Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin – Clinical Evidence for Optimised Management of Chronic Diseases Beyond Type 2 Diabetes

Abstract

The last decade has witnessed the role of dipeptidyl peptidase-4 (DPP-4) inhibitors in producing a conceptual change in early management of type 2 diabetes mellitus (T2DM) by shifting emphasis from a gluco-centric approach to holistically treating underlying pathophysiological processes. DPP-4 inhibitors highlighted the importance of acknowledging hypoglycaemia and weight gain as barriers to optimised care in T2DM. These complications were an integral part of diabetes management before the introduction of DPP-4 inhibitors. During the development of DPP-4 inhibitors, regulatory requirements for introducing new agents underwent substantial changes, with increased emphasis on safety. This led to the systematic collection of adjudicated cardiovascular (CV) safety data, and, where 95% confidence of a lack of harm could not be demonstrated, the standardised CV safety studies. Furthermore, the growing awareness of the worldwide extent of T2DM demanded a more diverse approach to recruitment and participation in clinical trials. Finally, the global financial crisis placed a new awareness on the health economics of diabetes, which rapidly became the most expensive disease in the world. This review encompasses unique developments in the global landscape, and the role DPP-4 inhibitors, specifically vildagliptin, have played in research advancement and optimisation of diabetes care in a diverse population with T2DM worldwide.

Clinical Safety and Tolerability of Vildagliptin – Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance

“… 12 As the events were prospectively adjudicated, and the upper bound of the 95% CI was <1.3, an additional outcome trial was not required to establish the CV safety of vildagliptin. 45 …”

Factors that may Account for Cardiovascular Risk Reduction with a Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, in Young Patients with Type 2 Diabetes Mellitus

“…Whether this favorable effect on cardio-metabolic risk factors might explain the observed relative risk reduction in MACE in the meta-analysis comparing vildagliptin 50 mg qd/bid versus all comparators in phase III and phase IV randomized controlled trials (RCTs) remains to be confirmed. In addition to the significant glucose-lowering effect [ 13 , 14 ], vildagliptin has been shown to reduce blood pressure and improve fasting lipid profiles in association with reductions in weight [ 15 ]. The lower incidence of hypoglycemic events in the younger patients may also have played a role in the reduction of the risk of MACE in this group.…”

Association between vildagliptin and risk of angioedema, foot ulcers, skin lesions, hepatic toxicity, and serious infections in patients with type 2 diabetes mellitus: A European multidatabase, noninterventional, postauthorization safety study

“…Vildagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor has accumulated extensive efficacy and safety data from various meta‐analyses of randomized controlled trials (RCTs), large RCTs, or noninterventional studies . Its glycemic efficacy, reduced risk of hypoglycaemia, weight‐neutral effect and favourable benefit‐risk profile have made it an attractive treatment option for the management of patients with type 2 diabetes mellitus (T2DM) including those with renal impairment, heart failure, the elderly, or patients fasting during Ramadan …”

“…1 Its glycemic efficacy, reduced risk of hypoglycaemia, weight-neutral effect and favourable benefit-risk profile have made it an attractive treatment option for the management of patients with type 2 diabetes mellitus (T2DM) including those with renal impairment, heart failure, the elderly, or patients fasting during Ramadan. [1][2][3] However, there has been an interest in specific safety outcomes that may be associated with DPP-4 inhibitors in general [4][5][6] as well as with vildagliptin specifically. 1 Findings from a small clinical study reported that decreased DPP-4 activity may increase substance P or bradykinin concentrations, which can potentially increase the risk of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.…”