Chronic
Kidney Disease - Evolving Treatments
Mrs.
Monisha S.
Assistant Professor,
School of Pharmacy, Sathyabama Institute of Science and Technology, Chennai.
*Correspondence: malarsuthakar@gmail.com
DOI: https://doi.org/10.71431/IJRPAS.2025.4310
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Article Information
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Abstract
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Review Article
Received: 29/03/2025
Accepted: 30/03/2025
Published: 31/03/2025
Keywords
SGLT2 Inhibitor; Chronic Kidney Disease; DAPA-CKD; MRA;
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There is currently an unmet need for effective
treatment of chronic kidney disease (CKD) that slows disease progression,
prevents development of end-stage kidney disease and cardiovascular disease,
and prolongs survival of patients with CKD. In the last 20 years, the only
agents to show a reduction in the risk of CKD progression in patients with
and without type 2 diabetes (T2D) were angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers, but neither drug class has
provided a decreased risk of all-cause mortality in patients with CKD and
evidence for their use in patients with CKD without T2D is relatively
limited. This review discusses the mechanisms underlying the progression of
CKD, its associated risk factors, and summarizes the potential therapeutic
approaches for managing CKD. There is increasing evidence to support the role
of sodium–glucose cotransporter 2 (SGLT2) inhibitor therapy in patients with
CKD, including data from the designated kidney outcome trials in patients
with T2D (CREDENCE) and in patients with or without T2D (DAPA-CKD). These
studies showed a significant reduction in the risk of CKD progression with
canagliflozin (in patients with T2D) or dapagliflozin (in patients with or
without T2D), respectively, with DAPA-CKD being the first trial to show a reduced
risk of all-cause mortality. On the basis of these data, individualized
treatment with SGLT2 inhibitors represents a promising therapeutic option for
patients with diabetic and nondiabetic CKD to slow disease progression.
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INTRODUCTION
Dapagliflozin, sold under the brand
names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat Type 2 Diabetes
[1]. It is also used to treat adults with heart failure and chronic
kidney disease. It works
by removing sugar from the body
with the urine [2].
Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor. By
inhibiting SGLT2, dapagliflozin
blocks reabsorption of filtered glucose in the kidney, increasing urinary
glucose excretion and reducing blood glucose levels. Its mechanism
of action is independent of pancreatic
β cell function and modulation of insulin sensitivity [3]. Common side effects
include hypoglycemia (low blood
sugar), urinary tract infections, genital infections, and volume depletion (reduced amount of water in the body). Diabetic
ketoacidosis is a common side effect in type 1 diabetic patients [4]. Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat Type 2 diabetes. It is used together with exercise and diet. It is not recommended in Type 1 diabetes. It is taken by mouth [5]. It works by increasing the amount of glucose lost in the urine
[6]. Canagliflozin is a Sodium-Glucose Co-Transporter-2 (SGLT-2) inhibitor [7].
Canagliflozin is an SGLT-2 inhibitor
that increases glucose excretion in the urine by reducing re-absorption of filtered glucose and lowering the renal
glucose threshold. It is also used to
lower the risk of heart attack,
stroke, or death in patients with type 2 diabetes and heart or blood vessel
disease. This medicine works in the
kidneys to prevent absorption of glucose (blood sugar) [8]. Common side effects include
vaginal yeast infections, nausea, constipation, and urinary tract infections. Serious
side effects may include low blood sugar, Fourier’s gangrene,
leg amputation, kidney problems, high blood potassium
and low blood pressure.
Diabetic ketoacidosis may occur despite
nearly normal blood sugar levels. Use in pregnant and breastfeeding is not recommended [9].
SGLT-2 INHIBITOR: SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in
adults with type 2 diabetes [10].
Medicines in the SGLT2 inhibitor
class include canagliflozin, dapagliflozin, and empagliflozin. They are available
as single-ingredient products and
also in combination with other diabetes medicines such as metformin [11]. SGLT2 inhibitors lower
blood sugar by causing the kidneys to remove sugar from the body through the urine. The safety and efficacy of SGLT2 inhibitors
have not been established in patients
with type 1 diabetes, and FDA has not approved them for use in these patients [12].
Non-steroidal mineralocorticoid receptor
antagonists (MRAs)
Non-steroidal mineralocorticoid receptor
antagonists (MRAs) slow down the progression of kidney damage. They do this by
blocking mineralocorticoid receptor (MR) overactivation in the kidneys, heart,
and blood vessels. MR overactivation may cause inflammation and scarring that
can escalate kidney damage. MRAs are used for people who have CKD associated
with T2D. Finerenone (Kerendia®) is the only MRA drug approved to
treat CKD in people with T2D. It reduces the level of protein (albumin) in
urine in people with T2D and CKD. Finerenone is the first medicine approved in
its class that slows the progression of CKD in people with T2D. It may delay
the need for dialysis.
ACE/ARBs (blood
pressure tablets) and Other drugs. These may include other drugs to lower
blood pressure, control blood glucose levels
(in diabetes), lower cholesterol levels,
treat anaemia (EPO), and
protect the bones (calcium and vitamin
D). At ;last, Dialysis:This treatment, required for the advanced CKD
(CKD5 or kidney failure), is a treatment to replicate the kidney’s filtration
function. It does not treat the underlying disease. There are two types:
peritoneal and haemodialysis. Both
provide about 5% of normal kidney filtration function.
Kidney transplant
This is a surgical procedure where a healthy
kidney from a donor is
transplanted into a person with CKD. It is also a treatment to replicate the
kidney’s filtration function. Like dialysis, it does not treat the underlying
disease.
It’s often the most effective treatment for
kidney failure (also called ESRF,
end-stage renal failure).
Kidney specialist (nephrologist)
If you have Stage 3B CKD or worse you should see
or be discussed with a nephrologist. If referred, do not allow yourself to
be discharged unless your CKD is stable and there is little/no likelihood
of progression to dialysis or a kidney transplant.
CHRONIC KIDNEY
DISEASE
Chronic kidney disease, also called
chronic kidney failure, involves a gradual loss of kidney function. Your kidneys filter wastes and
excess fluids from your blood, which are then
removed in your urine [13]. Advanced chronic kidney disease can cause
dangerous levels of fluid, electrolytes and wastes to build up in
your body [14]. In the early stages
of chronic kidney disease, you might have few signs or symptoms.
You might not realize that you have kidney disease until the condition is advanced. Treatment for chronic kidney
disease focuses on slowing the progression
of kidney damage, usually by controlling the cause. But, even controlling the cause might not keep kidney damage from
progressing [15]. Chronic kidney
disease can progress to end-stage
kidney failure, which is fatal without artificial filtering (dialysis) or a
kidney transplant [16].
Dapagliflozin and Canagliflozin are the first two Sodium Glucose
Co‐Transporter 2 (SGLT2)
inhibitors used as an adjunct to diet and exercise to improve glycemic
control in adults with type 2
diabetes mellitus (T2DM) and chronic kidney disease (CKD) [17]. CKD is a
condition in which the kidneys are
damaged and cannot filter blood as well as they should because of this, excess fluid and waste from blood remain
in the body and may cause other health problems such as heart disease and stroke
[18]. SGLT2 inhibitors, which are also called
gliflozins, are a class of drugs that lower your blood sugar
levels by preventing your kidneys from reabsorbing sugar
that is created by your body and the extra sugar leaves through in your
urine. In patients with severe CKD, the use of
SGLT2 inhibitors is contraindicated
[19].
TREATMENT
SGLT2 inhibitors have been studied
as monotherapy or in combination with other oral agents or insulin for the management of hyperglycemia in type 2 diabetes.
SGLT2 inhibitors achieve reduction in HbA1c of 4.4–12.1 mmol/mol
(0.4–1.1%), depending on the baseline HbA1c and the specific drug and dose used. In the last 20 years, the only agents
to show a reduction in the risk
of CKD progression in patients
with and without
type 2 diabetes (T2D) were angiotensin- converting enzyme inhibitors and
angiotensin receptor blockers, but neither drug class has provided a decreased risk of all-cause
mortality in patients with CKD and evidence for their use in patients with CKD without T2D is relatively limited.
There is increasing evidence to support the role of sodium–glucose cotransporter 2 (SGLT2) inhibitor therapy in patients
with CKD, including data from
the designated kidney outcome trials in patients. These studies showed a significant reduction in the risk
of CKD progression with Dapagliflozin (in patients with or without T2D) or canagliflozin (in patients with T2D),
respectively, with DAPA-CKD being the first trial to show a
reduced risk of all-cause mortality [20].
PREVALANCE
Communities who consume water from
natural springs showed a low prevalence of this disease. GPS mapping showed that most of the affected villages
were located below the reservoirs and
canals with stagnant water is developed with CKD [21]. The prevalence of CKD in Asia was estimated to be 434.3 million
(95% confidence interval (CI) 350.2 to 519.7) in a recent systematic review and meta-analysis.16 The average
prevalence of CKD stages 3–5 in Asia was 11.2%;
the prevalence of CKD stages 3–5 varied among subregions (East Asia: 8.6%, South-East
Asia: 12.0%, Western Asia: 13.1%, South Asia: 13.5%.17 In 2017, the prevalence of CKD in Southeast Asia was almost 70
million people. Asian patients with T2D have high rates of kidney disease with 58.6% having microalbuminuria or macroalbuminuria. Furthermore, a higher proportion of
Southeast Asian patients with T2D develop nephropathy and progressive kidney failure at a much younger age than their
European counterparts. There is an
unmet need for additional effective treatments for CKD that slow disease
progression, prevent development prolong survival of patients with CKD
[22].
SIGNIFICANCE
In the last 20 years, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor
blockers (ARBs) have been the only classes of agents recommended for
patients with CKD and hypertension,
with or without T2D. More recently, large, randomized placebo-controlled studies
of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with T2D investigated the cardiovascular safety of
this class of glucose-lowering therapies [23]. In addition to significantly reducing the risk of
cardiovascular events, SGLT2 inhibitors reduced the risk of clinically relevant
renal outcomes compared
with placebo, indicating that SGLT2 inhibitors are associated with significantly lower risk of worsening of
kidney function. However, these studies
were not designed to evaluate treatment benefits in patients with CKD, with
only 7– 26% of participants having an eGFR of less than 60 mL/min/1.73 m2. Subsequently, designated kidney
outcome trials showed
a marked reduction
in the risk of CKD progression with SGLT2 inhibitors in patients with diabetic
kidney disease (DKD) with canagliflozin in CREDENCE and DKD as well as nondiabetic CKD with dapagliflozin in
DAPA-CKD. Additionally, the FIDELIO-DKD
trial evaluating the long-term
effects of the mineralocorticoid antagonist (MRA)
finerenone on kidney and cardiovascular outcomes reported a reduced risk of CKD progression in patients with DKD [24].
Canagliflozin 300 mg and Dapagliflozin 10 mg
had similar effects on UGE and RTG for 4 h after dosing,
but Canagliflozin was associated with higher UGE and greater
RTG reductions for the
remainder of the day. Mean 24‐h UGE was ∼25% higher with Canagliflozin than with Dapagliflozin, and 24‐h mean RTG was ∼0.4 mmol/l lower with
Canagliflozin than with Dapagliflozin. Dapagliflozin had no effect on
PPG excursion. Canagliflozin delayed
and reduced PPG excursion (between‐treatment difference in PPGΔAUC 0–2 h from baseline expressed as a percentage of baseline mean, −10.2%; p = 0.0122). Canagliflozin and Dapagliflozin were generally well
tolerated. In healthy participants, Canagliflozin 300 mg provided greater
24‐h UGE, a lower RTG and
smaller PPG excursions than Dapagliflozin 10 mg [25].
(UGE – URINARY
GLUCOSE EXCRETION
RTG – RENAL THRESHOLD FOR GLUCOSE
PPG- POSTPRANDIAL GLUCOSE)
MATERIALS & METHOD
The Review study aims to assess the SGLT2 Inhibitors. A
literature was conducted between
[2014 and 2023]. The literature search was limited to SGLT2 uses in chronic
kidney disease with or without
diabetes. The study conducted to identify the wise choice of drug selection between SGLT2 inhibitors,
Dapagliflozin, Canagliflozin for treating the chronic kidney disease.
DISCUSSION
MARY C. BIRMINGHAM (2022) [26] she concludes that the benefits
of Canagliflozin is significantly improving patient’s symptom
burden, regardless of CKD, further underscoring the
benefits of SGLT2. This study is similar to the study conducted by KENNETH W. MAHAFFEY (2019)
[27], ANDREAS HEINZEL
(2019) [28], RAJIV AGARWAL
(2019) [29] and CLARE ARNOTT (2021) [30]
whereas, MICHAL NOWICKI (2022) [31] he concludes that
the Dapagliflozin has become the first SGLT2 inhibitor which are more often recommended in patients
with kidney disease regardless of the concomitance of diabetes which is similar
to the study conducted by S.SHA
(2014) [32], HIDDO J L HEERSPINK (2021) [33], DAVID C WHEELER
(2021) [34] and JIAOJIAO LIU (2021) [35]. This study results are controversial
to the above studies result. Thus, it concludes like CHRISTIAN W. MENDE (2021) [36] he concludes that his
study shows the risk of CKD progression with SGLT2 inhibitors canagliflozin and dapagliflozin in patient reduces and are effective with
and without T2D which is similar to the study conducted by KATHERINE R. TUTTLE
(2021) [37] and REY ISIDTO (2023) [38]
CONCLUSION
In Conclusion, SGLT2 Inhibitors have an
important role in the management of T2DM. SGLT2 Inhibitors could manage
uncontrolled glycemic in patients with T2DM. Adding to the currently available
treatment options that can assist with individualization of therapy. The
pleiotropic effects of SGLT2 Inhibitors have the potential to produce benefits
beyond blood glucose control, and there is increasing evidence to indicate that
these agents may reduce the risk of progression of renal impairment in patients
with T2D. The findings of ongoing and future clinical trials will help shed
further light on the role of SGLT2 Inhibitors in the long-term protection of
renal and CV function in patients with T2DM. The CREDENCE
and DAPA-CKD studies showed a significant reduction in the risk of CKD
progression with the SGLT2 Inhibitors Canagliflozin and Dapagliflozin in
patients with CKD. With DAPA-CKD being the first trial to report that
SGLT2 Inhibitors are effective in patients with or without T2D for shoeing CKD
progression and reducing the risk of all-cause mortality. On the basis of these
data, individualized treatment with SGLT2 Inhibitors represents an
unprecedented therapeutic option and an opportunity to slow the progression of
CKD and the development of associated cardiovascular complications in patients
with CKD, whether or not they also have T2D.
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