The role of dipeptidylpeptidase-4 inhibitors in management of cardiovascular disease in diabetes; focus on linagliptin

Overwhelming evidence indicates that CVD risk increases along with increases in glycated hemoglobin (HbA1c). For example, data from the Norfolk study indicated a linear relationship between HbA1c concentrations and CVD and mortality [1]. This analysis revealed that for every percentage point increase in HbA1c above 7%, the relative risk of CVD increases by 20–30% [1]. Surprisingly, this relationship also extended to those below the threshold for controlled T2DM, i.e., HbA1c between 5 and 6.9%. Nonetheless, there is conflicting evidence to support an intensive glucose-lowering regimen in T2DM to reduce major adverse CV events and deaths [2, 3]. Moreover, some conventional diabetes therapies, although effective at glucose control, may actually increase the risk of CVD events, increase hypoglycemic episodes and result in weight gain [4‐6]. Newer anti-hyperglycemic drugs, such as DPP-4 inhibitors, GLP-1 agonists and SGLT2 inhibitors, are well tolerated and effective and are increasingly prescribed. These drugs may exert beneficial CV effects beyond glycemic control [7‐9], thereby making them attractive strategies as either stand-alone or add-on therapy to conventional glucose lowering medications, such as metformin, sulfonylureas, thiazolidinediones and insulin. The emphasis on their CV safety is becoming an emerging issue. In this regard, large clinical trials have shown either neutral or beneficial effects for DPP-4 inhibitors [10]. Recently, the CV protective effects of different DPP-4 inhibitors have been reviewed [7, 11‐14]. It is noteworthy that the DPP-4 inhibitor, linagliptin, has unique kinetics, chemical nature and potent direct effects on the vasculature [15]. In this review we will update recent advances in our understanding of the cellular and molecular mechanisms of CV protection of DPP-4 inhibitors with a focus on linagliptin.

Prior to 2008, the US Food and Drug Administration (FDA) approval process for new diabetes therapies was based largely on whether a drug was effective at improving HbA1c and its general safety profile. Following reports that certain antihyperglycemic agents increased CV events [16, 17], the FDA issued new guidelines in 2008 requiring that drug developers perform comprehensive assessment of CV safety on any new diabetes drug to ensure that these therapies do not increase the risk of CV events. Results from three large randomized trials performed over the last 5 years to address the safety and efficacy of DPP-4 inhibitors in T2DM patients at high risk for CV events have been reported [18‐24]. The general consensus from these three trials is that DPP-4 inhibitors, relative to placebo, do not reduce or increase the risk of the primary composite endpoints of CV death, myocardial infarction, stroke or hospitalization for unstable angina (4 point MACE in TECOS only) when added to standard of care diabetes therapy. Nevertheless, some concerns have been raised for the CV safety profile of saxagliptin which led to slightly more hospitalizations for heart failure (HHF) (3.5 vs 2.8% versus placebo; hazard ratio, 1.27; 95% CI 1.07–1.51; p = 0.007) in the SAVOR-TIMI trial [18] and alogliptin which showed a non-statistically significant risk for HHF in subjects with pre-existing HF in the EXAMINE trial [25]. These adverse events were not detected in the TECOS trial that examined the CV profile of sitagliptin [20]. Whether the disparity between these clinical trials regarding HHF is related to the individual properties of the DPP-4 inhibitors, the subgroups of patients enrolled in the studies, differences in inclusion criteria or other aspects of clinical trial design remains to be determined. However, a recent survey of data from Medicare beneficiaries, older than 65 years of which 55% had baseline CVD, did not demonstrate increased risk of stroke, myocardial infarction or heart failure when comparing DPP-4 inhibitors with sulfonylureas (SU) or thiazolidinediones (TZDs) [26]. Similarly, an analysis of an insurance database in a Korean population reported no increased risk of HHF in DPP-4 inhibitor users (sitagliptin, linagliptin, vildagliptin and saxagliptin) when compared with SU [27]. It is notable that among the DPP-4 inhibitors examined in the Korean study, patients treated with sitagliptin or linagliptin were at lower risk for HF compared to SU therapy. Moreover, risk for MI in patients with pre-existing CVD and stroke were lower in patients treated with DPP-4 compared to SU. Furthermore, a Taiwanese case control study found that DPP-4 use was related to decreased risk of death after an acute myocardial infarction [28]. It is also noteworthy that small clinical studies (< 50 patients) examining the CV effects of DPP-4 inhibitors, including linagliptin, have shown protective effects, including decreases in aortic PWV, improved microvascular function and lower heart failure risk compared to SU [29, 30]. Most of the large trials investigating the CV safety profile of DPP-4 inhibitors (SAVOR-TIMI, TECOS, EXAMINE, and CARMELINA) were designed to compare the DPP-4 inhibitor to placebo; however the ongoing CAROLINA trial was designed to compare the CV effects of linagliptin to glimeperide as active comparator and will soon (second half of 2018) provide valuable information regarding the impact of DPP-4 inhibition in diabetic CV outcomes [27, 31, 32]. Lastly, a very recent systematic review and network meta-analysis, designed to evaluate the effects of long-term CV safety of DPP-4 inhibitors (and GLP-1 agonists), showed lower risk of MI compared to SU-based therapies when these drugs are administered for more than 1 year [33].

Both pre-clinical and clinical studies have shown beneficial effects of linagliptin on CV dysfunction associated with obesity and diabetes (Fig. 1). These benefits include improvement in diastolic dysfunction [34, 35], atherosclerosis [36], coronary artery disease (CAD) [37], myocardial infarction [38], hypertension and stroke [39‐41], arterial stiffness [29, 42, 43], endothelial dysfunction [30, 37, 44‐51], and immune and inflammatory response [35, 52], all of which are depicted in Fig. 1 and reviewed below.

Development of kidney disease is one of the major sequelae of T2DM with approximately 50% of diabetic individuals progressing to chronic kidney disease (CKD) [120, 121]. Moreover, CKD is associated with development of CVD including arterial stiffness, hypertension and cardiac dysfunction [122]. Compared to other tissues, the kidneys express the highest level of DPP-4 and it is likely that the presence of DPP-4 in the glomerular endothelium and proximal renal tubules contributes importantly to sodium retention, tubular injury and glomerular injury. We and others have shown renoprotective effects of DPP-4 inhibitors, including linagliptin, in preclinical studies [48, 123‐128]. Similarly, the potential beneficial effects of DPP-4 inhibitors, including linagliptin, in preventing and treating progression of kidney disease in patients with T2DM is supported by retrospective analyses of clinical trials [49, 129]. The ongoing Cardiovascular and Renal Microvascular Outcome study with Linagliptin in patients with T2DM (CARMELINA), which is powered to evaluate kidney outcomes and renoprotective effects of this inhibitor, should begin to fill in a gap in our knowledge regarding the efficacy of DPP-4 inhibitors in T2DM patients with CKD with our without CVD [130].

With regard to treating diabetic nephropathy, the pharmacokinetics and pharmacodynamics of linagliptin make it an especially attractive drug for several reasons. First, unlike other DPP-4 inhibitors that are excreted largely in urine, linagliptin is mainly eliminated by a biliary route [131] and therefore does not require dose adjustment in patients with kidney disease [132, 133]. Additionally, compared to other DPP-4 inhibitors, linagliptin can penetrate deeply into renal tissue and therefore has the largest volume of distribution, and has the highest binding affinity for DPP-4 protein that is richly present in kidney [134‐137]. Microvascular dysfunction is one of the major factors contributing to progression of diabetic nephropathy and DPP-4 inhibitors have been shown to exert microvascular protection in pre-clinical studies. Importantly, data from prospective clinical trials is beginning to emerge [44, 45, 138]. In this regard, linagliptin-mediated CV effects can occur both in response to better glycemic control, as well as by mechanisms independent of glycemic control in animal models of pre-diabetes [35, 42, 44‐48]. Emerging evidence from clinical studies conducted on small numbers of patients with T2DM reported improvement in microvascular function by linagliptin [30, 49‐51]. Impairment of NO signaling is one of the pathways that contributes to CVD and linagliptin has potent nitric oxide enhancing effects on vascular function [34, 118, 119]. The nephroprotective effects of DPP-4 inhibitors, including linagliptin, and their potential underlying mechanisms have been the focus of several very extensive and recent reviews [121, 129, 139].

The first line therapy for management of glycemia for T2DM throughout the world is metformin [203]; however, over time, the effectiveness of metformin monotherapy in achieving target HbA1c diminishes in a majority of patients [204]. This lack of adequate glycemic control necessitates the use of combinations of one or more additional anti-hyperglycemia agents to achieve target HbA1c. However, interest in the need for combination therapy as an initial treatment strategy is also increasing [205‐207]. Recent studies indicate that DPP-4 inhibitors, including linagliptin, could potentially complement the effects of other CV protective agents such as metformin [208], angiotensin type 2 receptor blockers (ARB) [41, 209], statins, and SGLT2 inhibitors [210‐212]. Importantly, there is little evidence of undesirable drug interactions between linagliptin and metformin, ARBs, statins and SGLT2 inhibitors [5, 213]. The increased risk of angioedema with combination DPP-4 and ACE inhibitor therapy is one potential limitation [214], however, this issue may be managed by consideration of replacing an ACE inhibitor with an ARB [128, 215].

Recent studies have shown that combination therapy of DPP-4 and SGLT2 inhibitors, either as an initial combination or stepwise addition, results in improvement in glycemic control [216‐221]. In contrast to other DPP-4 inhibitors, linagliptin does not require dose adjustment in patients with renal insufficiency given that it is not excreted by the kidneys [15]. Indeed, the evidence so far indicates that once daily single pill combination of linagliptin and the SGLT-2 inhibitor, empagliflozin, results in clinically meaningful and sustained reductions in HbA1c, fasting glucose, body weight and blood pressure [220, 222]. Other combinations of SGLT2 and DPP-4 inhibitors seem similarly promising [220]. The underlying mechanisms for these beneficial effects appears to be the convergence of complementary signaling pathways and physiological effects (e.g., reduced glucotoxicity, weight loss and BP reduction for SGLT2 inhibitor and reduced glucose-dependent glucagon secretion and anti-inflammatory effects for DPP-4 inhibitor) for beneficial effects on CV health or suppression of microvascular complications [220, 223].