Ishak A. Mansi

Objective: To evaluate the association of initiating glucagon‐like peptide‐1 receptor agonists versus dipeptidyl peptidase‐4 inhibitors (as active comparator) with frailty progression and falls and whether associations differed by baseline frailty. Research Design and Methods: Five propensity score‐matched retrospective cohorts using Veterans Health data (years 2006–2021), utilizing new‐user, active‐comparator design. The five matched cohorts were at progressive degrees of frailty at baseline and included adults with diabetes and 3 years of baseline data who initiated study medications with at least 90 days of therapy. Main Outcomes and Measures: Primary outcome was absolute change in Frailty Index from baseline to follow‐up. Secondary outcomes were increase in the frailty index and fall rate during follow‐up. Outcomes were assessed in an as‐treated framework. Results: The main matched cohort included 73 592 pairs. Over a mean follow‐up of approximately 27 months, glucagon‐like peptide‐1 receptor agonists initiation was associated with less worsening in frailty index (regression coefficient: −0.0010; 95% CI: −0.0018 to −0.0002; p = 0.011), lower odds of frailty index progression (OR: 0.97; 95% CI: 0.95–0.99; p = 0.003), and a lower fall rate (incidence rate ratio: 0.87; 95% CI: 0.84–0.91; p < 0.001) compared to dipeptidyl peptidase‐4 inhibitor initiation. Findings were generally consistent across the other four matched cohorts, with attenuation in the matched cohort with severe frailty at baseline. Conclusions: Initiation of glucagon‐like peptide‐1 receptor agonist was associated with slightly less frailty progression and fewer falls compared with dipeptidyl peptidase‐4 inhibitor initiation, but estimates were attenuated in severe frailty.

Aim: We aimed to examine the association between glucagon‐like peptide‐1 receptor agonists (GLP1‐RA) use and diabetic retinopathy and non‐arteritic anterior ischemic optic neuropathy (NAION), using dipeptidyl peptidase‐4 inhibitors (DPP4i) as active comparators. Methods: We created a retrospective propensity score (PS)‐matched cohort study of patients who initiated either GLP1‐RA or DPP4i (years 2006–2021). Using new‐users, we created two PS‐matched cohorts: patients with diabetes (overall cohort) and patients with diabetes and chronic kidney disease (CKD‐cohort); the latter represents patients at higher likelihood of diabetes microvascular complications. Primary outcomes were non‐vision‐threatening diabetic retinopathy (NVTDR), vision‐threatening diabetic retinopathy and diabetic macular edema (VTDR/DME), and NAION. Secondary outcomes included vision impairment or blindness and occurrence of retinopathy procedures. Results: PS‐matched overall cohort included 98 082 pairs of GLP1‐RA or DPP4i users. GLP1‐RA users had higher risk of NVTDR (11.05% vs. 9.98%; odds ratio [OR] 1.12, 95% confidence interval [95% CI]: 1.09–1.15), VTDR/DME (2.17% vs. 1.98%; OR 1.09, 95% CI: 1.03–1.16), and occurrence of retinopathy procedures (4.16% vs. 3.68%, OR 1.14, 95% CI: 1.09–1.19). There was no significant difference in risk of NAION (OR 1.11, 95% CI: 0.96–1.29) or vision impairment or blindness (OR 1.04, 95% CI: 0.97–1.11). In the CKD cohort (15 440 matched pairs), GLP1‐RA was associated with high risk of NVTDR (OR 1.10, 95% CI: 1.03–1.18), and occurrence of retinopathy procedures (OR 1.14, 95% CI: 1.03–1.26), but not other outcomes. Conclusions: GLP1‐RA use was associated with a modest increase in risk of diabetic retinopathy and retinopathy‐related procedures, independent of the presence of retinopathy at baseline. However, GLP1‐RA use was not associated with vision impairment or blindness, although administrative codes notably have low validity for blindness diagnosis.

Alcohol-related liver disease (ALD) causes approximately one-fifth of all alcohol-related deaths. Only 4% of patients with alcohol use disorder (AUD) receive medications for AUD, such as acamprosate. Medications for AUD may decrease progression of ALD. Challenges in treating AUD include limited primary care physician familiarity with medications. Gabapentinoids are occasionally used but are not approved for AUD treatment, and primary care physicians are familiar with them. This study aimed to examine the association between both therapies and progression of ALD among patients with AUD. This was a retrospective propensity score (PS)-matched cohort study using data from the Veterans Affairs healthcare records. Patients with AUD who were started on acamprosate or gabapentinoids after being diagnosed with AUD were identified. The primary outcome was the composite outcome of ALD progression (alcoholic hepatitis, compensated cirrhosis, decompensated cirrhosis and hepatocellular carcinoma). The secondary outcome was alcohol-related admission. A PS encompassing 80 variables was created and patients who used acamprosate and gabapentinoid were matched into pairs. Another PS-matched cohort was created that was restricted to patients who continued their medications for ≥120 days (persistent cohort). 24 477 pairs of patients who used acamprosate and gabapentinoid were PS matched. The primary outcome occurred in 15.78% of patients using acamprosate and 13.37% of those using gabapentinoid (OR 1.21; 95% CI 1.15 to 1.27). Alcohol-related admission occurred in 24.73% of patients using acamprosate and 18.01% of those using gabapentinoid (OR 1.50; 95% CI 1.43 to 1.56). Similar outcomes were observed in a PS-matched persistent cohort of 12 258 pairs. Gabapentinoids were associated with a decreased risk of ALD progression and alcohol-related admission compared with acamprosate. Gabapentinoids may be a viable tool to decrease progression of ALD in AUD. Further studies are needed to examine whether gabapentinoids are associated with less heavy drinking only or with higher abstinence.

Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease in the United States. MASLD can progress to liver cirrhosis and is associated with an increased risk of major acute cardiovascular events (MACE). This study aimed to examine the association of glucagon‐like peptide‐1 receptor agonists (GLP1‐RA) use with liver disease progression, MACE, and death from any cause among people with hepatic steatosis. Materials and Methods: This retrospective cohort study using national data from the Department of Veteran Affairs included people with non‐alcoholic hepatic steatosis who initiated either GLP1‐RA or dipeptidyl‐peptidase‐4 inhibitor (DPP4i) between 1 October 2005 and 30 September 2021. Primary outcomes were: (1) liver disease progression and (2) MACE and death from any cause (MACE/death). GLP1‐RA users and DPP4i users were propensity score matched on 73 baseline characteristics. Results: We matched 58 157 pairs of GLP1‐RA and DPP4i users. GLP1‐RA users had less liver disease progression (6.1%) compared with DPP4i users (7.0%), odds ratio (OR): 0.86; 95% confidence interval (95% CI): 0.82–0.90 and a lower risk of MACE/death (11.1% vs. 14.7%, respectively), OR: 0.72; 95% CI: 0.70–0.75. The number needed to treat to prevent one additional liver disease progression and MACE/death was 109 and 27 people, respectively. Conclusions: Among people with diabetes and hepatic steatosis, GLP1‐RA use was associated with a lower risk of liver disease progression and a lower risk of MACE/death compared to DPP4i use. In people with MASLD, a holistic approach that seeks to lower MACE/death, beyond lowering liver disease progression alone, should be prioritised.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown efficacy in reducing cardiovascular events in patients with diabetes mellitus (DM), but conflicting evidence exists regarding their impact on cardiac arrhythmias. Whereas some studies associated GLP-1RAs with arrhythmogenesis, other studies suggested a decreased association with atrial fibrillation (AF). The aim was to compare the risk of incident AF after initiation of GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP4is), as active comparators, in patients with DM. A retrospective propensity score-matched cohort study was conducted. The national data of Veterans Health Administration during fiscal years 2006-2021 were used for the study. Adults who initiated either GLP-1RA or DPP4i medications were included. The primary outcome was a composite outcome of AF (diagnosis of AF/flutter or undergoing an AF procedure). Out of 116,235 GLP-1RA users and 217,668 DPP4i users, we propensity score-matched 80,948 pairs, on 88 characteristics. The composite outcome of AF was similar in the GLP-1RA group (4.1%) and DPP4i group (4.3%); odds ratio (OR) 0.96, 95% confidence interval (CI) 0.92-1.01. Secondary analyses stratified by medication use duration showed no significant differences in composite AF risk (p > 0.05). Individuals achieving 5% weight loss from baseline body weight had significantly lower AF incidence (OR 0.83, 95% CI 0.78-0.89), whereas no significant differences were observed in those with no weight loss or weight gain (OR 1.05, 95% CI 0.97-1.12). GLP-1RA use was not associated with a decreased or increased risk of AF compared to DPP4i use. In subgroup analysis, lower AF risk was seen in GLP-1RA versus DPP4i users who achieved weight loss, which suggests weight loss as a potential modifier of response to GLP-1RAs.

Background The use of glucagon-like peptide-1 receptor agonists (GLP-1RA) has exponentially increased owing to their favorable cardio-renal-metabolic effects. Some studies have raised concerns about a potential association between GLP-1RA use and malignancy. This study aimed to examine the association between GLP-1RA use and risk of hepatocellular carcinoma (HCC). Methods This retrospective propensity score (PS)-matched cohort study used data from the Veterans Health Administration (years 2006–2021). Using a new-user active comparator design, the study included adults who initiated a GLP-1RA or dipeptidyl peptidase-4 inhibitor (DPP4i) as an active comparator and had no prior history of HCC or liver transplantation. The primary outcome was incident HCC. We developed a PS that included 133 variables encompassing diabetes severity, hepatic conditions, liver disease scores, vital signs, laboratory investigations, comorbidity scores, and use of other medication classes. Results Of 147,969 GLP-1RA and 263,664 DPP4i users, 100,248 pairs of GLP-1RA and DPP4i users were PS-matched. Hepatocellular carcinoma occurred in 302 (0.30%) GLP-1RA users and in 230 (0.23%) DPP4i users (odds ratio [OR]: 1.31, 95% confidence interval [95% CI]: 1.11–1.56). Secondary analysis, which stratified patients by duration of medication use, showed an increased risk of HCC in association with GLP-1RA use > 6 months, but similar HCC risk if medication use was < 6 months (OR: 0.96; 95% CI 0.68–1.35). Conclusions Glucagon-like peptide-1 receptor agonists use was associated with a modest but statistically significant increase in HCC risk versus DPP4i use. Although the reported benefits of GLP-1RA seem to far exceed this modest increased risk, further studies are warranted due to exponentially increasing GLP-1RA use and their broadening indications.