Pharmacy powerpoint
Ifeanyiucheson
FILE_7391.pptx
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes
RxKnowledge PLLC
trial is designed to assess whether treatment with once-weekly subcutaneous semaglutide delays the progression of kidney disease and lowers the risk of kidney failure, as well as kidney and CV disease mortality, compared with placebo in people with CKD and T2D
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Introduction
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Semaglutide part of the incretinmimetics is a glucagon-like peptide-1 receptor agonist commonly used for type 2 diabetes and obesity
Currently it is amongst the first line treatment in diabetes especially in patients with ASCVD
A few questions for discussion: have providers had any insight reggarding semaglutide use in their patients with diabetic retinopathy? Are they reluctant to use semaglutide?
Have providers changed their strategy with t2dm in using tirzepatide over semaglutide or what is the usual question if any when it comes to semaglutide vs tirzepatide
Have providers changed their standard of care with CKD/DM patients
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GLP-1 RA: Semaglutide
FDA Approved for Type 2 DM
Phase 3 Trial: FLOW
Methods
Participants were required to be on RAAS blockade unless treatment was contraindicated or not tolerated; overall, 95.3% were receiving RAAS inhibitors at baseline
Many participants had comorbidities such as neuropathy and retinopathy (43.0% and 44.9%, respectively) at baseline.
A medical history of CVD was also common (52.0%) and 19.1% of participants had previous heart failure.
The most frequently used glucose-lowering medications at baseline were insulin (61.5%) and metformin (51.6%), and 15.5% of participants were receiving SGLT2is
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Study Design
Phase 3b study
Randomized, double blind, parallel group, multinational
Study Population
3534 enrolled patients; average age of 66.6 years
Average hemoglobin A1c of 7.8%
Average duration of diabetes 17.4 years
Treatment Protocol
Dose escalation regimen
Expected duration of approximately 5 years
Funding
Novo Nordisk
Median follow up of 3.4 years
Methods
kidney outcomes trial to assess semaglutide, a once-weekly GLP-1RA, in a population with CKD and T2D at high risk of kidney disease progression.
FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial
randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with dose escalation (as tolerated) from 0.25 mg/week for 4 weeks to 0.5 mg for 4 weeks, followed by a maintenance dose of 1.0 mg/week throughout the remainder of the treatment period.
The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested as well and them being total eGFR slope, major CV event or death from CV causes and death from any cause
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Results
The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group
confidence interval [CI], 0.66 to 0.88; Pvalue=0.0003 meaning a very clinically significance
In the chart we see the eGFR rate and the slope was less steep indicating a slower decrease
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Results
This slide continues to show the primary and secondary endpoints in the semagltuide and placebo groups
The risk of major cardiovascular events was 18% lower in the semaglutide group than in the placebo
The risk of death from any cause was 20% lower in the semaglutide group than in the placebo group
At 104 weeks, the urinary albumin-to-creatinine ratio was reduced by 12% in the placebo group, as compared with 40% in the semaglutide group
Even the mean reduction in body weight was 4kg ggreater in the semaglutide group than placebo so we can see clinical significance with semaglutide use in these patients wtih a range of benefits
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Safety
Look at the safety profile, we see that serious adverse events were reported in fewer patients in the semaglutide group than in the placebo group (about 50% vs 54%). Althouggh this is a small incremental change, we can still say it is clinically significant. Also, less patients in the semaglutide group were reported to have serious infections or infestations (about 18% vs 21%) or serious CV disorders (15.4% vs 18.1%) which is something to keep in mind.
The most significant and most common serious event were eye disorders, which was more common in the semaglutide group than placebo (52 patients vs 30 patients), but both groups reported similar diabetic retinopathy events
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Strengths and Weaknesses of the FLOW trial
Strengths
Large Sample Size; Rigorous Study
Long Follow-Up Period
Target Population
Comprehensive Outcome Measures
Weaknesses/Limitations
Specific to Type 2 Diabetes
Short-Term Renal Outcomes
Lack of Racial Diversity
Limited Use of SGLT2 Inhibitors and MRAs
The trial included a large population, with well-conducted procedures which strengthens the reliability of the conclusions drawn about the benefits and risks of semaglutide. And also it being a randomized, double-blind, placebo-controlled trial, it is considered a gold standard in clinical trial design, minimizing bias and enhancing the reliability of results.
The trial’s follow-up duration (~5 years) ensures long-term data on both efficacy and safety, providing a better understanding of semaglutide’s impact on CKD progression
The inclusion of patients with CKD, a high-risk and often underrepresented population in clinical trials, addresses a significant unmet medical need, as many diabetes treatments are not suitable for these patients.
The trial assessed key outcomes like kidney and cardiovascular function, as well as overall mortality, offering significant clinical insights. And the conclusions are clear on the benefits and risks again showing significant benefits in reducing kidney and CV issues, all cause mortality and adding treatment decisions for CKD in type 2 DM patients
he trial focuses on patients with type 2 diabetes and CKD, so the results may not be applicable to those with CKD but without diabetes, limiting generalizability to the broader CKD population.
The trial does include long term follow up but some kidney improvement functions may take longer to manifest and the some of the putcomes may not fully capture the long term renal protective effects of semalgutide beyond the study duration
Most participants identified as White, whereas CKD disproportionately affects marginalized populations like Black and Indigenous people. This limits the generalizability of the findings across different racial groups.
At the beginning of the trial SGGLT2i and MRAs were not widely used for kidney protection, leading to smaller sample soze of participants on these agents which limits the assessment of combination therapies
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Conclusion
Clinical Impact: Semaglutide shows to reduce risk of clinically important kidney outcomes and death from cardiovascular events in patients with type 2 diabetes and chronic kidney disease
Provides a new potential option for kidney and cardiovascular protection in patients with CKD and type 2 diabetes.
Primary Endpoint: the study achieved notable reduction in loss of kidney function
Secondary Endpoints: demonstrated promising results in reducing the decrease in eGFR, major cardiovascular events and risk of death from any cause
Because three other therapies have been shown to have benefits in patients with type 2 diabetes and CKD (renin-angiotensin system inhibition, SGLT2 inhibition, and mineralocorticoid with finerenone), clinicians will need to consider the order and priority of use for semaglutide and will need to individualize therapy with a possible role for combination of these agents
Future Research Needed:
Further studies should explore combination therapies, diverse populations, and longer-term outcomes to enhance generalizability.
If I were to approach the FLOW trial differently: first I would Increase Diversity in the Study Population, prioritzing more racially diverse cohort especially populations disproportionately affected by CKD such as black and indigenous groups
Incorporate SGLT2 Inhibitors and MRAs Early: given the role SGLT2i and MRAs play in kidney protection, I would design the study to include higher proportion of participants on these agents to get a more comprehensive assessment of the effects of combo therapy with semaglutidse
I also would power the study for subgroup analysis to detect more meaningful differences within and between important subgroups like patients with different stages of CKD, or different racial/ethnic groups
I would also consider including kidney failure as a primary endpoint to provide more targeted data on the progression of CKD in relation to semaglutide treatment
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References
Perkovic V, Perkovic V, Perkovic V, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. New England journal of medicine/�The �New England journal of medicine. Published online May 24, 2024. doi:https://doi.org/10.1056/nejmoa2403347
Rossing P, Baeres FMM, Bakris G, et al. The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrology Dialysis Transplantation. Published online January 18, 2023. doi:https://doi.org/10.1093/ndt/gfad009
de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022;45:3075-3090.
Mann JFE, Buse JB, Idorn T, et al. Potential kidney protection with liraglutide and semaglutide: exploratory mediation analysis. Diabetes Obes Metab 2021;23:2058-2066.
