A single-arm pilot study of metformin in patients with autosomal dominant polycystic kidney disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease, characterized by multiple, bilateral renal cysts leading to an increased kidney volume and progressive loss of kidney function. It is a systemic disorder that also affects the liver, pancreas, spleen, seminal vesicles, arachnoid membrane and endothelium [1]. Recent epidemiologic studies reported an average prevalence of ADPKD in Europe of 2.7:10,000 (95% CI = 0.73–4.67) and a point prevalence of 3.96:10,000 (95% CI = 0.94–0.98) in countries from the European Union [2, 3]. According to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry, the estimated prevalence of ADPKD in Romania was 1.9:10,000 in 2012 [3]. PKD 1 and PKD 2 genes mutations are involved in the majority of cases, but recently new gene players were described, such as GANAB and DNAJB11 [4, 5]. Polycystin 1 and 2 encoded by PKD genes are expressed mainly in tubular epithelial cells and work physiologically as an unit with well defined functional and structural roles [6]. In ADPKD, the abnormality of polycystin 1 and 2 proteins leads to primary cilia dysfunction, activation of several intracellular pathways, increased fluid secretion, cell-cell adhesion issues and hyperproliferation. Among the most important intracellular pathways involved were cyclic adenosine monophosphate (cAMP), mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), adenosine monophosphate-activated protein kinase (AMPK), just another kinase/signal transducer and activator of transcription (JAK/STAT) [7]. During the last decade, different therapeutic agents were used to counteract cyst and kidney dysfunction progression [8]. Metformin, the most common used biguanide for the treatment of type 2 diabetes mellitus, with a good safety profile, has shown promising results regarding cystogenesis inhibition in preclinical studies [9, 10]. The proposed mechanism of action in ADPKD is by stimulating AMPK activation, which negatively regulates both the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR) from the apical membrane and mTOR pathway. CFTR activity is directly inhibited and that of the mTOR pathway is indirectly inhibited through phosphorylation protein of tuberous sclerosis 2 (TSC2) and Raptor, leading to the blockage of two essential processes of cystogenesis, fluid secretion and proliferation [9]. Evolution of kidney function in patients with ADPKD is characterized by a high individual variability. Several environmental, genetic, demographic, clinical, biological and structural factors were associated with disease progression [11]. Among them, overweight and particularly, obesity were associated with greater kidney function decline and disease progression [12]. It has already been demonstrated that Metformin promotes weight loss in overweight and obese patients [13]. Apart from the direct effect on cystogenesis, Metformin could have a beneficial additional effect in controlling the decline of renal function by producing a decrease in body mass index (BMI).

On the basis of these observations, we designed a prospective, preliminary, single-arm study to evaluate the tolerability, safety and the effect of Metformin on kidney function and BMI in Romanian patients with ADPKD.

Results from our study showed that treatment with Metformin was well tolerated in all stages of CKD, with few adverse events, and it was not associated with any changes in either eGFR or BMI at any time point. To our knowledge, this is the first report from a prospective, interventional study about Metformin in patients with ADPKD.

The most common adverse event found in our study was nausea (17.6%), but this manifestation was mild and transitory, no dose reduction or permanently discontinuation was required. This finding is in agreement with results from other studies, where nausea was among the most common adverse events in diabetic and non-diabetic patients treated with Metformin [16, 17]. It has been shown that the frequency of nausea was of 10% and that treatment discontinuation rate due to nausea was 3% in patients with type 2 diabetes treated with 1 g/day of Metformin [16]. Findings from our study do not exceed the current evidences regarding cyst infection in ADPKD patients and are in line with those of Sallée M. et al., who showed that 8.6% of patients developed cyst infection [18]. Hypoglycemia is a rare event in patients treated with Metformin, but the risk of hypoglycemia increases in those with CKD [19, 20]. In our study population, hypoglycemia was absent. The use of Metformin in patients with CKD is limited by guideline contraindications because of the fear for lactic acidosis. The European Medicines Agency and Food and Drug Association recommended to use Metformin up to an eGFR of 30 ml/min/1.73 m², but this cut-off value was not based on results from prospective studies of pharmacodynamics and pharmacokinetics [21, 22]. The incidence of Metformin-associated lactic acidosis was 4.3 per 100,000 patient-years in a 2010 Cochrane analysis [23]. In this systematic review, Salpeter et al. demonstrated that Metformin was not associated with an increased risk of lactic acidosis compared to other antidiabetic drugs. Moreover, 53% of the studies included patients with CKD, including 37,360 patient-years with no events of lactic acidosis [23]. This data is supported by an observational cohort study from the Swedish National Diabetes Register, which analyzed 51,675 patients with type 2 diabetes mellitus, including 12.3% with eGFR ≤60 ml/min/1.73m² and has shown that lactic acidosis is a rare event even in those with eGFR between 30 and 45 ml/min/1.73m² [24]. Duong et al. reported no adverse events or a relationship between Metformin, lactic acid levels or lactic acidosis in 7 patients with advanced CKD, including 2 patients on dialysis, who were treated with lower doses of Metformin, between 250 and 500 mg/day [25]. Of note, a recent study by Lalau et al. showed that adjusting the dose of Metformin in patients with moderate-severe CKD seems to be safe and remained pharmacologically efficient. A dose of 500 mg/day does not determine a drug concentration > 5 mg/L, considered the safe upper limit, not even in CKD stages 4–5 and a dose of 1000 mg/day produced a drug concentration > 5 mg/L in 1 patient from CKD stages 4–5. Lactate concentration did not exceed 5 mmol/L in any patient [26]. In accordance with these findings, our study included patients in all stages of CKD and no case of lactic acidosis was reported.

Analysis of the kidney function showed no change in kidney function after 24 months of treatment, but with an initial increase within the first 4 months. This initial, transitory improvement in eGFR could be associated with the weight loss and subsequent change in BMI. It is well known that Metformin produces weight loss and BMI reduction even in overweight or obese patients without diabetes [13]. Moreover, one study has shown that weight loss leads to kidney function improvement, in those with baseline eGFR< 60 ml/min/1.73m², especially in the first 6 months after dietary restriction [27]. In our study, the greater rate in BMI change occurred in the first 4 months (− 2.39%) and we also observed a concomitant variation in median serum creatinine (from 1.11 to 1.03 mg/dl) that could be influenced by muscle mass loss, thus affecting the eGFR value in this early period (mean eGFR change from baseline: + 1.71 ml/min/1.73m²). Two randomized control trials (NCT02656017; NCT02903511) involving Metformin safety and efficacy in ADPKD are ongoing. One retrospective, case-control study, which selected 7 diabetic ADPKD patients treated with Metformin and 7 matched non-diabetic ADPKD controls, evaluated the effect of Metformin on renal function progression during a 3 year follow-up. An overall crude loss of eGFR of – 0.9 ml/min/1.73m² estimated by a linear mixed model at 36 months was reported in the Metformin group [28]. Our ITT analysis was in line with these results, as we found a change in mean eGFR of – 1.57 ml/min/1.73 m² after 24 months of treatment. If we refer to other clinical trials testing medication to slow eGFR decline in ADPKD, in the TEMPO 3:4 study, which included patients with eGFR > 60 ml/min/1.73m², Tolvaptan slowed the decline in kidney function after 36 months (− 2.61 vs − 3.81 [mg/ml]^− 1 per year), but was associated with an increased rate of withdrawal due to adverse events [29]. REPRISE trial, which included patients with CKD stages 2–4, showed a mean eGFR change from baseline of − 2.34 ml/min/1.73 m² in the Tolvaptan group, as compared with − 3.61 ml/min/1.73 m² in the placebo group after 12 months (difference, 1.27 ml/minute/1.73 m²; 95% CI, 0.86 to 1.68; P < 0.001) [30]. The eGFR decline in these studies was higher than what we found at 12 and 24 months in ITT as well as in PP analysis. The efficacy of Sirolimus, an mTOR inhibitor, that partially shares some mechanisms of action with Metformin in cystogenesis inhibition, was tested in clinical trials. Despite the fact that SUISSE trial and the study of Braun et al. showed a favorable GFR evolution from baseline of + 0.2 ml/min/1.73m² after 12 months (P = 0.07) and + 1.6 ml/min/1.73m² after 18 months (P < 0.001) in the Sirolimus group, a meta-analysis demonstrated that mTORC1 inhibitors had no significant effect on eGFR change in patients with ADPKD (P = 0.22) [31‐33].

In our study population, 73.5% were obese or overweight at baseline and we found a progressive decline in BMI, more accelerated within the first 4 months. Nowak et al. proved that obesity and overweight patients with ADPKD have a greater decline in eGFR that normal weight ones [12]. Obesity and ADPKD seem to share some common pathways. Positive energy balance, overnutrition and obesity can produce a hyperactivity of mTOR pathway via PI3k/Akt activation, may activate mTORC1/S6K and reduce AMPK activity. Hyperactivation of mTORC1/S6K pathway and decreased activity of AMPK are important players in ADPKD cystogenesis, regarding proliferation and cyst fluid secretion [34, 35]. Based on this, the use of Metformin in ADPKD patients could decrease energy intake, stimulate AMPK activation and produce mTOR pathway inhibition, which promotes inhibition of cystogenesis and weight gain, the latter having in turn a favorable effect on disease progression and kidney function. In our patients, the slower decline in eGFR compared to other studies could be explained by the concomitant weight loss.

Our study has several limitations. The absence of a control group cannot distinguish between the effect of the treatment and the natural evolution of the disease. The reason that we chose a single-arm design was that we mainly wanted to point out preliminary results regarding the safety and tolerability of Metformin in ADPKD patients. Other limitations are the small sample size and the single-center study enrollment. Another important limitation of the study is the high rate of drop-out (54%), which requires cautious interpretation of tolerability and safety results. Regarding the 12 patients that were lost to follow-up, we do not have any information whether their decision to drop-out was based on medication intolerance or adverse reactions or not, which may lead to an under-estimation of tolerability. The strengths of our study were the prospective design, the intention-to-treat analysis, the length of the follow-up period and the inclusion of patients with advanced CKD stages. Given the small sample size, absence of a control arm and high rate of drop-out we consider that our findings need to be evaluated in a large randomized controlled trial.

In conclusion, the results from this single-arm pilot study showed that Metformin was well tolerated, with a good safety profile in patients with ADPKD, even in those with advanced CKD and it was not associated with change in eGFR or BMI across the 24 months of follow-up.