Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.

Adherence to GLP1-RA and SGLT2-I affects clinical outcomes and costs in patients with type 2 diabetes.

AIMS: To evaluate the impact of adherence to glucagon like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose transporter two inhibitors (SGLT2-I) on clinical outcomes and costs in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: The 121,115 residents of the Lombardy Region (Italy) aged ≥40 years newly treated with metformin during 2007-2015 were followed to identify those who started therapy with GLP1-RA or SGLT2-I. Adherence to drug therapy over the first year was defined as the proportion of days covered >80%. Within each drug class, for each adherent patient, one non-adherent patient was matched for age, sex, duration, adherence to metformin treatment and propensity score. The primary clinical outcome was a composite of insulin initiation, hospitalisation for micro- and macrovascular complications and all-cause mortality after the first year of drug treatment. Costs were evaluated based on reimbursements from the national healthcare system. RESULTS: After matching, 1182 pairs of adherent and non-adherent GLP1-RA users and 1126 pairs of adherent and non-adherent SGLT2-I users were included. In both groups, adherent patients experienced a significantly lower incidence of the primary outcome (HR: 0.85, 95% CI 0.72-0.98 for GLP1-RA and HR: 0.69, 95% CI 0.55-0.87 for SGLT2-I). A significant reduction in hospitalizations was found for adherent patients in the GLP1-RA group but not for the SGLT2-I group. Results were consistent when analyses were stratified by age and sex. While higher drug-related costs in the adherent group were counterbalanced by decreased hospitalisation costs in SGLT2-I treated patients, this was not the case for GLP1-RA. CONCLUSIONS: Higher adherence to drug treatment with GLP1-RA and SGLT2-I during the first year of the drug intake is associated with a lower incidence of adverse clinical outcomes in a real-world setting.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study.

BACKGROUND: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups. METHODS: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). RESULTS: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex. CONCLUSIONS: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Budget impact analysis for three glucagon-like peptide-1 receptor agonist-based therapies for type 2 diabetes mellitus management in Saudi Arabia.

BACKGROUND AND OBJECTIVES: This study presents a budget impact analysis (BIA) conducted in Saudi Arabia, evaluating the cost implications of adopting semaglutide, tirzepatide, or dulaglutide in the management of type 2 diabetes mellitus (T2DM) patients. The analysis aims to assess the individual budgetary impact of these treatment options on healthcare budgets and provide insights for decision-makers. METHODS: A prevalence-based BIA was developed using real-world and clinical trials data. The model considered disease epidemiology, medication prices, diabetes management expenses, cardiovascular (CV) complications costs, and weight reduction savings over a 5-year time horizon. One-way and probabilistic sensitivity analyses (OWSA, PSA) were performed to assess the robustness of the results. RESULTS: Over a 5-year period, the cumulative budget impact for semaglutide, tirzepatide, and dulaglutide were 85,923,089 USD, 169,790,195 USD, and 94,558,356 USD, respectively. Hypothetical scenarios considering price parity between semaglutide and tirzepatide are associated with financial impacts of 85,923,091 USD and 86,475,335 USD, respectively. In the public sector, semaglutide showed the lowest incidence of 3-point major adverse CV events (3P-MACE), with tirzepatide leading in weight loss and HbA1c reduction, and dulaglutide presenting the highest 3P-MACE rates and least improvements in HbA1c and weight. A breakeven analysis suggested that tirzepatide's list price would need to be $199.91 lower than its current list price to achieve budget impact parity with semaglutide based on currently available evidence. Results from the OWSA suggested that risk reductions for CV events were key drivers of budget impact. PSA results were confirmatory of base-case analyses. CONCLUSIONS: CV cost-offsets and drug acquisition considerations may make semaglutide a favorable use of resources for Saudi budget planners and decision-makers. These results were robust to assumptions regarding the list price of tirzepatide.

Geographic variation and racial disparities in adoption of newer glucose-lowering drugs with cardiovascular benefits among US Medicare beneficiaries with type 2 diabetes.

BACKGROUND: Prior studies have shown disparities in the uptake of cardioprotective newer glucose-lowering drugs (GLDs), including sodium-glucose cotranwsporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1a). This study aimed to characterize geographic variation in the initiation of newer GLDs and the geographic variation in the disparities in initiating these medications. METHODS: Using 2017-2018 claims data from a 15% random nationwide sample of Medicare Part D beneficiaries, we identified individuals diagnosed with type 2 diabetes (T2D), who had ≥1 GLD prescriptions, and did not use SGLT2i or GLP1a in the year prior to the index date,1/1/2018. Patients were followed up for a year. The cohort was spatiotemporally linked to Dartmouth hospital-referral regions (HRRs), with each patient assigned to 1 of 306 HRRs. We performed multivariable Poisson regression to estimate adjusted initiation rates, and multivariable logistic regression to assess racial disparities in each HRR. RESULTS: Among 795,469 individuals with T2D included in the analyses, the mean (SD) age was 73 (10) y, 53.3% were women, 12.2% were non-Hispanic Black, and 7.2% initiated a newer GLD in the follow-up year. In the adjusted model including clinical factors, compared to non-Hispanic White patients, non-Hispanic Black (initiation rate ratio, IRR [95% CI]: 0.66 [0.64-0.68]), American Indian/Alaska Native (0.74 [0.66-0.82]), Hispanic (0.85 [0.82-0.87]), and Asian/Pacific islander (0.94 [0.89-0.98]) patients were less likely to initiate newer GLDs. Significant geographic variation was observed across HRRs, with an initiation rate spanning 2.7%-13.6%. CONCLUSIONS: This study uncovered substantial geographic variation and the racial disparities in initiating newer GLDs.

A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes.

Hyperkalemia is a common adverse event in patients with chronic kidney disease (CKD) and type 2 diabetes and limits the use of guideline-recommended therapies such as renin-angiotensin system inhibitors. Here, we evaluated the comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of hyperkalemia. We conducted a population-based active-comparator, new-user cohort study using claims data from Medicare and two large United States commercial insurance databases (April 2013-April 2022). People with CKD stages 3-4 and type 2 diabetes who newly initiated SGLT-2i vs. DPP-4i (141671 patients), GLP-1RA vs. DPP-4i (159545 patients) and SGLT-2i vs. GLP-1RA (93033 patients) were included. The primary outcome was hyperkalemia diagnosed in inpatient or outpatient settings. Secondary outcomes included hyperkalemia diagnosed in inpatient or emergency department setting, and serum potassium levels of 5.5 mmol/L or more. Pooled hazard ratios and rate differences were estimated after propensity score matching to adjust for over 140 potential confounders. Initiation of SGLT-2i was associated with a lower risk of hyperkalemia compared with DPP-4i (hazard ratio 0.74; 95% confidence interval 0.68-0.80) and contrasted to GLP-1RA (0.92; 0.86-0.99). Compared with DPP-4i, GLP-1RA were also associated with a lower risk of hyperkalemia (0.80; 0.75-0.86). Corresponding absolute rate differences/1000 person-years were -24.8 (95% confidence interval -31.8 to -17.7), -5.0 (-10.9 to 0.8), and -17.7 (-23.4 to -12.1), respectively. Similar findings were observed for the secondary outcomes, among subgroups, and across single agents within the SGLT-2i and GLP-1RA classes. Thus, SGLT-2i and GLP-1RA are associated with a lower risk of hyperkalemia than DPP-4i in patients with CKD and type 2 diabetes, further supporting the use of these drugs in this population.

Medicare formulary restrictions for glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors used in type 2 diabetes mellitus: 2019-2023.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RAs) and sodium glucose cotransporter 2 inhibitors (SGLT2is) have proven benefits in patients with type 2 diabetes mellitus related to decreasing cardiovascular events and heart failure hospitalizations as well as preventing the progression of kidney disease. This led the American Diabetes Association (ADA) to update their guidelines in 2022 to recommend GLP1-RAs and SGLT2is as potential first-line options in patients with cardiorenal conditions. Formulary restrictions, such as step therapy and prior authorizations, can limit access to these beneficial medications. OBJECTIVE: To evaluate trends in Medicare formulary restrictions of GLP1-RAs and SGLT2is following the recommendations by the ADA for first-line use. METHODS: We conducted a retrospective cohort study of Quarter 1 Medicare formulary restrictions on GLP1-RAs and SGLT2is from 2019 to 2023. We analyzed changes in formulary restrictions by year, before and after the ADA first-line recommendations, single vs combination products, and products with and without other indications on a medication level (ie, each unique National Drug Code number on each unique formulary) and formulary level (ie, any prior authorization or step therapy requirements yield formulary restriction). RESULTS: We analyzed 12,212 unique Medicare formularies. GLP1-RAs were 12.5% less likely (relative risk [RR] = 0.87; 95% CI = 0.84-0.91; P < 0.001) and 33.2% less likely (RR = 0.67; 95% CI = 0.60-0.74; P < 0.001) to have restrictions after the ADA guideline changes on a medication and formulary level, respectively. SGLT2is were 87.8% less likely (RR = 0.12; 95% CI = 0.11-0.13; P < 0.001) and 53.0% less likely (RR = 0.47; 95% CI = 0.27-0.80; P = 0.005) to have restrictions after the ADA guideline changes on medication and formulary levels, respectively. CONCLUSIONS: Decreasing trends of medications and formularies with restrictions may indicate payers are recognizing GLP1-RAs and SGLT2is as potential first-line agents, aligning with ADA recommendations.

More questions than answers.

Weight loss and obesity have been challenging topics in science and public health for decades. While scientists have pursued understanding through studies of metabolism and the microbiome, public health scholars have shown that social factors such as poverty and inadequate health care are also major contributors. And though it is true that excess weight carries with it numerous comorbidities that lower life expectancy and add costs to the health care system, studies also show that it is possible to be overweight and healthy. That doesn't change the fact that obesity can be associated with poor mental health, in part because of the corrosive societal stigma that associates being overweight with mental weakness, not biochemistry.

Effectiveness and cost-effectiveness of six GLP-1RAs for treatment of Chinese type 2 diabetes mellitus patients that inadequately controlled on metformin: a micro-simulation model.

Objective: To systematically estimate and compare the effectiveness and cost-effectiveness of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) approved in China and to quantify the relationship between the burden of diabetic comorbidities and glycosylated hemoglobin (HbA1c) or body mass index (BMI). Methods: To estimate the costs (US dollars, USD) and quality-adjusted life years (QALY) for six GLP-1RAs (exenatide, loxenatide, lixisenatide, dulaglutide, semaglutide, and liraglutide) combined with metformin in the treatment of patients with type 2 diabetes mellitus (T2DM) which is inadequately controlled on metformin from the Chinese healthcare system perspective, a discrete event microsimulation cost-effectiveness model based on the Chinese Hong Kong Integrated Modeling and Evaluation (CHIME) simulation model was developed. A cohort of 30,000 Chinese patients was established, and one-way sensitivity analysis and probabilistic sensitivity analysis (PSA) with 50,000 iterations were conducted considering parameter uncertainty. Scenario analysis was conducted considering the impacts of research time limits. A network meta-analysis was conducted to compare the effects of six GLP-1RAs on HbA1c, BMI, systolic blood pressure, and diastolic blood pressure. The incremental net monetary benefit (INMB) between therapies was used to evaluate the cost-effectiveness. China's per capita GDP in 2021 was used as the willingness-to-pay threshold. A generalized linear model was used to quantify the relationship between the burden of diabetic comorbidities and HbA1c or BMI. Results: During a lifetime, the cost for a patient ranged from USD 42,092 with loxenatide to USD 47,026 with liraglutide, while the QALY gained ranged from 12.50 with dulaglutide to 12.65 with loxenatide. Compared to exenatide, the INMB of each drug from highest to lowest were: loxenatide (USD 1,124), dulaglutide (USD -1,418), lixisenatide (USD -1,713), semaglutide (USD -4,298), and liraglutide (USD -4,672). Loxenatide was better than the other GLP-1RAs in the base-case analysis. Sensitivity and scenario analysis results were consistent with the base-case analysis. Overall, the price of GLP-1RAs most affected the results. Medications with effective control of HbA1c or BMI were associated with a significantly smaller disease burden (p < 0.05). Conclusion: Loxenatide combined with metformin was identified as the most economical choice, while the long-term health benefits of patients taking the six GLP-1RAs are approximate.

Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes.

OBJECTIVE: To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. RESEARCH DESIGN AND METHODS: We performed three 1:1 propensity score-matched cohort studies, each stratified by three frailty strata, using data from Medicare beneficiaries (2013-2019) with T2D who initiated SGLT-2is, GLP-1RAs, or DPP-4is. In time-to-event analyses, we assessed the primary cardiovascular effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. The primary safety outcome was a composite of severe adverse events that have been linked to SGLT-2i or GLP-1RA use. RESULTS: Compared with DPP-4is, the overall hazard ratio (HR) for the primary effectiveness outcome associated with SGLT-2is (n = 120,202 matched pairs) was 0.72 (95% CI 0.69-0.75), corresponding to an incidence rate difference (IRD) of -13.35 (95% CI -15.06 to -11.64). IRD ranged from -6.74 (95% CI -8.61 to -4.87) in nonfrail to -27.24 (95% CI -41.64 to -12.84) in frail people (P for interaction < 0.01). Consistent benefits were observed for GLP-1RAs compared with DPP-4is (n = 113,864), with an overall HR of 0.74 (95% CI 0.71-0.77) and an IRD of -15.49 (95% CI -17.46 to -13.52). IRD in the lowest frailty stratum was -7.02 (95% CI -9.23 to -4.81) and -25.88 (95% CI -38.30 to -13.46) in the highest (P for interaction < 0.01). Results for SGLT-2is versus GLP-1RAs (n = 89,865) were comparable. Severe adverse events were not more frequent with SGLT-2is or GLP-1RAs than DPP-4is. CONCLUSIONS: SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.

Patents and Regulatory Exclusivities on GLP-1 Receptor Agonists.

Importance: Glucagon-like peptide 1 (GLP-1) receptor agonists were first approved for the treatment of type 2 diabetes in 2005. Demand for these drugs has increased rapidly in recent years, as indications have expanded, but they remain expensive. Objective: To analyze how manufacturers of brand-name GLP-1 receptor agonists have used the patent and regulatory systems to extend periods of market exclusivity. Evidence Review: The annual US Food and Drug Administration's (FDA) Approved Drug Products With Therapeutic Equivalence Evaluations was used to identify GLP-1 receptor agonists approved from 2005 to 2021 and to record patents and nonpatent statutory exclusivities listed for each product. Google Patents was used to extract additional data on patents, including whether each was obtained on the delivery device or another aspect of the product. The primary outcome was the duration of expected protection from generic competition, defined as the time elapsed from FDA approval until expiration of the last-to-expire patent or regulatory exclusivity. Findings: On the 10 GLP-1 receptor agonists included in the cohort, drug manufacturers listed with the FDA a median of 19.5 patents (IQR, 9.0-25.8) per product, including a median of 17 patents (IQR, 8.3-22.8) filed before FDA approval and 1.5 (IQR, 0-2.8) filed after FDA approval. Fifty-four percent of all patents listed on GLP-1 receptor agonists were on the delivery devices rather than active ingredients. Manufacturers augmented patent protection with a median of 2 regulatory exclusivities (IQR, 0-3) obtained at approval and 1 (IQR, 0.3-4.3) added after approval. The median total duration of expected protection after FDA approval, when accounting for both preapproval and postapproval patents and regulatory exclusivities, was 18.3 years (IQR, 16.0-19.4). No generic firm has successfully challenged patents on GLP-1 receptor agonists to gain FDA approval. Conclusions and Relevance: Patent and regulatory reform is needed to ensure timely generic entry of GLP-1 receptor agonists to the market.

Cost-Effectiveness of Newer Antidiabetic Drugs as Second-Line Treatment for Type 2 Diabetes: A Systematic Review.

INTRODUCTION: Evidence from cardiovascular outcome trials (CVOTs) for newer antidiabetic drugs is increasingly influencing revised recommendations for second-line therapy in type 2 diabetes (T2D). This systematic review aimed to compare the cost-effectiveness of newer antidiabetic drugs specified as sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), and dipeptidyl peptidase 4 inhibitor (DPP-4i) for T2D in a second-line setting. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines, and all relevant published studies were searched comprehensively in electronic databases, including PubMed, Embase, Web of Science, and International Health Technology Assessment database published from April 2023. The quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 reporting checklists. RESULTS: We included 28 studies that met the inclusion criteria. Overall reporting of the identified studies largely met CHEERS 2022 recommendations. The CORE and Cardiff models were the most frequently utilized for pharmacoeconomic evaluation in T2D. Four studies consistently discovered that SGLT2i was more cost-effective than GLP-1RA in T2D who were not adequately controlled by metformin monotherapy. Four studies compared GLP-1RA with DPP-4i, sufonylurea (SU), or insulin. Except for one that demonstrated SU was cost-effective, all were GLP-1RA. Five studies revealed that SGLT2i was more cost-effective than DPP-4i or SU. Eleven studies indicated that DPP-4i was more cost-effective than traditional antidiabetic drugs. Four additional studies explored the cost-effectiveness of various antidiabetic drugs as second-line options, indicating that SU, SGLT2i, or meglitinides were more economically advantageous. The most common driven factors were the cost of new antidiabetic drugs. CONCLUSION: Newer antidiabetic drugs as second line are the cost-effective option for T2D from the cost-effectiveness perspective, especially SGLT2i.

Association of Prescription Co-payment With Adherence to Glucagon-Like Peptide-1 Receptor Agonist and Sodium-Glucose Cotransporter-2 Inhibitor Therapies in Patients With Heart Failure and Diabetes.

Importance: Type 2 diabetes (T2D) and heart failure (HF) prevalence are rising in the US. Although glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes for these conditions, high out-of-pocket costs may be associated with reduced medication adherence. Objective: To compare 1-year adherence to GLP1-RA and SGLT2i therapies by prescription co-payment level in individuals with T2D and/or HF. Design, Setting, and Participants: This retrospective cohort study used deidentified data from Optum Insight's Clinformatics Data Mart Database of enrollees with commercial and Medicare health insurance plans. Individuals aged 18 years or older with T2D and/or HF who had a prescription claim for a GLP1-RA or SLGT2i from January 1, 2014, to September 30, 2020, were included. Exposures: Prescription co-payment, categorized as low (<$10), medium ($10 to<$50), and high (≥$50). Main Outcomes and Measures: The primary outcome was medication adherence, defined as a proportion of days covered (PDC) of 80% or greater at 1 year. Logistic regression models were used to examine the association between co-payment and adherence, adjusting for patient demographics, medical comorbidities, and socioeconomic factors. Results: A total of 94 610 individuals (mean [SD] age, 61.8 [11.4] years; 51 226 [54.1%] male) were prescribed GLP1-RA or SGLT2i therapy. Overall, 39 149 individuals had a claim for a GLP1-RA, of whom 25 557 (65.3%) had a PDC of 80% or greater at 1 year. In fully adjusted models, individuals with a medium (adjusted odds ratio [AOR], 0.62; 95% CI, 0.58-0.67) or high (AOR, 0.47; 95% CI, 0.44-0.51) co-payment were less likely to have a PDC of 80% or greater with a GLP1-RA compared with those with a low co-payment. Overall, 51 072 individuals had a claim for an SGLT2i, of whom 37 339 (73.1%) had a PDC of 80% or greater at 1 year. Individuals with a medium (AOR, 0.67; 95% CI, 0.63-0.72) or high (AOR, 0.68; 95% CI, 0.63-0.72) co-payment were less likely to have a PDC of 80% or greater with an SGLT2i compared with those with a low co-payment. Conclusions and Relevance: In this cohort study of individuals with T2D and/or HF, 1-year adherence to GLP1-RA or SGLT2i therapies was highest among individuals with a low co-payment. Improving adherence to guideline-based therapies may require interventions that reduce out-of-pocket prescription costs.

Primary Occurrence of Cardiovascular Events After Adding Sodium-Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes.

BACKGROUND: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease. OBJECTIVE: To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention. DESIGN: Retrospective cohort study of U.S. veterans from 2001 to 2019. SETTING: Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index. PATIENTS: Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease. MEASUREMENTS: Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates. RESULTS: The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i. LIMITATION: Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined. CONCLUSION: The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention. PRIMARY FUNDING SOURCE: VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research.

Persistence on Novel Cardioprotective Antihyperglycemic Therapies in the United States.

Selected glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) have cardioprotective effects in patients with type 2 diabetes mellitus (T2D) and elevated cardiovascular risk. Prescription and consistent use of these medications are essential to realizing their benefits. In a nationwide deidentified United States administrative claims database of adults with T2D, the prescription practices of GLP-1RAs and SGLT-2i were evaluated across guideline-directed co-morbidity indications from 2018 to 2020. The monthly fill rates were assessed for 12 months after the initiation of therapy by calculating the proportion of days with consistent medication use. Of 587,657 subjects with T2D, 80,196 (13.6%) were prescribed GLP-1RAs and 68,149 (11.5%) SGLT-2i from 2018 to 2020, representing 12.9% and 11.6% of patients with indications for each medication, respectively. In new initiators, 1-year fill rate was 52.5% for GLP-1RAs and 52.9% for SGLT-2i, which was higher for patients with commercial insurance than those with Medicare Advantage plans for both GLP-1RAs (59.3% vs 51.0%, p <0.001) and SGLT-2i (63.4% vs 50.3%, p <0.001). After adjusting for co-morbidities, there were higher rates of prescription fills for patients with commercial insurance (odds ratio 1.17, 95% confidence interval 1.06 to 1.29 for GLP-1RAs, and 1.59 [1.42 to 1.77] for SGLT-2i); and higher income (odds ratio 1.09 [1.06 to 1.12] for GLP-1RAs, and 1.06 [1.03 to 1.1] for SGLT-2i). From 2018 to 2020, the use of GLP-1RAs and SGLT-2i remained limited to fewer than 1 in 8 patients with T2D and indications, with 1-year fill rates around 50%. The low and inconsistent use of these medications compromises their longitudinal health outcome benefits in a period of expanding indications for their use.

Cardiovascular outcomes with SGLT2 inhibitors versus DPP4 inhibitors and GLP-1 receptor agonists in patients with heart failure with reduced and preserved ejection fraction.

BACKGROUND: No study has compared the cardiovascular outcomes for sodium-glucose cotransporter-2 inhibitors (SGLT2i) head-to-head against other glucose-lowering therapies, including dipeptidyl peptidase 4 inhibitor (DDP4i) or glucagon-like peptide-1 receptor agonist (GLP-1RA)-which also have cardiovascular benefits-in patients with heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction. METHODS: Medicare fee-for-service data (2013-2019) were used to create four pair-wise comparison cohorts of type 2 diabetes patients with: (1a) HFrEF initiating SGLT2i versus DPP4i; (1b) HFrEF initiating SGLT2i versus GLP-1RA; (2a) HFpEF initiating SGLT2i versus DPP4i; and (2b) HFpEF initiating SGLT2i versus GLP-1RA. The primary outcomes were (1) hospitalization for heart failure (HHF) and (2) myocardial infarction (MI) or stroke hospitalizations. Adjusted hazards ratios (HR) and 95% CIs were estimated using inverse probability of treatment weighting. RESULTS: Among HFrEF patients, initiation of SGLT2i versus DPP4i (cohort 1a; n = 13,882) was associated with a lower risk of HHF (adjusted Hazard Ratio [HR (95% confidence interval)], 0.67 (0.63, 0.72) and MI or stroke (HR: 0.86 [0.75, 0.99]), and initiation of SGLT2i versus GLP-1RA (cohort 1b; n = 6951) was associated with lower risk of HHF (HR: 0.86 [0.79, 0.93]), but not MI or stroke (HR: 1.02 [0.85, 1.22]). Among HFpEF patients, initiation of SGLT2i versus DPP4i (cohort 2a; n = 17,493) was associated with lower risk of HHF (HR: 0.65 [0.61, 0.69]) but not MI or stroke (HR: 0.90 [0.79, 1.02]), and initiation of SGLT2i versus GLP-1RA (cohort 2b; n = 9053) was associated with lower risk of HHF (0.89 [0.83, 0.96]), but not MI or stroke (HR: 0.97 [0.83, 1.14]). Results were robust across range of secondary outcomes (e.g., all-cause mortality) and sensitivity analyses. CONCLUSIONS: Bias from residual confounding cannot be ruled out. Use of SGLT2i was associated with reduced risk of HHF against DPP4i and GLP-1RA, reduced risk of MI or stroke against DPP4i within the HFrEF subgroup, and comparable risk of MI or stroke against GLP-1RA. Notably, the magnitude of cardiovascular benefit conferred by SGLT2i was similar among patients with HFrEF and HFpEF.

Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: A model-based cost-effectiveness analysis using real-world data.

AIMS: To evaluate the cost-effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1RAs) versus long-acting insulins (LAIs) in patients with type 2 diabetes (T2D) using real-world data. METHODS: A Markov model was utilized to estimate healthcare costs (US$) and quality-adjusted life-years (QALYs) of receiving treatments over 10 years from the healthcare sector perspective. Model inputs were derived from the analyses of Taiwan's National Health Insurance Research Database or published literature on Taiwanese T2D populations. Base-case analysis was performed for the overall study cohort and subgroup analyses were stratified by the presence or absence of established cardiovascular diseases (CVDs) or chronic kidney diseases (CKDs). RESULTS: Overall, using GLP-1RAs versus LAIs cost $6,053 per QALY gained. Results were robust across sensitivity and scenario analyses. Among patients with established CVDs and CKDs, GLP-1RA versus LAI therapy saved $673 (cost-saving) and cost $1,675 per QALY gained, respectively. Among patients without established CVDs and CKDs, GLP-1RA versus LAI therapy cost $9,093 and $7,659 per QALY gained, respectively. CONCLUSIONS: Using GLP-1RAs versus LAIs for T2D patients represented good economic value in real-world practice. Pronounced economic benefits of GLP-1RA therapy among those with prior CVDs or CKDs support rational treatment decisions and optimal healthcare resource allocation for these patients.

Glucagon and energy expenditure; Revisiting amino acid metabolism and implications for weight loss therapy.

Glucagon receptor (GCGR)-targeted multi-agonists are being developed for the treatment of obesity and metabolic disease. GCGR activity is utilised for its favourable weight loss and metabolic properties, including increased energy expenditure (EE) and hepatic lipid metabolism. GLP1R and GIPR activities are increasingly present in a multi-agonist strategy. Due to the compound effect of increased satiety, reduced food intake and increased energy expenditure, the striking weight loss effects of these multi-agonists has been demonstrated in pre-clinical models of obesity. The precise contribution and mechanism of GCGR activity to enhanced energy expenditure and weight loss in both rodents and humans is not fully understood. In this review, our understanding of glucagon-mediated EE is explored, and an amino acid-centric paradigm contributing to this phenomenon is presented. The current progress of GCGR-targeted multi-agonists in development is also highlighted with a focus on the implications of glucagon-stimulated hypoaminoacidemia.