A review of dipeptidyl peptidase‐4 inhibitors. Hot topics from randomized controlled trials

Abstract

The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have investigated DPP-4 inhibitors in patient groups which are often under-represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP-4 inhibitors are not associated with any additional CV risk in these already-at-high-risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP-4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP-4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP-4 inhibitors in other circumstances, including for in-hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP-4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.

A randomized clinical trial of the efficacy and safety of sitagliptin compared with dapagliflozin in patients with type 2 diabetes mellitus and mild renal insufficiency: The CompoSIT‐R study

“…DPP-4 inhibitors are often used in patients with type 2 diabetes and renal disease because these agents maintain efficacy and demonstrate good tolerability across the spectrum of renal disease. 3 On the other hand, the efficacy of SGLT-2 inhibitors is reduced in patients with moderate renal insufficiency and is contraindicated in patients with severe renal insufficiency. 11 These clinical observations are consistent with the distinct mechanisms of action of the two classes of agents.…”

“…2 The interval between Visit 1 and Visit 2 for eligible subjects was to be at least 2 weeks and no more than approximately 6 weeks. 3 Subjects entering the study on metformin remained on a stable dose of metformin; subjects entering on metformin + an SU remained on stable doses of both agents between-group rate differences computed using the Miettinen and Nurminen method. 7 For this analysis, multiple imputations of missing A sample size of 278 participants per treatment group was estimated to provide >99% power to establish that sitagliptin is noninferior to dapagliflozin in lowering HbA1c at an overall one-sided, 2.5% α-level, assuming an underlying treatment difference of 0%, and 90% power to demonstrate the superiority of sitagliptin versus dapagliflozin in lowering HbA1c at an overall one-sided, 2.5% α-level, if the underlying treatment difference in HbA1c is −0.2%.…”

“…Among the classes of oral AHAs available for treatment of type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors are considered both efficacious and well tolerated across the range of renal function, although dose adjustment to control drug exposure is sometimes required. 3 In contrast, the sodium/glucose transporter-2 (SGLT-2) inhibitors have reduced efficacy in patients with moderate to severe renal insufficiency due to their mechanism of action. 4 The CompoSIT-R (comparison of sitagliptin with dapagliflozin in mild renal impairment) study was a prospective, randomized clinical trial comparing the efficacy and safety of the DPP-4 inhibitor sitagliptin with the SGLT-2 inhibitor dapagliflozin in patients with type 2 diabetes and mild renal insufficiency.…”

Mechanistic insights from sequential combination therapy with a sodium glucose co‐transporter‐2 inhibitor and a dipeptidyl peptidase‐4 inhibitor: Results from the CANARIS Trial using canagliflozin and teneligliptin

“…Pharmacological antidiabetic therapies, improving insulin resistance or secretion or its supplementation, have presented some evidence of managing diabetes and preventing complications; however, their disadvantages, such as body weight gain and hypoglycaemia, have been reported and remain as issues to be resolved . The recent development of the dipeptidyl peptidase‐4 inhibitor (DPP‐4i) and the glucagon‐like peptide‐1 receptor agonist (GLP1RA) has resolved some of those disadvantages, probably because of the inhibition of inappropriately enhanced glucagon secretion and improvement in the sensitivity of insulin secretion to glucose . Moreover, sodium glucose co‐transporter‐2 inhibitor (SGLT2i), a new class of antidiabetic agent which promotes urinary glucose excretion, thereby reducing plasma glucose without dependence on insulin despite an increased glucagon level, has succeeded in showing superiority in cardiovascular outcomes .…”

“…1,2 The recent development of the dipeptidyl peptidase-4 inhibitor (DPP-4i) and the glucagon-like peptide-1 receptor agonist (GLP1RA) has resolved some of those disadvantages, probably because of the inhibition of inappropriately enhanced glucagon secretion and improvement in the sensitivity of insulin secretion to glucose. [3][4][5] Moreover, sodium glucose co-transporter-2 inhibitor (SGLT2i), a new class of antidiabetic agent which promotes urinary glucose excretion, thereby reducing plasma glucose without dependence on insulin despite an increased glucagon level, 6 has succeeded in showing superiority in cardiovascular outcomes. 7 By the progressive nature of the disease, however, most patients with type 2 diabetes eventually require multiple medications to achieve glycaemic targets.…”