Safety concerns associated with DPP-4 inhibitors


There were several adverse events of special interests, including hypoglycemia, hypersensitivity reactions, renal and hepatic events, severe cutaneous adverse reactions, and pancreatitis, linked to dipeptidyl peptidase-4 ( DPP-4 ) inhibitors.

Hypoglycemia

The glucose-dependent manner in which incretin-based therapies control hyperglycemia reduces the risk for hypoglycemia with these drugs except in the setting of co-administration with other anti-diabetics that can cause hypoglycemia ( e.g., Insulin secretagogues or Insulin ).
The potentiation for risk of hypoglycemia with co-administration of DPP4-inhibitors and Insulin secretagogues has been observed in the currently marketed DPP4-inhibitors. The overall incidence of investigator-defined hypoglycemia in the placebo-controlled trials was 8.7% in Linagliptin vs 5.3% in placebo. The highest incidence occurred in the trials with sulfonylurea background treatment in which hypoglycemia was reported from 4.8% to 23.7% of patients.

Hypersensitivity, reactions and immune-related adverse events

Shortly after the approval of Januvia ( Sitagliptin ), spontaneous postmarketing reports of allergic and hypersensitivity reactions were received resulting in labeling changes to the Warnings and Precautions section as follows:

‘ There have been postmarketing reports of serious allergic and hypersensitivity reactions in patients treated with Januvia such as anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome.’

Other DPP4-inhibitors have also had clinical and nonclinical findings of hypersensitivity-like reactions. Alogliptin had hypersensitivity-like reactions in its chronic dog studies and a higher rate of similarly-coded reactions was observed with Alogliptin in the clinical trials.
The premarketing application for Saxagliptin also identified a higher incidence of hypersensitivity reactions with Saxagliptin over comparators as well as adverse events of urticaria.
In the pooled database of placebo-controlled trials for this NDA, 18 patients ( 0.7% ) in the Linagliptin group vs 6 ( 0.5% ) on placebo had an adverse event reported as hypersensitivity. Urticaria was reported in 6 patients on Linagliptin versus 1 on placebo. Angioedema was reported in 2 patients treated with Linagliptin; one case occurred 11 days post-therapy; however, angioedema, facial swelling, and mouth ulcerations have also been reported. There was one report of angioedema / face swelling in a 65 yr-old woman who received Linagliptin 1 mg in a phase 2 study and one report in placebo group. The event in the Linagliptin group was not serious and the event resolved with study drug discontinuation.
In the active-controlled trial, 1218.20, there was 1 report of angioedema in a Linagliptin patient versus 3 in Glimepiride.

Renal adverse events

The majority of patients in the placebo-controlled trials evaluating Linagliptin had no or only mild renal impairment. Only 162 patients had moderate renal impairment and 3 had severe renal impairment. No differences in adverse events were noted between Linagliptin and placebo for the no and mild renal impairment population whereas a slightly higher incidence of adverse events was reported in the moderate renal impairment population but without any single predominant event. No signal of deteriorating renal status was noted in her assessment of shifts in renal function.

Hepatic adverse events

ALT ( alanine aminotransaminase ) and AST ( aspartate aminotransferase ) increases were reported at similar frequencies between placebo and Linagliptin groups in the placebo-controlled trials ( 0.3-0.4% ). There were no cases of Hy’s law. Two cases of jaundice in the Linagliptin group were reported: one in a patient with pancreatic cancer and another in a patient with documented gallstones requiring ERCP ( Endoscopic Retrograde Cholangiopancreatography ).

Severe cutaneous adverse reactions

Severe cutaneous adverse reactions have been noted in preclinical development programs of some DPP4 inhibitors. In one program of a DPP4 inhibitor not approved in the U.S. ( Vildagliptin ), severe peripheral edema of the feet occurred in 5 subjects enrolled in a phase 1 study. One individual who had severe edema of his hands and feet had CPK and AST elevations with onset occurring within 3 days of drug initiation.
In the NDA there were reports of rash and pruritus; there were 5 reports of exfoliative dermatitis or skin exfoliation occurring in the Linagliptin group and only one report in control in a patient receiving Glimepiride. In all but one of the cases, exfoliation, skin peeling or desquamation was noted in the hands. One patient reported exfoliation of his heels. Although all of the cases were reported as mild or moderate, one case was deemed drug related as follows:

‘ Patient 81804 was a 46-year old Asian male without a medical history of allergic reactions or skin problems. He was enrolled in study 1218.18 on 6 May 2008; started placebo run-in on 13 May 2008 and randomized to Linagliptin 5 mg on 29 May 2008. Concomitant medications included Metformin 2000 mg daily, Glyburide 20 mg daily, and Rosuvastatin 20 mg daily. On 19 August 2008 it was noted that CK levels increased from 238 U/L at baseline to 468 U/L. Rosuvastatin was discontinued on 22 August 2008; however, CK value remained elevated on 3 September 2008 at 813 U/L. On 14 September 2008, the patient noted moderate peeling of the hands, feet, and shins, and also a rash. Linagliptin was interrupted, then permanently discontinued on 2 October 2008. Linagliptin was discontinued with a positive dechallenge; patient was not rechallenged. Patient discontinued from the trial. Most recent CK on 20 April 2009 was 295 U/L. ‘

Pancreatitis

Spontaneous postmarketing adverse event reports for Exenatide and Sitagliptin and some publications from rodent models have suggested an increased risk of pancreatitis for the incretin mimetics. However, data from several observational studies of healthclaims databases have suggested no excess risk over other anti-diabetic therapies and instead have raised the possibility of increased risk of pancreatitis related to diabetes overall.
In the NDA there were 8 patients, all receiving Linagliptin, who were diagnosed with pancreatitis while on treatment. This numeric imbalance must also consider that overall number of exposure and duration of treatment were heavily weighted towards Linagliptin. Correcting for this imbalance reveals an incidence of pancreatitis of 1 per 538 pt-yrs in Linagliptin versus 0 per 433 pt-yrs in comparator group.

Cancer

There have been speculative reports on potential risk for thyroid and pancreatic cancer with DPP-4 inhibitors. Detection of risk for developing cancer is limited in typical NDA databases. One case of thyroid cancer and one pancreatic carcinoma out of 5 neoplasms were identified post-treatment.
There are too few events to make any conclusions based on these observations.

QT interval

Linagliptin is not associated with any clinically relevant effect on the QT interval. The 5 mg dose and a supratherapeutic dose of 100 mg were both evaluated in a thorough QT ( tQT ) study. The upper bound of the 90% CI for the QTcI was well below the regulatory threshold for concern ( 10 ms ). The study included a positive control, Moxifloxacin, whose results demonstrated the expected effects of Moxifloxacin on increasing the QT interval, establishing assay sensitivity of the study. The mean Cmax achieved with Linagliptin 100 mg in this study was 267 nmol/L, exceeding the Cmax anticipated under the worse-case scenario of clinical use including varying degrees of renal impairment or in the presence of a potent CYP3A4/P-gp inhibitor.
Linagliptin did not have any clinically significant effect on PR or QRS interval.
Overall, this NDA has provided sufficient cardiovascular ( CV ) safety data to conclude that an unacceptable CV risk does not exist for Linagliptin to preclude its approval.

Source: FDA, 2011

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