Changes in Overactive Bladder Symptoms After Sodium Glucose Cotransporter-2 Inhibitor Administration to Patients with Type 2 Diabetes

Original article

Changes in overactive bladder symptoms after sodium glucose cotransporter-2 inhibitor administration to patients with type 2 diabetes

Junpei Shikuma1 Abstract MD, PhD The aim of this study was to investigate the changes in overactive bladder symptoms after Rokuro Ito1 selective sodium glucose cotransporter-2 (SGLT2) inhibitor administration to patients with MD, PhD type 2 diabetes. Outpatients with type 2 diabetes who consented to participate in this study between Junko Sasaki-Shima1 September 2014 and August 2015 were included. Overactive bladder assessments were MD, PhD conducted before and one month after SGLT2 inhibitor administration using the Overactive Bladder Symptom Score (OABSS). Akiko Teshima1 Fifty-eight patients were enrolled. OABSSs indicated that 17.2% of the subjects had MD, PhD overactive bladder. Comparison of OABSSs before and after SGLT2 inhibitor administration 1 indicated that Q1 (daytime frequency) and total scores increased significantly. Kazuo Hara Post-hoc analysis indicated that in the group without overactive bladder according to MD, PhD, Professor pre-administration OABSSs, statistically significant increases were observed for Q1 (daytime Tomono Takahashi1 frequency), Q3 (urgency), and total scores. Conversely, in the group with overactive bladder, MD, PhD there were no significant differences. The mean score for Q1 (daytime frequency) increased, whereas that for Q3 (urgency) decreased. Hiroyuki Sakai1 It was concluded that SGLT2 inhibitor administration to patients with type 2 diabetes, MD, PhD but without overactive bladder, caused significant increases in daytime frequency but not in night-time frequency. However, in patients with overactive bladder prior to SGLT2 inhibitor 1 Takashi Miwa administration, blood glucose control was possible without worsening overactive bladder. MD, PhD, Associate Professor Copyright © 2018 John Wiley & Sons. Practical Diabetes 2018; 35(2): 47–50 Akira Kanazawa1 MD, PhD Key words Masato Odawara1 type 2 diabetes mellitus; SGLT2 inhibitor; overactive bladder; Overactive Bladder Symptom MD, PhD, Professor Score (OABSS)

1Department of Diabetology, Metabolism, and Endocrinology, Tokyo Medical University Hospital, Introduction The relationship between type 2 Tokyo, Japan SGLT2 inhibitors are a new class of diabetes and lower urinary tract dys- oral antidiabetic drugs with a novel function was first reported in the mechanism that prevents proximal mid 19th century, and this condition Correspondence to: renal tubules from reabsorbing is generally known as ‘diabetic cysto Masato Odawara, MD, PhD, Department of glucose and thus lowers blood pathy’. A recently published study Diabetology, Metabolism and Endocrinology, Tokyo glucose levels by increasing the reported that 21.4% of patients with Medical University Hospital, 6-7-1 Nishishinjuku, amount of urinary glucose excre- type 2 diabetes have overactive blad- Shinjuku-ku, Tokyo 160-0023, Japan; email: 2 [email protected] tion. The EMPA-REG OUTCOME der. Urination is more frequent in trial exhibited a decrease in the such patients than in age- and sex- 3 Received: 1 December 2017 3-point major adverse cardiovascu- matched individuals without diabetes. Accepted in revised form: 16 January 2018 lar event.1 SGL2 inhibitors are SGLT2 inhibitor administration extremely effective drugs; however, increases urinary output, but no previ- because an increase in urinary ous studies have assessed the changes glucose excretion also means a con- in overactive bladder symptoms after current increase in urinary output, administration. Therefore, in this attention must be paid to the occur- study, we evaluated the changes in rence of dehydration and urinary overactive bladder symptoms after tract and genital infections with SGLT2 inhibitor administration. the use of these drugs. In addition, because of the mechanism of action, Materials and methods patients commonly present with This was a before–after comparative frequent urination and overactive study. The subjects were patients bladder symptoms following SGLT2 with type 2 diabetes undergoing inhibitor administration. outpatient treatment at Tokyo

Medical University Hospital between Question Frequency Score September 2014 and August 2015 and who consented to participate in Q1. How many times do you typically urinate from ≤7 0 this study. The inclusion criteria waking in the morning until sleeping at night? were age ≥20 years, HbA1c levels 8–14 1 ≥52mmol/mol, body mass index (BMI) ≥25kg/m2, and estimated ≥15 2 glomerular filtration rate (eGFR) ≥60ml/min/1.73m2. The exclusion Q2. How many times do you typically wake up to 0 0 urinate from sleeping at night until waking in criteria were contraindications for 1 1 SGLT2 inhibitor use, history of the morning? kidney and urinary tract disease, 2 2 and currently undergoing treatment for urinary disorders. ≥3 3 Fifty-eight patients were included Q3. How often do you have a sudden desire to Not at all 0 in this study: 34 men and 24 women. urinate, which is difficult to defer? Patients were taking other glu- Less than once a week 1 cose-lowering treatments at the beginning of this study: metformin Once a week or more 2 hydrochloride (86.2%), DPP4- inhibitor (56.9%), sulphonylurea About once a day 3 (39.7%), insulin (25.9%), GLP-1 2–4 times a day 4 receptor agonist (17.2%), alpha- glucosidase inhibitor (5.2%) and 5 times a day or more 5 thiazolidinediones (3.4%). Overactive bladder symptoms Q4. How often do you leak urine because you Not at all 0 assessments were conducted prior to cannot defer the sudden desire to urinate? and one month after administration Less than once a week 1 using the Overactive Bladder Once a week or more 2 Symptom Score (OABSS). (Table 1.) The primary outcome measures About once a day 3 were changes in overactive bladder symptoms after SGLT2 inhibitor 2–4 times a day 4 administration. Secondary outcome 5 times a day or more 5 measures were changes in weight, HbA1c, serum lipid level, and Table 1. Overactive Bladder Symptom Scores according to patient response to 4 questions hepatic and renal functions. On the basis of the results of the age of 55.2±9.2 years. The mean weight p<0.001), but scores for Q2, Q3 and OABSS conducted prior to SGLT2 was 75.8±13.0kg, mean BMI was Q4 did not show statistically signifi- inhibitor administration, the sub- 28.1±3.5kg/m2, mean HbA1c level was cant differences (0.93±0.84 vs jects were divided into two groups 62±11mmol/mol, and mean eGFR 1.10±0.89, p=0.079; 0.74±1.10 vs (with and without overactive blad- was 82.3±22ml/min/1.73m2. The 0.88±1.29, p=0.422; and 0.17±0.46 vs der), and a post-hoc analysis of mean weight significantly decreased 0.29±0.86, p=0.158, respectively). changes in overactive bladder symp- to 74.7±13.1kg after SGLT2 inhibitor However, the post-administration toms was conducted in each of administration, and the mean HbA1c total score (Q1 + Q2 + Q3 + Q4) the two groups. SGLT2 inhibitors level significantly improved to showed a significant increase administered to the subjects were 59±10mmol/mol; eGFR significantly (2.22±1.81 vs 2.98±2.57, p=0.004; ipragliflozin and tofogliflozin. decreased to 78.3±19.9ml/min/ Table 3). 1.73m2, and alanine aminotransferase The subjects were divided into Statistical analysis levels significantly decreased from groups with and without overactive Data were statistically analysed 37.8±28.4 to 33.9±23.6 U/L. (Table 2.) bladder, and a post-hoc analysis of the using SPSS statistics version 24 These results were consistent with two groups was performed. There (IBM Corporation, New York, US). those of previous studies. were no significant differences in Differences in OABSS results before The results of OABSS indicated subjects’ demographics (sex, age, and after SGLT2 inhibitor administra- that 17.2% of the enrolled subjects BMI, blood pressure, eGFR) in the tion were calculated using Wilcoxon (10/58) had overactive bladder. two groups. In the group without signed-rank test. The significance level Comparisons of scores for Q1 before overactive bladder, there were statis- of statistical data was set at p<0.05. and after SGLT2 inhibitor adminis- tically significant increases in the tration indicated that scores signifi- scores for Q1 and Q3 and total Results cantly increased after administration scores (Q1: 0.40±0.54 vs 0.69±0.55, Fifty-eight patients (34 men and 24 (pre-administration versus post-ad- p=0.001; Q3: 0.29±0.46 vs 0.67±1.16, women) were enrolled, with a mean ministration: 0.38±0.93 vs 0.71±0.56, p=0.023; and total score: 1.58±1.03

vs 2.60±2.29, p<0.001). In the group Variable Baseline After 1 month P-value with overactive bladder, all items Participant nos. (male/female) 58 (34/24) – – showed no statistically significant changes; furthermore, examination SGLT2 inhibitor (ipragliflozin/tofogliflozin) 58 (35/23) – – of the mean scores indicated that the score for Q1 increased, whereas Age (years) 55.2±9.2 – – that for Q3 and total score decreased (Q1: 0.30±0.48 vs 0.80±0.63, Body weight (kg) 75.8±13.0 74.7±13.1 <0.001 p=0.059; Q3: 2.90±0.57 vs 1.90±1.45, Body mass index (kg/m2) 28.1±3.5 27.7±3.6 <0.001 p=0.065; and total score: 5.30±1.57 vs 4.80±3.19, p=0.357; Table 3). Systolic blood pressure (mmHg) 135.7±15.4 133.9±21.4 0.532 Discussion Diastolic blood pressure (mmHg) 82.1±12.5 81.2±13.9 0.561 According to the results of the EMPA- REG OUTCOME trial, in recent HbA1c (mmol/mol) 62±11 59±10 <0.001 years many patients are being admin- Total cholesterol (mg/dl) 189.9±40.2 186.4±40.3 0.300 istered SGLT2 inhibitors. Initially, those administered SGLT2 inhibitors Triglycerides (mg/dl) 211.5±190.6 175.5±79.4 0.346 were limited to younger patients with obesity whose renal function was in HDL cholesterol (mg/dl) 50.8±14.6 51.1±14.7 0.88 the normal range. However, SGLT2 LDL cholesterol (mg/dl) 103.9±33.7 104.4±32.8 0.633 inhibitor administration is also currently indicated for patients with a Aspartate transaminase (U/ml) 32.1±20.9 29.1±16.0 0.487 cardiovascular disease risk. In addition, on the basis of the results of the Alanine aminotransferase (U/ml) 37.8±28.4 33.9±23.6 0.033 EMPA-REG OUTCOME renal trial, SGLT2 inhibitors are even indicated Gamma glutamyl transpeptidase (U/ml) 53.2±56.5 44.1±41.4 <0.001 for patients with low eGFRs who are Urinalysis (mg/dl) 5.4±1.3 5.0±1.4 0.001 expected to experience less improve- ment in blood glucose levels as a eGFR (ml/min/1.73m2) 82.3±22.0 78.3±19.9 0.010 result of SGLT2 inhibitor administration because these drugs aid in the KEY: HDL = high density lipoprotein; LDL = low density lipoprotein; eGFR = estimated glomerular maintenance of renal function.4 filtration rate. Although the superior efficacy of Table 2. Demographic and clinical characteristics of subjects at baseline and 1 month after SGLT2 SGLT2 inhibitors is extremely bene- inhibitor administration. Data are expressed as mean±SD ficial to a large number of patients

Variable All (n=58) With overactive bladder (n=10) Without overactive bladder (n=48)

Baseline After 1 P-value Baseline After 1 P-value Baseline After 1 P-value month month month

No. (male/female) 10 (4/6) 48 (30/18) 0.291

Age (years) 59.2±8.7 54.3±9.4 0.099

BMI (kg/m2) 28.5±3.2 28.1±3.6 0.902

SBP (mmHg) 136.7±16.9 135.4±15.3 0.959

DBP (mmHg) 80.2±11.5 82.5±12.8 0.943

eGFR (ml/min/1.73m2) 80.5±12.8 82.7±23.5 0.883

OABSS Question no. 1 0.38±0.93 0.71±0.56 <0.001 0.30±0.48 0.80±0.63 0.059 0.40±0.54 0.69±0.55 0.001

OABSS Question no. 2 0.93±0.84 1.10±0.89 0.079 1.40±1.08 1.40±1.07 1.000 0.83±0.75 1.04±0.85 0.079

OABSS Question no. 3 0.74±1.10 0.88±1.29 0.422 2.90±0.57 1.90±1.45 0.065 0.29±0.46 0.67±1.16 0.023

OABSS Question no. 4 0.17±0.46 0.29±0.86 0.158 0.70±0.82 0.70±1.34 1.000 0.06±0.25 0.21±0.71 0.121

OABSS Total 2.22±1.81 2.98±2.57 0.004 5.30±1.57 4.80±3.19 0.357 1.58±1.03 2.60±2.29 <0.001

Table 3. Demographics of subjects and changes in Overactive Bladder Symptom Score (OABSS) in the with or without overactive bladder groups versus baseline. Data are expressed as mean±SD

with diabetes, there are many cases peripheral neuropathy is classified as in which they are not administered a peripheral neuropathy, but the Key points because of concern regarding the underlying mechanism that causes possibility of worsening overactive overactive bladder remains unknown. ● SGLT2 inhibitor administration bladder symptoms. On the basis of Non-neurogenic causes include the increases daytime frequency of the data obtained in the present involvement of metabolic syn- urination study, however, no worsening of drome.5–10 It has been reported that ● SGLT2 inhibitor administration does overactive bladder was observed the components of metabolic syn- not lead to noticeable increases in even when SGLT2 inhibitors were drome (obesity, impaired glucose night-time frequency of urination administered to patients who had tolerance, hypertension, hyperlipi- ● Even in patients with overactive previously not received the drug daemia, and hyperuricaemia) cause bladder, blood glucose control was due to overactive bladder. The dysfunction of the vascular endothe- possible without worsening overactive OABSS results for patients with lium, increases in proinflammatory bladder symptoms overactive bladder indicated no cytokines derived from visceral fat, statistically significant changes, and activation of the sympathetic from Astellas, Boehringer Ingelheim, although the findings indicating nervous system, which in turn Daiichi Sankyo, Eli Lilly, Kowa, MSD, that the score for Q1 showed a exacerbate overactive bladder. Given Tanabe Mitsubishi, Novartis, Ono, tendency to increase and the score that SGLT2 inhibitors improve all Sanofi Aventis, Taisho Toyama, and for Q3 and total score decreased are components of metabolic syndrome, AstraZeneca. of great interest. According to the positive effects of these drugs on results of this study, when SGLT2 overactive bladder symptoms may References inhibitors were administered to be related to this mechanism. 1. Zinman B, et al. Empagliflozin, cardiovascular outpatients with type 2 diabetes with comes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. overactive bladder, quality of life was Conclusions 2. Lawrence JM, et al. Pelvic floor disorders, diabetes, not negatively affected; therefore, it SGLT2 inhibitor administration to and obesity in women: findings from the Kaiser appears that SGLT2 inhibitors can patients with type 2 diabetes, with- Permanente Continence Associated Risk Epidemiology Study. Diabetes Care 2007;30:2536–41. be administered to such patients. out overactive bladder, significantly 3. Chiu AF, et al. Higher glycosylated hemoglobin It is likely that patients with over- increases daytime frequency but levels increase the risk of overactive bladder active bladder did not experience does not lead to noticeable increases syndrome in patients with type 2 diabetes mellitus. worsening of Q3 (urgency) because in night-time frequency. However, Int J Urol 2012;19:995–1001. 4. Wanner C, et al. Empagliflozin and progression of patients with overactive bladder are in patients with overactive bladder kidney disease in type 2 diabetes. N Engl J Med already accustomed to frequent mic- prior to SGLT2 inhibitor adminis- 2016;375:323–34. turition, and the sense of urgency, tration, blood glucose control was 5. Ponholzer A, et al. The association between vascular risk factors and lower urinary tract symptoms in therefore, did not manifest even possible without worsening over both sexes. Eur Urol 2006;50:581–6. when the amount of urine increased. active bladder. 6. Kupelian V, et al. Association of lower urinary tract However, data in the present symptoms and the metabolic syndrome: results Limitations from the Boston Area Community Health Survey. study indicated that, although not J Urol 2009;182:616–24. statistically significant, there was a Given the small number of subjects 7. Uzun H, Zorba OÜ. Metabolic syndrome in female tendency towards decreased fre- in this study, data may not be accu- patients with overactive bladder. Urology 2012; quency in the sense of urgency. This rate. On the basis of the results of 79:72–5. 8. Ohgaki K, et al. Association between metabolic syn- indicates the possibility that SGLT2 this study, further clinical study of drome and male overactive bladder in a Japanese inhibitors have some positive effect this issue with larger numbers of population based on three different sets of criteria on the sense of urgency experienced subjects is required. for metabolic syndrome and the Overactive Bladder Symptom Score. Urology 2012;79:1372–8. by patients with overactive bladder. 9. Yang TK, et al. Metabolic syndrome associated The causes of overactive bladder Declaration of interests with reduced lower urinary tract symptoms in are both neurogenic and non-neuro- JS, RI and TM have received research middle-aged men receiving health checkup. genic. Neurogenic causes include funds from MSD. JSS, AT, KH, TT, Urology 2012;80:1093–7. 10. Kirby MG, et al. Overactive bladder: Is there a link brain disorders, spinal disorders HS and AK declare no conflicts of to the metabolic syndrome in men? Neurourol and peripheral neuropathy. Diabetic interest. MO has received honoraria Urodyn 2010;29:1360–4.