Appendix_Figures

Report
Effect of SGLT-2 inhibitors is different from that of carbohydrate restriction
140
130
120
110
100
40
35
30
25
20
15
10
5
0
per day
1170
Calorie
1722
Protain
31
Fat
13
Carbohydrate
57
Sodium
4266
NaCl
10.7
FBG, insulin, and glucagon con. during use of
SGLT-2 inhibitors
FBG(mg/dL)
90
insulin
glucagon
80
70
60
Before
tofogliflozin(20) tofogliflozin(20)
1st day
2nd day
OFF
ipragliflozin(50) ipragliflozin(100) OFF 7 days after
3days
4days
50
yen
kcal
%
%
%
mg
g
58M, diet:1722kcal/day
Although restriction of carbohydarate reduces post-prandial BG,
SGLT-2 inhibitors can protect pancreatic beta cells by reducing insulin requirement during fasting state.
Beer
Beer 330ml (alcohol 6%) caused
hypoglycemia
Report of adverse event
FBG (3-4 days)
(mg/dL)
mean ± SD
130
FPG
125
FPG(+beer)
120
115
110
105
100
Luseogliflozin Luseogliflozin ipragliflozin
2.5mg
5mg
50mg
ipragliflozin dapagliflozin tofogliflozin
100mg
10mg
20mg(2nd)
Mean BG (CGM) (3-4 days)
160
mean ± MAGE
150
140
130
120
110
Cost 205.5
308.3
205.5
411.0
308.3
205.5 yen per day
100
Luseogliflozin Luseogliflozin ipragliflozin
2.5mg
5mg
50mg
ipragliflozin dapagliflozin tofogliflozin
100mg
10mg
20mg(2nd)
Fasting urinary glucose excretion after
mg/gCr
cessation of SGLT-2 inhibitors
18000
last dose
off 1st
off 2nd
16000
off 3rd
14000
12000
10000
8000
6000
4000
2000
0
luseogliflozin
2.5mg
luseogliflozin
5mg
ipragliflozin
50mg
Tofogliflozin has the shorter duration of life.
ipragliflozin
100mg
dapagliflozin
10mg
tofogliflozin
20mg
Homeostasis model analysis (HOMA)
First description in 1979 Turner et al.
Turner R, Holman RR, Matthews D, Hockaday TR, Peto J : Insulin deficiency and insulin
resistance interaction in diabetes : estimation of relative contribution by feedback
analysis from basal plasma insulin and glucose concentrations.
(Metabolism 28:1086-1096, 1979.)
HOMA INDEX( Insulin resistance)=rl=rp
During basal steady state:
0= HGP & Splanchnic ( fPG,fIRI,rl) - Brain (fPG) - Muscle (fPG,fIRI, rp)
This is converted to the below formula. The unit of PG is mmol/min.
0=
0= 3-1.86
3-1.86×
log
log
fIRI
-1.5
-1.5 ×× log(fPG)
log(fPG)
rl
--
0.4
1.2
11
11
0.4
1.2
-××
××
0.1
14
0.1
0.4
66
14
0.4
1+
1+
1+
1+
1+
1+
fPG
fPG
fIRI
fPG
fIRI
fPG
+2
+2
rp
rp
Where
fIRI : fasting insulin conc. [mU/L], fPG : fasting PG [mmol/L]
rl : liver insulin resistance, rp : peripheral (or muscle) insulin resistance
Assuming that rl=rp(=R), the above formula can be solved for R after
substituting fPG and fIRI for actual measured values.
NOTE: the function above is in steady state.
Calculation of HOMA-IR (example)
0=
0= 3-1.86
log
3-1.86× log
fIRI
0.4
1.2
0.4
1.2
-1.5×
--1.5 × log(fPG)
log(fPG) -0.1
14
rl
0.1
14
1+
1+
1+
1+
fPG
fPG
rl=rp(=R),fIRI=8 [mU/ml] , fPG=6
××
fIRI
fIRI
+2
+2
rp
rp
[mmol/L]
11
11
××
0.4
6
0.4
1+
1+ 6
fPG
fPG
Then,
0= 3-1.86 × log
8
R
Thus,
0.4
-1.5 × log(6)
1+
0.1
6
-
1
1.2
14
1+
8
×
1
×
0.4
1+
+2
6
6
R
R=2.1
(when fIRI=8 mU/ml, fPG=108mg/dl(=6mmol/L))
It was possible to solve this equation by a large frame
computer in 1979. Now it is easy to solve this equation by
an EXCEL file.
Note: this calculation was estimated from the figures found in the original Metabolism paper
published in 1979. It may possible that Dr. Turner used a different formuola.
M. Matsuda: index of insulin secretion and insulin resistance, Internal Medicine [Japanese] 105:39-44, 2010.
Induction of Simplified HOMA formula
Reduced formula
(1985 by Matthews D et al.)
HOMA-IR=
fIRI
fIRI fPG
 ln fPG  
22.5e
22.5
HOMA-b%=
20  fIRI
fPG  3.5
Diabetologia 28:412-419, 1985
Personal communication
Subject: Re: HOMA-IR under use of SGLT-2 inhibitors
Hi,
HOMA doesn't give the correct answer when used with SGLT2 inhibitors since
the effect of insulin appears greater as more glucose is cleared... So you
need to use iHOMA, and change the renal threshold appropriately as described
in our Diabetes Care paper:
Hill NR, Levy JC, Matthews DR. Expansion of the homeostasis model assessment
of beta-cell function and insulin resistance to enable clinical trial outcome
modeling through the interactive adjustment of physiology and treatment
effects: iHOMA2. Diabetes Care. 2013; 36:2324-30.
Best wishes
David
Prof. David R. Matthews
Professor of Diabetes Medicine, University of Oxford Emeritus Chairman,
Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM).
Medical tutor, Harris Manchester College, Oxford
iHOMA2
http://www.ihoma.co.uk/
Diabetes Care. 2013; 36:2324-30.

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