De-indexed estimated glomerular filtration rates for the dosing of oral antidiabetic drugs in patients with chronic kidney disease.

Introduction: Adjusting drug dose levels based on equations that standardize the estimated glomerular filtration rate (eGFR) to a body surface area (BSA) of 1.73 m2 can pose challenges, especially for patients with extremely high or low body mass index (BMI). The objective of the present study of patients with CKD and diabetes was to assess the impact of deindexing creatinine-based equations on estimates of kidney function and on the frequency of inappropriate prescriptions of oral antidiabetic drugs (OADs). Methods: The prospective CKD-REIN cohort is comprised of patients with eGFR <60 mL/min/1.73 m2. The inclusion criteria for this study were the use of OADs and the availability of data on weight, height and serum creatinine. We compared data for three BMI subgroups (group 1 <30 kg/m2; group 2 30-34.9 kg/m2; group 3 ≥35 kg/m2). Inappropriate prescriptions (contraindicated or over-dosed drugs) were assessed with regard to the summary of product characteristics and the patient's kidney function estimated with the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the 2021 CKD-EPI equation, the Modification of Diet in Renal Disease (MDRD) equation, the European Kidney Function Consortium (EKFC) equation, their deindexed estimates, and the Cockcroft-Gault (CG) formula. The impact of deindexing the equations was evaluated by assessing 1) the difference between the indexed and deindexed eGFRs, and 2) the difference in the proportion of patients with at least one inappropriate OAD prescription between the indexed and deindexed estimates. Results: At baseline, 694 patients were receiving OADs. The median BMI was 30.7 kg/m2, the mean BSA was 1.98 m2, and 90% of patients had a BSA >1.73 m2. Deindexing the kidney function estimates led to higher eGFRs, especially in BMI group 3. The proportion of patients with at least one inappropriate prescription differed greatly when comparing indexed and deindexed estimates. The magnitude of the difference increased with the BMI: when comparing BMI group 1 with BMI group 3, the difference was respectively -4% and -10% between deindexed 2021 CKD-EPI and indexed CKD-EPI. Metformin and sitagliptin were the most frequent inappropriately prescribed OADs. Conclusion: We highlight significant differences between the BSA-indexed and deindexed versions of equations used to estimate kidney function, emphasizing the importance of using deindexed estimates to adjust drug dose levels - especially in patients with an extreme BMI.

Adherence to newer second-line oral antidiabetic drugs among people with type 2 diabetes-A systematic review.

The adherence to oral antidiabetic drugs (OADs) among people with type 2 diabetes (T2D) is suboptimal. However, new OADs have been marketed within the last 10 years. As these new drugs differ in mechanism of action, treatment complexity, and side effects, they may influence adherence. Thus, the aim of this study was to assess the adherence to newer second-line OADs, defined as drugs marketed in 2012-2022, among people with T2D. A systematic review was performed in CINAHL, Cochrane Trials, Embase, PubMed, PsycINFO, and Scopus. Articles were included if they were original research of adherence to newer second-line OADs and reported objective adherence quantification. The quality of the articles was assessed using JBI's critical appraisal tools. The overall findings were reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines and summarized in a narrative synthesis. All seven included articles were European retrospective cohort studies investigating alogliptin, canagliflozin, dapagliflozin, empagliflozin, and unspecified types of SGLT2i. Treatment discontinuation and medication possession ratio (MPR) were the most frequently reported adherence quantification measures. Within the first 12 months of treatment, 29%-44% of subjects on SGLT2i discontinued the treatment. In terms of MPR, 61.7%-94.9% of subjects on either alogliptin, canagliflozin, dapagliflozin, empagliflozin or an unspecified SGLT2i were adherent. The two investigated adherence quantification measures, treatment discontinuation and MPR, suggest that adherence to the newer second-line OADs may be better than that of older OADs. However, a study directly comparing older and newer OADs should be done to verify this.

Relationship between the early initiation of insulin treatment and diabetic complications in patients newly diagnosed with type 2 diabetes mellitus in Korea: A nationwide cohort study.

AIMS/INTRODUCTION: To evaluate the relationship between early insulin initiation within a year after type 2 diabetes mellitus diagnosis and the risk of diabetic complications. MATERIALS AND METHODS: We carried out a cohort study using the Korean National Health Insurance Service database. The study participants were newly diagnosed with type 2 diabetes mellitus between 2009 and 2013. After applying propensity score matching (1:1) to the cohort of patients who received two or more oral antidiabetic drugs (OADs) or insulin as the first prescription within 1 year after type 2 diabetes mellitus diagnosis, we computed hazard ratios (HRs) and 95% confidence intervals (CIs) using a Cox proportional hazards regression to compare the risk of diabetes-related microvascular and macrovascular complications and all-cause mortality in insulin versus OAD initiators. RESULTS: Within the cohort, 52,188 and 1,804 patients received OAD and insulin, respectively. After matching, each group contained 534 patients. Compared with the OAD group, the risk of overall microvascular complications was significantly higher for insulin (HR 1.48, 95% CI 1.28-1.71). No increased risks of overall macrovascular complications (HR 0.90, 95% CI 0.62-1.30) and all-cause mortality were observed (HR 1.06, 95% CI 0.67-1.68). CONCLUSIONS: In the present study, early insulin treatment was not associated with the risk of macrovascular complications and all-cause mortality compared with OAD treatment; however, the risk of microvascular complications was higher in the insulin group.

[Which place to be reserved to sulphonylureas and which precautions to be taken ?] / Comment je traite Quelle place encore réserver aux sulfamides hypoglycémiants et avec quelles précautions ?

Sulphonylureas (SU) for a long time occupied an essential role in the management of type 2 diabetes (T2D). However, the launch of new oral antidiabetic drugs (OAD), firstly DPP-4 inhibitors (gliptins) and more recently SGLT2 inhibitors (gliflozins), has markedly changed the scene. Indeed, in contrast to SU, these new OAD (of course more expensive) offer the advantage of a very low risk of hypoglycaemia and a beneficial impact on bodyweight. Furthermore, gliflozins have proven to exert a cardiovascular and renal protection in patients at high risk. SU keep a place in the management of T2D, yet it becomes more and more limited. For sure, SU should be avoided among elderly frailty people and patients at high risk of hypoglycaemia.

: Les sulfamides hypoglycémiants (SU) ont longtemps occupé une place essentielle dans le traitement du diabète de type 2 (DT2). La commercialisation de nouveaux antidiabétiques oraux, d'abord les inhibiteurs de la DPP-4 (gliptines) puis les inhibiteurs des SGLT2 (gliflozines), a modifié la donne. En effet, contrairement aux SU, ces médicaments, certes plus coûteux, offrent l'avantage d'être associés à un risque minimal d'hypoglycémies et de ne pas faire prendre du poids. De plus, les gliflozines ont démontré une protection cardio-rénale chez les patients à haut risque. Les SU gardent une place dans le traitement du DT2, mais force est de constater qu'elle devient de plus en plus limitée. Les SU doivent certainement être évités chez les personnes âgées fragiles et chez les patients à risque hypoglycémique.

SGLT2 Inhibitors as Add-On Therapy to Metformin for People with Type 2 Diabetes: A Review of Placebo-Controlled Trials in Asian versus Non-Asian Patients.

Metformin remains the first pharmacological choice for treating hyperglycemia in type 2 diabetes (T2DM) in most international guidelines. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are increasingly used as add-on therapy. T2DM pathophysiology is different in Asian and non-Asian (mainly Caucasian) patients. The aim of this systematic review is to compare the efficacy of SGLT2is vs placebo added to metformin in randomized controlled trials (RCTs: range 12-52 weeks) in Asian versus non-Asian patients with T2DM. The primary endpoint is the reduction in glycated hemoglobin (HbA1c) from baseline and key secondary endpoints are reductions in fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Systematic literature search collected 7 RCTs (3 with 2 doses) in Asian patients (10 analyses, n=1164, iSGLT2: canagliflozin, dapagliflozin, ertugliflozin, ipragliflozin, tofogliflozin)) and 10 RCTs (6 with two doses) in non-Asian patients (16 analyses, n=2482, iSGLT2: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin). Baseline values of HbA1c (7.98±0.19 vs 7.89±0.27%), FPG (8.80 ±0.46 vs 9.11±0.49 mmol/l) and SBP (128.4±1.6 vs 130.2±3.1 mmHg) were not significantly different in Asian vs non-Asian patients, but BW was lower in Asian patients (71.6±4.8 vs 88.0±2.5 kg, p<0.001). The placebo-adjusted weighed mean differences (WMD, 95% CI) were similar in Asian versus non-Asian patients regarding the reductions in HbA1c -0.60 (-0.68, -0.53) % versus -0.54 (-0.59, -0.49) % (p=0.568), FPG -1.37 (-1.53, -1.22) mmol/l vs -1.37 (-1.47, -1.27) mmol/l (p=0.627), BW when expressed in percentage of baseline BW -2.23 (-2.55, -1.90) % vs -2.16 (-2.37, -1.96) % (p=0.324), and SBP -4.53 (-5.53, -3.53) mmHg vs -4.06 (-4.83, -3.29) mmHg) (p=0.223). In conclusion, clinical efficacy of SGLT2i, as an add-on treatment to metformin monotherapy in patients with T2DM, is similar in Asian versus non-Asian patients, despite known ethnic differences in phenotype and pathophysiology of T2DM.

Simultaneous detection of 24 oral antidiabetic drugs and their metabolites in urine by liquid chromatography-tandem mass spectrometry.

Drugs are the most frequent cause of hypoglycemia. Though the drug history is usually obvious in diabetic patients, the diagnosis could be a challenge in patients without a history of such exposure. Screening for oral antidiabetic drugs has been recommended as part of the hypoglycemia workup in patients without diabetes. Many published analytical methods of oral antidiabetic agents were usually of limited coverage and restricted to parent drugs only. In the current study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical system for the simultaneous detection of 24 oral antidiabetic drugs and their metabolites in urine was established and validated. The method covered both conventional as well as the newer antidiabetic drugs such as dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors. Following sample preparation by solid phase extraction, analytes were detected by LC-MS/MS with multiple reaction monitoring triggered enhanced product ion scan. The method was successfully applied to 233 cases of unexplained hypoglycemia, with 83 oral antidiabetic drugs detected in 51 of the urine samples.

Assessing the trend of diabetes mellitus by analyzing metformin as a biomarker in wastewater.

According to International Diabetes Federation estimates, China has the highest rate of diabetes in the world. To monitor the prevalence of diabetes mellitus (DM) in near real-time, a first-line medication for the treatment of type 2 diabetes, metformin, was used. Wastewater-based epidemiology (WBE) was applied to estimate the consumption of metformin in Dalian from 2015 to 2018. Quantification of metformin was undertaken using solid-phase extraction (SPE) and N-methyl-bis (trifluoroacetamide) derivatization prior to GC-MS analysis. The concentrations of metformin in eleven wastewater treatment plants (WWTPs) ranged from 1.7 µg/L to 239.0 µg/L, with an average value of 68.3 µg/L. For metformin consumption, there was a gradual increase from 12.1 mg/d/capita in 2015 to 28.4 mg/d/capita in 2018. Meanwhile, the prevalence of metformin in the Dalian population ranged from 1.6% in 2015 to 3.8% in 2018. Similarly, the prevalence of DM showed an increasing trend from 12.2% in 2015 to 21.6% in 2018, which is consistent with the data predicted by traditional surveys (15.2-19.8%). Additionally, the prevalence of DM in 2015 estimated based on WBE was 12.2%, which agreed with the results from the traditional survey (12.3%). These results indicated that the proposed method provided a feasible way to reveal the prevalence of DM through metformin monitoring by the WBE approach.

Clinical and Economic Outcomes of Patients with Type 2 Diabetes on Multiple Daily Injections of Basal-bolus Insulin (MDI) Therapy: A Retrospective Cohort Study.

PURPOSE: Therapy for patients with type 2 diabetes (T2DM) not achieving hemoglobin (Hb) A1c targets may progress from an oral antidiabetic drug (OAD) to added basal insulin and then to multiple daily injections of basal-bolus insulin (MDI); however, the relative clinical and economic burden experienced by patients prescribed MDI for T2DM is not well quantified. The intent of this work was to describe direct medical costs, health care resource utilization, and glycemic control in patients with T2DM exposed to MDI in a clinical practice setting. METHODS: This retrospective cohort study used administrative claims data (2012-2015, United States) from patients aged 18 to 64 years with T2DM prescribed OAD, basal insulin, or MDI therapy. Eligible patients had continuous enrollment from ≥6 months before to 12 months after the date of the index prescription drug claim. Patients eligible for inclusion in the MDI cohort had ≥2 pharmacy claims each for basal and bolus insulin from the index date through the postindex period. Glycemic control, defined as an HbA1c value of <7% during the last 9 postindex months, was assessed in a subset of patients with HbA1c data available from that period. Descriptive analyses were performed. FINDINGS: We identified 225,135 patients with T2DM and claims for an OAD (n = 188,230), basal insulin (n = 23,724), or MDI (n = 13,181). The mean age was 51 or 52 years in each cohort; 54% to 59% of patients in each cohort were men. The mean Charlson comorbidity index scores were 0.8, 1.4, and 1.8, respectively; the percentages of patients with obesity and diabetes-related complications were greatest in the MDI cohort compared with OAD and basal insulin cohorts. The mean direct medical costs (all-cause; year-2015 US $) were $9368 in the OAD cohort, $14,420 in the basal insulin cohort, and $25,624 in the MDI cohort; diabetes-related costs were $3396, $7285, and $13,538. In the OAD, basal insulin, and MDI cohorts, 7%, 9%, and 14% of patients had ≥1 hospitalization, and 17%, 20%, and 24% had ≥1 emergency department visit, while 5%, 7%, and 11% had ≥1 diabetes-related hospitalization, and 8%, 11%, and 15% had ≥1 diabetes-related emergency department visit. Glycemic control was found in 64%, 22%, and 15% of patients in the OAD, basal insulin, and MDI cohorts. IMPLICATIONS: These findings suggest that patients prescribed MDI therapy for T2DM have greater disease burden, experience greater medical costs and health care resource utilization, and exhibit poorer glycemic control than do patients treated with OAD or basal insulin therapy.

Status of hypoglycemic medication in patients with type 2 diabetes mellitus in Beijing Chaoyang District / 中华全科医师杂志

One thousand and forty-six patients with type 2 diabetes mellitus (T2DM) aged ＞18 years from 11 community health service centers in Beijing Chaoyang district were enrolled in the study.The body weight,height,fasting plasma glucose level and glycosylated hemoglobin A 1c (HbAlc) were measured.A door-to-door questionnaire survey on the use of oral antidiabetic drugs and insulin was conducted between January to December 2017.Of 1 046 T2DM patients,182 (17.4％) received lifestyle intervention,257 (24.6％) used single oral antidiabetic drug (OAD),326 (31.2％) with combined OAD,and 281(26.9％) with insulin and OAD.The average HbA1c in T2DM patients with lifestyle intervention,single OAD drug,combined OAD,and insulin and OAD were (8.1±2.3) ％,(7.6±2.0) ％,(7.8±2.0) ％,and (8.7±2.1) ％,respectively (F=18.35,P＜0.01).Proportions of the T2DM patients with HbAlc lower than 7.0％ were 45.1％,55.6％,43.6％ and 36.8％ in groups,respectively (x2=55.55,P＜0.01).Patients with single or combined OAD aged 18-＜45 years had a worse HbA1c control than those aged 45-＜65 years and≥65 years.It was found that 59.4％,52.6％and 30.8％of the patients receiving one OAD,two OADs and three or more OADs achieved glucose control target.The proportion of drug use was 62.6％ for α-glucosidase inhibitors,50.8％ for metfomain,32.5％ for insulin,18.2％ for sulfonylureas,4.9％ for glinides,3.2％ for thiazolidinediones and 3.1％ for dipeptidyl peptidase-Ⅳs.Among the combined treatment regimens,meffomain+a-glucosidase inhibitors was the most frequently used as compared with α-glucosidase inhibitors + sulfonylureas and metfomain + sulfonylureas.The survey showed that the target-reaching rate of HbA1c was 44.9％,and α-glucosidase inhibitors were frequently used for patients with T2DM in community health service centers in Beijing Chaoyang district south medical alliance.

Status of hypoglycemic medication in patients with type 2 diabetes mellitus in Beijing Chaoyang District / 中华全科医师杂志

One thousand and forty-six patients with type 2 diabetes mellitus (T2DM) aged >18 years from 11 community health service centers in Beijing Chaoyang district were enrolled in the study. The body weight, height, fasting plasma glucose level and glycosylated hemoglobin A1c (HbAlc) were measured. A door-to-door questionnaire survey on the use of oral antidiabetic drugs and insulin was conducted between January to December 2017. Of 1 046 T2DM patients, 182 (17.4%) received lifestyle intervention, 257 (24.6%) used single oral antidiabetic drug (OAD), 326 (31.2%) with combined OAD, and 281(26.9%) with insulin and OAD. The average HbA1c in T2DM patients with lifestyle intervention, single OAD drug, combined OAD, and insulin and OAD were (8.1±2.3)%, (7.6±2.0)%, (7.8±2.0)%, and (8.7±2.1)%, respectively (F=18.35, P<0.01). Proportions of the T2DM patients with HbAlc lower than 7.0% were 45.1%, 55.6%, 43.6% and 36.8% in groups, respectively (χ2=55.55, P<0.01). Patients with single or combined OAD aged 18-<45 years had a worse HbA1c control than those aged 45-<65 years and≥65 years. It was found that 59.4%, 52.6%and 30.8%of the patients receiving one OAD, two OADs and three or more OADs achieved glucose control target. The proportion of drug use was 62.6% for α-glucosidase inhibitors, 50.8% for metfomain, 32.5% for insulin, 18.2% for sulfonylureas, 4.9% for glinides, 3.2% for thiazolidinediones and 3.1% for dipeptidyl peptidase-Ⅳs. Among the combined treatment regimens, metfomain+a-glucosidase inhibitors was the most frequently used as compared with α-glucosidase inhibitors+sulfonylureas and metfomain+sulfonylureas. The survey showed that the target-reaching rate of HbA1c was 44.9%, and α-glucosidase inhibitors were frequently used for patients with T2DM in community health service centers in Beijing Chaoyang district south medical alliance.

Comparison of Oral Antidiabetic Drugs as Add-On Treatments in Patients with Type 2 Diabetes Uncontrolled on Metformin: A Network Meta-Analysis.

We assessed the efficacy and safety of oral antidiabetic drugs (OADs) as an add-on treatment in patients with type 2 diabetes uncontrolled on metformin. PubMed, the Cochrane Library, and Embase were searched from inception to October 20, 2017. Pairwise and network meta-analyses were conducted using Stata 14.1 software. Odds ratios (ORs) and weighted mean differences (WMDs) were used to evaluate outcomes. Sixty-eight trials including 36,746 patients were analyzed. No significant differences in the risk of major adverse cardiovascular events (MACEs) and all-cause mortality were observed among any class of OADs when combined with metformin. All classes of OADs as add-ons to metformin improved glucose control, while sodium-glucose co-transporter-2 (SGLT-2) inhibitors showed greater fasting plasma glucose (FPG) reductions {WMD, - 1.49 [95% confidence interval (CI) - 1.69 to - 1.28] mmol/l} and 2 h postprandial glucose (2 h PPG) reductions [WMD, - 3.07 (95% CI - 4.12 to - 2.03) mmol/l]. Thiazolidinediones and sulfonylureas were associated with weight gain [WMD, 2.53 (95% CI 1.95-3.10) kg and 2.00 (95% CI 1.63-2.36) kg, respectively] when added to metformin. Sulfonylureas [WMD, 6.52 (95% CI 4.07-10.45)] were associated with the highest ORs of hypoglycemia. Our results suggest that the seven classes of OADs were not associated with any increased risk of MACEs or all-cause mortality when combined with metformin. Most OADs were associated with similarly large reductions in HbA1c levels when added to metformin, while SGLT-2 inhibitors might be the best option for reducing body weight, FPG, and 2-h PPG.

Survey of the Attitudes of Community Pharmacists regarding Oral Combination Antidiabetic Drugs / 医薬品情報学

Objective: In this study, we surveyed the attitudes of community pharmacists regarding oral antidiabetic drugs that need to be continuously administered, focusing especially on recently available oral‐combination antidiabetic drugs, in terms of their positioning and medication adherence.　In addition, we identified relevant problems from the survey results and discussed the proper use of the combination drugs.Methods: We conducted a questionnaire‐based survey on health insurance‐covered dispensing pharmacies belonging to Kanazawa, Koga, Takasaki, Hitachi, and Hitachinaka Pharmaceutical Associations via fax or post from September 1, 2017 to November 30, 2017.Results: The overall response rate to the survey was 29.8%.　Although combination drugs were considered useful in terms of improved motivation to take medication, i.e., medication adherence, there were also opinions claiming that combination drugs are not particularly useful due to the following reasons: there are problems in discarding residual drugs, they are less economical than individual drugs, it is difficult to ingest tablets of combination drugs because of their large size, it is difficult to adjust doses of combination drugs, and medication adherence does not change because of concomitant drug use.Conclusion: Based on the results there was the opinion that a combination oral diabetes drug improves medication adherence but problems such as the generation of leftover unused drugs due to switching and an increase in the risk of overuse when taking medication was pointed out.　It is necessary for pharmacists to give advice in recognition of the risks with each active ingredient of the oral diabetes combination drug and to continuously monitor any development of side effects.　Furthermore, as with other diabetes remedies, pharmacists need to advise regarding the patient's lifestyle as well as monitor laboratory test results such as kidney function.　The patient's swallowing ability is also an important consideration at the time of medication instruction.

The Retrospective Chart Review : Prevalence of Incidents Related to Brought-in Medicine / 社会薬学

<p>Consultations with patients who bring drugs, especially on the high risk drug list, to a hospital is an important role of pharmacists. However, many incident reports occur though pharmacists generally make an effort to check such medications. In Japan, incidents are mostly reported just in terms of numbers but not in terms of the prevalence of a target group. We aim to reveal the prevalence of incidents related to medicine brought-in by patients undergoing surgery in National Hospital Organization (NHO) hospitals. For our study, we extracted patients undergoing surgery who were prescribed antidiabetic agents from the Medical data bank (MIA) in NHO. Chart reviews were performed on patients to evaluate the number of incidents in relation to brought-in medicine. The prevalence of incidents of interest was 4.4% (41/931, 95%CL : 3.2-5.9%). Pre-avoidable incidents represented 56.1% (23/41, p<0.0001). We found that pharmacists play a role in making incidents less severe.</p>

Relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetic patients (JDDM38).

AIMS/INTRODUCTION: We carried out an observational cohort study to examine the relationship between the efficacy of oral antidiabetic drugs and clinical features in type 2 diabetics. MATERIALS AND METHODS: We analyzed the CoDiC(®) database of the Japan Diabetes Data Management Study Group across 67 institutions in Japan. In a total of 3,698 drug-naïve patients who were initiated with metformin, dipeptidyl peptidase-4 inhibitor (DPP-4i) or sulfonylurea (SU) from 2007 to 2012, we evaluated body mass index (BMI) and hemoglobin A1c (HbA1c). The patients were stratified according to their clinical features, and matched using a propensity score to adjust for baseline factors. RESULTS: HbA1c was reduced with all drugs, with the largest effect elicited by DPP-4i and the smallest by SU (P = 0.00). HbA1c increased with SU after 6 months in the patients stratified by an age-of-onset of <50 years (P = 0.00). BMI increased with SU in the patients stratified by a BMI of <25 (P = 0.00), and decreased with metformin in the patients with a BMI >25 (P = 0.00). The reduction in HbA1c was larger in patients with HbA1c of ≥8%, compared with that in patients with HbA1c of <8% (P = 0.00). HbA1c during the study period was higher in patients who were added to or swapped with other drug(s), than in patients continued on the original drug (P = 0.00). CONCLUSIONS: The effect on bodyweight and glycemic control differed among metformin, DPP-4i and SU, and the difference was associated with clinical features.

A missense variant in GLP1R gene is associated with the glycaemic response to treatment with gliptins.

Gliptins act by increasing endogenous incretin levels. Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic peptide receptor (GIPR) are their indirect drug targets. Variants of GLP1R and GIPR have previously been associated with the incretin effect. The aim of the present pilot study was to examine associations of the GLP1R and GIPR gene variants with the glycaemic response to gliptins. A total of 140 consecutive patients with type 2 diabetes were followed-up 6 months after initiation of gliptin treatment. GLP1R rs6923761 (Gly168Ser) and GIPR rs10423928 genotyping was performed using real-time PCR, with subsequent high-resolution melting analysis. The main study outcome was reduction in glycated haemoglobin (HbA1c) after treatment. GLP1R Gly168Ser variant was significantly associated with reduction in HbA1c in an additive model (ß = -0.33, p = 0.011). The mean reduction in HbA1c in Ser/Ser homozygotes was significantly lower compared with Gly-allele carriers [0.12 ± 0.23% vs. 0.80 ± 0.09% (1.3 ± 2.5 mmol/mol vs. 8.7 ± 1.0 mmol/mol); p = 0.008]. In conclusion, GLP1R missense variant was associated with a reduced response to gliptin treatment. The genotype-related effect size of ∼0.7% (8 mmol/mol) is equal to an average effect of gliptin treatment and makes this variant a candidate for use in precision medicine.

Liraglutide is effective and well tolerated in combination with an oral antidiabetic drug in Japanese patients with type 2 diabetes: A randomized, 52-week, open-label, parallel-group trial.

INTRODUCTION: The safety and efficacy of liraglutide in combination with an oral antidiabetic drug (OAD) compared with combination of two OADs were assessed in Japanese patients with type 2 diabetes. MATERIALS AND METHODS: This was a 52-week, open-label, parallel-group trial in which patients whose type 2 diabetes was inadequately controlled with a single OAD (glinide, metformin, α-glucosidase inhibitor or thiazolidinedione) were randomized 2:1 to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group; n = 240) or pretrial OAD in combination with an additional OAD (additional OAD group; n = 120). The primary outcome measure was the incidence of adverse events (AEs). RESULTS: Overall, 86.3% of patients in the liraglutide group and 85.0% of patients in the additional OAD group experienced AEs; these were similar in nature and severity. Adverse event rates were 361 and 331 per 100 patient-years of exposure, respectively. Confirmed hypoglycemia was rare (seven episodes in two patients on liraglutide, and two in two patients on additional OAD). There were no reported pancreatitis events, and no unexpected safety signals were identified. Mean reductions in glycosylated hemoglobin were significantly greater in the liraglutide group than the additional OAD group [estimated mean treatment difference -0.27% (95% confidence interval (CI) -0.44, -0.09; P = 0.0026)]; reductions in mean fasting plasma glucose levels were also greater with liraglutide [estimated mean difference -5.47 mg/dL (-0.30 mmol/L; 95% CI: -10.83, -0.10; P = 0.0458)]. CONCLUSIONS: Liraglutide was well tolerated and effective as combination therapy with an OAD in Japanese patients with type 2 diabetes.

SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment.

INTRODUCTION: Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) offer a new opportunity for the management of type 2 diabetes mellitus. These agents reduce hyperglycemia by decreasing the renal glucose threshold and thereby increasing urinary glucose excretion. Subsequent reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity. AREAS COVERED: This article analyzes the efficacy and safety data of canagliflozin, dapagliflozin and empagliflozin in randomized controlled trials of 24 - 104 weeks duration, compared with placebo or an active comparator, in patients treated with diet/exercise, metformin, dual oral therapy or insulin. EXPERT OPINION: SGLT2 inhibitors significantly and consistently reduce glycated hemoglobin, with a minimal risk of hypoglycemia. The improvement of glucose control is similar or slightly better compared with metformin, sulfonylureas or sitagliptin, with the add-on value of significant reductions in body weight and blood pressure. However, caution is recommended in fragile elderly patients and patients with chronic kidney disease. An increased risk of genital mycotic infections is observed, but urinary tract infections are rare. Concern about an unexpected risk of euglycemic ketoacidosis has been recently reported. A possible renal protection deserves further attention. A remarkable reduction in cardiovascular mortality was reported in EMPA-REG OUTCOME with empagliflozin.

Efficacy and safety of luseogliflozin added to various oral antidiabetic drugs in Japanese patients with type 2 diabetes mellitus.

INTRODUCTION: Two studies were carried out to investigate the efficacy and safety of luseogliflozin added to existing oral antidiabetic drugs (OADs) in Japanese type 2 diabetic patients inadequately controlled with OAD monotherapy. MATERIALS AND METHODS: In the trial involving add-on to sulfonylureas (study 03-1), patients were randomly assigned to receive luseogliflozin 2.5 mg or a placebo for a 24-week double-blind period, followed by a 28-week open-label period. In the open-label trial involving add-on to other OADs; that is, biguanides, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, glinides and α-glucosidase inhibitors (study 03-2), patients received luseogliflozin for 52 weeks. RESULTS: In study 03-1, luseogliflozin significantly decreased glycated hemoglobin at the end of the 24-week double-blind period compared with the placebo (-0.88%, P < 0.001), and glycated hemoglobin reduction from baseline at week 52 was -0.63%. In study 03-2, luseogliflozin added to other OADs significantly decreased glycated hemoglobin from baseline at week 52 (-0.52 to -0.68%, P < 0.001 for all OADs). Bodyweight reduction was observed in all add-on therapies, even with agents associated with weight gain, such as sulfonylureas and thiazolidinediones. Most adverse events were mild in severity. When added to a sulfonylurea, incidences of hypoglycemia during the double-blind period were 8.7% and 4.2% for luseogliflozin and placebo, respectively, but no major hypoglycemic episodes occurred. The frequency and incidences of adverse events of special interest for sodium glucose cotransporter 2 inhibitors and adverse events associated with combined OADs were acceptable. CONCLUSIONS: Add-on therapies of luseogliflozin to existing OADs improved glycemic control, reduced bodyweight and were well tolerated in Japanese type 2 diabetic patients. These trials were registered with the Japan Pharmaceutical Information Center (add on to sulfonylurea: JapicCTI-111507; add on to other OADs: JapicCTI-111508).

Effectiveness and Content Analysis of Interventions to Enhance Oral Antidiabetic Drug Adherence in Adults with Type 2 Diabetes: Systematic Review and Meta-Analysis.

OBJECTIVES: To estimate the pooled effect size of oral antidiabetic drug (OAD) adherence-enhancing interventions and to explore which of the behavior change techniques (BCTs) applied in the intervention groups modified this pooled intervention effect size. METHODS: We searched relevant studies published until September 3, 2013, on MEDLINE, Embase, PsycInfo, the Cochrane Library, CINAHL, Current Contents Connect, and Web of Science. Selected studies were qualitatively synthesized, and those of at least medium quality were included in the meta-analysis. A random-effects model was used to pool effectiveness (Hedges's g) and to examine heterogeneity (Higgins I(2)). We also explored the influence on the pooled effectiveness of unique intervention BCTs (those delivered to the intervention groups but not control groups in a trial) by estimating their modifying effects. RESULTS: Fourteen studies were selected for the qualitative synthesis and 10 were included in the meta-analysis. The pooled effectiveness of the interventions was 0.21 (95% confidence interval -0.05 to 0.47; I(2) = 82%). Eight unique BCTs were analyzed. "Cope with side effects" (P = 0.003) and "general intention formation" (P = 0.006) had a modifying effect on the pooled effectiveness. The pooled effectiveness of the interventions in which "cope with side effects" was applied was moderate (0.64; 95% confidence interval 0.31-0.96; I(2) = 56%). CONCLUSIONS: The overall effectiveness of OAD adherence-enhancing interventions that have been tested is small. Helping patients cope with side effects or formulate desired treatment outcomes could have an impact on the effectiveness of OAD adherence-enhancing interventions. Only those interventions that include helping patients to cope with side effects appear to be particularly effective in improving OAD adherence.

Magnetic solid-phase extraction based on mesoporous silica-coated magnetic nanoparticles for analysis of oral antidiabetic drugs in human plasma.

In the present work, magnetic nanoparticles embedded into mesoporous silica were prepared in two steps: first, magnetite was synthesized by oxidation-precipitation method, and next, the magnetic nanoparticles were coated with mesoporous silica by using nonionic block copolymer surfactants as structure-directing agents. The mesoporous SiO2-coated Fe3O4 samples were functionalized using octadecyltrimethoxysilane as silanizing agent. The pure and functionalized silica nanoparticles were physicochemically and morphologically characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), N2 adsorption, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The resultant magnetic silica nanoparticles were applied as sorbents for magnetic solid-phase extraction (MSPE) of oral antidiabetic drugs in human plasma. Our results revealed that the magnetite nanoparticles were completely coated by well-ordered mesoporous silica with free pores and stable pore walls, and that the structural and magnetic properties of the Fe3O4 nanoparticles were preserved in the applied synthesis route. Indeed, the sorbent material was capable of extracting the antidiabetic drugs from human plasma, being useful for the sample preparation in biological matrices.