DPP-4 Inhibitors Comparison

Dipeptidyl peptidase‐4 inhibitors

• 5 inhibitors are globally available [alogliptin, linagliptin,saxagliptin, sitagliptin, vildagliptin (although vildagliptin is not marketed in the USA/Canada)
• others have a more limited geographic distribution (anagliptin, evogliptin, gemigliptin, omarigliptin, teneligliptin, trelagliptin, presently only available in Japan and/or Korea).

 

Table 2. Pharmacokinetics and pharmacodynamics characteristics of dipeptidyl peptidase-4 inhibitors.

 

*Dose may vary in some countries.

  

Table 3. Prescribing characteristics of commonly used dipeptidyl peptidase-4 inhibitors (data taken from prescribing information of the individual inhibitors; precise indications may vary by country).

 

§Studies in severe hepatic impairment are lacking.

†Dose reduction of sulphonylureas or insulin may be recommended when used together with a dipeptidyl peptidase-4 inhibitor.

*Including those with transaminase levels ≥3 times upper limit of normal.

Renal Impairment

• all can be used in subjects with renal impairment
• declining renal function requires larger dose reductions for alogliptin and sitagliptin than for inhibitors, such as saxagliptin and vildagliptin
• dose reductions are not for safety reasons, but are based solely on pharmacokinetics, with a lower clearance simply meaning that less drug is needed to reach the same plasma concentration.
• it is doubtful that any accumulation would lead to unfavourable outcomes if normal therapeutic doses were inadvertently used in subjects with impaired renal function because of the wide therapeutic window.
• a number of safety analyses and large clinical trials in patients with T2DM and kidney disease, including end-stage renal disease and those undergoing dialysis, all indicate that DPP-4 inhibitors are well tolerated
• If DPP-4 inhibitors are going to be used in patients with chronic kidney disease (estimated glomerular filtration rate [eGFR] <30 mL/min), linagliptin preferred because it is primarily eliminated via the enterohepatic system.

Hepatic impairment

• Although saxagliptin is metabolized by the liver, even severe hepatic impairment only modestly increases exposure to the drug, most likely because of the kidneys’ role in the final elimination pathway.
• An association between vildagliptin and elevated liver enzymes has been reported, but despite this not appearing to be associated with any increase in actual hepatic adverse effects, vildagliptin is currently contraindicated in subjects with any degree of hepatic impairment, including those with pretreatment elevated transaminase levels.

Drug-drug interactions

• Drug–drug interactions between DPP-4 inhibitors and other medications are minimal and, for most combinations, do not necessitate dose adjustment of either agent;
• however, because of its hepatic metabolism, exposure to saxagliptin can be increased if used concomitantly with strong CYP3A4/5 inhibitors, so that dose reduction of saxagliptin is recommended.
• Although linagliptin is only minimally metabolized, exposure may be reduced to sub-therapeutic levels if linagliptin is co-administered with CYP3A4 inducers (e.g. rifampicin), which may reduce maximum efficacy.

Efficacy

• meta-analyses reveal no major differences between them with regard to improvements in glycaemic control.
• A few large direct head-to-head comparisons (duration ≥18 weeks) have shown non-inferiority for HbA1c-lowering for saxagliptin compared with sitagliptin as add-on to metformin, although in the latter study, effects of sitagliptin on fasting plasma glucose appeared to be modestly greater than those of saxagliptin; whether this might be related to differences in the extent of DPP-4 inhibition seen 24 h post-dose requires further investigation.
• Sitagliptin and vildagliptin had similar effects on glucose homeostasis in several small 12-week studies, with similar conclusions being drawn from a larger 24-week study in subjects with T2DM and severe renal impairment.

Cardiovascular effects

• Meta-analysis suggests a small increased risk of admission for heart failure with DPP-4 inhibitor use in patients with type 2 diabetes who have existing CVD or multiple risk factors for it.
• It is unclear if the risk is specific to certain DPP-4 inhibitors and whether it extends to patients without CVD.
• The SAVOR-TIMI 53 clinical trial has shown that the use of saxagliptin is associated with increased risk for hospital admission for heart failure.
• The more recent TECOS study did not show any increased risk of hospitalisation for heart failure.
• The FDA recommends discontinuation specifically of saxagliptin and alogliptin in patients who develop heart failure and monitoring to determine if alternative therapy for diabetes is required.

References 

1. Deacon, C. F., & Lebovitz, H. E. (2016). Comparative review of dipeptidyl peptidase‐4 inhibitors and sulphonylureas. Diabetes, Obesity and Metabolism.

2. Malaysian Clinical Practice Guidelines: Management of Type 2 Diabetes Mellitus, 5^th Edition

3. www.uptodate.com