Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme

Despite continuing medical and pharmacological efforts, patients with type 2 diabetes mellitus (T2DM) still bear a substantial burden of increased cardiovascular (CV) morbidity and premature mortality [1, 2]. Although many risk factors are involved, hyperglycaemia remains an important contributor to increased CV disease incidence and seems to potentiate the deleterious effects of lipids and blood pressure elevation [2, 3]. Nonetheless, recent large outcomes trials of glycaemic intervention in general and of intensive treatment in particular have shown conflicting results in terms of CV benefits for patients with T2DM [4‐7]. The ambivalence of these findings has led to development of the hypothesis that the effectiveness of intensive glucose control likely depends on individualizing treatment (e.g. treatment modality and glycaemic target) to account for CV risk and other factors [8]. In particular, weight gain and increased hypoglycaemia are often associated with established glucose-lowering treatments that increase insulin secretion (in a glucose-independent manner) or insulin sensitivity and may heighten CV risk. Some agents, such as rosiglitazone, have been shown to increase risk for CV events possibly due to unanticipated pleiotropic CV effects [9]. In light of these concerns, regulatory authorities, including the US Food and Drug Administration (FDA) and the European Medicines Agency, have issued guidance that the development programmes for all new glucose-lowering therapies must show that treatment confers no unacceptable increases in CV risk [10, 11].

The need to improve glycaemic control while minimizing harmful side effects has led to interest in therapeutic approaches aimed at avoiding such pitfalls. Dipeptidyl peptidase (DPP)-4 inhibitors, which enhance postprandial levels of the incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), have limited side effects [12]. The glucoregulatory actions of incretins include glucose-dependent promotion of insulin secretion, glucagon suppression, delayed gastric emptying, and increased satiety.

Linagliptin is a DPP-4 inhibitor that was recently approved as a once-daily oral glucose-lowering drug in the USA, Japan, and Europe. Its molecular structure is xanthine-based, which differs from that of other DPP-4 inhibitors. Linagliptin has pharmacokinetic properties that confer a prolonged terminal half-life (t_1/2 > 100 h), and potent and durable DPP-4 inhibition (maximal inhibition of > 90% and inhibition 24 h after dosing of ~ 85% with linagliptin 5 mg at steady state); and unlike other DPP-4 inhibitors, it is primarily excreted via bile and the gut [13‐15]. In Phase 3 trials, linagliptin has demonstrated clinically meaningful glycaemic efficacy and favourable safety/tolerability compared with placebo as monotherapy or in combination with metformin, metformin plus sulphonylurea, or pioglitazone [16‐19].

To thoroughly determine the CV safety of linagliptin, we undertook a meta-analysis of the CV risk associated with linagliptin versus placebo or active comparators in patients with T2DM participating in the linagliptin Phase 3 study programme. This was a pre-specified meta-analysis in which suspected CV events were prospectively captured and adjudicated in a blinded fashion by an independent CV expert committee.

This CV meta-analysis indicates that linagliptin may have a beneficial or neutral impact on CV outcomes in a large population of patients with T2DM compared with control treatments. Furthermore, the risk for CV events was unchanged, or lowered, across a number of pre-specified subgroups based on key demographic and clinical characteristics. These results include comparisons with placebo, as well as two active comparators, namely glimepiride (a second-generation sulphonylurea frequently used as second-line therapy in the USA and Europe) and voglibose (an α-glucosidase inhibitor commonly used in Asia), either as monotherapy or in combination with common oral glucose-lowering drugs.

The clinical characteristics of the overall study population were generally comparable to those reported in general T2DM populations. In this study, mean age was 58 years, BMI was 29 kg/m², and 44.5% were females compared with age of 60 years, BMI of 32 kg/m², and 52.4% females in the US National Health and Nutrition Examination Survey (NHANES) in 2003-2004 [20]. In this study versus the 2002 Cost of Diabetes in Europe (CODE)-2 study, the prevalence of previous MI was 10.6% versus 9.0% and of previous stroke was 2.5% versus 5% [21]. Furthermore, in the current study population, 44.6% had some degree of renal impairment versus 43.8% of those with self-reported T2DM in the NHANES population in 2009 (based on the MDRD equation) [22].

The incidence rates for CV events in this meta-analysis of linagliptin Phase 3 trials were relatively consistent with those observed in previous CV meta-analyses of other DPP-4 inhibitors' clinical trial programmes. The incidence rates (per 1000 patient-years) for the primary CV endpoint were 5.3 for linagliptin versus 16.8 for total comparators. In comparison, other CV meta-analyses reported incidence rates for custom MACE ranging from 5.8 to 14.6 with sitagliptin, saxagliptin, or vildagliptin and 9.0 to 14.1 with comparators [23‐25]. Importantly, these CV meta-analyses have all reported relative risk for CV outcomes with DPP-4 inhibitors versus comparators that were below 1.0. However, not all of these risk estimates achieved statistical significance (based on upper bounds of 95% CI below 1.0). Risk reductions were significant in the present meta-analysis of linagliptin [HR 0.34 (95% CI 0.16-0.70)] and in the previous analysis of saxagliptin 2.5-10 mg [HR 0.43 (95% CI 0.23-0.80)] [23]. In contrast, risk estimates were non-significant for sitagliptin 100 mg [RR 0.68 (95% CI 0.41-1.12)] and vildagliptin 50 mg and 100 mg [RR 0.84 (95% CI 0.64-1.14) and 0.88 (95% CI 0.37-2.11)] [24, 25].

Although the results of the different meta-analyses of DPP-4 inhibitors are not entirely comparable (due to differences in primary composite endpoints and CV adjudication methods), all are supportive of the hypothesis that, in general, DPP-4 inhibitor treatment does not have a deleterious impact on the incidence of CV events. The present analysis shows that linagliptin treatment does not increase CV risk and may even yield CV benefits in patients with T2DM. Meta-analyses of other DPP-4 inhibitors were frequently retrospective in nature. However, the pre-specified design of the present meta-analysis involved prospective and blinded adjudication of CV events, which should strengthen the validity of the current findings. In addition, this meta-analysis was based on individual patient data from a consistently designed, large clinical development programme; this allows consistent derivation of endpoints and extensive subgroup analyses and minimizes between-study heterogeneity that can confound analyses of unrelated studies.

There are several mechanisms that could underlie potential CV benefits for linagliptin. First, linagliptin may confer the beneficial effects of improved glycaemic control, including the lowering of postprandial glucose, without the potentially harmful effects of weight gain or increased hypoglycaemia [12, 26]. Second, linagliptin increases GLP-1 and GIP levels which may provide beneficial cardioprotection; experimental and clinical data suggest that GLP-1 elevation can positively modulate lipid metabolism [26], reduce infarct size and improve cardiac function [26, 27]. Third, DPP-4 substrates include not only incretins but also vasoactive peptides involved in inflammation, immunity, and CV function; some evidence, mainly from preclinical studies, indicates that reduced DPP-4 activity can lessen inflammation, stimulate endothelial repair, and blunt ischaemic injury [28]. Finally, linagliptin holds inherent anti-oxidative properties, most likely due to its xanthine-based molecular structure [29]. These properties, both directly through reduction of reactive oxygen species and indirectly through beneficial effects on inflammatory mediators and endothelial function, could reduce the atherosclerotic burden [30].

This analysis has several potential limitations. First, despite a large total patient exposure of 3432 years, individual patient exposure was of a maximum duration of 1.7 years; further longer-term data are needed to confirm the current findings. Second, the low incidence of CV events, low rates of triple oral therapy, and lack of insulin treatment all suggest that a large proportion of patients had less advanced T2DM, and thus a lower CV risk than those with more advanced T2DM. However, around 30% of patients had a baseline Framingham 10-year CV risk score of > 15% and more than a half also had > 5 years' known disease duration, which indicates a proportion of the population were at increased CV risk. Finally, the observed CV risk reductions for the primary and secondary endpoints were influenced by the differences in CV events in one study with linagliptin versus glimepiride. Despite this, it is important to note that glimepiride is an established and recommended second-line therapy with a well-characterized safety profile, which has not been directly linked to increased CV risk either as part of intensive treatment regimens or when compared with other conventional treatments [31]. Moreover, analysis of the pooled placebo studies alone confirmed that linagliptin did not increase CV risk against placebo.

In summary, this pre-specified CV meta-analysis of a large Phase 3 programme that involved prospective and independent adjudication of CV events provides valuable new insights on the CV safety profile of linagliptin. Although a meta-analysis, with distinct limitations, the data indicate that linagliptin does not increase CV risk and, moreover, support a potential reduction of CV events with linagliptin compared with pooled comparators. These results suggest that linagliptin may be a valuable new therapeutic option for improving glycaemic control in patients with T2DM. The hypothesis that linagliptin may have CV benefits is currently being tested prospectively in the CAROLINA study (NCT01243424), the first large outcomes study to directly compare a DPP-4 inhibitor versus a sulphonylurea (glimepiride), predominantly as second-line therapy (i.e. on a background of metformin).