Review of the cardiovascular safety of dipeptidyl peptidase-4 inhibitors and the clinical relevance of the CAROLINA trial

Table 1 Summary of the effects of DPP-4 inhibitors and SU agents on CV outcomes

Clinical trial	Intervention	Primary outcome	CV risk	HR, OR or RR (95% CI)
DPP-4 inhibitors
EXAMINE [8] N = 5380	Alogliptin versus placebo	3-point MACE	↔	HR 0.96 (≤ 1.16)^a
SAVOR-TIMI 53 [7] N = 16,492	Saxagliptin versus placebo	3-point MACE	↔	HR 1.00 (0.89–1.12)
TECOS [5] N = 14,671	Sitagliptin versus placebo	4-point MACE	↔	HR 0.98 (0.88–1.09)
CARMELINA [6] N = 6979	Linagliptin versus placebo	3-point MACE	↔	HR 1.02 (0.89–1.17)^b
CAROLINA N = 6041	Linagliptin versus glimepiride	3-point MACE	c [lc]	c [lc]
SUs ^d
Rados et al., 2016 [92] MA, 47 RCTs ≥52 wk	SUs (2nd/3rd generation only) versus other comparators	All-cause mortality	↔	P-OR 1.12 (0.96–1.30)
Rados et al., 2016 [92] MA, 47 RCTs ≥52 wk	SUs (2nd/3rd generation only) versus other comparators	CV mortality	↔	P-OR 1.12 (0.87–1.42)
Monami et al., 2013 [93] MA, 115 RCTs (62 reported MACE), ≥24 wk	All SUs versus other comparators	MACE^e	↔	MH-OR 1.08 (0.86–1.36)^f
	All SUs versus other comparators	Mortality	↑	MH-OR 1.22 (1.01–1.49)^g
Phung et al., 2013 [94] MA, 12 RCTs, 21 Observational, 6 mo to 10 yr	All SUs versus other comparators	4-point MACE	↑	RR 1.10 (1.04–1.16)
		RCTs only	↔	RR 0.98 (0.73–1.32)
		Observational only	↑	RR 1.11 (1.05–1.18)
		CV mortality	↑	RR 1.27 (1.18–1.34)
		RCTs only	↔	RR 1.22 (0.63–2.39)
		Observational only	↑	RR 1.26 (1.18–1.34)

^aUpper boundary of one-sided repeated CI
^bP < 0.001 for non-inferiority
^cTrial completed; publication of final data awaited
^dThere are no dedicated CVOTs for SUs; data are taken from meta-analyses of randomized clinical trials and observational studies involving SUs
^eDefined by Monami et al. as CV death, non-fatal myocardial infarction, stroke, acute coronary syndromes, and/or heart failure reported as serious adverse events
^fP = 0.52
^gP = 0.047
↑ = increase in CV risk; ↔ = neutral effect on CV risk; CV cardiovascular, CVOT cardiovascular outcomes trial, HR Hazard ratio, MA meta-analysis, MACE major adverse cardiovascular event (3-point: CV death, non-fatal MI, or non-fatal stroke; 4-point: 3-point MACE plus hospitalization for unstable angina), MH-OR Mantel-Haenzel odds ratio, P-OR Peto odds ratio, RCT randomized clinical trial, RR relative risk, SU sulfonylurea

ISSN: 1471-2261