Clinical trial simulation methods for estimating the impact of DPP-4 inhibitors on cardiovascular disease

Figures & data

Figure 1 The Kaplan–Meier cumulative incidence of MACE.

Notes: The solid black and dashed gray lines correspond to the standard of care and DPP-4 inhibitor treatment arms, respectively. MACE was defined as the first occurrence of MI, stroke, or cardiovascular death.
Abbreviations: MACE, major adverse cardiovascular events; MI, myocardial infarction.

Table S1 Characteristics of the studies included in the meta-analysis

Source	Number	Follow-up (week)	Group	Design	Added to	Baseline HbA1c %	Change in HbA1c%	Change in weight (kg)	Change in SBP (mmHg)
Pratley, 2010^Citation1	219	26	Sitagliptin 100 mg	R, O, P	Metformin	8.50	−0.9	−0.96	−0.94
Bergenstal, 2010^Citation2	166	26	Sitagliptin 100 mg	R, DB, P	Metformin	8.50	−0.9	−0.8	0.2
Ristic, 2005^Citation3	63	12	Vildagliptin 100 mg qd	R, DB, P	None	7.64	−0.53	“Not significant”
Pi-Sunyer, 2007^Citation4	83	24	Vildagliptin 50 mg bid	R, DB, P	Naive	8.40	−0.7	0
Pi-Sunyer, 2007^Citation4	91	24	Vildagliptin 100 mg qd	R, DB, P	Naive	8.30	−0.8	−0.4
Schweizer, 2007^Citation5	526	52	Vildagliptin 100 mg qd	R, DB, P	Naive	8.70	−1	0.3
Dejager, 2007^Citation6	92	24	Vildagliptin 100 mg qd	R, DB, P	Naive	8.40	−0.9
Dejager, 2007^Citation6	90	24	Vildagliptin 50 mg bid	R, DB, P	Naive	8.60	−0.8
Rosenstock, 2007^Citation7	154	24	Vildagliptin 100 mg qd	R, DB, P	Naive	8.60	−1.1	0.2
Garber, 2007^Citation8	136	24	Vildagliptin 50 mg bid	R, DB, P	Pio	8.70	−1	“Only between group values”
Rosenstock, 2007^Citation9	459	24	Vildagliptin 100 mg qd	R, DB, P	Naive	8.70	−1.1	“Only between group values”
Bosi, 2007^Citation10	143	24	Vildagliptin 50 mg bid	R, DB, P	Metformin	8.40	−0.9	0.2
Garber, 2008^Citation11	132	24	Vildagliptin 100 mg qd	R, DB, P	Su	8.60	−0.63	1.3
Bolli, 2008^Citation12	295	24	Vildagliptin 50 mg bid	R, DB, P	Metformin	8.40	−0.88	“No change”
Pan, 2008^Citation13	441	24	Vildagliptin 50 mg bid	R, DB, P	None	8.60	−1.4	−0.4
Ferrannini, 2009^Citation14	1,118	52	Vildagliptin 50 mg bid	R, DB, P	Metformin	7.30	−0.44	−0.23
Goodman, 2009^Citation15	119	24	Vildagliptin 100 mg qd	R, DB, P	Metformin	8.50	−0.66
Goodman, 2009^Citation15	119	24	Vildagliptin 100 mg qd	R, DB, P	Metformin	8.50	−0.53
Bosi, 2009^Citation16	300	24	Vildagliptin 50 mg bid	R, DB, P	None	8.68	-1.1	−0.59
Schweizer, 2009^Citation17	167	24	Vildagliptin 100 mg qd	R, DB, P	Naive	7.80	−0.64	−0.45
Filozof, 2010^Citation18	513	52	Vildagliptin 50 mg bid	R, DB, P	Metformin	8.50	−0.81	0.08
Charbonnel, 2006^Citation19	453	24	Sitagliptin 100 mg	R, DB, P	Metformin	7.90	−0.67	“Not significant”
Raz, 2006^Citation20	193	18	Sitagliptin 100 mg	R, DB, P	None	8.04	−0.48	−0.6
Rosenstock, 2006^Citation21	163	24	Sitagliptin 100 mg	R, DB, P	Pio	8.10	−0.85	1.8
Aschner, 2006^Citation22	229	24	Sitagliptin 100 mg	R, DB, P	None	8.01	−0.61	1.5
Hermansen, 2007^Citation23	222	24	Sitagliptin 100 mg	R, SB, P	Met/Met + Su	8.34	−0.45	0.8
Goldstein, 2007^Citation24	175	24	Sitagliptin 100 mg	R, DB, P	None	8.87	−0.66	0
Hanefeld, 2007^Citation25	107	12	Sitagliptin 100 mg	R, DB, P	None	7.78	−0.44	“No change”
Nauck, 2007^Citation26	382	52	Sitagliptin 100 mg	R, DB, P	Metformin	7.48	−0.67	−1.5
Scott, 2006^Citation27	124	12	Sitagliptin 100 mg	R, DB, P	None	7.80	−0.54	“Not significant”
Scott, 2008^Citation28	91	12	Sitagliptin 100 mg	R, DB, P	Metformin	7.75	−0.73	“Not significant”
Raz, 2008^Citation29	95	30	Sitagliptin 100 mg	R, DB, P	Metformin	9.30	−1	−0.5
Nonaka, 2008^Citation30	75	12	Sitagliptin 100 mg	R, DB, P	None	7.50	−0.65	−0.1
Mohan, 2009^Citation31	339	18	Sitagliptin 100 mg	R, DB, P	None	8.70	−0.7	0.6
Derosa, 2010^Citation32	75	52	Sitagliptin 100 mg	R, DB, P	Pio	8.50	−1.4	“Not significant”
Rigby, 2010^Citation33	56	16	Sitagliptin 100 mg	R, O, P	Metformin	8.17	−0.4	−1.15
Seck, 2010^Citation34	248	104	Sitagliptin 100 mg	R, DB, O	Metformin	7.30	−0.54	−1.6
Aschner, 2010^Citation35	455	24	Sitagliptin 100 mg	R, DB, O	Naive	7.20	−0.43	−0.6
Arechavaleta, 2011^Citation36	433	30	Sitagliptin 100 mg	R, DB, P	Metformin	7.50	−0.47	−0.8
Scheen, 2010^Citation37	334	18	Sitagliptin 100 mg	R, DB, P	Metformin	7.70	−0.62	−0.4
Scheen, 2010^Citation37	343	18	Saxagliptin 5 mg	R, DB, P	Metformin	7.68	−0.52	−0.4
Rosenstock, 2008^Citation38	47	12	Saxagliptin 5 mg	R, DB, P	Naive	7.90	−0.9	−0.1
DeFronzo, 2009^Citation39	186	24	Saxagliptin 5 mg	R, DB, P	Met	8.10	−0.69	−0.87
Hollander, 2009^Citation40	183	24	Saxagliptin 5 mg	R, DB, P	Tzd	8.40	−0.94	1.4
Rosenstock, 2009^Citation41	106	24	Saxagliptin 5 mg	R, DB, P	Naive	8.00	−0.46	−0.1
Chacra, 2009^Citation42	253	24	Saxagliptin 5 mg	R, DB, P	Su	8.50	−0.64	0.8
Göke, 2010^Citation43	293	52	Saxagliptin 5 mg	R, DB, P	Metformin	7.46	−0.74	−1.1
DeFronzo, 2008^Citation44	131	26	Alogliptin 25 mg	R, DB, P	Naive	7.90	−0.59	−0.22
Nauck, 2008^Citation45	210	26	Alogliptin 25 mg	R, DB, P	Metformin	7.90	−0.6	“Not significant”
Pratley, 2009^Citation46	198	26	Alogliptin 25 mg	R, DB, P	Su	8.09	−0.53	0.68
Pratley, 2009^Citation47	198	26	Alogliptin 25 mg	R, DB, P	Pio/+Met/+Su	100.00	−0.8
Rosenstock, 2010^Citation48	164	26	Alogliptin 25 mg	R, DB, P	Naive	8.80	−0.96	−0.3
Del Prato, 2011^Citation49	333	26	Linagliptin 5 mg	R, DB, P	None	8.00	−0.44
Taskinen, 2011^Citation50	523	24	Linagliptin 5 mg	R, DB, P	Met	8.09	−0.49
Forst, 2010^Citation51	66	12	Linagliptin 5 mg	R, DB, P	Met	8.50	−0.5

Abbreviations: HbA_1c, glycated hemoglobin; Tzd, thiazolidinediones; Met, metformin; Su, sulfonylurea; Pio, Pioglitazone; SBP, systolic blood pressure; R, randomized trial; DB, double-blind trial; SB, single-blind trial; O, open-label trial; P, parallel-group trial.

Table S2 Baseline characteristics of the simulated cohort, based on the actual SAVOR-TIMI 53 cohort

Characteristics	CV safety trial population
N	11,000
Age (years)	65.0 (8.67)
Male	0.67
SBP (mmHg)	137 (19.76)
DBP (mmHg)	79 (9.417)
TC (mg/dL)	187.7 (37.8)
HDL (mg/dL)	49.2 (14.16)
LDL (mg/dL)	100.4 (29.25)
TG (mg/dL)	191.7 (121.3)
HbA1c (%)	8.0 (1.23)
BMI (kg/m^2)	31.2 (5.02)
Smoker (fraction)	0.13
Prior MI	0.38
Prior stroke	0.09
Stage 3 CKD and above	0.29
ESRD	0.02
CHF	0.10

Notes: Values are means with standard deviations in parentheses unless otherwise indicated.

Abbreviations: N, number in sample; BMI, body mass index; TC, total cholesterol; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TG, triglycerides; SBP, systolic blood pressure; DBP, diastolic blood pressure; MI, myocardial infarction; CKD, chronic kidney disease; ESRD, end-stage renal disease; CHF, chronic heart failure; CV, cardiovascular; HbA_1c, glycated hemoglobin; SAVOR-TIMI, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus – Thrombolysis in Myocardial Infarction.

Table S3 Sensitivity of the absolute MACE risk reduction associated with the DPP-4 inhibitor class, at 5 years, to different effect assumptions

Intervention sensitivity analysis	Absolute MACE incidence reduction at 5 years
DPP-4 inhibitor class (base case)	−0.0027 (−0.0038; −0.0016)
DPP-4 inhibitor class with HbA1c effect only (no weight effect)	−0.0027 (−0.0038; −0.0016)
DPP-4 inhibitor class + lipid effects	−0.0035 (−0.0047; −0.0022)
DPP-4 inhibitor class based on lower 95% confidence limit effects from meta-analysis	−0.0026 (−0.0037; −0.0015)
DPP-4 inhibitor class based on upper 95% confidence limit effects from meta-analysis	−0.0030 (−0.0041; −0.0018)

Notes: For reference, in the standard of care arm the incidence of MACE at 5 years was 0.1253 (0.1189; 0.1316). MACE was defined as the first occurrence of MI, stroke, or cardiovascular death.

Abbreviations: MACE, major adverse cardiovascular events; DPP-4, dipeptidyl peptidase-4; HbA_1c, glycated hemoglobin; MI, myocardial infarction.

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