Commentary Article
In January 1, 2025, the standard of
care (SoC)-2025 has been presented by American Diabetes Association (ADA) [1].
It has been the cornerstone of diabetic diagnosis and treatment for decades. In
the chapter of pharmacotherapy of the diabetes, various types of oral
hypoglycemic agents (OHAs) have been found [2]. Among them, first-line drug
therapy includes sodium-glucose cotransporter 2 inhibitor (SGLT2i) (initiate if
estimated glomerular filtration rate (eGFR) is >20 mL/min/1.73m2;
continue until dialysis or transplant), metformin (if eGFR >30 mL/min/1.73m2),
renin-angiotensin system (RAS) inhibitor at maximum tolerated dose (if albuminuria
and/or hypertension) and moderate-or high-intensity statin.
In order to decrease cardiovascular
disease (CVD) mortality and morbidity in type 2 diabetes (T2D) cases with high
risk for CVD, two important agents of SGLT2i and/or glucagon-like peptide-1
receptor agonist (GLP-1RA) would be considered [3]. Other oral hypoglycemic
agents (OHAs) may remain necessary for control T2D, whereas they do not show
cardiovascular effects. Although both agents have attracted attention for
practical benefit, metformin has been re-evaluated for its clinical efficacy
that has been the first-line agent for long years.
The selection of glucose-lowering
medications for people with T2D and established chronic kidney disease (CKD) is
made with special considerations including limitations to available medications
when eGFR is diminished and there is a desire to mitigate risks of CKD
progression, CVD, and hypoglycemia [4,5]. Medication dosing may require
modification with eGFR <60 mL/min/1.732 [6].
Figure 1 shows the ADA and Kidney
Disease: Improving Global Outcomes (KDIGO) consensus recommendation algorithm
for medications in people with diabetes and CKD [2].
Concerning the clinical effect of
diabetic kidney disease (DKD), a comparative study was conducted for OHAs of
DPP4i and SGLT2i [7]. The protocol included the investigation of Taiwan's
National Health Insurance Research Database for SGLT-2is (n = 1524) and DPP-4is
(n = 6005). As a result, SGLT-2i users showed reduced risk of composite renal
endpoint (HR 0.16) compared with DPP-4i users. Furthermore, they revealed
prolonged time to 50% or higher eGFR decrease (HR 0.17), renal failure (HR
0.14), and less renal death (HR 0.10). SGLT-2i users showed better composite CV
outcome (HR 0.74), lower stroke risk (HR 0.76), and less hospitalization for
heart failure (HR 0.68). Thus, superior cardiorenal benefits of SGLT2is were
found when compared with DPP-4is for DKD cases.
A retrospective cohort study showed CKD progression for T2D patients. The protocol included 1003 cases followed for up to 11 years, and CKD cases with stages 3-5 were found for 388 cases [8]. The cumulative incidence was 38.7% for 38 cases per 1000 person-years. High intensity statin users seemed to develop CKD stage 3-5 rather than low/moderate intensity users and no statin users (44.3%, 37.9%, 30.9%, respectively). On the other hand, biguanide users showed decreased probability of CKD progression as 37.9% vs 52.8%, p=0.001). Further, insulin users showed higher risk as 54.6% vs 34.1%, p<0.001).
Figure 1: Holistic approach for improving outcomes for diabetes and CKD.
A comparative investigation held in
Hong Kong for discontinued-Met group and continued-Met group for DKD patients
with stage 4 [9]. The protocol included 33586 cases with metformin prescription
and decreased eGFR less than < 30 ml/min/1.73 m2. Among them, 7500
(22.3%) cases discontinued metformin within 6 months, but 26,086 (77.7%)
continued metformin. During follow-up 3.8 years in median, incidents occurred
as 16.4% in major adverse cardiac event (MACE), 30.1% in end-stage kidney
disease (ESKD), 7.1% in cancer, respectively, and 44.4% died. In comparison
with the continued-Met group, the discontinued-Met group showed higher risk of
MACE as 1.40 of Hazard Ratio (HR), ESKD (HR 1.52), and death (HR 1.22). There
was no relationship for cancer (HR 0.93). The discontinued-Met group showed
higher HbA1c change at 6 months compared with continued-Met group as +0.5% vs +0.2%, respectively. For a separate
register-based study (n=3235), no relationship was found for metformin use and
lactic acidosis risk (HR 0.94).
For CKD patients, metformin may
give long-term benefits associated with the first-line agent for diabetes.
However, eGFR should be assessed regularly, in order to minimize the risk of
metformin accumulation. When eGFR becomes below 30 mL/min/1.73m2,
metformin has been recommended to be discontinued so far [10]. This notion was
initially based on the data regarding increased lactic acidosis risk in
phenformin use [11]. Metformin accumulation may elevate the risk of lactic
acidosis. However, recent research has re-evaluated the previous method of
metformin for CKD and DKD.
Metformin has been prevalent
worldwide for T2D treatment. It is readily affordable, available and has a good
safety profile [12].
Its adverse effects include
GI-tract disturbances and vitamin B12 deficiency, which are both
easily managed. Metformin-associated lactic acidosis has been very rarely
observed [13]. From a basic point of view, it can primarily impart its
therapeutic actions through the activation of adenosine monophosphate
(AMP)-activated protein kinase. It subsequently inactivates the molecular
target of rapamycin and also its postulated downstream fibrogenic effects on
the kidney [14]. Consequently, metformin may improve outcomes in CKD as well as
improving blood glucose control. Since metformin is predominantly excreted
unchanged in the urine, the risk of accumulation and adverse events would be
found when renal function is impaired [13]. Consequently, it has been avoided in
later CKD stages so far associated with few data in stage 3-4.
Impressive results were found from
the latest report on DKD and metformin administration. The research was 10-year
Scottish nationwide observational cohort study with all T2D patients in stage 4
CKD (eGFR < 30mL/min/1.73m2) [15]. Among 371,742 Scottish T2D
cases, 4,278 showed prevalent metformin with incident CKD stage 4. As clinical
situation, 1,713 (40.1%) cases stopped metformin within 6 month of entering
stage 4. In comparison with cases of continuing metformin, stopped metformin
cases showed lower 3-year survival (63.7% vs
70.5%) with HR 1.26, and MACE incidence showed similarity (HR 1.05). By
marginal structural model analyses, higher risk of all-cause mortality and
similar risk of MACE was observed for stopped vs continued metformin group, as mortality HR 1.34, and MACE HR
1.04. Consequently, continued metformin use may be adequate when eGFR falls
under 30mL/min/1.73m2. A randomized controlled trial (RCT) will be
required for confirming these findings.
In summary, this article described
recent topics concerning the first-line agent as metformin. It has been avoided
when diabetic patient shows decreased eGFR to 30 mL/min/1.73m2.
However, several beneficial effects have been found for stage 4 nephropathy.
Consequently, further evaluation in the future will be expected.
Conflict
of Interest
The authors declare no conflict of
interest.
Funding
There was no funding received for
this paper.
References