Comparative Efficacy of Lobeglitazone Versus Pioglitazone on Albuminuria in Patients with Type 2 Diabetes Mellitus

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Good renal function is important in patients with type 2 diabetes mellitus (T2DM) [1‐3]. Diabetic kidney disease (DKD), defined as a decrease in kidney function in persons with diabetes, is an important risk factor for various cardiovascular diseases and is the most common cause of end-stage renal disease worldwide [4‐8]. Many drugs are excreted through the kidneys, and when kidney function is poor, the metabolites of these drugs accumulate in the body. In patients with T2DM, reduced renal function can result in limitations in the use of anti-diabetic medications and increased risk of complications [9, 10]. The diagnosis of DKD is based on the presence of albuminuria and/or a reduced estimated glomerular filtration rate (eGFR) without other primary causes of kidney damage [5]. In particular, albuminuria, a marker for DKD, is an independent predictor of cardiovascular diseases and its appropriate management is of great importance [11‐13].

Thiazolidinediones (TZDs) are a class of oral anti-diabetic drugs that decrease insulin resistance through their activation of peroxisome proliferator-activated receptor gamma (PPARγ) [14]. Although fluid retention, weight gain, and an elevated risk for bone fractures are known side effects of TZDs, these drugs also have many beneficial effects on cardiovascular disease, nonalcoholic fatty liver disease (NAFLD), and inflammation [15, 16]. Recently, anti-diabetic drugs have attracted increased interest for their renoprotective effects, such as improvement of albuminuria, in addition to their glucose-lowering effects. TZDs have neutral effects on DKD progression and do not require dose adjustments based on renal function [9, 16]. Several studies have shown that TZDs improve albuminuria values in patients with T2DM [17‐20].

Lobeglitazone is a novel TZD developed in Korea that has been used in several countries to treat patients with T2DM [21]. However, to date, the efficacy of lobeglitazone for reducing albuminuria has not been studied. The aim of this analysis was to evaluate the efficacy of lobeglitazone versus pioglitazone on albuminuria in patients with T2DM in a 24-week clinical trial.

The baseline characteristics of the participants are shown in Table 1. Demographic, anthropometric, and clinical characteristics were comparable between the lobeglitazone and pioglitazone groups. There were also no significant between-group differences in serum Cr, eGFR, and UACR values nor in medication history, including use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker that was not reported previously (Table 1; Electronic Supplementary Material [ESM] Table S1).

The reduction in HbA1c levels between baseline and week 24 of treatment was statistically significant in both groups (Table 2). Serum Cr and eGFR were not altered at 24 weeks compared with baseline. Baseline UACR did not differ between the two groups (lobeglitazone group 25.1 mg/g Cr; pioglitazone group 66.7 mg/g Cr). At 24 weeks, the UACR had decreased in the lobeglitazone group relative to baseline (− 4.3 mg/g Cr) and increased in the pioglitazone group (5.2 mg/g Cr), although the difference in either group was not statistically significant (P = 0.476) (Fig. 1). These trends appeared more apparent in patients with micro- and macroalbuminuria than in those with normoalbuminuria (lobeglitazone group − 25.4 mg/g Cr; pioglitazone group 15.3 mg/g Cr), although the difference was not statistically significant (P = 0.467).

The proportion of patients with normoalbuminuria did not differ between the two groups at baseline (81.2 vs. 73.6%, lobeglitazone vs. pioglitazone group) (Table 3). At 24 weeks, the incidence of new-onset microalbuminuria (2.4% [2/84] vs. 6.8% (5/73), lobeglitazone vs. pioglitazone group) and the progression of albuminuria by > 1 stage in the lobeglitazone group (2.9% [3/103] vs. 6.1% [6/99], lobeglitazone vs. pioglitazone group) was lower in the lobeglitazone than in the pioglitazone group. However, 50.0% (10/20) of the patients in the lobeglitazone group had regressed to normoalbuminuria compared to 39.3% (11/28) in the pioglitazone group.

A 73% reduction of risk for new-onset microalbuminuria and a 52% reduction of risk for the progression of albuminuria by > 1 stage was observed in the lobeglitazone group after adjustment for age, sex, body mass index, systolic blood pressure, and HbA1c (ESM Table S2); however, these reductions were not significantly different from those observed in the pioglitazone group. In addition, compared to pioglitazone group, more patients in the lobeglitazone group showed an improvement in albuminuria, as estimated by the regression of albuminuria by > 1 stage (odds ratio [OR] 1.56, 95% confidence interval [CI] 0.43–5.79) and regression to normoalbuminuria (OR 1.24, 95% CI 0.34–4.51).

In the lobeglitazone group, patients with micro- and macroalbuminuria showed a greater reduction in HbA1c than did patients with normoalbuminuria (P = 0.014); however, no similar difference was observed in the pioglitazone group (Fig. 2a). In addition, there was no difference in the level of HbA1c reduction according to albuminuria categories in patients with eGFR < 90 mL/min/1.73 m² and those with eGFR ≥ 90 mL/min/1.73 m² (P = 0.697) (Fig. 2b). The association between UACR and change of HbA1c was not statistically meaningful in either treatment group (data not shown).

The results of our study show that in patients with T2DM, lobeglitazone (0.5 mg/day) tended to improve albuminuria and was not inferior to pioglitazone (15 mg/day) in this respect. During the study period, the UACR decreased slightly in the lobeglitazone group and increased in the pioglitazone group, with no change in the eGFR in either group. Compared to the pioglitazone group, the progression of albuminuria in the lobeglitazone group tended to be low and the regression tended to be high. None of these results were statistically significant, but they suggest that lobeglitazone has similar effects on albuminuria as pioglitazone, with demonstrated beneficial effects. To the best of our knowledge, this is the first study to evaluate the efficacy of treatment with lobeglitazone versus pioglitazone on albuminuria for 24 weeks in patients with T2DM.

TZDs are PPARγ agonists and are important anti-diabetic drugs that improve insulin resistance [14]. They have beneficial effects on cardiovascular disease, NAFLD, and inflammation, but are associated with side effects of fluid retention, weight gain, and an elevated risk of bone fracture [14‐16]. Renal outcomes in patients with T2DM treated with TZDs have recently been gaining interest, with several studies showing that TZDs have protective effects on renal function [17‐20]. A meta-analysis of 15 studies involving 2860 patients with T2DM found that treatment with TZDs significantly decreased urinary albumin and protein excretion [23]. In studies with pioglitazone, the weighted mean difference of proportional change between the pioglitazone and control groups was − 16.2% (95% CI − 20.8 to − 11.6) of UACR [23]. In the present study, treatment with lobeglitazone decreased the UACR, but treatment with pioglitazone had the opposite effect. In addition, new-onset microalbuminuria and the progression of albuminuria by > 1 stage was lower in the lobeglitazone group than in the pioglitazone group, while the regression of albuminuria by > 1 stage and regression to normoalbuminuria was higher in the lobeglitazone, although these difference were not statistically significant. No differences were observed between the two groups regarding the incidence of AEs, severe AEs, or drug-related AEs in the original study [22] and this study (data not shown). While these results do not allow the conclusion to be drawn that lobeglitazone is superior to pioglitazone, they do demonstrate that lobeglitazone tended to improve albuminuria in patients with T2DM with negligible differences compared to pioglitazone.

Lobeglitazone is a new PPARγ agonist and has been used in patients with T2DM. In one study, lobeglitazone administered 0.5 mg per day achieved a HbA1c reduction of approximately 0.6% versus placebo [21] and approximately 0.88% in patients taking triple therapy [24]. It has been shown that the efficacy of lobeglitazone (0.5 mg/day) is not inferior to pioglitazone (15 mg/day) as an add-on to metformin in terms of reducing the HbA1c level after 24 weeks (− 0.74 vs. − 0.74%, lobeglitazone vs. pioglitazone) [22], with both drugs exhibiting similar effects on weight, edema, and lipid profiles [21, 22]. Like pioglitazone, treatment with lobeglitazone resulted in significantly improved hepatic steatosis in patients with T2DM with NAFLD [25, 26] and exhibited anti-atherosclerotic properties [27]. However, in terms of bone metabolism, lobeglitazone has been reported to have no detrimental effect on bone mineral density while pioglitazone exhibits negative effects [28, 29]. In an in vivo study of db/db (diabetic) mice, lobeglitazone showed beneficial effects on beta cell survival and function and was comparable to other TZDs [30]. Several studies have evaluated the efficacy of pioglitazone on the UACR. In one study that compared pioglitazone and metformin for 52 weeks, the UACR was reduced by 19% following pioglitazone treatment in 597 drug-naive patients with T2DM [19]. The authors of another study reported that the UACR was reduced by 10% in the metformin + pioglitazone (15 mg/day) treatment group compared to an increase of 6% in the metformin + gliclazide (80 mg/day) treatment group [31]. In the present study, the UACR was reduced by 15.6% in the lobeglitazone group compared to an increase of 8.4% in the pioglitazone group over the course of 24 weeks. One possible explanation for the increase of the UACR in the pioglitazone group may be the relatively short duration of the study and the low number of participants. In addition, although the renal benefit of pioglitazone was generally positive when administered at a dose of 30-45 mg, the dose of pioglitazone used in the present study was 15 mg/day because this was the highest dose covered by the Korean national health insurance system during the study period. Thus, the results of this study alone cannot determine whether pioglitazone has negative effects on UACR. More importantly, these results do suggest that lobeglitazone has beneficial effects on albuminuria and is that it is comparable to pioglitazone in this respect. Further studies comparing higher doses of lobeglitazone and pioglitazone are needed because lobeglitazone has been shown to be well tolerated at doses of up to 4 mg for 7 days in a short-term study conducted in healthy volunteers [32].

TZDs reduce renal damage by improving hyperglycemia as well as modifying several mechanisms that are independent of hyperglycemia [33‐39]. The anti-inflammatory and anti-oxidative effects of TZDs are well known and could be a possible mechanism of renal protection [33‐35]. In addition, TDZs have been shown to downregulate the activity of the renin–angiotensin system and found to improve renal microcirculation and endothelial function [33, 36, 37]. Several studies have demonstrated that TZDs can protect against renal injury through a direct action on PPARγ receptors at the level of the renal glomerular and tubular segments [33, 38, 39]. Lobeglitazone shares many properties with other TZDs, which may explain its renal protective effect. In animal studies, lobeglitazone has shown a renoprotective effect on renal fibrosis through inhibition of the transforming growth factor β/Smad3 pathway [40]. In the present study, there was a greater decrease in UACR and a greater reduction in HbA1c in subjects in the lobeglitazone group who had micro- and macroalbuminuria than in those with normoalbuminuria. These results may support the theory that lobeglitazone is able to be safely used by patients with reduced renal function even though its renoprotective mechanism has yet to be identified.

Several limitations should be considered in the interpretation of our findings. First, the sample size was calculated based on the primary outcome of the original study. Therefore, it may not have been appropriate to evaluate the effect on albuminuria. Second, this study was not designed primarily to investigate the renoprotective effect of lobeglitazone. As a result, many renal parameters that would be helpful to test the efficacy of the drug were not included in the study. Third, a single random urine sample was used to calculate the UACR without adjusting for day-to-day biological variability. Finally, the relatively short study duration did not provide enough time to evaluate the long-term renal outcomes of lobeglitazone.

The results of this post hoc analysis of the 24-week, randomized, double-blind study showed that lobeglitazone tended to improve albuminuria values in patients with T2DM. The UACR was slightly decreased in the lobeglitazone group with no change in eGFR. In addition, lobeglitazone exhibited similar effects on albuminuria compared with pioglitazone with its proven beneficial effects. Large-scale, longer-term mechanistic studies are warranted to confirm these findings.