Inhibidores de SGLT2.
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The kidneys filter and reabsorb 180 g of glucose per day in the nephrons by active transport 180 g glucose filtered each day
Glomerulus
Proximal tubule
S1
Distal tubule
Collecting duct
S2
Glucose filtration
SGLT2 90%
SGLT1 10%
S3
Glucose reabsorption Loop of Henle Up to ~90% of glucose is reabsorbed from the S1/S2 segments
~10% of glucose is reabsorbed from the S3 segment
Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Brown GK. J Inherit Metab Dis 2000;23:237–246.
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Special glucose transporters (SGLT) are responsible for this reabsorption in the kidneys
Sodium-glucose co-transporters (SGLTs) are present throughout the body Major site of action
Function
SGLT1
Small intestine, heart, trachea and kidneys
Co-transports sodium, glucose and galactose across the brush border of the intestine and proximal tubule of the kidneys
SGLT2
Kidney
Co-transports sodium and glucose in the S1 segment of the proximal tubule of the kidneys
SGLT3
Small intestine, uterus, lungs, thyroid and testis
Transports sodium (not glucose)
SGLT4
Small intestine, kidneys, liver, stomach and lung
Transports glucose and mannose
SGLT5
Kidneys
Unknown
SGLT6
Spinal cord, kidneys, brain and small intestine
Transports myoinositol and glucose
Bays H. Curr Med Res Opin 2009;25:671–681; Abdul-Ghani MA, et al. Endocr Pract 2008;14:782-790.
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Transporter
SGLT2 and GLUT2 mechanism of transport Basolateral membrane
Tubular lumen
Interstitial space
SGLT2 GLUT2
Na+ Glucose
Glucose Glucose Na+
Na+
K+ K+
Tight junction Lateral intercellular space Adapted from Wright EM, et al. Physiology 2004;19:370–376;
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Na+/K+ pump
SGLT2 inhibition reduces renal glucose reabsorption and increases glucose elimination
Glomerulus
Proximal tubule
Distal tubule
Collecting duct
S1
Glucose filtration
SGLT2
Reduced glucose reabsorption
SGLT1
S3
SGLT2 inhibitor
Loop of Henle
Increased glucose excretion
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Wright EM. Am J Physiol Renal Physiol 2001;280:F10–8; Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; Han S. Diabetes 2008;57:1723–1729.
Development of SGLT2 inhibitors The search for a potent, selective SGLT2 inhibitor‌.from apple trees to candidate drugs
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Discovery of phlorizin by French chemists in the early 1800s Isolated from apple tree bark (1835)
Glycosuric effect revealed (1865)
Renal effects identified in rat (1903) and man (1933)
Antidiabetic effect discovered (1987) and SGLT2 Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21:31–38.
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Found to inhibit SGLT1
To make a long story short - from phlorizin to dapagliflozin - the best clinical candidate Replace with lipophilic group
Shorten spacer
Remove hydroxyl to increase lipophilicity Change position of attachment
Phlorizin
Excise intervening atom
Replace with a lipophilic small group
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Dapagliflozin
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Sergliflozin-A
Dapagliflozin – An extensive clinical program 14 Phase 3 double-blind, randomised, controlled clinical trials >5000 randomised patients >30% of patients originating from Europe
Early disease
Advanced Disease
Treatment-naive patients
Add-on after initial treatment failure
Combination with metformin as initial therapy
Versus SU - added to: • Metformin
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Safety and efficacy versus placebo: • Patients with moderate renal insufficiency
• Patients at increased risk of CV events
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Monotherapy versus placebo
Versus placebo - added to: • Metformin • Sulphonylurea (SU) • Insulin • TZD • DPP4 inhibitor
Special at-risk populations
Sustained long-term efficacy of dapagliflozin as add-on to metformin (1) Mean change from baseline in HbA1c (102 weeks) Week 24
Week 50
Week 102
Adjusted mean change from baseline at week 102 (95% CI)
0.2
0.02 (-0.20,0.23)
Adjusted mean change from baseline in HbA1c (%)
0.0
-0.2
-0.4
-0.48 (-0.68, -0.29) -0.6
-0.58 (-0.77, -0.39)
-0.8
-0.78 (-0.97, -0.60)
-1.0
Placebo
0
16
32
48
64
80
96
112
5 mg/d
Time (weeks) 10 mg/d Bailey CJ, et al. Lancet 2010;375:2223–2233. Bailey CJ et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 988-P].
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2.5 mg/d
-1.2
Consistent reductions in body weight with dapagliflozin Baseline Weight
24-wk Monotherapy
24-wk add-on to Met2
52-wk add-on to Met3
24-wk add-on to Glim4
24 wk-add-on to Ins5
24-wk add-on to Pio6
24-wk Dapa + Met XR7
90.2kg
88kg
85.9kg
81.1kg
93.8kg
86.3kg
81.1kg
1.64
24- and 52-week adjusted from baseline weight (kg)
1.44
0.02 -0.14
*
-0.72
-0.89
-1.36
-1.67 -2.19
-2.26 -2.86
-3.16 NS
*
-3.22
*
* *
*p <0.001 vs. comparator NS: not significant 1Ferrannini
E, et al. Diabetes Care 2010;33:2217–2224; 2Bailey CJ, et al. Lancet 2010;375:2223–2233; 3Nauck MA, et al. Diabetes Care 2011;34:2015-2022; K, et al. Diabetes Obes Metab 2011;13:928-938 5Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21–A22 [Abstract 0078-OR]; 6Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24–28 June, 2011 [Abstract 0986-P]; 7Henry R, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 Abstract 307-OR. 4Strojek
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*
-3.33
Dapagliflozin reduces total body weight and fat mass at week 24 DXA: dual X-ray absorptiometry
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Langkilde A.M, Study D1690C00012. Internal Presentation January, 2011.
Blood pressure reductions consistently observed with dapagliflozin in phase III studies Mean changes in systolic blood pressure (mmHg) Monotherapy AM only1
Add-on to Met vs. SU2
Add-on to Met3
Add-on to SU4
Add-on to TZD5
48 week add-on to insulin6
1
0
-1
-2
-3
-4
-5 -6
1Ferrannini
E, et al. Diabetes Care 2010;33:2217-2224; 2Nauck MA, et al. Diabetes Care 2011;34:2015-22; 3Bailey CJ, et al. Lancet 2010;375:2223-33; K, et al. Diabetes Obes Metab 2011;13:928-38; 5Rosenstock J, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 0986-P]; 6Wilding J, et al. Diabetes 2010;59 (Suppl 1):A21-A22 [Abstract 0078-OR]. 4Strojek
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Week 24 or 48 mean change from baseline mmHg
2
Events of Genital Infections Summary of 102 weeks
24 weeks
102 weeks
10
Patients (%)
All mild-to-moderate in intensity with dapa Most responded to initial course of standard treatment
8.2
8 6
4.8
4 2 0
1.3
0.9 Dapa 10mg
Placebo
Dapa 10mg
Placebo
Most patients who had an event had only one over 102 weeks (74.6% dapa vs 77.8% placebo)
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Rarely led to discontinuation (0.2%)
Events of Urinary Tract Infections Summary All mild-to-moderate in intensity with dapa
24 weeks
Most responded to initial course of standard treatment
102 weeks
Patients (%)
10 7.7
8
6
6.3 4.3
3.7
Dapa 10mg
Placebo
4 2 0
Dapa 10mg
Placebo
Rarely led to discontinuation (0.3%) Most patients who had an event had only one over 102 weeks (74.6% of dapa vs 86.4% placebo)
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Upper UTI were rare and balanced between groups
Dapagliflozin has a low propensity to cause hypoglycaemia in patients with type 2 diabetes 70 60 50 40 30 20 10 0 PLA
Pattern of hypoglycaemic episodes in relation to change in HbA1c
DAPA 10 mg
PLA
DAPA 10 mg
PLA
DAPA 10 mg
Monotherapy* (24 weeks)
Add-on to metformin (102 weeks)
Add-on to glimepiride (48 weeks)
DAPA PLA 10 mg
DAPA PLA 10 mg
DAPA PLA 10 mg
PLA DAPA 10 mg
Add-on to insulin Âą other OADS (48 weeks)
DAPA PLA 10 mg
GLI
DAPA
vs. glipizide (52 weeks)
GLI
DAPA
0.0 -0.1 -0.2 -0.3 -0.4 -0.5 -0.6
-0.8 -0.9
DAPA: dapagliflozin; GLIP: glipizide; PLA: placebo; OAD: oral antidiabetic drug. Rohwedder K, et al. 71st ADA Scientific Sessions, San Diego, 24-28 June, 2011 [Abstract 1042-P].
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-0.7
*Morning treatment groups only
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Add-on to Met Compared to SU
004
Results (continued) Glycemia HbA1c adjusted mean change from baseline with dapagliflozin was statistically non-inferior to glipizide (both −0.52%) at 52 weeks.3
Figure 2. Change in HbA1c over Time
Initial HbA1c reduction at 52 weeks was sustained with dapagliflozin but this effect had attenuated with glipizide at 104 weeks (Figure 2). HbA1c difference vs glipizide at 104 weeks −0.18% (95% CI; −0.33, −0.03).
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Add-on to Met Compared to SU
004
Results (continued) Weight Initial weight reduction with dapagliflozin and weight gain with glipizide at 52 weeks remained stable at 104 weeks (Figure 4).
Figure 4. Change in Total Body Weight over Time
Weight difference vs glipizide at 104 weeks −5.06 kg (95% CI; −5.73, −4.4).
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All Disease Education materials must be reviewed in accordance with local review requirements
All Disease Education materials must be reviewed in accordance with local review requirements
All Disease Education materials must be reviewed in accordance with local review requirements
All Disease Education materials must be reviewed in accordance with local review requirements
Resumen. Nuevo grupo de tto oral para la diabetes tipo 2.
Eficacia similar a otros ADO, mรกs sostenibilidad de efecto que SU. No hipoglucemias.
Perdida de peso de entre 1-3kg Efectos adversos frecuentes de infecciones genitales y menos frecuentes urinarias. Combinable con otras drogas orales e incluso con insulina.
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