Efficacy and Safety of Vildagliptin in NODAT – a randomized, double- blind, placebo-controlled trial Haidinger et al AJT 2014; 14: 115-123 Presented by.

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Efficacy and Safety of Vildagliptin in NODAT – a randomized, double- blind, placebo-controlled trial Haidinger et al AJT 2014; 14: Presented by Dr Sourabh Chand QEHB ST6/Clinical Academic Fellow

Introduction Post-transplant hyperglycaemia = morbidity, mortality – IFG – IGT Ischaemic heart disease HR 1.39 – NODAT premature graft failure – at 12yrs, 48% vs 70% without NODAT Ischaemic heart disease RR 3.21 Rx with T2DM strategies traditionally NODAT – insulin sensitivity vs secretion

OGTT – 0 & 3 months 1°outcome: 1.1mmol/l (20) difference Stable 3 months renal function STOP DRUG 1 month, then OGTT 4 months – FPG, HbA1c, fasting insulin, rate S/E, ∆GFR, ACR, ∆LFTs & CNI levels GFR<30 LFTS > % 2°outcomes:

-0.91mmol/l-0.18mmol/l-0.3mmol/l-4mmol/l Primary outcome OGTT 4 months no difference from baseline Lifestyle at 4 months (placebo) -2.2 mmol/l (±6)

HbA1c significantly different at 4 months (unsurprisingly) – “robust improvement”

Suppl. Table S2: calculated metabolic parameters Baseline3 months4 months p-value Baseline-to-3 mo p-value Baseline-to-4 mo Vildaglitpin OGIS (mL min-1m-2)292.3 ±18.6 (N=12)335.4 ±18.90 (N=13)273.3 ±15.80 (N=14) Quicki0.444 ±0.00 (N=14)0.464 ±0.02 (N=15)0.437 ±0.02 (N=15) ISIcomp23.6 ±4.72 (N=12)23.5 ±5.15 (N=13)18.6 ±3.76 (N=14) AUCg (g/dL 2h)26.7 ±1.44 (N=12)21.9 ±1.49 (N=13)26.8 ±1.47 (N=14) AUCi (g/dL 2h)3.4 ±1.02 (N=12)5.2 ±1.35 (N=13)5.1 ±1.57 (N=14) AUCcp (g/dL 2h)1.0 ±0.11 (N=11)1.1 ±0.13 (N=13)1.1 ±0.12 (N=14) Insgenic Indx/deltAUCi tot (pmoL INS/mmoL G)23.1 ±5.73 (N=12)69.3 ±20.96 (N=13)44.5 ±15.06 (N=14) Insgenic Indx/deltAUCcp tot (pmoL CP/mmoL G)0.31 ±0.05 (N=11)0.62 ±0.13 (N=13)0.36 ±0.06 (N=14) Hepatic Extraction (%)72.9 ±5.65 (N=11)63.5 ±6.38 (N=13)68.8 ±4.46 (N=13) Placebo OGIS (mL min-1m-2)285.4 ±16.00 (N=10)310.0 ±18.10 (N=12)293.9 ±19.90 (N=8) Quicki0.427 ±0.02 (N=12)0.410 ±0.02 (N=16)0.411 ±0.02 (N=13) ISIcomp13.7 ±2.8 (N=10)11.2 ±1.44 (N=12)11.9 ±3.42 (N=6) AUCg (g/dL 2h)27.4 ±1.38 (N=10)24.8 ±0.99 (N=12)26.1 ±1.68 (N=8) AUCi (g/dL 2h)4.2 ±0.74 (N=10)4.8 ±0.70 (N=12)5.0 ±0.83 (N=6) AUCcp (g/dL 2h)1.1 ±0.13 (N=10)1.3 ±0.14 (N=12)2.1 ±0.08 (N=6) Insgenic Indx/deltAUCi tot (pmoL INS/mmoL G)33.0 ±6.22 (N=10)39.9 ±8.84 (N=12)50.6 ±11.98 (N=5) Insgenic Indx/deltAUCcp tot (pmoL CP/mmoL G)0.34 ±0.05 (N=10)0.35 ±0.06 (N=12)0.46 ±0.09 (N=5) Hepatic Extraction (%)65.2 ±3.63 (N=10)64.8 ±2.72 (N=12)59.2 ± 4.93 (N=6) Insgenic Index - insulin secretion as a marker of β cell function

Will changes in lipid profile affect CV outcomes (esp metabolic syndrome)

Conclusions DPP-4 inhibitors stabilise incretin hormone GLP-1 Reduction in postprandial hyperglycaemia – Evidenced by 2hr OGTT results No increase in BMI, relatively safe profile Maybe more importantly in NODAT β cell protective effect No effect on short-term effects on insulin sensitivity

Remaining questions Long term effects – Especially on CV outcome – Lipid profile – Compare other hypoglycaemics (eg metformin (eGFR)) Is this a particular NODAT or metabolic syndrome profile? – 5 yrs post transplant, genetics, pancreatic decompensation – Deceased vs live donor – IFG/IGT patients Other parameters – HLA mismatch, rejection episodes, multivariate analysis (∆weight, diagnoses, Bp)