Efficacy,Safety and Tolerability of Fesoterodine in Asian Patients with Overactive Bladder

Objectives: To assess the efficacy, safety, and tolerability of fesoterodine 4 and 8 mg once daily (QD) compared with placebo in Asian subjects with overactive bladder (OAB) after 12 weeks of treatment. Methods: This phase II, dose‐finding study consisted of a 2‐week placebo run‐in period followed by a 12‐week, randomized, double‐blind, placebo‐controlled, treatment period. Eligible subjects were aged ≥20 years with ≥8 micturitions per 24 h and ≥1 urgency urinary incontinence (UUI) episodes per 24 h reported in a 3‐day diary. The subjects were randomized to receive placebo, fesoterodine 4 mg, or fesoterodine 8 mg QD for 12 weeks. Results: Of 1232 subjects who entered the placebo run‐in period, 951 received double‐blind treatment. The mean number of UUI episodes per 24 h at baseline was 2.2 among the three treatment groups. The two fesoterodine groups showed statistically significant decreases from baseline in the mean number of UUI episodes per 24 h at week 12 (primary endpoint) compared with placebo. Most all‐causality adverse events (e.g. dry mouth and constipation) were mild or moderate. The percentage of subjects with severe adverse events was low and similar among the treatment groups (placebo, 1.3%; fesoterodine 4 mg, 1.9%; fesoterodine 8 mg, 1.0%). Conclusion: Fesoterodine 4 and 8 mg QD were significantly better than placebo in improving OAB symptoms. Overall, the two fesoterodine dosing regimens were well tolerated. These results suggest that fesoterodine 4 and 8 mg QD are effective and well‐tolerated treatments for OAB in Asian subjects.     

Randomized,Single‐Blind,Parallel Study of the Effectiveness and Safety of Solifenacin versus Propiverine in the Treatment of Overactive Bladder

Objectives: To compare the effectiveness and safety of solifenacin versus propiverine in the treatment of overactive bladder (OAB), in a single‐blind, randomized parallel study. Methods: Sixty‐six patients with OAB (14 men and 52 women) were randomly assigned to groups: solifenacin (5 mg/day) or propiverine (20 mg/day) and treated for 8 weeks. The primary outcome variable was mean change from baseline to end of treatment in urgency of the OAB symptom score (OABSS). Secondary outcomes were bladder diary variables: change over 24 h in the mean number of voids (daytime and nighttime), episodes of micturition urgency and incontinence, and mean volume voided. Patients also completed total OABSS and the King's Health questionnaires. Results: Group backgrounds were comparable except for the male to female proportion; 11:22 for solifenacin (n = 33) versus 3:30 for propiverine (n = 33). Adverse events were 6 of 29 (21%) for solifenacin versus 14 of 26 (54%) for propiverine (P = 0.017). Three patients were withdrawn for voiding difficulty (one in solifenacin and two in propiverine) and one patient for dry mouth (propiverine group). Change in OABSS urgency score was ?2.3 ± 1.4 for solifenacin (n = 28) versus ?1.3 ± 1.7 for propiverine (n = 23), (P = 0.0169). Total OABSS and other individual scores, and voiding diary parameters for both drugs showed improvements; however, between‐group difference was not established. Conclusion: Although both solifenacin 5 mg and propiverine 20 mg were effective in the treatment of OAB, solifenacin appeared to be more effective and tolerable.     

Tolterodine: A Safe and Effective Treatment for Older Patients with Overactive Bladder

OBJECTIVE: To investigate the clinical safety and efficacy of two dosages of tolterodine in older patients with symptoms attributable to overactive bladder. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group, multinational, phase III study. SETTING: Incontinence, older care, urological, and urogynecological clinics in the United Kingdom, France, and the Republic of Ireland. PARTICIPANTS: One hundred and seventy-seven older patients (age > or =65 years) with symptoms of urinary urgency, increased frequency of micturition (> or =8 micturitions/24 hours), and/or urge incontinence (> or =1 episode/24 hours). INTERVENTION: Tolterodine 1 mg or 2 mg twice daily (bid), or placebo, for 4 weeks. MEASUREMENTS: Safety and tolerability were evaluated through spontaneously reported adverse events, electrocardiogram, and blood pressure measurements. Efficacy was assessed using micturition diary variables: mean change from baseline in frequency of micturition and number of incontinence episodes/24 hours. RESULTS: The mean age of the patient population was 75 years. Overall, > or =87% of patients completed the study. Neither dosage of tolterodine was associated with serious drug-related adverse events during the study. No cardiac arrythmogenic events were noted. Dry mouth (mild to moderate intensity) was the most common adverse event in both the placebo and tolterodine treatment groups. Three percent of patients in the tolterodine 2 mg bid group discontinued treatment because of dry mouth, compared with 2% of placebo-treated patients. Compared with placebo, statistically significant decreases in micturition frequency were apparent in both tolterodine treatment groups. Furthermore, patients treated with tolterodine 2 mg bid had statistically significant decreases in urge incontinence episodes/24 hours and increases in volume voided per micturition compared with placebo. CONCLUSION: Tolterodine (taken for 4 weeks) is safe and shows efficacy, particularly at a dosage of 2 mg bid, in the treatment of older patients with urinary symptoms attributable to overactive bladder.     

Efficacy of Propiverine in Improving Symptoms and Quality of Life in Female Patients with Wet Overactive Bladder

Objectives: The present prospective study was conducted to assess the effects of propiverine hydrochloride in improving symptoms and quality of life (QoL) in female patients with wet OAB. Methods: Propiverine was administered orally for 8 weeks to 58 female patients who had urgency incontinence. Prior to administration, and at 4 and 8 weeks after administration, symptoms and QoL of the patients were assessed using a micturition diary, the International Consultation on Incontinence Questionnaire‐Short Form (ICIQ‐SF), and the King's Health Questionnaire (KHQ). In addition, the relationships between changes in frequency of urinary incontinence or amount of urine leakage following treatment and changes in each domain of the KHQ were investigated by multiple regression analysis. Results: After administration of propiverine, the mean numbers of daily micturitions, incontinence episodes, and urgency episodes assessed on the basis of the micturition diary significantly improved in comparison to the baseline: from 11.7 to 9.6 for daily micturitions, from 2.8 to 1.1 for incontinence episodes, and from 5.9 to 2.3 for urgency episodes in 8 weeks. The mean of the ICIQ‐SF total scores significantly decreased, from 8.4 to 4.6 points at 4 weeks and to 3.6 points at 8 weeks. The mean scores for three individual items in the ICIQ‐SF, namely, frequency of incontinence episodes, amount of leakage, and impact on everyday life also significantly improved. The KHQ scores significantly improved at both 4 and 8 weeks post‐administration in all domains except personal relationships. In the multiple regression analysis, improvement in frequency of incontinence was significantly related to the domain of severity measure of the KHQ, while improvement in amount of leakage was significantly related to the domains of general health perception and social limitations. Conclusion: Propiverine hydrochloride contributed to improvements not only in symptoms but also in QoL in female patients with wet OAB.     

The placebo effect in overactive bladder syndrome

Overactive bladder syndrome (OAB) is a condition that involves urinary urgency and affected individuals are usually treated with behavioral therapy and antimuscarinic agents as first-line therapies. Existing evidence from clinical trial data suggests that a positive placebo effect occurs in patients receiving treatment for OAB. In our systematic Review of placebo-controlled, randomized trials in OAB, we show statistically significant improvements in three patient-reported outcomes-incontinence episodes per day, micturition episodes per day and mean micturition volume from baseline-after placebo in randomized studies for OAB. The findings could highlight the brain's role in the pathophysiology of OAB or the role of additional bladder training conducted as part of OAB clinical trials. More research is needed to determine the underlying mechanisms of the placebo effect in OAB.     

Efficacy,safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients

OBJECTIVES: To evaluate the efficacy, safety, and tolerability of a new, once-daily extended-release (ER) formulation of tolterodine in treating overactive bladder in older (> or =65) and younger (<65) patients. DESIGN: A 12-week double-blind, placebo-controlled clinical trial. SETTING: An international study conducted at 167 medical centers. PARTICIPANTS: One thousand fifteen patients (43.1% aged > or =65) with urge incontinence and urinary frequency. INTERVENTION: Patients were randomized to treatment with tolterodine ER 4 mg once daily (qd) (n = 507) or placebo (n = 508) for 12 weeks. MEASUREMENTS: Efficacy, measured with micturition charts (incontinence episodes, micturitions, volume voided per micturition) and subjective patient assessments, safety, and tolerability endpoints were evaluated, relative to placebo, according to two age cohorts: younger than 65 and 65 and older. RESULTS: Mean age in the older and younger patient cohorts was 74 (range 65-93) and 51 (range 20-64), respectively. Compared with placebo, significant improvements in micturition chart variables with tolterodine ER showed no age-related differences. Irrespective of age, significantly more tolterodine ER recipients than placebo recipients reported an improvement in urgency symptoms. After 12 weeks of treatment with tolterodine ER, a fivefold increase in the percentage of patients able to finish tasks before voiding in response to urgency was noted in both age groups (<65: from 6.5-32.8%, > or =65: from 5.1-26.2%). Tolterodine ER recipients, irrespective of age, also had significant improvements in their bladder condition than did placebo recipients. Overall, a greater percentage of patients, irrespective of age, perceived any benefit with tolterodine ER than with placebo (P <.001). Dry mouth (of any severity) was the most common adverse event in both the tolterodine ER and placebo treatment arms, irrespective of age (<65: ER 22.7%, placebo 8.1%; > or =65: ER 24.3%, placebo 7.2%). Few patients (<2%) experienced severe dry mouth. No central nervous system, visual, cardiac (per electrocardiogram), or laboratory safety concerns were noted. Withdrawal rates due to adverse events on tolterodine ER 4 mg qd were comparable in the two age cohorts (<65: 5.5%; > or =65: 5.1%; P =.87). CONCLUSIONS: The new, once-daily ER formulation of tolterodine is efficacious, safe, and well tolerated in the treatment of patients with symptoms of overactive bladder, irrespective of age.     

What to do if percutaneous tibial nerve stimulation (PTNS) works? A pilot study on home-based transcutaneous tibial nerve stimulation

Introduction: Aim of this pilot study was to assess the feasibility of a home-based transcutaneous tibial nerve stimulation (TTNS) protocol in patients responding to percutaneous tibial nerve stimulation (PTNS ). Materials and methods: 16 overactive bladder syndrome (OAB) patients, responding to PTNS, were included. Patients performed a flexible home protocol of TTNS. Satisfied patients were considered "subjective responders"; patients not showing a =10% increase of urgency/urgency incontinence episodes/day were considered "objective responders".Results: 14/16 patients were followed up for a mean of 19.7 months. All patients were considered subjective responders; 13 were considered objective responders. The mean number of stimulations/week was 1.6 (1-3). Conclusions: After this pilot study, it is possible to conclude that home-based TTNS is feasible. Nevertheless, further randomized trials are needed before drawing any conclusions.     

Efficacy of Synthetic Suburethral Slings in Female Urinary Stress Incontinence with Overactive Bladder

Objectives: The aim of the present study was to investigate the efficacy of synthetic suburethral slings in female stress urinary incontinence (SUI) patients with overactive bladder (OAB). Methods: From May 2002 to April 2005, a total of 295 women with SUI underwent suburethral sling procedure. Of the 295 women, only those who were followed up for at least 12 months were included in the study, yielding 236 patients. The patients were divided into three groups: pure SUI; SUI with OAB dry; and SUI with OAB wet. Telephone questionnaires by were used to evaluate the postoperative improvement of SUI and storage symptoms. Results: There were significant differences in preoperative symptom score, quality of life (QoL) score, and preoperative voided volume among the three groups. There were no significant differences among the three groups in terms of the cure rate for the stress component (group 1, 88.6%; group 2, 86.2%; group 3, 86.7%; P = 0.943). Eighty percent of group 1 patients improved in frequency, but two patients (2.3%) complained of de novo urgency. In group 2, 81.5 and 82.7% improved in frequency and urgency, respectively, but one patient (1.7%) complained of de novo urge incontinence. In group 3, 76.9 and 84.4% improved in frequency and urge incontinence, respectively. Conclusion: Suburethral slings are simple, safe and highly effective in treating SUI with OAB.     

Lower urinary tract symptoms are elevated with depression in Japanese women

Objectives

Depression might worsen lower urinary tract symptoms (LUTS), but the correlation is still disputed. This study examined the influence of depression on LUTS in Japanese women.

Methods

This study used a web-based questionnaire to evaluate the mental status of depression and LUTS. The mental status of depression was evaluated using the Quick Inventory of Depressive Symptomatology-Japanese version (QIDS-J), and LUTS was assessed based on the Overactive Bladder Symptom Score (OABSS) and responses to the International Consultation on Incontinence Questionnaire-Short Form.

Results

A total of 4151 of 5400 (76.9%) women responded to the questionnaire. The mean age was 48.3 ± 13.8 years. The OABSS gradually increased with the QIDS-J score. The incidence of overactive bladder (OAB) and urgency urinary incontinence (UUI) also increased along with the QIDS-J score. In the younger age group (20–39 years old), the risks of OAB and UUI were higher than in the elderly group (7.42 for OAB and 7.44 for UUI).

Conclusions

This study revealed that worsening of LUTS was correlated with depression.     

Randomized Controlled Trial to Treat Benign Prostatic Hyperplasia with Overactive Bladder Using an Alpha‐blocker Combined with Anticholinergics

Objectives: TAABO was a randomized, controlled trial to evaluate the efficacy and safety of combination therapy of tamsulosin (TAM) with propiverine (PROP) in men with both benign prostatic hyperplasia and overactive bladder. Methods: It enrolled men 50 years or older who had an international prostate symptom score (IPSS) of 8 or higher, an urgency item score of 1 or higher, and a quality of life (QOL) score of 2 or higher. After 8 weeks of TAM 0.2 mg/day, patients who met the inclusion criteria (8 micturitions per 24 h and 1 urgency per 24 h, evaluated by bladder diary) and were eligible for 12‐weeks of continued Treatment II. Five hundred and fifteen patients were enrolled. Thereafter, 214 patients were assigned randomly to receive either TAM alone (n = 67), TAM plus PROP 10 mg (n = 72), or TAM plus PROP 20 mg (n = 75) in Treatment II. The primary efficacy end point was a change in micturitions per 24 h documented in the bladder diary. The change from baseline in urgency episodes per 24 h, IPSS, IPSS/QOL subscore, urinary flow rate and postvoid residual volume were assessed as secondary efficacy measures. Results: A total of 141 men (47 TAM, 49 TAM plus PROP 10 mg, and 45 TAM plus PROP 20 mg patients) were assessed by week 12. Compared with the TAM, TAM plus PROP 10 mg patients experienced significantly fewer micturitions (P = 0.0261), urgencies (P = 0.0093) per 24 h, lower IPSS storage (P = 0.0465), and IPSS urgency (P = 0.0252) subscores. Conclusions: These results suggest that combining TAM and 10 mg of PROP for 12 weeks provides added benefit for men with both benign prostatic hyperplasia and overactive bladder.     

Conservative treatment of severe defecatory urgency and fecal incontinence: minor strategies with major impact

Background

Bowel disturbances have been identified as the most important risk factor for fecal incontinence (FI). However, few studies have evaluated the impact of fiber supplementation. Our aim was to assess the correlation between the improvement in stool consistency by fiber supplementation and the changes in urgency and number of FI episodes and in the QoL of patients with FI.

Methods

Eighty-three patients who came to our institution with FI and/or fecal urgency associated with loose stools or diarrhea were prospectively included in the study The intervention included dietary advice and methylcellulose 500 mg every 8 h for 6 weeks. All assessments were carried out at baseline and 6 weeks after the start of the intervention, and included a Bristol Stool Scale, a 3-week bowel diary, the St Mark’s score, the Fecal Incontinence Quality of Life scale (FIQL) and a bowel satisfaction score.

Results

Sixty-one patients completed the study. At baseline 50 reported episodes of urge incontinence, while 11 did not report FI episodes because they rarely left home to avoid leakage. The Bristol score improved to normal stools in 65.6% of patients after treatment. Bowel diaries showed a statistically significant reduction in the number of bowel movements, urge episodes, urge fecal incontinence episodes and soiling per week. The St Mark’s score and the bowel satisfaction score significantly improved after methylcellulose and overall deferment time also increased. FIQL significantly improved in two subdomains (lifestyle, coping/behavior). Thirty-one patients (51.7%) were discharged with methylcellulose as the only treatment.

Conclusions

FI may significantly improve with methylcellulose in selected cases. Assessment of fecal consistency and initial treatment with methylcellulose could be started at primary care level to reduce the need for specialist referral.

     

Efficacy and quality of life 2 years after treatment for faecal incontinence with injectable bulking agents

Background

Stabilized non-animal hyaluronic acid/dextranomer (NASHA^® Dx) gel as injectable bulking therapy has been shown to decrease symptoms of faecal incontinence, but the durability of treatment and effects and influence on quality of life (QoL) is not known. The aim of this study was to assess the effects on continence and QoL and to evaluate the relationship between QoL and efficacy up to 2 years after treatment.

Methods

Thirty-four patients (5 males, mean age 61, range 34–80) were injected with 4 × 1 ml NASHA Dx in the submucosal layer. The patients were followed for 2 years with registration of incontinence episodes, bowel function and QoL questionnaires.

Results

Twenty-six patients reported sustained improvement after 24 months. The median number of incontinence episodes before treatment was 22 and decreased to 10 at 12 months (P = 0.0004) and to 7 at 24 months (P = 0.0026). The corresponding Miller incontinence scores were 14, 11 (P = 0.0078) and 10.5 (P = 0.0003), respectively. There was a clear correlation between the decrease in the number of leak episodes and the increase in the SF-36 Physical Function score but only patients with more than 75 % improvement in the number of incontinence episodes had a significant improvement in QoL at 24 months.

Conclusions

Anorectal injection of NASHA Dx gel induces improvement of incontinence symptoms for at least 2 years. The treatment has a potential to improve QoL. A 75 % decrease in incontinence episodes may be a more accurate threshold to indicate a successful incontinence treatment than the more commonly used 50 %.     

Percutaneous tibial nerve stimulation (PTNS) in females with faecal incontinence: the impact of sphincter morphology and rectal sensation on the clinical outcome

Background

Percutaneous tibial nerve stimulation (PTNS) is an acceptable second line treatment for patients with faecal incontinence (FI) unresponsive to conservative measures. There is however a paucity of data in the literature regarding its efficacy. The aim of this prospective study was to evaluate the efficacy of PTNS in an exclusively female cohort of patients and to identify factors that may predict treatment response.

Method

A prospective cohort of female patients with FI underwent evaluation of sphincter morphology, anorectal pressures and rectal sensation as part of their physiologic assessment prior to treatment. PTNS was performed according to a specific departmental protocol. The clinical outcomes measured were: (1) Cleveland Clinic incontinence scores, (2) deferment time and (3) weekly incontinence episodes. Outcomes were compared at baseline and following treatment using appropriate statistical tests. Clinical outcomes were correlated with the results of the anorectal physiology testing (i.e. sphincter morphology, rectal sensation).

Results

Eighty-eight female patients with a mean age of 58.0?±?13.6?years were included in the analysis. FI was predominantly a late consequence of obstetric injury. The mean incontinence score improved from 12.2?±?4.0 at baseline to 9.1?±?4.6 following treatment (p?<?0.0001). Statistically significant improvements were also seen in the median deferment time and median number of weekly incontinence episodes. Sphincter damage and altered rectal sensation did not appear to influence the outcomes.

Conclusions

PTNS is an effective treatment in female patients with FI. Improvements in clinical outcomes were independent of damage to the anal sphincter complex in patients with normal rectal sensation.     

Sacral neuromodulation for fecal incontinence and “low anterior resection syndrome” following neoadjuvant therapy for rectal cancer

Background

It was the aim of this prospective study to analyze both feasibility and effectiveness of sacral neuromodulation for fecal incontinence and “low anterior resection syndrome” following neoadjuvant therapy for rectal cancer.

Methods

All patients who underwent sacral neuromdulation following neoadjuvant therapy for rectal cancer (preoperative radiochemotherapy, oncologic rectal resection with total mesorectal excision) were prospectively enrolled in the study. Only patients with failure of conservative treatment and without any evidence of residual or recurrent tumor disease were candidates for sacral neuromdulation which was performed by a two-stage procedure (diagnostic percutaneous test stimulation followed by definite implant). In addition to feasibility, primary end points included success (reduction of incontinent episodes), continence and defecation status (assessed by Cleveland Clinic Incontinence Score and Altomare score), and quality of life (EQ-5D). Anal manometry was performed preoperative and at 12-month follow-up. Follow-up information was derived from clinical examination 3, 6, and 12 months postoperatively.

Results

Nine patients (three females, six males) with a mean age of 61 years underwent sacral neuromodulation following neoadjuvant therapy for rectal cancer. Implantation rate was 100 %. No septic morbidity was observed. After a mean follow-up of 12 months, mean Cleveland Clinic Incontinence Score was reduced from 18.2 to 6.0 (p?<?0.01). Incontinence episodes were significantly reduced from 7 to 0.5 (per day) and 20 to 8 (per week). Fecal urgency, fragmented defecation, and soiling were improved or resolved in two thirds. Altomare score was significantly reduced from 21.0 to 9.3 (p?<?0.01). Anorectal manometry did not correlate with clinical success. Quality of life was significantly improved (EQ-5D generic: 0.42 vs. 0.74, EQ-5D-VAS score: 20 vs. 90, p?<?0.01).

Conclusions

Preliminary results of sacral neuromodulation in patients with fecal incontinence and symptoms of “low anterior resection syndrome” are promising and enrich the therapeutic modalities if conservative management has failed.     

Cystometric characteristics in continent adults of various ages

Cystometry was carried out in 40 women and 31 men without incontinence symptoms. The average patient age was 73.3 +/- 8.34 and 68.7 +/- 11.4 years, respectively. Three parameters were analysed: (1) bladder volume at first urgency (VolFU), (2) bladder volume at the point of involuntary micturition (VolM) and (3) difference between the volumes at involuntary micturition and at first urgency (continence reserve, CR). The results demonstrated an age-related progressive drop in all three parameters in women as well as in men, VolM and CR being the most affected values. The average age of individuals with a < 50 ml was 78.7 +/- 5.59 years with a CR between 50 and 99 ml it was 73.3 +/- 7.26 years; and with a CR of 100 ml or more it was 68.5 +/- 10.1 years. These data underline the fact that age impairs micturition patterns even in subjects without overt incontinence problems.     

Effect of Sacral Neuromodulation Rate on Overactive Bladder Symptoms: A Randomized Crossover Feasibility Study

Objectives: This was a single‐center, institutional review board‐approved study, conducted in the USA that used a 3 × 3 orthogonal Latin squares crossover design to assess variability in overactive bladder symptoms and adverse events when subjects were exposed to three rate settings of sacral neuromodulation. Methods: Thirteen female subjects who had urgency frequency and urinary urge incontinence were enrolled into the study. Twelve subjects completed the study. Upon enrollment, each subject was randomized to one of three rate‐setting sequences: 5.2, 14, and 25 Hz. Each rate setting was tested for 1 week in every subject. Results: When subjects were programmed to 5.2, 14, and 25 Hz, they had an average of 3.83 ± 2.27, 2.37 ± 1.83, and 2.82 ± 2.1 incontinence episodes per day and an average of 2.61 ± 1.64, 1.84 ± 1.43, and 1.94 ± 1.61 pad changes per day, respectively. Rate had a statistically significant effect on the number of incontinent episodes (P < 0.001) and number of pad changes (P = 0.039) with more incontinent episodes in the 5.2‐Hz setting compared to the 14‐ and 25‐Hz settings (P < 0.04) for both measurements. Nine subjects reported 21 adverse events. None of the adverse events was considered either a serious or an unanticipated adverse device effect (UADE). Conclusion: Rate significantly affected the number of incontinence episodes and pad changes per day. The number of adverse events was similar across the three rate settings with programming‐related adverse events lowest in the 14 Hz group.     

Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial

Aims/Introduction

Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose‐lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase‐4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia.

Materials and Methods

This was a post‐hoc subgroup analysis of a multinational, parallel‐group clinical trial in which 316 newly diagnosed type 2 diabetes mellitus patients with glycated hemoglobin A1c (HbA1c) 8.5–12.0% were randomized to double‐blind oral treatment with linagliptin/metformin or linagliptin monotherapy. The primary end‐point was the change from baseline in HbA1c at week 24. We evaluated data for the 125 participants from Asian countries.

Results

After 24 weeks, the mean ± standard error reduction from baseline in HbA1c (mean 10.0%) was ?2.99 ± 0.18% with linagliptin/metformin and ?1.84 ± 0.18% with linagliptin; a treatment difference of ?1.15% (95% confidence interval ?1.65 to ?0.66, P < 0.0001). HbA1c <7.0% was achieved by 60% of participants receiving linagliptin/metformin. The mean bodyweight change after 24 weeks was ?0.45 ± 0.41 kg and 1.33 ± 0.45 kg in the linagliptin/metformin and linagliptin groups, respectively (treatment difference ?1.78 kg [95% confidence interval ?2.99 to ?0.57, P = 0.0043]). Drug‐related adverse events occurred in 9.7% of participants receiving linagliptin/metformin and 4.8% of those receiving linagliptin. Hypoglycemia occurred in 6.5% and 4.8% of the linagliptin/metformin and linagliptin groups, respectively, with no severe episodes. Gastrointestinal disorders occurred in 12.9% and 12.7% of the linagliptin/metformin and linagliptin groups, respectively, with no associated treatment discontinuations.

Conclusions

In people from Asia with newly diagnosed type 2 diabetes mellitus and marked hyperglycemia, the initial combination of linagliptin and metformin substantially improved glycemic control without weight gain and with infrequent hypoglycemia. Initial oral combination therapy might be a viable treatment for such individuals.

     

Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis

Aim

To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease.

Methods

We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs).

Results

We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate.

Conclusions

The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.     

Pathophysiology of refractory overactive bladder

Overactive bladder (OAB) is a common condition. The International Continence Society defines OAB as a symptom complex characterized by urgency with or without urge incontinence, usually with frequency and nocturia. The first‐line treatment for OAB includes behavioral therapy, such as caffeine reduction, fluid intake modification, weight reduction, bladder training, and pelvic floor muscle training, as well as treatment with antimuscarinic or β₃‐adrenoceptor agonist medications. However, less than half of all cases achieve satisfactory outcomes following first‐line treatment. Second‐line therapy considered if satisfactory responses are not achieved after 8 to 12 weeks treatment with first‐line therapy include intradetrusor botulinum toxin injection, neuromodulation, and surgical treatment. Patients with refractory OAB may have more severe symptoms or underlying pathophysiologies that were not resolved by the initial medication. The pathophysiologies of refractory OAB include occult neurogenic bladder, undetected bladder outlet obstruction, urethral‐related OAB, urothelial dysfunction with aging, chronic bladder ischemia, chronic bladder inflammation, central sensitization, and autonomic dysfunction. This article discusses the possible pathophysiologies of refractory OAB.     

Effects of calcium channel blockers on nocturnal polyuria in the elderly

Factors reducing the quality of life (QOL) related to micturition and their treatment were studied based on frequency volume chart for 52 consecutive patients with hypertension (the administration of calcium channel blockers) and 28 controls without hypertension, aged 50 years and over (mean age 68.6, range 50-85) without lower urinary tract dysfunction. The micturition records for two days and the QOL index related to urinary symptoms were reviewed. The factors reducing the QOL were increase of the voided volume and frequency during the night and the ratio of night-time voided volume to 24-hour urine output, which significantly increased in the controls (p < 0.05, respectively). Especially, the voiding frequency during the night and the ratio of night-time voided volume increased significantly in the controls aged 70 years and over (p < 0.01, p < 0.05, respectively). Overall, it was suggested that the administration of calcium channel blockers for control of blood pressure might be effective to reduce the nocturnal polyuria in the elderly.