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.