Efficacy and Safety of Adding Sitagliptin in Type 2 Diabetes Patients on Insulin: Age-Stratified Comparison at One Year in the ASSIST-K Study.

BACKGROUND: Sitagliptin, the first dipeptidyl peptidase-4 inhibitor, has demonstrated efficacy and safety as monotherapy and as add-on therapy to oral antidiabetic agents or insulin. However, there have been few reports about sitagliptin in elderly patients. The ASSIST-K observational study was performed in patients with type 2 diabetes mellitus (T2DM) receiving sitagliptin as add-on therapy to insulin. Changes of hemoglobin A1c (HbA1c), body weight, and the estimated glomerular filtration rate (eGFR), as well as adverse events, were investigated over 12 months in age-stratified groups. METHODS: Among outpatients with T2DM treated at member institutions of Kanagawa Physicians Association, those starting sitagliptin as add-on therapy to insulin were followed for 12 months. HbA1c (National Glycohemoglobin Standardization Program), body weight, and eGFR were the efficacy endpoints, while adverse events were investigated to assess safety. Patients were stratified into three age groups (≤ 64 years, 65 - 74 years, and ≥ 75 years) for comparison of the endpoints. RESULTS: Among 937 patients on insulin before starting sitagliptin, 821 patients were analyzed after excluding those without HbA1c data at baseline and 12 months. The two groups of elderly patients (65 - 74 years and ≥75 years) had more complications and their HbA1c was lower at initiation of sitagliptin therapy. The dose of sitagliptin, daily number of insulin injections, and number of concomitant oral antidiabetic agents were all lower in the elderly patients. HbA1c showed a significant decrease after initiation of sitagliptin in all age groups, and there were no significant intergroup differences in the change of HbA1c at 12 months. Body weight did not change significantly in any group. eGFR decreased significantly in all groups, with no significant intergroup differences at 12 months. Regarding adverse events, there were no significant intergroup differences in the incidence of severe hypoglycemia, gastrointestinal symptoms, or constipation. CONCLUSIONS: Despite baseline differences in demographic factors and medications, sitagliptin showed good efficacy and safety in all age groups of patients receiving it as add-on therapy to insulin during routine management of T2DM. Adding sitagliptin to insulin achieves similar efficacy and safety outcomes at 12 months in both elderly and non-elderly T2DM patients.

Effectiveness of Ipragliflozin for Reducing Hemoglobin A1c in Patients With a Shorter Type 2 Diabetes Duration: Interim Report of the ASSIGN-K Study.

BACKGROUND: Ipragliflozin is a selective sodium glucose co-transporter 2 inhibitor. The ASSIGN-K study is investigating the efficacy and safety of ipragliflozin for type 2 diabetes mellitus (T2DM) in the real-world clinical setting. METHODS: Japanese T2DM patients with inadequate glycemic control despite diet and exercise with/without pharmacotherapy were enrolled in an investigator-driven, multicenter, prospective, observational study examining the efficacy and safety of ipragliflozin treatment (50 mg/day for 52 weeks). We performed interim analysis after 24 weeks. RESULTS: In 367 patients completing 24-week ipragliflozin therapy, hemoglobin A1c (HbA1c) decreased significantly from 8.07% at baseline to 7.26% in week 24 (P < 0.001). The change in HbA1c from treatment initiation to week 24 was -0.88% in patients < 65 years old versus -0.55% in those ≥ 65 years and -0.92% in men versus -0.70% in women (all P < 0.001). When baseline HbA1c was < 7%, 7% to < 8%, and ≥ 8%, the change was -0.18%, -0.45%, and -1.48%, respectively (P = 0.5352, P < 0.001, and P < 0.001, respectively). When baseline body mass index (BMI) was < 25, 25 to < 30, and ≥ 30, the change was -1.05%, -0.65%, and -0.87%, respectively (all P < 0.001). Multiple regression analysis showed that HbA1c decreased more in patients with a higher baseline HbA1c or shorter duration of diabetes. An HbA1c < 7% was achieved in 33.3% of the patients, and their baseline HbA1c was significantly lower than that of patients failing to achieve it (P < 0.001). Adverse events (AEs) occurred in 106/451 patients (23.5%), including 29.1% of patients aged 65 or older. Common AEs were vulvovaginal candidiasis (3.1%) and genital pruritus (1.8%). Serious AEs included urinary tract infection, unstable angina, and ketosis, which occurred in patients who did not suspend medication during acute illness. CONCLUSIONS: Ipragliflozin significantly improved HbA1c in T2DM patients with inadequate glycemic control. Improvement in HbA1c was significant irrespective of age, sex, baseline HbA1c, or BMI, but efficacy was greater with a higher baseline HbA1c and shorter duration of diabetes. For safe continuation of treatment, patients should be advised to suspend medication during acute illness.

Ipragliflozin Improves Glycemic Control and Decreases Body Fat in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Ipragliflozin, a sodium-glucose transporter 2 inhibitor, was administered to patients with type 2 diabetes mellitus for 24 weeks to evaluate its effect on glycemic control and body composition. METHODS: This was an investigator-initiated multicenter prospective intervention study in which ipragliflozin (50 mg) was administered once daily and glycemic control, blood pressure, body weight (BW), body composition (measured by a biological impedance method), the lipid profile, and adverse events were evaluated after 4, 12, and 24 weeks of treatment. RESULTS: Efficacy and safety up to 24 weeks of ipragliflozin therapy were analyzed in 367 patients and 451 patients, respectively. Hemoglobin A1c decreased significantly from 8.07% at the start of ipragliflozin therapy to 7.26% in week 24 (P < 0.001). Fasting and postprandial blood glucose levels were significantly reduced by ipragliflozin. In week 24, there were significant decreases from baseline in BW (-2.6 kg), waist circumference (-2.9 cm), and body fat mass (-1.9 kg) (P < 0.001). The body water mass and mineral mass were decreased significantly by 0.5 and by 0.1 kg, respectively (P < 0.001), whereas the protein mass did not change significantly. Intracellular water mass did not change significantly, whereas extracellular water mass showed a significant decrease of 0.5 kg (P < 0.001). Muscle mass did not change in the upper and lower limbs, but that of the trunk decreased significantly (P < 0.001). There was a significant decrease in the fasting triglyceride level and a significant increase in fasting high-density lipoprotein cholesterol level, while low-density lipoprotein cholesterol was unchanged. Adverse events occurred in 23.5% of the patients, with a high frequency of genital infections, such as vulvovaginal candidiasis (3.1%) and genital pruritus (1.8%). Adverse drug reactions were noted in 13.7% of the patients. CONCLUSIONS: Administration of ipragliflozin for 24 weeks improved glycemic control and decreased BW. Reduction of body fat accounted for more than 70% of the total weight loss and reduction of extracellular water accounted for about 20%.

Factors Influencing Changes in Hemoglobin A1c and Body Weight During Treatment of Type 2 Diabetes With Ipragliflozin: Interim Analysis of the ASSIGN-K Study.

BACKGROUND: Ipragliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that blocks glucose reabsorption in the proximal tubules. SGLT2 inhibitors are expected to be effective in patients with insulin resistance and obesity, but it is important to select treatment according to patient background factors that minimizes the risk of adverse events. There have been a limited number of investigations into the relationship between the clinical efficacy (reducing hemoglobin A1c (HbA1c) and body weight (BW)) or safety of SGLT2 inhibitors and patient characteristics. METHODS: ASSIGN-K is an investigator-initiated, multicenter, prospective observational study examining the efficacy and safety of ipragliflozin (50 - 100 mg/day for 52 weeks) in Japanese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with HbA1c ≥ 6.0% (National Glycohemoglobin Standardization Program) despite diet and exercise therapy or diet and exercise plus antidiabetic drug therapy. We conducted an interim analysis of the relationship between changes in HbA1c or BW and characteristics in patients who had been on treatment for more than 12 weeks. RESULTS: In 257 patients completing 12 weeks of treatment, HbA1c decreased significantly from 8.23% to 7.55% (-0.68%, P < 0.01). The change in HbA1c after 12 weeks was -0.17%, -0.33%, and -1.16% when baseline HbA1c was < 7%, 7% to < 8%, and ≥ 8%, respectively (P < 0.05, P < 0.01, and P < 0.01, respectively), and -1.30%, -0.62%, and -0.62% when baseline body mass index (BMI) was < 25, 25 to < 30, and ≥ 30, respectively (all P < 0.01). Stratified analysis showed that age, gender, or BMI did not have a significant influence on the improvement in HbA1c. Multiple regression analysis showed that reduction in HbA1c was greater as baseline HbA1c increased and the duration of diabetes decreased. A higher baseline HbA1c was associated with less weight loss. CONCLUSIONS: Ipragliflozin significantly improved HbA1c in patients with T2DM. HbA1c improved more when baseline HbA1c was higher and the duration of diabetes was shorter, suggesting that current treatment policies for diabetes could be re-examined.

Correction: Efficacy and Safety of Ipragliflozin in Japanese Patients With Type 2 Diabetes: Interim Outcome of the ASSIGN-K Study.

[This corrects the article DOI: 10.14740/jocmr2417w.].

Efficacy and Safety of Ipragliflozin in Japanese Patients With Type 2 Diabetes: Interim Outcome of the ASSIGN-K Study.

BACKGROUND: Ipragliflozin is a sodium-glucose co-transporter 2 inhibitor that can improve glycemic control and reduce body weight and blood pressure in patients with type 2 diabetes mellitus (T2DM). We evaluated the efficacy and safety of ipragliflozin in the real-world clinical setting, with a focus on the changes of body composition up to 3 months of treatment. METHODS: This was a prospective multicenter interventional trial. We investigated changes of the blood pressure, body composition, blood glucose, hemoglobin A1c (HbA1c), ketone bodies, lipids, and insulin after treatment with ipragliflozin (50 - 100 mg/day) for 12 weeks in Japanese patients with T2DM who showed poor glycemic control despite receiving diet and exercise therapy with or without oral antidiabetic drugs for more than 12 weeks. RESULTS: Two hundred and fifty-seven subjects were included in the efficacy analysis up to 12 weeks of treatment and 301 subjects were included in the safety analysis. From baseline to 12 weeks, HbA1c showed a change of -0.68% (95% confidence interval (CI): -0.83, -0.53) and fasting blood glucose showed a change of -23.9 mg/dL (95% CI: -30.5, -17.2), with both parameters displaying a significant reduction (P < 0.001). The difference of body weight from baseline was -1.82 kg (95% CI: -2.14, -1.50), and it also showed significant reduction (P < 0.001). Analysis of body composition revealed that body fat changed by -1.46 kg (95% CI: -1.79, -1.14, P < 0.001) and body water changed by -0.37 kg (95% CI: -0.60, -0.14, P < 0.01). Laboratory tests demonstrated improvement of liver function and the lipid profile. Adverse events (AEs) occurred in 22.6% of the subjects, with frequent events being vulvovaginal candidiasis in 2.7% and cystitis in 2.0%. Serious AEs occurred in three subjects. CONCLUSIONS: In patients with T2DM, ipragliflozin improved glycemic control after 1 month of treatment and caused weight loss by reducing body fat more than body water.

Factors Predicting Therapeutic Efficacy of Combination Treatment With Sitagliptin and Insulin in Type 2 Diabetic Patients: The ASSIST-K Study.

BACKGROUND: It is unclear whether dipeptidyl peptidase-4 inhibitors decrease hemoglobin A1c (HbA1c) in a glucose-dependent manner in patients on insulin therapy who have impaired insulin secretion. This study investigated factors influencing the efficacy of sitagliptin when used concomitantly with insulin to treat type 2 diabetes mellitus (T2DM) in the real-world setting. METHODS: A retrospective study was conducted of 1,004 T2DM patients at 36 Japanese clinics associated with the Diabetes Task Force of the Kanagawa Physicians Association. Eligible patients had been on insulin for at least 6 months, with a baseline HbA1c of 7.0% (53 mmol/mol) or higher. Baseline characteristics and laboratory data from 495 patients were subjected to multiple regression analysis to identify factors influencing the change of HbA1c. RESULTS: Most patients (n = 809) received sitagliptin at a dose of 50 mg. In the 1,004 patients, HbA1c decreased by 0.74% (6 mmol/mol) and body weight increased by 0.1 kg after 6 months of combination therapy. Multiple regression analysis showed that a higher baseline HbA1c, older age, and lower body mass index influenced the change of HbA1c after 6 months. Hypoglycemic symptoms occurred in 7.4%, but none were severe. CONCLUSIONS: These results emphasize the importance of a higher HbA1c at the commencement of sitagliptin therapy in patients on insulin. Glucose-dependent suppression of glucagon secretion by sitagliptin may be useful in patients with impaired insulin secretion. Sitagliptin can be used concomitantly with insulin irrespective of the insulin regimen, duration of insulin treatment, and concomitant medications.

Two-year assessment of the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes: Post hoc analysis of the ASSET-K study.

BACKGROUND: There have only been a few reports about use of dipeptidyl peptidase 4 (DPP-4) inhibitors in elderly patients with type 2 diabetes mellitus (T2DM), suggesting that the safety of these agents has not been sufficiently demonstrated. We performed a comparative review of the efficacy and safety of sitagliptin for Japanese patients with T2DM managed in the real-world clinical setting. METHODS: An age-stratified analysis was performed of 831 patients who were treated with sitagliptin for 2 years. Parameters assessed included the hemoglobin A1c (HbA1c), body weight, serum creatinine, and adverse events. HbA1c and the incidence of hypoglycemia were also evaluated in patients treated with sitagliptin and a sulfonylurea (SU), who were divided into three age groups (<65 years, 65-74 years, and ≥75 years). RESULTS: Comparison of glycemic control parameters, laboratory values, and adverse events revealed significant improvement of HbA1c, casual postprandial plasma glucose, and fasting plasma glucose in each age group with no change in body weight. Serum creatinine increased significantly in all age groups. Hypoglycemia only occurred in patients who received combined treatment with an SU and sitagliptin, and there was no age-related difference in its incidence. CONCLUSIONS: HbA1c was improved by 2 years of sitagliptin therapy in all three age groups, and age did not seem to influence the incidence of hypoglycemic events. These results confirm the efficacy and safety of sitagliptin in patients ≥ 75 years old, suggesting that it is also useful for treating elderly patients with T2DM.

Safety and efficacy of adding sitagliptin to insulin in patients with type 2 diabetes: the ASSIST-K study.

We retrospectively studied more than 1000 patients with type 2 diabetes attending 36 Japanese clinics to investigate the efficacy and safety of adding sitagliptin to various insulin regimens. We found that the treatment with add-on sitagliptin for 6-months was effective, irrespective of the type or dose of concomitant insulin.

Pleiotropic effects of sitagliptin in the treatment of type 2 diabetes mellitus patients.

BACKGROUND: Sitagliptin is a DPP-4 inhibitor that became available for use in Japan three years ago. This study was conducted to identify the pleiotropic effects of sitagliptin other than blood glucose lowering in Japanese type 2 diabetes mellitus patients. METHODS: A retrospective, observational study of 940 type 2 diabetes mellitus patients was conducted. The primary outcome measures were HbA1c, blood pressure, and lipid profiles measured at 0, 4, and 12 weeks of sitagliptin therapy. RESULTS: After 12 weeks of sitagliptin treatment, compared with baseline, HbA1c decreased 0.64% ± 0.86%; systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased significantly; and serum creatinine (Cr) and uric acid (UA) levels were mildly but significantly elevated. A correlation analysis of the changes in systolic blood pressure, diastolic blood pressure, creatinine, and uric acid (ΔSBP, ΔDBP, ΔCr, ΔUA) from baseline to 12 weeks showed significant negative correlations between ΔSBP and ΔCr, ΔSBP and ΔUA, and ΔDBP and ΔCr. Total cholesterol and postprandial triglycerides were significantly decreased at both 4 and 12 weeks. Alkaline phosphatase (ALP) decreased significantly, and there was a significant positive correlation between changes in ALP and HbA1c. CONCLUSIONS: Sitagliptin seems to be effective not only in lowering blood glucose but also in lowering blood pressure, lipid, and ALP levels. Sitagliptin appears to contribute to a Na-diuretic action due to GLP-1.

Efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients.

UNLABELLED: (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00221.x, 2012) Aims/Introduction: To determine the efficacy and safety of sitagliptin monotherapy and combination therapy in Japanese type 2 diabetes patients after 3 months' therapy. MATERIALS AND METHODS: A retrospective, observational study of 741 type 2 diabetes patients was carried out; 110 received sitagliptin monotherapy, and 631 received combination therapy with sitagliptin when other oral medications were insufficient. The primary outcome measure was glycated hemoglobin (HbA1c) measured at 0, 4 and 12 weeks of sitagliptin therapy. RESULTS: In the monotherapy and combination therapy groups, HbA1c decreased significantly after 12 weeks. Target HbA1c (<7%) was achieved in 39.1% overall. On logistic regression analysis, baseline HbA1c was the strongest contributing factor for achieving target HbA1c; baseline body mass index and duration of diabetes were also significant factors. A total of 82 patients (11%) were unresponsive to sitagliptin. These patients' baseline body mass index was significantly higher and their baseline HbA1c was significantly lower than those of patients who responded to sitagliptin. The most commonly co-administered drugs were sulfonylureas (508 patients). In these patients, the dose of sulfonylurea decreased with time. In 66 patients whose sulfonylurea dosage was reduced when sitagliptin was started, HbA1c and bodyweight decreased significantly after 12 weeks. A total of 24 patients receiving sulfonylureas had mild hypoglycemia, but none discontinued sitagliptin. CONCLUSIONS: Sitagliptin was effective and safe as both monotherapy and combination therapy in Japanese type 2 diabetes patients. When sulfonylureas were ineffective, sitagliptin improved glycemic control. In patients whose sulfonylurea dose was reduced at the start of sitagliptin, blood glucose improved and bodyweight decreased after 12 weeks.

Molecular characteristics of outbreaks of nosocomial infection with influenza A/H3N2 virus variants.

OBJECTIVE: To describe outbreaks of nosocomial influenza infection with molecular methods and to elucidate the viral linkages among outbreak case patients including both inpatients and healthcare workers (HCWs). SETTING: A 180-bed acute and long-term care hospital in Japan. METHODS: Retrospective observational study of nosocomial outbreaks of infection with influenza A/H3N2. Together with information about onset dates and vaccination history, we obtained nasopharyngeal swab samples from individuals with cases of influenza or influenza-like illness (ILI). The hemagglutinin genes of the recovered viruses were sequenced and compared, along with those of community-circulating strains, for similarity by phylogenetic tree analysis. RESULTS: The outbreaks occurred from February 26 through April 3, 2007, during the 2006-2007 epidemic season, and they involved 11 patients and 13 HCWs. The 2 outbreaks involved 2 different genotypes of influenza A/H3N2 viruses. These virus variants were closely related to the influenza strains that were circulating in the community during the same epidemic season. CONCLUSION: This study showed the dissemination of highly homologous influenza virus variants among inpatients and HCWs within a short period, as a result of nosocomial transmission. These strains were also similar to influenza strains that were circulating in the community.

Molecular analysis of intrafamiliar transmission of Moraxella catarrhalis.

The possible intrafamiliar transmission of Moraxella catarrhalis was evaluated in 3 pairs between children and their parents, and 8 pairs between siblings from 11 families. Of the 22 isolates, all were found producing beta-lactamase. Molecular typing by pulsed-field gel electrophoresis (PFGE) with Not I and Spe I showed that the PFGE patterns in 2 of 3 pairs between children and their parents, and 4 of 8 pairs between siblings were indistinguishable and those of the remaining pairs were different. These data indicate a possible high rate of intrafamiliar transmission of M. catarrhalis.

Possible high rate of transmission of nontypeable Haemophilus influenzae, including beta-lactamase-negative ampicillin-resistant strains, between children and their parents.

The possible transmission of nontypeable Haemophilus influenzae between children and their parents was evaluated in 18 pairs of subjects from 15 families. Of the 33 isolates, 31 were found to be beta-lactamase negative, including 10 beta-lactamase-negative, ampicillin (AMP)-resistant (BLNAR) strains (AMP MIC, >or=1.0 microg/ml) and 2 were beta-lactamase producing. Molecular typing by pulsed-field gel electrophoresis (PFGE) showed that 10 BLNAR isolates had 6 patterns, 23 non-BLNAR isolates had 13 patterns, and these patterns were different from each other, except for 1 pattern. As a result, the PFGE patterns in 14 of 18 pairs were indistinguishable and those in 4 pairs were different. These data indicate a possible high rate of intrafamilial transmission of nontypeable H. influenzae, including BLNAR strains, between children and their parents.

Antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae and molecular characterization of multidrug-resistant serotype 19F, 6B, and 23F Pneumococci in northern Thailand.

Penicillin-resistant Streptococcus pneumoniae is widely spread worldwide. Our study was undertaken to examine the susceptibility and serotypes of S. pneumoniae in northern Thailand. Ninety-three S. pneumoniae strains were isolated from 93 patients at Chiang Mai University Hospital, Chiang Mai, Thailand, from September 1999 to June 2000. The strains were isolated from sputum (n = 51), blood (n = 15), nasopharynges (n = 14), and other sources (e.g., pus, ears, ascites, and cerebrospinal fluid) (n = 13). Of the 93 isolates, 29 (31.2%) were susceptible, 24 (25.8%) showed intermediate resistance (MIC, 0.12 to 1.0 micro g/ml), and 40 (43.0%) were fully resistant (MIC, >/=2.0 micro g/ml) to penicillin G. Seven (46.7%) from blood, 5 (35.7%) from nasopharynges, 15 (29.4%) from sputum, and 2 (15.4%) from other sources were susceptible isolates. Serotyping with the use of antiserum revealed differences in the predominant types that were susceptible (6A, 11A, and 19A), intermediately resistant (6B and 23F), and fully resistant (6B, 19F, and 23F). Molecular typing by pulsed-field gel electrophoresis of multidrug-resistant pneumococci showed four patterns (A, B, C, and D) for 16 isolates of serotype 19F, with pattern B being predominant (12 isolates). This finding was different from that with the Taiwan multidrug-resistant serotype 19F clone. Eleven isolates of serotype 6B all showed pattern E, and nine isolates of serotype 23F showed two patterns (F and G), with pattern F being predominant (seven isolates). This finding was similar to that with the Spanish multidrug-resistant serotype 23F clone. Our results indicated that the resistance of pneumococci to antibiotics in northern Thailand is progressing rapidly and that effort should be intensified to prevent any spread of pandemic multidrug-resistant serotypes 19F, 6B, and 23F.

High rate of transmission of penicillin-resistant Streptococcus pneumoniae between parents and children.

Transmission of Streptococcus pneumoniae between children and their parents was evaluated in 29 pairs from 25 families. The serotypes of 35 pneumococcal isolates from 18 (62.1%) of 29 child-parent pairs were identical. Of the 35 isolates, 23 showed intermediate resistance and 10 were fully resistant to penicillin G. PCR indicated that all 35 strains had at least one alteration in penicillin-binding protein genes pbp1a, pbp2x, and pbp2b and 33 strains had macrolide resistance genes mef(A) and/or erm(B). As a result, the PCR patterns of 16 of 18 pairs were identical. Molecular typing by pulsed-field gel electrophoresis showed that 12 pairs were indistinguishable, 3 pairs were closely related, 2 pairs were possibly related, and only one pair was different. Our data indicate the presence of a high rate of transmission of penicillin-resistant S. pneumoniae between children and their parents.