The impact of tirzepatide and glucagon-like peptide 1 receptor agonists on oral hormonal contraception.

BACKGROUND: Tirzepatide is a dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist (RA) whose mechanism of action leads to a greater effect of gastric emptying (GE) than typical GLP-1 RAs. After the first dose of tirzepatide, GE is most substantially delayed. The drug then undergoes tachyphylaxis after subsequent doses. Although data on GLP1-RAs have historically demonstrated a lack of impact on bioavailability of oral hormonal contraceptives, manufacturer recommendations for tirzepatide indicate an interaction exists. OBJECTIVES: The objectives of this literature review were to review trial data on differences in the impact of tirzepatide and GLP-1 RAs on oral hormonal contraceptives and provide an analysis of safety data between oral contraceptives and incretin agents. METHODS: PubMed and Google Scholar were searched using the generic name for the GLP-1/GIP agent, the generic names for GLP-1 RAs and hormonal contraceptives, followed by the generic names plus the interacting medication. A total of 6 clinical trials were selected for inclusion in the literature review. RESULTS: Of the 6 articles included in the review, one investigated the use of tirzepatide and showed a statistically significant reduction in area under the plasma drug concentration-time curve, maximum concentration, and time to maximum plasma concentration when tirzepatide was concomitantly administered with an oral hormonal contraceptive. The remaining 5 studies involving GLP-1 RAs did not show a statistically or clinically significant difference of impact of the agents on oral hormonal contraceptives. CONCLUSION: It could be suggested that tirzepatide had a greater impact on absorption of oral hormonal contraceptives than other GLP-1 RAs. The rapid dose escalation and greater delay on GE enhanced the impact on oral medications such as contraceptives. This differed from other GLP-1 RAs and creates a unique need for enhanced provider and patient education regarding the management of this interaction and future studies to evaluate this interaction further.

Incretin-based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes: A systematic review and meta-analysis of observational studies.

AIM: The results from the SUSTAIN-6 trial generated some uncertainty regarding the association between incretin-based drugs [dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] and the risk of diabetic retinopathy. Our objective was to synthesize the available evidence from observational studies regarding the use of incretin-based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes. MATERIALS AND METHODS: We systemically searched Cochrane Library, Embase and Medline to identify observational studies of interest. Risk of bias was assessed using the ROBINS-I tool. Data from included studies were pooled using the DerSimonian and Laird random-effect model with the Hartung-Knapp extension. RESULTS: We included 14 studies in the systematic review, with 10 examining DPP-4 inhibitors and seven examining GLP-1 RAs. Nine studies investigated incident diabetic retinopathy, six investigated diabetic retinopathy progression and two investigated both outcomes. Seven studies were at moderate risk of bias, four at serious risk of bias and three at critical risk of bias. Data pooled across studies showed no association between the use of DPP-4 inhibitors (risk ratio: 0.98, 95% confidence interval: 0.83, 1.17) or GLP-1 RAs (risk ratio: 0.87, 95% confidence interval: 0.56, 1.34) and the risk of diabetic retinopathy. CONCLUSION: This study suggests that the use of incretin-based drugs is not associated with the risk of diabetic retinopathy among individuals with type 2 diabetes. However, these findings should be interpreted with caution considering the limited quality of some of the available evidence.

Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial.

Importance: The effect of continued treatment with tirzepatide on maintaining initial weight reduction is unknown. Objective: To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction. Design, Setting, and Participants: This phase 3, randomized withdrawal clinical trial conducted at 70 sites in 4 countries with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period included adults with a body mass index greater than or equal to 30 or greater than or equal to 27 and a weight-related complication, excluding diabetes. Interventions: Participants (n = 783) enrolled in an open-label lead-in period received once-weekly subcutaneous maximum tolerated dose (10 or 15 mg) of tirzepatide for 36 weeks. At week 36, a total of 670 participants were randomized (1:1) to continue receiving tirzepatide (n = 335) or switch to placebo (n = 335) for 52 weeks. Main Outcomes and Measures: The primary end point was the mean percent change in weight from week 36 (randomization) to week 88. Key secondary end points included the proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period. Results: Participants (n = 670; mean age, 48 years; 473 [71%] women; mean weight, 107.3 kg) who completed the 36-week lead-in period experienced a mean weight reduction of 20.9%. The mean percent weight change from week 36 to week 88 was -5.5% with tirzepatide vs 14.0% with placebo (difference, -19.4% [95% CI, -21.2% to -17.7%]; P < .001). Overall, 300 participants (89.5%) receiving tirzepatide at 88 weeks maintained at least 80% of the weight loss during the lead-in period compared with 16.6% receiving placebo (P < .001). The overall mean weight reduction from week 0 to 88 was 25.3% for tirzepatide and 9.9% for placebo. The most common adverse events were mostly mild to moderate gastrointestinal events, which occurred more commonly with tirzepatide vs placebo. Conclusions and Relevance: In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction. Trial Registration: ClinicalTrials.gov Identifier: NCT04660643.

Retatrutide: a triple incretin receptor agonist for obesity management.

INTRODUCTION: Obesity treatment is evolving rapidly with the emergence of agents targeting incretin receptors. Retatrutide, a triple agonist of these receptors, shows promise in obesity management. AREAS COVERED: Retatrutide, in phase-2 trials, exhibited significant reductions in glycated hemoglobin (HbA1c) and dose-dependent weight loss in individuals with type 2 diabetes mellitus (T2DM). In non-T2DM individuals, it produced substantial weight loss and improved glucose levels, albeit with gastrointestinal side effects. The role of glucagon receptor agonism in the management of heart failure and its potential impact on eating patterns have also been covered in this article. EXPERT OPINION: Although the reductions in HbA1c and dose-dependent weight loss among individuals with T2DM were significantly more for higher doses of retatrutide, it needs to be observed that the active comparator was dulaglutide, which is not approved for the treatment of obesity, at a dose of 1.5 mg, which is much lower than the highest approved dose of 4.5 mg. Dose-dependent increase in heart rate and incidents of mild to moderate cardiac arrythmias raise cardiovascular safety concerns and signify that carrying out long-term cardiovascular outcome trials (CVOTs) will be critical. In addition, retatrutide's potential in heart failure management is intriguing given the series of positive findings of semaglutide on cardiovascular outcomes.

GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics.

G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.

Sodium-Glucose Cotransporter 2 Inhibitors vs Incretin-Based Drugs and Risk of Fractures for Type 2 Diabetes.

Importance: Postmenopausal individuals with type 2 diabetes are susceptible to fractures due to the interaction of elevated blood glucose levels and a deficiency of the hormone estrogen. Despite continued concerns of fracture risks associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), existing evidence in this high-risk population is lacking. Objective: To assess the risk of fractures associated with SGLT2i vs incretin-based drugs of dipeptidyl-peptidase 4 inhibitors (DPP4i) and glucagon-like peptide 1 receptor agonists (GLP1RA), separately, in postmenopausal individuals with type 2 diabetes. Design, Setting, and Participants: This active-comparator, new-user cohort study used nationwide claims data of Korea and took place from January 1, 2013, to December 31, 2020. Postmenopausal individuals (aged ≥45 years) with type 2 diabetes were included. Exposures: New users of SGLT2i or comparator drugs. Main Outcomes and Measures: The primary outcome was overall fractures, comprising vertebral, hip, humerus, and distal radius fractures. Patients were followed up from the day after drug initiation until the earliest of outcome occurrence, drug discontinuation (90-day grace period) or switch, death, or end of the study period. After propensity score fine stratification, hazard ratios (HRs) with 95% CIs were estimated using weighted Cox models. Results: Among 37 530 (mean [SD] age, 60.6 [9.7] years) and 332 004 (mean [SD] age, 60.6 [9.9] years) new users of SGLT2i and DPP4i, respectively, a lower rate of incident overall fractures was presented with SGLT2i vs DPP4i (weighted HR, 0.78; 95% CI, 0.72-0.84). Among 111 835 (mean [SD] age, 61.4 [9.8] years) and 8177 (mean [SD] age, 61.1 [10.3] years) new users of SGLT2i and GLP1RA, respectively, no association with an increased risk of overall fractures was presented with SGLT2i vs GLP1RA (weighted HR, 0.92; 95% CI, 0.68-1.24). Results from several subgroup and sensitivity analyses presented consistent results from main analysis. Conclusions and relevance: This population-based cohort study suggests that SGLT2i was not associated with an increased rate of incident fractures compared with DPP4i and GLP1RA, separately, among postmenopausal individuals with type 2 diabetes.

Mechanisms and clinical applications of incretin therapies for diabetes and chronic kidney disease.

PURPOSE OF REVIEW: Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Development of DKD increases risks for cardiovascular events and death. Glucagon-like peptide-1 (GLP-1) receptor agonist have demonstrated improved cardiovascular and kidney outcomes in large-scale clinical trials. RECENT FINDING: GLP-1 and dual GLP-1/glucose-depending insulinotropic polypeptide (GIP) receptor agonists have robust glucose-lowering efficacy with low risk of hypoglycemia even in advanced stages of DKD. Initially approved as antihyperglycemic therapies, these agents also reduce blood pressure and body weight. Cardiovascular outcome and glycemic lowering trials have reported decreased risks of development and progression of DKD and atherosclerotic cardiovascular events for GLP-1 receptor agonists. Kidney and cardiovascular protection is mediated partly, but not entirely, by lowering of glycemia, body weight, and blood pressure. Experimental data have identified modulation of the innate immune response as a biologically plausible mechanism underpinning kidney and cardiovascular effects. SUMMARY: An influx of incretin-based therapies has changed the landscape of DKD treatment. GLP-1 receptor agonist use is endorsed by all major guideline forming organizations. Ongoing clinical trials and mechanistic studies with GLP-1 and dual GLP-1/GIP receptor agonists will further define the roles and pathways for these agents in the treatment of DKD.

Tirzepatide: Clinical review of the "twincretin" injectable.

PURPOSE: To provide an overview of the safety and efficacy, pharmacology, dosing, place in therapy, and clinical trials for tirzepatide, a novel glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist for treatment of type 2 diabetes. SUMMARY: Diabetes is a chronic disease state with a high burden on healthcare spending and patient quality of life. Incretin-influencing agents such as GLP-1 receptor agonists have gained favor as diabetes therapeutic options due to their impact on multiple glycemic factors as well as resulting weight loss and cardiovascular benefits. Tirzepatide was approved in 2022 for the management of type 2 diabetes and utilizes GLP-1 receptor agonism along with GIP agonism to simultaneously address 2 incretin pathways. Thus far, the SURPASS and SURMOUNT trials, for which findings have been published, have shown great efficacy of tirzepatide in glycosylated hemoglobin and weight reduction in multiple subgroup populations with and without diabetes. Tirzepatide has similar gastrointestinal adverse reactions and contraindications as traditional GLP-1 receptor agonists. CONCLUSION: Tirzepatide is a novel agent on the market for type 2 diabetes management that offers targeting of a familiar pathway along with the new GIP pathway to address glycemic control in patients with diabetes. Tirzepatide is approved for use in patients with diabetes and may serve as a strong option for patients requiring improved glycemic and weight control.

Use and Interchange of Incretin Mimetics in the Treatment of Metabolic Diseases: A Narrative Review.

PURPOSE: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and now tirzepatide, a dual GLP-1 RA/glucose-dependent insulinotropic polypeptide agonist, have numerous advantages in the treatment of type 2 diabetes and obesity, yet only 11% of patients with type 2 diabetes are prescribed a GLP-1 RA. This narrative review addresses the complexity and cost issues surrounding incretin mimetics to support clinicians. METHODS: This narrative review summarizes key trials on the differing effects of incretin mimetics on glycosylated hemoglobin and weight, provides a table with rationale for how to interchange among agents, and summarizes the key factors that guide drug selection beyond guidance from the American Diabetes Association. To support proposed dose interchanges, we preferentially selected high-quality, prospective randomized controlled trials with direct comparisons of agents and doses when available. FINDINGS: Tirzepatide produces the greatest reductions in glycosylated hemoglobin and weight, but its impact on cardiovascular events is still under investigation. Subcutaneous semaglutide and liraglutide are approved for weight loss specifically and are effective in the secondary prevention of cardiovascular disease. Although producing less weight loss, only dulaglutide has effectiveness in the primary and secondary prevention of cardiovascular disease. Semaglutide is the only orally available incretin mimetic; however, the oral formulation produces less weight loss versus its subcutaneous alternative and did not have cardioprotection in its outcomes trial. Although effective in controlling type 2 diabetes, exenatide extended release has the least impact on glycosylated hemoglobin and weight among commonly used agents, while not having cardioprotection. However, exenatide extended release may be preferred on some restrictive insurance formularies. IMPLICATIONS: Although trials have not explicitly studied how to interchange among agents, interchanges can be guided by comparisons between agents' impact on glycosylated hemoglobin and weight. Efficient changes among agents can help clinicians optimize patient-centered care, particularly in the face of changing patient needs and preferences, insurance formularies, and drug shortages.

Cardiovascular effects of incretins: focus on glucagon-like peptide-1 receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been used to treat patients with type 2 diabetes since 2005 and have become popular because of the efficacy and durability in relation to glycaemic control in combination with weight loss in most patients. Today in 2022, seven GLP-1 RAs, including oral semaglutide are available for treatment of type 2 diabetes. Since the efficacy in relation to reduction of HbA1c and body weight as well as tolerability and dosing frequency vary between agents, the GLP-1 RAs cannot be considered equal. The short acting lixisenatide showed no cardiovascular benefits, while once daily liraglutide and the weekly agonists, subcutaneous semaglutide, dulaglutide, and efpeglenatide, all lowered the incidence of cardiovascular events. Liraglutide, oral semaglutide and exenatide once weekly also reduced mortality. GLP-1 RAs reduce the progression of diabetic kidney disease. In the 2019 consensus report from European Association for the Study of Diabetes/American Diabetes Association, GLP-1 RAs with demonstrated cardio-renal benefits (liraglutide, semaglutide and dulaglutide) are recommended after metformin to patients with established cardiovascular diseases or multiple cardiovascular risk factors. European Society of Cardiology suggests starting with a sodium-glucose cotransprter-2 inhibitor or a GLP-1 RA in drug naïve patients with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (CVD) or high CV Risk. However, the results from cardiovascular outcome trials (CVOT) are very heterogeneous suggesting that some GLP-1RAs are more suitable to prevent CVD than others. The CVOTs provide a basis upon which individual treatment decisions for patients with T2D and CVD can be made.

A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer.

BACKGROUND: Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness. These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice. METHODS: The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs. RESULTS: A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6 months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI 1.25, 1.78) or non-insulin (RR 1.15, 95% CI 0.93, 1.42) antidiabetic drugs, and in the studies with serious risk of bias due to confounding (RR 1.18, 95% CI 0.56, 2.49). CONCLUSIONS: In summary, the totality of evidence from observational studies does not support the claim that the use of incretin-based therapies is associated with an increased risk of pancreatic cancer in routine clinical practice. The increased risk of pancreatic cancer observed in observational studies reflects bias resulting from suboptimal methodological approaches, which need to be avoided by future studies.

Incretin based therapy and pancreatic cancer: Realising the reality.

Incretin-based therapies like glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors help maintain the glycaemic control in patients with type 2 diabetes mellitus with additional systemic benefits and little risk of hypoglycaemia. These medications are associated with low-grade chronic pancreatitis in animal models inconsistently. The incidence of acute pancreatitis was also reported in some human studies. This inflammation provides fertile ground for developing pancreatic carcinoma (PC). Although the data from clinical trials and population-based studies have established safety regarding PC, the pathophysiological possibility that low-grade chronic pancreatitis leads to PC remains. We review the existing literature and describe the relationship between incretin-based therapies and PC.

DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits.

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory roles in the incretin system. Though these drugs have been deemed effective in treating T2DM, the Food and Drug Administration (FDA) and some members of the scientific community have questioned the safety of these therapeutics relative to important cardiovascular endpoints. As a result, since 2008, the FDA has required all new drugs for glycemic control in T2DM patients to demonstrate cardiovascular safety. The present review article strives to assess the safety and benefits of incretin-based therapy, a new class of antidiabetic drug, on the health of patient cardiovascular systems. In the process, this review will also provide a physiological overview of the incretin system and how key components function in T2DM.

Incretin-Based Drugs and the Risk of Acute Liver Injury Among Patients With Type 2 Diabetes.

OBJECTIVE: To determine whether the use of dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1 RAs), separately, is associated with an increased risk of acute liver injury compared with the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors. RESEARCH DESIGN AND METHODS: We used the U.K. Clinical Practice Research Datalink linked with the Hospital Episode Statistics Admitted Patient Care and the Office for National Statistics databases to assemble two new-user, active-comparator cohorts. The first included 106,310 initiators of DPP-4 inhibitors and 27,277 initiators of SGLT-2 inhibitors, while the second included 9,470 initiators of GLP-1 RAs and 26,936 initiators of SGLT-2 inhibitors. Cox proportional hazards models with propensity score fine stratification weighting were used to estimate hazard ratios (HRs) and 95% CIs of acute liver injury. RESULTS: Compared with SGLT-2 inhibitors, DPP-4 inhibitors were associated with a 53% increased risk of acute liver injury (HR 1.53, 95% CI 1.02-2.30). In contrast, GLP-1 RAs were not associated with an overall increased risk of acute liver injury (HR 1.11, 95% CI 0.57-2.16). However, an increased risk was observed among female users of both DPP-4 inhibitors (HR 3.22, 95% CI 1.67-6.21) and GLP-1 RAs (HR 3.23, 95% CI 1.44-7.25). CONCLUSIONS: In this population-based study, DPP-4 inhibitors were associated with an increased risk of acute liver injury compared with SGLT-2 inhibitors in patients with type 2 diabetes. In contrast, an increased risk of acute liver injury was observed only among female GLP-1 RA users.

A Novel Dual Incretin Agent, Tirzepatide (LY3298176), for the Treatment of Type 2 Diabetes Mellitus and Cardiometabolic Health.

ABSTRACT: The incretin hormone system is the target of multiple type 2 diabetes mellitus (T2DM) treatments because defects in this system play major roles in the pathogenesis of diabetes. Currently, the glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are recommended for patients with atherosclerotic cardiovascular (CV) disease and those at high risk for atherosclerotic CV disease. In addition to the favorable CV effects, GLP-1 RAs also provide robust lowering of hemoglobin A1c and weight. Although these factors make GLP-1 RAs attractive options for T2DM, the currently available agents have no effect on glucose-dependent insulinotropic polypeptide (GIP). Patients with T2DM are known to have GIP defect which is significant due to its profound insulinotropic effects. Tirzepatide is a novel incretin agent currently recently approved by the Food and Drug Administration for the treatment of T2DM. This first-in-class agent serves as a coagonist for both the GLP-1 and GIP receptors. In this review, we report on the pharmacologic mechanism of GLP-1, GIP, and coagonist effects on the cardiometabolic system. In addition, we review the glycemic lowering, weight loss effects, and other cardiometabolic outcomes of tirzepatide based on phase 2 and 3 data. The safety profile of tirzepatide is consistent across all phase 3 trials. The most common adverse effects are gastrointestinal symptoms, but they generally have a low risk for discontinuation. Overall, preliminary data suggest that tirzepatide is an efficacious and safe agent for the treatment of T2DM.

Switching to Versus Addition of Incretin-Based Drugs Among Patients With Type 2 Diabetes Taking Sodium-Glucose Cotransporter-2 Inhibitors.

Background Evidence is limited in comparing treatment modification by substitution or add-on of glucose-lowering medications in patients with type 2 diabetes. This observational study aims to compare switching versus add-on of incretin-based drugs among patients with type 2 diabetes on background sodium-glucose cotransporter-2 inhibitors (SGLT2i). Methods and Results This population-based, retrospective cohort study was conducted using the IQVIA Medical Research Data, including adults with type 2 diabetes on background SGLT2i from 2005 to 2020. New users of incretin-based drugs were allocated into the "Switch" group if they had discontinued SGLT2i treatment, or the "Add-on" group if their background SGLT2i was continued. Baseline characteristics of patients were balanced between groups. Study outcomes were all-cause mortality, cardiovascular diseases, kidney diseases, hypoglycemia, and ketoacidosis. Patients were observed from the index date of initiating incretin-based drugs until the earliest of an outcome event, death, or data cut-off date. Changes in anthropometric and metabolic parameters were also compared between groups from baseline to 12-month follow-up. A total of 2888 patients were included, classified into "Switch" (n=1461) or "Add-on" group (n=1427). Median follow-up was 18 months with 5183 person-years. Overall, no significant differences in the risks of study outcomes were observed between groups; however, patients in the "Add-on" group achieved significantly greater reductions in glycated hemoglobin, weight, percentage weight loss, and systolic blood pressure than their "Switch" counterparts. Conclusions Initiating incretin-based drugs as add-on among patients with type 2 diabetes on background SGLT2i was associated with risks of clinical end points comparable to switching treatments, in addition to better glycemic and weight control observed with the combination approach.

Real-world effectiveness of liraglutide versus dulaglutide in Japanese patients with type 2 diabetes: a retrospective study.

Real-world data comparing the effectiveness of various glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in type 2 diabetes mellitus (T2DM) are limited. We investigated the clinical effectiveness of liraglutide and dulaglutide in Japanese T2DM in a real-world setting. This retrospective study included 179 patients with T2DM who were treated with GLP-1 RA for at least 12 months (liraglutide, n = 97; dulaglutide, n = 82). We used stabilized propensity score-based inverse probability of treatment weighting (IPTW) to reduce selection bias and confounding by observed covariates. Changes in glycated hemoglobin (HbA1c) at the end of the 12-month treatment were evaluated. After adjustment by stabilized propensity score-based IPTW, no significant differences were observed in patient characteristics between the liraglutide and dulaglutide groups. HbA1c was significantly lower at 12 months in both groups (liraglutide, 8.9 to 7.4%; dulaglutide, 8.7 to 7.5%). Multivariate linear regression analysis showed no differences in the extent of changes in HbA1c at 12 months between the two agents. High baseline HbA1c, the addition of GLP-1 RA treatment modality, and in-hospital initiation of GLP-1 RA treatment were identified as significant contributing factors to HbA1c reduction. The effects of liraglutide and dulaglutide on lowering HbA1c levels at 12 months were comparable in a real-world setting.

Incretin-Based Drugs and Risk of Intestinal Obstruction Among Patients With Type 2 Diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors might increase the risk of intestinal obstruction, but real-world evidence for this severe adverse event is lacking. Thus, the objective of this study was to determine whether GLP-1 RAs and DPP-4 inhibitors are associated with an increased risk of intestinal obstruction compared with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. We used the United Kingdom Clinical Practice Research Datalink and linked databases to assemble two new-user, active comparator cohorts (2013-2019). The first included 25,617 and 67,261 GLP-1 RA and SGLT-2 inhibitor users, respectively. The second included 131,927 and 40,615 DPP-4 inhibitor and SGLT-2 inhibitor users, respectively. Propensity score fine stratification weighted Cox proportional hazards models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of intestinal obstruction requiring hospitalization. GLP-1 RAs were associated with an increased risk of intestinal obstruction compared with SGLT-2 inhibitors (1.9 vs. 1.1 per 1,000 person-years, respectively; HR: 1.69, 95% CI: 1.04-2.74). The highest HR was observed after 1.6 years of use (HR: 3.48, 95% CI: 1.79-6.79). DPP-4 inhibitors were also associated with an increased risk (2.7 vs. 1.0 per 1,000 person-years; HR: 2.59, 95% CI: 1.52-4.42), with the highest HR observed after 1.8 years of use (HR: 9.53, 95% CI: 4.47-20.30). The number needed to harm after 1 year of use was 1,223 and 603 for GLP-1 RAs and DPP-4 inhibitors, respectively. In this large real-world study, GLP-1 RAs and DPP-4 inhibitors were associated with an increased risk of intestinal obstruction.

Pharmacometabolomic profiles in type 2 diabetic subjects treated with liraglutide or glimepiride.

BACKGROUND: Treatment with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) leads to multiple metabolic changes, reduction in glucose levels and body weight are well established. In people with type 2 diabetes, GLP-1 RAs reduce the risk of cardiovascular (CV) disease and may also potentially represent a treatment for fatty liver disease. The mechanisms behind these effects are still not fully elucidated. The aim of the study was to investigate whether treatment with liraglutide is associated with favourable metabolic changes in cases of both CV disease and fatty liver disease. METHODS: In a prespecified post-hoc analysis of a double-blind, placebo-controlled trial in 62 individuals with type 2 diabetes (GLP-1 RA liraglutide or glimepiride, both in combination with metformin), we evaluated the changes in plasma molecular lipids and polar metabolites after 18 weeks of treatment. The lipids and polar metabolites were measured by using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS). RESULTS: In total, 340 lipids and other metabolites were identified, covering 14 lipid classes, bile acids, free fatty acids, amino acids and other polar metabolites. We observed more significant changes in the metabolome following liraglutide treatment compared to with glimepiride, particularly as regards decreased levels of cholesterol esters hexocyl-ceramides, lysophosphatidylcholines, sphingolipids and phosphatidylcholines with alkyl ether structure. In the liraglutide-treated group, lipids were reduced by approximately 15% from baseline, compared to a 10% decrease in the glimepiride group. At the pathway level, the liraglutide treatment was associated with lipid, bile acid as well as glucose metabolism, while glimepiride treatment was associated with tryptophan metabolism, carbohydrate metabolism, and glycerophospholipid metabolism. CONCLUSIONS: Compared with glimepiride, liraglutide treatment led to greater changes in the circulating metabolome, particularly regarding lipid metabolism involving sphingolipids, including ceramides. Our findings are hypothesis-generating and shed light on the underlying biological mechanisms of the CV benefits observed with GLP-1 RAs in outcome studies. Further studies investigating the role of GLP-1 RAs on ceramides and CV disease including fatty liver disease are warranted. TRIAL REGISTRATION: NCT01425580.