Letter by Tampaki et al Regarding Article, "Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors".

Letter by Tampaki et al Regarding Article, “Cardiovascular Effects of New Oral GlucoseLowering Agents: DPP-4 and SGLT-2 Inhibitors” To the Editor: It was a pleasure to go through the article by Scheen, which focuses on cardiovascular effects of new oral glucose-lowering agents, as he brings up excellent discussion topics. In the Leader trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), liraglutide addition reduced cardiovascular mortality creating a slightly favorable harmbenefit balance, because the randomization process didn’t create comparable groups. The LEADERs inclusion criteria defined 2 populations with different characteristics, whereas the protocol didn’t plan separate randomization and analysis of the 2 patient populations, consequently weakening the results. During the trial, the protocol permitted hypoglycemic agents addition if the HbA1c remained >7%, except of GLP-1 (glucagon-like peptide-1) receptor agonists and gliptins, leading to unbalanced treatment distribution between the groups, weakening the results. The consequences caused by imbalance about the β-blocker and glitazone treatment were not further investigated, meaning a possible liraglutide efficacy overestimate. Uncertainty about the consequences of GLP-1 receptor agonists long-term use highlights safety issues including pancreatic and thyroid cancer risk. In the Leader trial, patients at increased risk were excluded, whereas 13 patients in the liraglutide group versus 5 patients (6 patients would make the difference statistically significant) in the placebo group developed pancreatic cancer. Five key efficacy phase 3 trials and a CVOT (cardiovascular outcome trial) revealed that the patients proportion discontinuing trial product prematurely because of adverse events was 20% higher with semaglutide compared with placebo, whereas the study-wise type I error was not controlled. The prespecified primary analysis in CVOT was a mixed model for repeated measurements analysis using on-treatment data before the onset of rescue therapy and hypothesized missing data were randomly missing (MAR), a not acceptable approach, as some off-treatment measurements were replaced with on-treatment measurements acquired at early treatment discontinuation visits. After Food Drug Administration’s advice, a retrieved dropout analysis for the HbA1c and body weight end points was conducted, where missing data were multiply imputed based on subjects who stopped treatment but were still measured at the end point visit. One limitation is that because of the retrieved dropouts small number, relatively simple imputation models were used without considering the discontinuing treatment time, overestimating the treatment effect of semaglutide. No screening for neoplasms and no specific information collecting about neoplasms was conducted at baseline. Events for adjudication were identified by a MedDRA (Medical Dictionary for Regulatory Activities) query and showed a higher proportion of malignancy in semaglutide patients, driven by skin, breast, lung, and pancreatic cancer. In addition to pancreatic cancer, breast cancer events increased incidence was documented with other GLP1 RAs. Thyroid neoplasms were analyzed separately because of C-cell hyperplasia concern with long-acting GLP-1 RAs. Additionally, 2-year animal carcinogenicity studies showed a statistically significant combined C-cell adenomas and carcinomas incidence increase, an established class effect of GLP-1R agonists, highlighting that the human relevance of the tumors remains unknown requiring postmarketing surveillance studies. The last Food and Drug Administration Pharmacology/ Toxicology Summary in animal studies reveals food intake and body weight reduction observed additionally to ECG abnormalities (a bigeminal rhythm with episodes of sinus tachycardia in week 13 and a continuous left bundle branch block-like recording that persisted from week 26 to week 52), a slight multifocal myocardial vacuolation and degeneration with karyomegaly. In the EMPA-REG trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), mainly cardiovascular death drives the differences in the 3 and 4-point major adverse cardiovascular events (MACE) results and was included as a component of the primary and key secondary MACE end point not being prespecified from the beginning. The not assessable deaths were more than one-third (40.1%) of the trials all cardiovascular deaths, whereas death was underestimated in patients that had a protracted illness with an earlier qualifying event. Hospitalization for heart failure (HF) and other HF-related end points were not prespecified as part of the composite MACE end points and were not controlled for type I error. Assessing whether patients who had HF were on HF guideline-directed therapy or whether they had HF with a reduced ejection fraction or a preserved one was not clear. Silent myocardial infarctions were not included in the primary analysis for MACE but were ineffectively incorporated with additional analyses to the composite 3-point MACE, using postrandomization variables as part of the inclusion criteria, producing incorrect outcomes. Most importantly, cancer occurrence was not stated clearly in the EMPA-REG trial, rationalizing close drug pharmacovigilance.