Finerenone Therapy In CKD and Type 2 Diabetes
The aim of this study is to assess the effect of finerenone on the duration, progression and complications of type 2 diabetes mellitus. This was achieved by estimating the values of baseline glycated hemoglobin (HbA1c) levels, glycated hemoglobin level variabilities, and the development of complications like cardio-renal syndrome with the use of baseline insulin. Outcomes used to assess the effect of finerenone included kidney pathologies (such as persistent decline in glomerular filtration rate of greater than or equal to 57%, kidney failure or renal death), Progression of diabetes (initiation of new insulin, increased hypoglycemic medication for diabetes, a 1.0% rise in glycated hemoglobin levels from baseline, poorly controlled diabetes or new diagnosis of diabetic keto-acidosis) and cardiovascular pathologies (such as myocardial infarction and stroke which are not fatal, hospital admission for heart failure or cardiovascular death).
In a total of 13,026 participants included in this study, finerenone was seen to reduce the risk of cardio-renal complications associated with type 2 diabetes mellitus compared to the placebo given. This result was obtained irrespective of baseline HbA1c levels, HbA1c level variations, duration of diabetes and use of insulin. Glycated hemoglobin levels during the first year of treatment was seen to be related to an increased risk of cardiovascular and renal complications. Both finerenone and the placebo had no effect on the duration and progression of diabetes. All participant subgroups tolerated finerenone well with minimal cases of discontinuation on the basis of hyperkalemia.
The efficacy of finerenone was not in any way affected by factors such as baseline HbA1c levels, minimal HbA1c level variability, duration of diabetes and use of baseline insulin. However, higher HbA1c level variability was observed to be closely related to an increased risk of cardio-renal complications.
Diabetes is a metabolic disorder characterized by increased blood glucose levels. Based on its etiology, diabetes is classified into 3 main types which include type 1, type 2 and gestational diabetes. However, only type 2 diabetes is covered in the scope of this study.
537 million adults (10.5% of the general population) suffered from diabetes in 2021, and by 2045, the number of diabetics were estimated to rise up to 783 million (12.2% of the general population).
Chronic kidney disease (CKD) is a common complication of type 2 diabetes. Two in five type 2 diabetics have a coexisting CKD as a complication. HbA1c levels between 6% to 9% are closely related to an increased risk of mortality among type 2 diabetics who also have CKD. Additionally, HbA1c levels greater than 9% are closely related to an increased risk of cardiovascular complications and events, increased rate of decline in estimated glomerular filtration rate (eGFR) and faster progression of chronic kidney disease to end-stage kidney disease. The variability of HbA1c levels are also associated with a higher risk of cardio-renal complications and death among type 2 diabetics. Evidence has also shown that an increased risk of microvascular and macrovascular complications is independently associated with the duration of type 2 diabetes.
Type 2 diabetics who are unable to achieve glycemic control with oral medication therapies may need to begin treatment with insulin. However, type 2 diabetics who are on insulin treatment are seen to have an increased risk of developing co-morbidities leading to higher rates of hospitalization for heart failure and cardiovascular deaths.
Finerenone is a selective, distinct, non-steroidal mineralocorticoid receptor antagonist which has been demonstrated in a sub-analysis to slow the progression of chronic kidney disease and renal failure in diabetic kidney disease trials and lower the risk of cardio-renal complications in type 2 diabetics with chronic kidney disease regardless of insulin use or HbA1c levels. Finerenone was also observed to lower the risk of cardiovascular complications and slow the progression of kidney disease when compared with the placebo given in the FIDELITY pre-specified pooled analysis.
Additionally, excess aldosterone levels and the resultant activation of mineralocorticoid receptor (MR) was seen to be associated with an impaired insulin secretion and metabolic signaling which plays a role in the pathogenesis of type 2 diabetes. It can also be thought that the antagonistic effect of finerenone on mineralocorticoid receptors can slow the development and disease progression of type 2 diabetes.
In this study, we aim to assess the effect of finerenone using parameters such as baseline HbA1c levels, HbA1c level variability, duration of diabetes and the effect of insulin use on diabetes progression and cardio-renal complications.
Data was obtained from phase 3 clinical trials of FIGARO-DKD and FIDELIO-DKD combined in a pre-specified pooled analysis called FIDELITY. The clinical trials were carried out in conformity to the Declaration of Helsinki principles, and were given approval by the ethics committee and regulatory authorities of each trial site. Informed consent was received from all included participants.
Randomization was carried out on participants such that they received a single daily oral treatment with finerenone or a placebo. The use of oral hypoglycemic medications was not prohibited. Study participants were randomized to 10mg or 20mg daily finerenone doses, or placebo.
People aged 18 years and above with chronic kidney disease (characterized by an estimated glomerular filtration rate (eGFR) of ≥ 25 to ≤ 90 ml/min/1.73m2 and urine albumin to creatinine ratio (UACR) of ≥ 30 to < 300 mg/g or estimated glomerular filtration rate (eGFR) of ≥ 25 ml/min/1.73m2 and urine albumin to creatinine ratio (UACR) of ≥ 300-≤ 5000 mg/g) and type 2 diabetes with serum potassium levels of ≤ 4.8 mmol/L, who are on renin-angiotensin system therapy were included in the study.
Those excluded from the trial included people with symptomatic chronic heart failure with lowered ejection fraction (i.e class II-IV of New York Heart Association classification) or with HbA1c level of greater than 12%.
Categorical subgroups such as baseline glycated hemoglobin quartiles, baseline duration of diabetes quartiles, and baseline use of insulin were used to analyze composite outcomes.
The analysis consisted of time-to-event analyses, descriptive statistics, sufficient sample size with a given subgroup, mixed models for repeated measures and a statistical test for interaction.
Corresponding confidence intervals (CI) with hazard ratios (HR) were used to express time-to-event effects of treatment. In each subgroup variable, hazard ratios and P interaction of the treatment group were based on the estimated stratified Cox proportional hazards model.
The FIDELITY analysis included a total of 13,026 participants with a total mean baseline HbA1c level of 60.7 mmol/mol (7.7%), mean duration of diabetes of 15.5 years and 7,630 (58.6%) using baseline insulin, with a median follow-up of 3 years.
3471 participants had a glycated hemoglobin level of less than 6.7%, 3245 had a glycated hemoglobin level of 6.7% to 7.5%, 3118 had a glycated hemoglobin level of 7.5% to 8.5%, while 3170 had a glycated hemoglobin level of greater than 8.5%.
3259 participants had a diabetes duration of less than 9.1 years, 3246 had a diabetes duration of 9.1 to 15.1 years, 3251 had a diabetes duration of 15.1 to 20.2 years, while 3252 participants had a diabetes duration of greater than 20.2 years.
It was observed that participants with higher glycated hemoglobin levels had a longer diabetes duration, higher median urine albumin to creatinine ratio, higher BMI and increased likelihood of previous diabetic neuropathy and retinopathy, myocardial infarction, heart failure or coronary artery disease.
Cardiovascular complications were more common in incidence among participants who had a higher baseline HbA1c levels. 406 (13%) out of 3118 participants who had HbA1c values of 7.5% to 8.5% developed cardiovascular complications cardiovascular complications, while 531 (16.8%) out of 3170 participants who had HbA1c values of greater than 8.5% were observed to develop cardiovascular complications.
429 (12.4%) out of 3471 of participants who had HbA1c levels less than 6.7% developed cardiovascular complications, while 391 (12%) out of 3245 participants with HbA1c levels of 6.7% to 7.5% developed cardiovascular complications.
The incidence of cardiovascular complications were seen to be highest in participants who had longer duration of diabetes compared to other participants with shorter duration of diabetes. 333 (10.2%) out of 3259 participants with diabetes duration of less than 9.1 years developed cardiovascular complications, 403 (12.4%) out of 3246 participants with diabetes duration of 9.1 to 15.1 years developed cardiovascular complications, 518 (15.9%) out of 3251 participants with diabetes duration of 15.1 to 20.2 years developed cardiovascular complications while 508 (15.6%) out of 3252 participants with diabetes duration of more than 20.2 years developed cardiovascular complications.
Use of baseline insulin for type 2 diabetes was shown to be associated with an increased incidence of cardiovascular symptoms compared to other participants who did not use baseline insulin.
It was also noted that participants who used baseline insulin had a longer duration of diabetes, higher glycated hemoglobin levels and likely history of cardiovascular disease compared to other participants who do not use baseline insulin.
Finerenone was observed to lower the risk of developing cardiovascular complications compared with placebo irrespective of diabetes duration, use of baseline insulin, HbA1c levels and variability.
Generally, it was observed from the entire population in the FIDELITY analysis that finerenone was associated with lowered risk of renal complications compared to the placebo.
Participants who had extremes of HbA1c levels, i.e. those with the highest HbA1c levels (>8.5%) and lowest HbA1c levels (≤6.7%) were seen to have the highest incidence of renal complications. 198 (6.2%) out of 3170 participants who had the highest HbA1c levels developed renal complications, while 252 (7.3%) out of 3471 participants who had the lowest HbA1c levels developed renal complications.
Participants who had diabetes duration of 15.5 to 20.2 years were seen to have the highest incidence of renal complications (7.3%), while participants with diabetes duration above 20.2 years had the lowest incidence of renal complications (5.8%).
Participants who used baseline insulin were seen to have a higher incidence of renal complications (7%) compared to other participants who do not use baseline insulin (5.3%).
Finerenone was observed to lower the risk of developing renal complications compared with placebo irrespective of diabetes duration, use of baseline insulin, HbA1c levels and variability.
The results reported where in in accordance to the FIDELIO-DKD sub-analyses where the cardiovascular and renal benefits of finerenone were seen to be consistent irrespective of the use of baseline insulin, diabetes duration and glycated hemoglobin levels in participants with type 2 diabetes and chronic kidney disease. Finerenone therapy was not shown to change diabetic disease progression when compared to placebo. As a new drug on the market, expanded uses and benefits of finerenone are still being discovered via this and upcoming research studies.
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