Transcript Efficacy and Safety of Vildagliptin in NODAT – a

Efficacy and Safety of Vildagliptin in
NODAT – a randomized, doubleblind, placebo-controlled trial
Haidinger et al
AJT 2014; 14: 115-123
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
12%
>10.9
GFR<30
LFTS
Stable 3 months renal
function
OGTT – 0 & 3 months
1°outcome:
OGTT – 0 & 3 months
1.1mmol/l (20)
difference
2°outcomes:
STOP DRUG 1 month, then OGTT 4 months – FPG, HbA1c, fasting insulin, rate S/E, ∆GFR,
ACR, ∆LFTs & CNI levels
Primary outcome
-0.91mmol/l
-0.18mmol/l
-4mmol/l
-0.3mmol/l
• 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”
Insgenic Index - insulin secretion as a marker of β cell function
Suppl. Table S2: calculated metabolic parameters
Baseline
Vildaglitpin
OGIS (mL min-1m-2)
3 months
4 months
p-value
p-value
Baseline-to-3
mo
Baseline-to-4
mo
292.3 ±18.6 (N=12)
335.4 ±18.90 (N=13)
273.3 ±15.80 (N=14)
0.118
0.308
Quicki
0.444 ±0.00 (N=14)
0.464 ±0.02 (N=15)
0.437 ±0.02 (N=15)
0.525
0.674
ISIcomp
23.6 ±4.72 (N=12)
23.5 ±5.15 (N=13)
18.6 ±3.76 (N=14)
0.988
0.829
AUCg 0-120 (g/dL 2h)
26.7 ±1.44 (N=12)
21.9 ±1.49 (N=13)
26.8 ±1.47 (N=14)
0.031
0.923
AUCi 0-120 (g/dL 2h)
3.4 ±1.02 (N=12)
5.2 ±1.35 (N=13)
5.1 ±1.57 (N=14)
0.313
0.436
AUCcp 0-120 (g/dL 2h)
1.0 ±0.11 (N=11)
1.1 ±0.13 (N=13)
1.1 ±0.12 (N=14)
0.591
0.195
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)
0.052
0.321
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)
0.047
0.950
Hepatic Extraction (%)
72.9 ±5.65 (N=11)
63.5 ±6.38 (N=13)
68.8 ±4.46 (N=13)
0.288
0.252
OGIS (mL min-1m-2)
285.4 ±16.00 (N=10)
310.0 ±18.10 (N=12)
293.9 ±19.90 (N=8)
0.331
0.727
Quicki
0.427 ±0.02 (N=12)
0.410 ±0.02 (N=16)
0.411 ±0.02 (N=13)
0.527
0.918
ISIcomp
13.7 ±2.8 (N=10)
11.2 ±1.44 (N=12)
11.9 ±3.42 (N=6)
0.422
0.208
AUCg 0-120 (g/dL 2h)
27.4 ±1.38 (N=10)
24.8 ±0.99 (N=12)
26.1 ±1.68 (N=8)
0.129
0.549
AUCi 0-120 (g/dL 2h)
4.2 ±0.74 (N=10)
4.8 ±0.70 (N=12)
5.0 ±0.83 (N=6)
0.560
0.297
AUCcp 0-120 (g/dL 2h)
1.1 ±0.13 (N=10)
1.3 ±0.14 (N=12)
2.1 ±0.08 (N=6)
0.365
0.256
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)
0.548
0.541
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)
0.813
0.713
Hepatic Extraction (%)
65.2 ±3.63 (N=10)
64.8 ±2.72 (N=12)
59.2 ± 4.93 (N=6)
0.920
0.285
Placebo
• 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)