Glucagon-Like Peptide-1 Receptor Agonists and Risk for Gastroesophageal Reflux Disease in Patients With Type 2 Diabetes: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 178, No 9

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), medications used to treat type 2 diabetes and obesity, are associated with delayed gastric emptying, which is a risk factor for gastroesophageal reflux disease (GERD). However, evidence linking these drugs to GERD is limited. Objective: To estimate the effect of GLP-1 RAs compared with sodium–glucose cotransporter-2 (SGLT-2) inhibitors on the risk for GERD and its complications among patients with type 2 diabetes. Design: Active-comparator new-user cohort study emulating a target trial. Setting: U.K. Clinical Practice Research Datalink. Participants: Adults aged 18 years or older with type 2 diabetes initiating GLP-1 RAs or SGLT-2 inhibitors between 1 January 2013 and 31 December 2021, with follow-up until 31 March 2022. Measurements: The primary outcome was incident GERD, and the secondary outcome was its complications. Three-year risk differences (RDs) and risk ratios (RRs) were estimated and weighted using propensity score fine stratification. Results: The study included 24 708 new users of GLP-1 RAs and 89 096 new users of SGLT-2 inhibitors. Over a median follow-up of 3.0 years, the RRs were 1.27 (95% CI, 1.14 to 1.42) for GERD, with an RD of 0.7 per 100 patients, and 1.55 (95% CI, 1.12 to 2.29) for its complications, with an RD of 0.8 per 1000 patients, among GLP-1 RA users compared with SGLT-2 inhibitor users. Limitation: Residual confounding due to lack of information on dietary or lifestyle factors. Conclusion: The estimated effect of GLP-1 RAs compared with SGLT-2 inhibitors suggested a higher risk for GERD and its complications in patients with type 2 diabetes. Clinicians should be aware of this potential adverse effect to provide timely prevention and treatment strategies. Primary Funding Source: Canadian Institutes of Health Research.

After COVID-19 diagnosis, risk for incident type 2 diabetes was elevated for up to 2 y

Source Citation Taylor K, Eastwood S, Walker V, et al. Incidence of diabetes after SARS-CoV-2 infection in England and the implications of COVID-19 vaccination: a retrospective cohort study of 16 million people. Lancet Diabetes Endocrinol. 2024;12:558-568. 39054034

National Trends in Glucagon-Like Peptide-1 Receptor Agonist Use in Adults Without Diabetes, 2018 to 2022

Glucagon-Like Peptide-1 Receptor Agonists and Incidence of Dementia Among Older Adults With Type 2 Diabetes: A Target Trial Emulation: Annals of Internal Medicine: Vol 178, No 9

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to decrease blood glucose levels, promote weight loss, and prevent cardiovascular events. However, evidence is limited regarding their effect on dementia, although emerging observational studies, some with serious methodological limitations, have suggested large reductions in dementia associated with GLP-1RAs that may not be entirely causally related. Objective: To compare the effect of GLP-1RAs versus dipeptidyl peptidase-4 inhibitors (DPP4is) as second-line therapy for type 2 diabetes on risk for dementia among older adults. Design: Target trial emulation. Setting: United States from January 2016 to December 2020. Participants: Medicare fee-for-service beneficiaries aged 66 years or older with diabetes who used metformin and did not have dementia at baseline and initiated GLP-1RAs or DPP4is between January 2017 and December 2018. Measurements: Onset of dementia was defined as 1 year before the date of a new dementia diagnosis. Risks were calculated at 30 months in GLP-1RA and DPP4i groups matched in a 1:2 ratio on an estimated propensity score and compared via ratios and differences. Results: Among 2418 patients initiating GLP-1RAs and 4836 matched patients initiating DPP4is, the mean age was 71 years, and 55% were female. Over a median follow-up of 1.9 years, the outcome occurred in 96 patients in the GLP-1RA group and 217 in the DPP4i group. The estimated risk difference at 30 months was −0.93 (95% CI, −2.33 to 0.23) percentage points, and the estimated risk ratio was 0.83 (95% CI, 0.61 to 1.05). The estimated risk ratios were 0.64 (95% CI, 0.46 to 0.93) and 1.22 (95% CI, 0.74 to 1.66) among those younger than 75 years and aged 75 years or older, respectively. Limitations: Potential residual confounding (no data on body mass index, glycemic control, or duration of diabetes), outcome misclassification, and short follow-up. Conclusion: Among older adults with diabetes, no clear evidence was found that the incidence of dementia differed overall between patients using GLP-1RAs versus DPP4is. Under conventional statistical criteria, an effect of GLP-1RAs between a 39% decrease and a 5% increase in risk for dementia was highly compatible with the data, although estimates differed by age. Randomized trials are needed to quantify the effect of GLP-1RAs on dementia. Primary Funding Source: Gregory Annenberg Weingarten, GRoW @ Annenberg.

In adults with BMI ≥27 kg/m2 and CVD, but without diabetes, semaglutide reduced MACE, regardless of baseline HbA1c level

Source Citation Lingvay I, Deanfield J, Kahn SE, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes by baseline HbA1c and change in HbA1c in people with overweight or obesity but without diabetes in SELECT. Diabetes Care. 2024;47:1360-1369. 38907684

Effect of Social Vulnerability on Efficacy of Bariatric Surgery Versus Medical and Lifestyle Intervention for Type 2 Diabetes: Analysis of the ARMMS-T2D Consortium of Randomized Trials

Background: Social determinants of health (SDOH) can affect metabolic health. Objective: To determine the effect of social vulnerability on the comparative effectiveness of metabolic bariatric surgery or medical and lifestyle intervention on glycemia and weight outcomes in people with type 2 diabetes (T2D). Design: Analysis of the effect modification of baseline Area Deprivation Index (ADI; a metric of social vulnerability) on longitudinal outcomes between randomized treatment groups using linear mixed-effects models. (ClinicalTrials.gov: NCT02328599) Setting: 4 U.S. academic centers. Participants: 258 participants with T2D enrolled in 4 randomized controlled trials of surgical versus medical management and a longitudinal observational follow-up study. Measurements: ADI linked to ZIP code data at randomization; weight loss and hemoglobin A1c (HbA1c) level at the end of the active intervention period (7 to 12 years). Results: Baseline characteristics were well balanced between the surgical and medical therapy groups after adjustment for study site and stratification by high versus low ADI. Surgery was more effective than medical therapy in reducing HbA1c level among persons with high ADI (net difference, −1.29% [95% CI, −1.95% to −0.63%]) and those with low ADI (net difference, −0.95% [CI, −1.29% to −0.62%]). Surgery was also more effective than medical therapy at producing weight loss across ADIs, with respective net differences of −10.6% (CI, −15.2% to −5.9%) for high ADI and −13.3% (CI, −15.7% to −10.9%) for low ADI. The interaction between ADI and intervention group was not significant for either HbA1c (P = 0.37) or weight loss (P = 0.31). Limitations: Small sample size; parent trials were not designed to address effect modification by ADI. Conclusion: Surgery was superior to medical therapy for people with T2D regardless of social deprivation. This study did not detect statistically significant differences in the comparative advantage of surgery over medical therapy by ADI. Primary Funding Source: National Institutes of Health.

Annals On Call - ACP Recommendation: Pharmacologic Treatment of Type 2 Diabetes

Availability of Cardioprotective Medications for Type 2 Diabetes in the Medicaid Program

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only type 2 diabetes medications that reduce cardiovascular disease and death, yet their availability in Medicaid is unclear. Objective: To assess the unrestricted availability of SGLT2is and GLP-1 RAs, using dipeptidyl peptidase-4 inhibitors (DPP4is) as a benchmark. Design: National cross-sectional study using publicly available data. Setting: All 50 state Medicaid fee-for-service (FFS) plans and 273 nonelderly adult managed care organization (MCO) plans with comprehensive coverage in March 2024. Participants: Medicaid plans and enrollees with diabetes in those plans as of March 2024. Measurements: Unrestricted availability was defined as having at least 1 medication in each class listed on the preferred drug list without prior authorization or step therapy. Results: Of 50 FFS plans (including Washington, DC, and excluding 1 state, which had 5 MCO plans), 40 (80%) had unrestricted availability of SGLT2is, 30 (60%) of GLP-1 RAs, 41 (82%) of either, 29 (58%) of both, and 42 (84%) of DPP4is. Among 273 MCO plans (39 states; median, 6 plans [range, 2 to 24 plans]), 182 (67%) had availability of SGLT2is, 131 (48%) of GLP-1 RAs, 184 (67%) of either, 129 (47%) of both, and 204 (75%) of DPP4is. The proportion of MCO enrollees with availability varied markedly among states (SGLT2i range, 24% to 100%; GLP-1 RA range, 0% to 99%; DPP4i range, 41% to 100%). Primarily because of more MCO restrictions, 1.7 million enrollees (lower to upper bound, 1.33 million to 2.17 million enrollees; 25%) had restricted SGLT2i availability, 2.72 million (lower to upper bound, 2.12 million to 3.45 million; 40%) had restricted GLP-1 RA availability, and 1.5 million (lower to upper bound, 1.17 million to 1.90 million; 22%) had restricted DPP4i availability. Availability increased from 2020 to 2024, especially in FFS, but MCO GLP-1 RA availability has plateaued at below 60% since 2022. Tirzepatide was almost entirely restricted. Limitations: Diabetes enrollment was estimated using plan size and state and national prevalence data. The appropriateness of prior authorization restrictions was unknown. Conclusion: Many Medicaid enrollees have restricted access to cardioprotective medications, particularly in MCO plans for GLP-1 RA medications, with substantial state variation. Formulary coverage is a potential lever to increase availability of these medications while balancing pharmaceutical costs. Primary Funding Source: University of California, San Francisco, Action Research Center for Health Equity.

Glucagon-Like Peptide-1 Receptor Agonists and Risk for Depression in Older Adults With Type 2 Diabetes: A Target Trial Emulation Study: Annals of Internal Medicine: Vol 178, No 3

Background: Although glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential antidepressant effects, population studies yield inconsistent results. Objective: To compare the risk for depression in older adults with type 2 diabetes (T2D) initiating treatment with GLP-1RAs versus sodium–glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is). Design: Target trial emulation study. Setting: U.S. National Medicare administrative data from January 2014 to December 2020. Patients: Adults aged 66 years or older with T2D initiating treatment with a GLP-1RA were matched 1:1 on propensity score with those initiating treatment with either an SGLT2i or a DPP4i. Measurements: The primary end point was incident depression. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% CI within matched groups. Results: A total of 14 665 matched pairs of older adults were included in the cohort for GLP-1RAs versus SGLT2is; the rate difference of depression between GLP-1RA users and SGLT2i users was 3.48 (95% CI, −0.81 to 7.78) per 1000 person-years, with an HR of 1.07 (CI, 0.98 to 1.18). In the cohort for GLP-1RAs versus DPP4is (13 711 matched pairs), the rate difference was −5.78 (CI, −10.49 to −1.07) per 1000 person-years, with an HR of 0.90 (CI, 0.82 to 0.98). Limitation: Unmeasured confounders (such as hemoglobin A1c levels and body mass index), outcome misclassification, and limited generalizability to all GLP-1RA users (for example, younger populations or those without T2D receiving the drug for obesity treatment). Conclusion: Among older adults with T2D, the incidence of depression was relatively low. Use of GLP-1RAs was associated with a modestly lower risk for depression compared with use of DPP4is, but not SGLT2is. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

How Would You Treat This Inpatient With Type 2 Diabetes Mellitus? Grand Rounds Discussion From Beth Israel Deaconess Medical Center

Management of hospitalized patients with type 2 diabetes mellitus (T2DM) presents unique challenges. Two recently released guidelines, one from the American Diabetes Association and the other from the Endocrine Society, provide useful recommendations and evidence review to inform the care of medical inpatients with T2DM. These guidelines mostly agree, although there are slight differences in their recommendations. In these rounds, 2 expert diabetologists discuss their approach to inpatient management of T2DM, specifically regarding inpatient glycemic goals on the medical ward, the use of noninsulin antihyperglycemic medications, and patient safety strategies for patients receiving long-acting insulin. They conclude with recommendations for Mr. D, a real patient with T2DM admitted with a recurrent foot infection.