Transcript Appendix_Figures
Effect of SGLT-2 inhibitors is different from that of carbohydrate restriction 140 130
40 35 30 25
FBG, insulin, and glucagon con. during use of SGLT-2 inhibitors
FBG(mg/dL) insulin glucagon
90 80 120 110
20 15 10
70 60 100
5 0 Before tofogliflozin(20) 1st day tofogliflozin(20) 2nd day OFF ipragliflozin(50) 3days ipragliflozin(100) 4days OFF 7 days after
50
per day Sodium NaCl 1170 yen Calorie Protain Fat Carbohydrate 1722 kcal 31 % 13 % 57 % 4266 mg 10.7
g Although restriction of carbohydarate reduces post-prandial BG,
58M, diet:1722kcal/day
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
(mg/dL) 130 125 120 115 110 105 FPG FPG(+beer) FBG (3-4 days) mean ± SD 100 Luseogliflozin 2.5mg
Luseogliflozin 5mg ipragliflozin 50mg ipragliflozin 100mg dapagliflozin 10mg tofogliflozin 20mg(2nd) Mean BG (CGM) (3-4 days) mean ± MAGE 160 150 140 130 120 110
Cost 205.5 308.3 205.5 411.0 308.3 205.5 yen per day
100 Luseogliflozin 2.5mg
Luseogliflozin 5mg ipragliflozin 50mg ipragliflozin 100mg dapagliflozin 10mg tofogliflozin 20mg(2nd)
Fasting urinary glucose excretion after
mg/gCr 18000
cessation of SGLT-2 inhibitors
16000 14000 12000 10000 8000 6000 4000 2000 0 luseogliflozin 2.5mg
luseogliflozin 5mg ipragliflozin 50mg ipragliflozin 100mg dapagliflozin 10mg tofogliflozin 20mg last dose off 1st off 2nd off 3rd Tofogliflozin has the shorter duration of life.
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.
3-1.86
× -
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.
3-1.86
×
Calculation of HOMA-IR (example)
-1.5
× log(fPG) rl=rp(=R)
，
fIRI=8 [
m
U/ml] [mmol/L] , fPG=6 Then, 0= 3-1.86 × log Thus,
R=2.1
8 -1.5
× log(6) 0.4
1.2
× 1 × R 1+ 0.1
1+ 14 0.4
6 8 +2 R (when fIRI=8
m
U/ml, fPG=108mg/dl(=6mmol/L)) 1+ 1 6 6
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.)
22 .
5
HOMA-IR=
fIRI
e
ln fPG fIRI fPG 22 .
5
HOMA-b%=
2 0 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.