DPP4 inhibitors for type 2 diabetes found not to raise angioedema risk
However, risk for those on ACE inhibitors needs more study, researchers say
People with type 2 diabetes who use DPP4 inhibitors to manage their disease do not seem to have a higher risk of developing angioedema compared with those taking other oral antidiabetic medications.
That’s according to a study in South Korea, which found that new cases of angioedema occurred at nearly the same rate in both treatment groups.
“However, further studies are needed to determine this risk in those on ACE inhibitor treatment,” researchers wrote. Angiotensin-converting enzyme (ACE) inhibitors are commonly prescribed to manage high blood pressure and kidney disease in people with diabetes, and are known to increase the risk of angioedema.
The study, “Risk for Angioedema with the Use of Dipeptidyl Peptidase 4 Inhibitors: A Population Based Cohort Study,” was published in the Journal of Allergy and Clinical Immunology.
DPP4 inhibitors used to lower blood sugar levels in type 2 diabetes
Dipeptidyl peptidase 4 (DPP4) inhibitors are a commonly used group of oral medications to lower blood sugar levels for people with type 2 diabetes. While generally considered safe and effective, concerns have been raised about a possible link to angioedema, a rare disorder marked by sudden swelling of the skin, mucous membranes, and deeper tissues. In severe cases, swelling can affect the throat and airway, leading to life-threatening respiratory symptoms.
Angioedema is driven by the accumulation of certain signaling molecules in the body, particularly bradykinin. Since DPP4 helps break down bradykinin and another molecule called substance P, its inhibition increases their levels and potentially raises the risk of angioedema, especially when combined with other drugs like ACE inhibitors.
Earlier clinical trials and safety reports have suggested a potential association, but these studies were too small, had few angioedema cases, and were often complicated by the use of ACE inhibitors.
“Considering that angioedema remains a potentially life-threatening condition and continues to be a notable cause of hospitalization for allergic and immunologic diseases, a large scale epidemiological study with an adequate sample size is warranted to evaluate this potential safety issue with the use of DPP4 inhibitors,” the researchers wrote.
To address this concern, a team of researchers retrospectively analyzed data from 1,610,722 patients with type 2 diabetes collected through South Korea’s National Health Insurance Service database. The study compared patients who started treatment with DPP4 inhibitors to those who began other second-line oral antidiabetic drugs (OADs) from January 2011 to December 2022.
Each patient was followed from the date of starting treatment (index date) until diagnosis of angioedema, discontinuation of the initial drug, a switch to a different group, death, or the end of the study period.
To ensure comparability between the groups, patients were matched based on age, sex, and other clinical factors, resulting in two groups of 805,361 patients each. The average age was 59.4 years, and 58.5% were male.
Among DPP4 inhibitor users, the most prescribed drug was sitagliptin (29.1%), followed by linagliptin (23.1%). In the comparator group, sulfonylureas (61.2%) and sodium-glucose cotransporter-2 inhibitors (26.5%) were the most frequently used agents.
Over a mean follow-up period of approximately 1.5 years (603.6 days for DPP4 users vs. 476.2 days for OAD users), 621 cases of angioedema occurred in the DPP4 inhibitor group, compared with 499 in the OAD group.
No significant differences in angioedema risk between groups
This translated to a rate of 0.47 new cases per 1,000 person-years in the DPP4 group and 0.48 per 1,000 person-years in the OAD group, meaning fewer than one new case for every 1,000 people followed for a year, a difference that did not indicate a significantly increased risk of angioedema with DPP4 inhibitor use.
Serious angioedema, defined as cases requiring intensive care, intubation, or surgical airway intervention, was extremely rare in both groups, with three cases reported in each group.
Subgroup analyses showed consistent findings across age groups, sexes, and among individual DPP4 inhibitors, including sitagliptin, linagliptin, saxagliptin, gemigliptin, and vildagliptin.
Consistent with previous findings, among the small subset of 739 patients using both DPP4 inhibitors and ACE inhibitors, a numerically higher risk of angioedema was observed, with two reported events. However, the sample size was too small to draw definitive conclusions, according to the researchers.
“We found that the risk for angioedema with the use of DPP4 inhibitors was similar compared with other second-line OADs,” the researchers concluded. “However, 99.1% of patients were not on concomitant ACE inhibitor therapy, and thus further studies are needed to determine this risk in those on ACE inhibitor treatment.”
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