Type 1 Diabetes; T2D, Type 2 Diabetes; TmG, maximal transport rate for glucose. 1) Mogensen CE. Scand J Clin Lab Invest. 1971;28:101–109. 2). Farber SJ, et al. J Clin
Invest. 1951;30:125–129. SGLT2, sodium glucose cotransporter; T2D, Type 2 Diabetes; CPM, counts per minute. *p < 0.05–0.01. Data presented are mean
(SE).Rahmoune H, et al. Diabetes. 2005;54:3427–3434 AMG: analogue methyl-α-D-[U14C]-glucopyranoside .
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 Ideal oral agent
• Efficacious.
• No hypoglycemia
• No weight gain
• C.V benefit
• Renal benefit
• Cost effective
• Durability
Gliflozin inhibits SGLT-2 by an insulin-independent mechanism
to remove excess glucose in the urine
 SGLT2 Inhibitors
Compounds Development Status
Europe EMA approval given in November 2012
Dapagliflozin
USFDA approval given in January 2014
FDA approval given in March 2013
Canagliflozin EMA approval given in November 2013
DCGI/CDSCO approval given in November 2014
EMA approval given in May 2014
Empagliflozin
FDA approval given in August 2014
Launched in Japan
Ipragliflozin
Japanese MHLW approval given in January 2014
Pre-registration Marketing application made to MHLW,
Luseogliflozin
Japan in April 2013
Pre-registration Marketing application made to MHLW,
Tofogliflozin
Japan in June 2013

Ertugliflozin Phase III trials commenced in October 2013

Sotagliflozin Phase III

Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014 Sep
11;8:1335-80
 Change in Body Weight: All clinical trials
Add-on combinations with

Monotherapy Metformin SU Met/SU Met/Pio Insulin Current Therapy

(DIA3005) (DIA3006) (DIA3008) (DIA3002) (DIA3012) (DIA3008) in Older Subjects
N =584 N = 1284 N = 127 N = 469 N = 342 N = 1718 (DIA3010)
BL Mean N = 714
Weight (kg) 86.8 87.2 83.0 92.8 94.1 97.0 89.5
% Change in Body Weight (95% CI)
Placebo-subtracted LS Mean

CANA 100 mg CANA 300 mg

* p <0.001; † p <0.05
Based on ANCOVA models, data prior to rescue (LOCF)
Janssen Core Slides for the JanuStenlof et al. Diabetes Obes Metab. 2013 Apr;15(4):372-82. doi: 10.1111/dom.12054. Epub 2013 Jan 24
Matthews D. et al. Poster presented at the 48th European Association for the Study of Diabetes (EASD);2012;Oct.1-5: Berlin, Germany, (P764).
Forst T et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain, (P64).
Bode B. et al. Poster presented at the 48th European Association for the Study of Diabetes (EASD);2012;Oct.1-5: Berlin, Germany, (P765).
Wilding J et al. Poster presented at the 4th World Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy), 2012;Nov.8-11; Barcelona, Spain,
(P73).ary 10, 2013 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee
 Weight reduction majorly due to loss of fat
mass
Change in Body Composition
(DXA Analysis Subgroup)
N=312

Glimepiride
CANA CANA
100 mg 300 mg

Lean Mass Fat Mass

Weight changes relative to glimepiride in DXA analysis subgroup

(-5.3 kg and -5.0 kg for CANA 100 mg and 300 mg, respectively)
were similar to overall cohort.

Cefalu et al. Lancet 2013; 382: 941–50

 Canagliflozin Effect on blood pressure
Systolic BP Diastolic BP*
Baseline (mmHg) 127.7 126.7 128.5 77.4 77.7 79.1

†
P <0.001 vs placebo; *Statistical comparison for Canagliflozin 100 and 300 mg vs placebo not performed (not pre-specified).
BP, blood pressure; LS, least squares; SE, standard error; PBO, placebo; CANA, canagliflozin; mITT, modified intent-to-treat; LOCF, last
observation carried forward.

Minimal changes in pulse rate were observed with canagliflozin 100 and 300 mg
compared with placebo (−1.6, −0.5 and 1.4 beats per min, respectively)
Stenlof et al. Diabetes Obes Metab. 2013 Apr;15(4):372-82.
 Summary of Adverse Drug Reactions :
≥2% and >Placebo in the Placebo-controlled Studies Dataset

Placebo CANA 100  mg CANA 300 mg

N=646 N=833 N=834
Adverse Event n (%) n (%) n (%)
Gastrointestinal Disorders
Constipation 6 (0.9) 15 (1.8) 19 (2.3)
Thirst 1 (0.2) 23 (2.8) 19 (2.3)
Renal and Urinary Disorders
Polyuria or pollakiuria 5 (0.8) 44 (5.3) 38 (4.6)

Urinary tract infection (UTI) 26 (4.0) 48 (5.8) 36 (4.3)

Genital Tract Infections
Balanitis or balanoposthitis 2 (0.6) 17 (4.2) 15 (3.7)
Vulvovaginal candidiasis 10 (3.2) 44 (10.4) 49 (11.4)

Other ADR’s: Hypotension, Impaired renal function, Hypoglycemia with concomitant insulin or insulin secretatgoues, Hypersensitivty
reactions, Increased LDL-C, Pancreatitis, Bone fractures
Increases in: Potassium, Magnesium, Phosphate, and Hemoglobin
 Summary of Overall AEs and Selected AEs in the
Overall Population and Indian Subgroup (Safety
Population)
Overall population Indian subgroup
Patients, n (%) CANA CANA CANA CANA
Non-CANA 100 mg 300 mg Non-CANA 100 mg 300 mg
(n = 3,262) (n = 3,092) (n = 3,085) (n = 349) (n = 342) (n = 347)
Any AE 2,160 (66.2) 2,083 (67.4) 2,133 (69.1) 206 (59.0) 206 (60.2) 219 (63.1)
AEs leading to discontinuation 121 (3.7) 129 (4.2) 173 (5.6) 5 (1.4) 6 (1.8) 14 (4.0)
AEs related to study drug* 585 (17.9) 765 (24.7) 912 (29.6) 54 (15.5) 53 (15.5) 68 (19.6)
UTI rates were similar
Serious AEs 271 (8.3)in the
239overall
(7.7) population
249 (8.1) and the
24 (6.9) Indian16 (4.6)
24 (7.0)
Deaths 18 (0.6) 12 (0.4) 13 (0.4) 2 (0.6) 2 (0.6) 2 (0.6)
subgroup
Selected AEs
UTI Rates of genital mycotic
141 (4.3) infections,
Genital mycotic infection
171 (5.5) osmotic
175 (5.7) diuresis–
13 (3.7) and
21 (6.1) volume
20 (5.8)

Male† 20 (0.6) 104 (3.4) 140 (4.5) 0 4 (1.2) 11 (3.2)

Female‡ 31 (1.0) 161 (5.2) 162 (5.3) 1 (0.3) 6 (1.8) 7 (2.0)
depletion–related AEs were lower in patients from India
Osmotic diuresis–related AEs§
Volume depletion–related AEs||
48 (1.5)
49 (1.5)
174 (5.6)
71 (2.3)
177 (5.7)
105 (3.4)
1 (0.3)
0
2 (0.6)
3 (0.9)
5 (1.4)
5 (1.4)

*Possibly, probably, or very likely related to study drug, as assessed by investigators.

†
‡
Including balanitis, balanoposthitis, genital infection fungal, and posthitis. Incidence of GMIs
Including genital infection fungal, vaginal infection, vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginal pruritus, and
in Asian patients
vulvovaginitis.
§
Including dry mouth, dry throat, micturition disorder, micturition urgency, nocturia, pollakiuria, polydipsia,Type ofthirst,
polyuria, GMI tongue dry, Placebo Cana 100
and urine output increased.
||Including dehydration, dizziness postural, hypotension, orthostatic hypotension, orthostatic intolerance, presyncope, and syncope.
Male GMI 0 0.8 %
Female GMI 2% 1%
Kumar et al. Poster presented at IDF 2014 Diabetes, Obesity and Metabolism 17: 23–31, 201
 Liver dysfunction

  Canagliflozin Dapagliflozin Empagliflozin

Metbolism Mainly hepatic Mainly hepatic Dual renal and

97:3 hepatic 50:50

Severe Hepatic In lower dose

Do not use Do not use
Dysfunction 5 mg

• No dose adjustment for CANA is necessary in

patients with mild to moderate hepatic
dysfunction
Disclaimer: Data are from individual prescribing information of respective drugs,
and should not to be used as the basis for direct Head-to-Head comparisons among
SGLT2 agents
Cardiovascular and renal outcome in EMPA
Reg trial
DECLARE-TIMI
VERTIS-CV
Proposed pathways of renal protective effects
with SGLT2i

Curr Diab Rep. 2018 Mar 27;18(5):27

META-ANALYSIS
 Ideal oral agent
• Efficacious ---- Yes
• No hypoglycemia----Yes
• No weight gain-----Yes
• C.V benefit------Yes
• Renal benefit-----Yes
• Cost effective-----Yes
• Durability ------Yes
Glucose lowering medication in type 2 diabetes
overall approach
Thank you
Appropriate use of SGLT2 inhibitors: Not indicated in
• Patients suffering moderate (CKD Stage 3B) to severe (Stage 4) impaired renal
function (estimated glomerular filtration rate < 45 mL/min/1.73 m2 or
creatinine clearance < 45 mL/min.
• Patients with end-stage renal disease (ESRD) or on dialysis
• Elderly patients (aged ≥ 85 years) at risk of experiencing volume depletion
events/hypotension due to co-morbidities or related medications.
• Pregnant and breast-feeding women
• Patients with Type 1 Diabetes or for the treatment of diabetic ketoacidosis

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