Use Of Insulin Secretagogues Research Articles

Causes of In-Hospital Death and Pharmaceutical Associations with Age of Death during a 10-Year Period (2011-2020) in Individuals with and without Diabetes at a Japanese Community General Hospital.

Since diabetes and its complications have been thought to exaggerate cardiorenal disease, resulting in a short lifespan, we investigated causes of death and lifespans in individuals with and without diabetes at a Japanese community general hospital during the period from 2011 to 2020. Causes of death and age of death in individuals with and those without diabetes were compared, and associations between medications used and age of death were statistically analyzed. A total of 2326 deaths were recorded during the 10-year period. There was no significant difference between the mean ages of death in individuals with and those without diabetes. Diabetic individuals had higher rates of hepato-pancreatic cancer and cardio-renal failure as causes of death. The prescription rates of antihypertensives, antiplatelets, and statins in diabetic individuals were larger than those in non-diabetic individuals. Furthermore, the use of sulfonyl urea or glinides and insulin was independently and inversely associated with the age of death. In conclusion, individuals with diabetes were treated with comprehensive pharmaceutical interventions and had life spans comparable to those of individuals without diabetes. This study's discovery of an inverse relationship between the use of insulin secretagogues or insulin and the age of death suggests that the prevention of life-threatening hypoglycemia is crucial for individuals with diabetes.

Clinical course of different long-acting insulin therapies-glargine U100, U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes: a multicenter retrospective observational study (JDDM65 study).

This study aimed to retrospectively compare the clinical efficacy of different types of long-acting insulin therapies-glargine U100, glargine U300, degludec, and insulin degludec/insulin aspart-among Japanese patients with type 2 diabetes after insulin use was initiated in an outpatient setting. The study consisted of 822 insulin-naïve patients in Japan who started using long-acting insulin for treatment of type 2 diabetes and continued for over 12 months. In addition, the impact of insulin type on insulin withdrawal was investigated by dividing the participants into two groups: those who achieved insulin withdrawal and those who did not, during the 12-month observation period based on a Cox proportional hazards model. As a result, HbA1c was decreased, and BMI was increased in all participants regardless of the insulin type used. A total of 185 participants succeeded in insulin withdrawal. After adjustment was made for several confounders, the positive determinant factors for withdrawal were short duration of diabetes and the choice of IDegAsp when compared with Gla100; the negative determinant factor was use of insulin secretagogues at the start of the study. In conclusion, all long-acting insulins were a powerful tool for treatment of type 2 diabetes, and patients with short duration of diabetes and/or no usage of insulin secretagogues resulted in favorable outcomes in terms of insulin withdrawal within a year in an outpatient setting. In addition, insulin degludec/insulin aspart was found to possibly be a better choice for treatment when it was compared with glargine U100 among the four types of insulin.

Clinical Characteristics of Withdrawal of Basal Insulin Therapy Among Japanese Patients with Type 2 Diabetes: A Multicenter Retrospective Observational Study.

IntroductionThis study aimed to examine retrospectively the clinical backgrounds of Japanese patients with type 2 diabetes (T2D) who successfully withdrew from insulin use after being started on basal insulin in an outpatient setting.MethodsThe study population comprised 376 insulin-naïve patients who were started on basal insulin (glargine U100, glargine U300, or degludec) for the management of T2D and followed the treatment regimen for at least 6 months in 13 institutions in Japan. The clinical courses of the study participants were compared based on outpatient clinic medical records for the three different types of basal insulin prescribed by categorizing the participants into two groups retrospectively: those who successfully withdrew from insulin therapy and those who did not, during a 6-month observation period. The clinical determinants for insulin withdrawal were assessed using a Cox proportional hazard model.ResultsGlycated hemoglobin was improved in all participants regardless of basal insulin type. Of the 376 study participants, 61 successfully withdrew from basal insulin therapy. After adjustment was made for several confounders, the positive determinant factors for successful withdrawal of insulin were short duration of diabetes and high body mass index at the start of study, and the negative determinant factor was use of insulin secretagogues at the start. The types of basal insulin used by the study participants were not significant determinants of successful insulin withdrawal in this study.ConclusionsUse of basal insulin is a powerful option for the treatment of T2D. In patients with high BMI and/or short duration of diabetes, short-term insulin therapy is a promising strategy for the treatment of T2D before the initiation of insulin secretagogues, since such patients have the potential to successfully withdraw from basal insulin use even in an outpatient setting.

Clinical Effectiveness and Safety of Once-Weekly GLP-1 Receptor Agonist Dulaglutide as Add-On to Metformin or Metformin Plus Insulin Secretagogues in Obesity and Type 2 Diabetes.

Aims and methods: The aim of this monocentric retrospective observational study was to evaluate the 18-month safety and effectiveness of GLP-1 receptor agonist (GLP-1 RA) dulaglutide (DU) 1.5 mg/once weekly as an add-on to metformin (MET) or MET plus conventional insulin secretagogues in a study cohort with excess body weight and type 2 diabetes (T2D). Comparative efficacy versus liraglutide (LIRA) 1.2–1.8 mg/once daily in a study sample naïve to GLP-1 RAs, frequency matching for age, gender, T2D duration, degree of glycemic impairment, cardiovascular comorbidities, and medications, was addressed as a secondary aim. Clinical and biochemical data for efficacy outcomes and information on drug discontinuation due to adverse events (AEs) were collected from digital records. Results: Initial analysis included 126 overweight and obese T2D patients (48.4% females). Out of these, 13 discontinued DU due to moderate–severe gastrointestinal AEs after a mean follow-up of 6 (4 standard deviations (SD)) months, while 65 completed 18 months of continuous therapy. At 6 months, there was a significant mean HbA1c reduction of −0.85% (1.17 SD) with respect to baseline values (p < 0.001), which remained stable during 18 months follow-up. These results were accompanied by a moderate weight loss sustained over time, with a mean reduction of −2.0% (4.3 SD) at 6 months and −1.3% (4.8 SD) at 18 months (p = 0.091). At univariate analysis, a negative correlation between baseline body mass index (BMI) and risk of drug discontinuation due to gastrointestinal AEs was observed. The protective effect of obesity against drug discontinuation was confirmed by logistic regression analysis. Neither gender, nor age, nor T2D duration, nor concomitant conventional insulin secretagogue use, nor switching to DU from other GLP-1 RAs influenced its long-term effectiveness. However, higher baseline HbA1c values emerged as predictors of clinically relevant efficacy outcomes, either in terms of HbA1c reduction ≥ 0.5% or body weight loss ≥ 5%. The efficacy outcomes were corroborated by head-to-head comparison with LIRA, a GLP-1 RA with durable beneficial effects on glycemic control and body weight in real-world experiences. With the advantage of once-weekly administration, at 18-month follow-up, a significantly larger fraction of patients on DU therapy reached glycemic targets (HbA1c ≤ 7.0%) when compared to those on LIRA: from 14.8% at baseline (both groups) to 64.8% with DU and 42.6% with LIRA (p = 0.033). Conclusions: Although limited by a retrospective design and lack of constant up-titration for LIRA to the highest dose, these findings indicate that the beneficial responses to DU on a background of MET or MET plus insulin secretagogues are durable, especially in the presence of obesity and greater HbA1c impairment.

Effects of linagliptin vs glimepiride stratified by prior insulin secretagogue use in the cardiovascular outcome study of linagliptin versus glimepiride in type 2 diabetes (CAROLINA) trial

Abstract Background/Introduction The cardiovascular outcome study of linagliptin versus glimepiride in type 2 diabetes (CAROLINA) was designed to compare the effects on cardiovascular (CV) events, and other outcomes, of linagliptin with glimepiride in patients with relatively early type 2 diabetes with elevated CV risk Purpose These post hoc analyses of the CAROLINA randomized controlled trial explore outcomes in subgroups stratified by prior sulfonylurea (SU) or glinide use. Methods Participants with relatively early type 2 diabetes, high CV risk and HbA1c 6.5–8.5% were randomized to linagliptin 5 mg or glimepiride 1–4 mg once daily with standard of care. 29.5% of patients had prior SU/glinide use. SU/glinides were discontinued at trial entry. Outcomes included time to first CV death/MI/stroke (3P-MACE), time to all-cause mortality, HbA1c change from baseline and time to first hypoglycaemia event. Results 6033 participants received ≥1 study drug dose (mean [SD] age 64.0 [9.5] yrs, HbA1c 7.2 [0.6] %, median diabetes duration 6.3 yrs, 42% with CV disease); 897 linagliptin and 884 glimepiride participants had prior SU/glinide use. Results for 3P-MACE and all-cause mortality were consistent across subgroups with/without prior SU/glinide use (interaction p&amp;gt;0.05; Fig). After some initial differences, there was no meaningful difference in HbA1c between linagliptin vs glimepiride across SU/glinide subgroups and overall. Hypoglycaemia rates were lower with linagliptin vs glimepiride overall and across SU/glinide subgroups, with some heterogeneity for prior SU/glinide use (interaction p&amp;lt;0.01; Fig). Conclusion There was no difference in linagliptin versus glimepiride on 3P-MACE and all-cause mortality, with consistent results across subgroups irrespective of prior SU/glinide use. Hypoglycaemia rates were consistently lower with linagliptin vs glimepiride, regardless of prior SU/glinide use. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim and Eli Lilly and Company

Characteristics of hypoglycaemic episodes in diabetic patients treated at the emergency room of a Portuguese tertiary centre, 2012-2016.

ObjectiveTo analyse changes in the characteristics of hypoglycaemic episodes treated in the emergency room of a tertiary hospital in Portugal between 2012 and 2016.Research Design and MethodsWe retrospectively analysed all emergency room reports for patients discharged with a diagnosis of hypoglycaemia between 2012 and 2016 and analysed demographic characteristics, type of diabetes and treatments, causes of hypoglycaemia and discharge destination. Patients without diabetes were excluded.ResultsIn total, 676 hypoglycaemic episodes were analysed. Most patients were female (59%) and the median age of the patients was 71 years (interquartile range, 57‐81). The proportion of hypoglycaemic episodes relative to all emergency episodes decreased from 1.5% in 2012 to 1.0% in 2016 (P < .001). The proportion of patients with type 1 diabetes increased from 15.6% to 23.8%, while that of patients with type 2 diabetes decreased from 80.3% to 72.3% (nonsignificant differences). There was an increase in the use of insulin (67.1% to 85.4%, P = .02) and a decrease in the use of insulin secretagogues (26.6% to 11.5%, P = .03) over the study period. The rate of hospitalization dropped significantly from 11% in 2012 to 4.3% in 2015 and 5.4% in 2016 (P = .02).ConclusionsDespite the increasing use of newer diabetes medications associated with a lower risk of hypoglycaemia, these episodes still require emergency care. The proportion of patients receiving insulin increased over the years, probably due to the slight increase in the prevalence of type 1 diabetes and the increasing replacement of secretagogues with insulin in type 2 diabetes.

Associations of fear of hypoglycemia with second-line use of insulin secretagogues or insulin and subsequent glycemic control in patients with type 2 diabetes: An analysis using data from the DISCOVER study.

Associations of fear of hypoglycemia with prescription of second-line insulin secretagogues (IS) or insulin and subsequent glycemic control in patients with type 2 diabetes were analysed using data from the DISCOVER study-a large, prospective, observational study. Patients with type 2 diabetes initiating a second-line treatment after a first-line oral therapy were enrolled. Fear of hypoglycemia was assessed using baseline Hypoglycemia Fear Survey (HFS) worry score. Glycemic control was assessed using glycated haemoglobin (HbA1c) levels at 6-month and 1-year follow-up, and HbA1c change from baseline was analysed. To examine the association of baseline HFS worry scores with second-line use of IS or insulin, a hierarchical logistic model with country as random effect was used. A total of 6217 patients were analysed. The mean HFS worry score was 6.9±11.4, while patients in the upper quartile had an HFS worry score≥9. We divided patients into three groups according to their baseline HFS worry score (0, 1-8, ≥9). HFS worry score was associated with the use of first-line IS, but not the second-line treatment. Compared to treatments with no IS and insulin, a better HbA1c response to second-line IS or insulin was noted in patients with a baseline HFS worry score of 0 or 1-8, but not in patients with a baseline HFS worry score≥9. HFS worry score was associated with the use of first-line IS and glycemic response to second-line IS or insulin in patients with type 2 diabetes. ClinicalTrials.gov NCT02322762. Registered 23 December 2014.

Epidemiology of hypoglycemia among ambulatory Type 2 diabetic patients in a primary care clinic of a tertiary hospital in Southeastern Nigeria

Aim: The study was aimed at describing the epidemiology of hypoglycemia among ambulatory type 2 diabetic patients in a primary care clinic in Eastern Nigeria. Materials and Methods: A cross-sectional descriptive study was carried out on 145 type 2 diabetic patients in a primary care clinic in Nigeria. Data were collected using pretested, structured, and interviewer-administered questionnaire containing information on relevant epidemiological variables. Experience of hypoglycemia was defined as self-reported symptoms of hypoglycemia in the previous 1 year. Results: The age of type 2 diabetic patients ranged from 32 to 78 years with mean age of 44 ± 10.2 years. There were 59 (40.7%) males and 86 (59.3%) females. The prevalence of hypoglycemia was 35.2%. Hypoglycemia occurred predominantly among the elderly (72.5%), male gender (54.9%), outside home environment (72.5%), during the daytime (82.4%), duration of diabetes ≤1 year (58.8%), and patients on insulin secretagogues alone (46.2%). The most common symptom was dizziness (76.5%). Experience of hypoglycemia was significantly associated with elderly age (P = 0.025), duration of diabetes ≤1 year (P = 0.021), and use of insulin secretagogues alone (P = 0.043). The most significant predictor of hypoglycemic events was use of insulin and insulin secretagogues (odds ratio = 3.15 [1.74–5.66]; P = 0.002). Type 2 diabetic patients on insulin and insulin secretagogues were three times more likely to experience hypoglycemic events compared to their counterparts who were on insulin sensitizers. Conclusion: The study has shown variable epidemiology of hypoglycemia. The incident occurred predominantly among the elderly, male gender, during daytime, outside home environment, duration of diabetes ≤1 year, and patients on insulin and insulin secretagogues. Interventional measures for hypoglycemia should consider relevant epidemiological factors that predispose to hypoglycemia.

Insulinoma in a Patient with Type 2 Diabetes: A Case Report

ABSTRACT Objective: To describe a case of insulinoma in a patient with pre-existing type 2 diabetes mellitus. Methods: We report a case, with clinical, biochemical, and imaging findings, and give a literature review. Results: The most common causes of recurrent hypoglycemia in a patient with diabetes mellitus are insulin excess and use of insulin secretagogues. If these are completely ruled out, other causes must be considered. The co-existence of diabetes mellitus and insulinoma is very rare, with less than 40 cases reported in the literature. We report the case of a 66-year-old woman with obesity, hypertension, and type 2 diabetes mellitus treated with premixed insulin, who was diagnosed with an insulinoma in the setting of a 6-month history of severe recurrent hypoglycemia that persisted despite discontinuation of insulin therapy. A computed tomography of the abdomen revealed a 14-mm tumor in the pancreatic tail that was removed through laparoscopic distal pancreatectomy. Histopathologic examination co...

Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study

AimTo evaluate the association between insulin secretagogues and adverse cardiovascular sequelae in type 2 diabetes patients hospitalized for ischemic heart disease (IHD). MethodsAdministrative health records from Alberta, Canada between 1998 and 2010 were used to identify 2,254 gliclazide, 3,289 glyburide and 740 repaglinide users prior to an IHD-related hospitalization. Multivariable Cox regression models were used to compare the 30-day risk of a composite outcome of all-cause mortality or new onset of atrial fibrillation, stroke, heart failure or myocardial infarction according to insulin secretagogue use. ResultsMean (SD) age was 76.1 (6.9) years, and 60.7% were men. The composite outcome occurred in 322 (30.2%) gliclazide users, 455 (28.1%) glyburide users and 81 (23.4%) repaglinide users within 30days of IHD hospitalization. There were no differences in risk for glyburide use (adjusted hazard ratio [aHR] 0.91; 95% confidence interval [CI] 0.78–1.05) or repaglinide use (aHR 0.80; 95% CI 0.63–1.03) compared to gliclazide. Similar results were observed in analyses for each element of the composite outcome. ConclusionsIn older patients with type 2 diabetes hospitalized for IHD, prior use of gliclazide, glyburide, or repaglinide appears to be associated with a similar risk of adverse cardiovascular sequelae.

Journal of Diabetes NEWS

<i>Journal of Diabetes</i> NEWS

GPR40 Modulators: New Kid on the Block

Impairments in insulin secretion and action are the pathophysiological hallmarks of type 2 diabetes (1,2). Pharmacological approaches to restore β-cell function have led to the use of insulin secretagogues that include sulphonylureas, glinides, and glucagon-like peptide-1–based therapies. Of these, the latter hold particular clinical advantage because glucagon-like peptide-1–modulated insulin secretion is glucose dependent (3,4), thereby minimizing the risk for hypoglycemia—the bane of clinicians managing diabetes across the world. Fatty acids have long been known (5) to modulate human β-cell function. While acutely fatty acids amplify glucose-stimulated insulin secretion, chronic elevation of free fatty acid (FFA) levels has been thought to inhibit insulin secretion through the phenomenon of “lipotoxicity” (6,7). The cellular/molecular intermediates that are involved in this complex modulation, elegantly summarized in ref. 5, include malonyl CoA/long-chain acyl-CoA, triglyceride/FFA cycling through diacylglycerol, G-protein–coupled receptor 40 (GPR40) and phospholipase A2. G-protein–coupled receptors have recently emerged as novel therapeutic targets because they appear to be closely involved in the pathology of various metabolic disorders including obesity, dyslipidemia, and type 2 diabetes (8). Since the seminal article (9) in 2003 about the role of GPR40 (also known as FFA1R: free fatty acid 1 receptor) in long-chain fatty acid–mediated glucose-stimulated insulin secretion from rodent and human β-cells, there have been over 60 publications investigating the properties and modulators of this receptor as yet another potential therapeutic approach for the management of type 2 diabetes. GPR40 is expressed most abundantly in humans in pancreatic β-cells …

Hiperinsulinismo endógeno: revisão e seguimento de 24 casos

Hypoglycemia due to endogenous hyperinsulinism (EH) is diagnosed in a symptomatic patient with low levels of plasma glucose concomitant with elevated plasma insulin and C-peptide. Causes of EH are pancreatic islet-cells disease, use of insulin secretagogues, and autoimmune hypoglycemia. In this review, the authors studied 24 patients with hypoglycemia due to endogenous hyperinsulinism in order to describe aspects of diagnosis and treatment. Our study demonstrated that after 12 hours of fasting (mini-fasting test; at least three samples), all patients presented the diagnostic criteria for EH. Additionally, we found that 11 of 12 patients (91.7%) who underwent glucagon test achieved glucose levels less than 50 mg/dL and below baseline after 120 minutes. Mini-fasting (3 samples) and glucagon test may be useful to prevent prolonged fasting test to clarify the diagnosis of endogenous hyperinsulinism.

Insulin lispro protamine suspension in the treatment of patients with type 1 and type 2 diabetes mellitus: a systematic review of published data

Introduction: Insulin lispro protamine suspension (ILPS) is a protamine-based insulin lispro formulation that allows 24-h coverage while limiting the number of daily injections. ILPS was developed to be the basal insulin component of premixed biphasic formulations with insulin lispro, i.e., the lispro/ILPS 25/75 and 50/50 mixed compounds, but has recently also been marketed as a basal insulin analog formulation, with an indication for the therapy of diabetic patients.Areas covered: This article reviews the available literature on pharmacokinetics/pharmacodynamics (PK/PD), efficacy and safety of ILPS administered as basal insulin, or in premixed biphasic formulations, in patients with type 1 and type 2 diabetes mellitus.Expert opinion: The results of this review suggest that ILPS may be associated with a favorable time–action profile, basal and postprandial glycemic control, and efficacy in terms of rates of patients reaching glycosylated hemoglobin targets; an increased risk of hypoglycemic episodes, compared to other basal insulins, seems to be related to the percentage of patients upgrading from once- to twice-daily injections. This increased risk might be linked with the concomitant use of insulin secretagogues in patients on higher daily dosages and is generally not observed in patients using one injection of ILPS a day. Thus, ILPS can be considered a valid option both as basal insulin and as basal component of the actual premixed formulations of lispro for the therapy of diabetic patients.

Exendin-4 increases islet amyloid deposition but offsets the resultant beta cell toxicity in human islet amyloid polypeptide transgenic mouse islets.

In type 2 diabetes, aggregation of islet amyloid polypeptide (IAPP) into amyloid is associated with beta cell loss. As IAPP is co-secreted with insulin, we hypothesised that IAPP secretion is necessary for amyloid formation and that treatments that increase insulin (and IAPP) secretion would thereby increase amyloid formation and toxicity. We also hypothesised that the unique properties of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 to maintain or increase beta cell mass would offset the amyloid-induced toxicity. Islets from amyloid-forming human IAPP transgenic and control non-transgenic mice were cultured for 48 h in 16.7 mmol/l glucose alone (control) or with exendin-4, potassium chloride (KCl), diazoxide or somatostatin. Human IAPP and insulin release, amyloid deposition, beta cell area/islet area, apoptosis and AKT phosphorylation levels were determined. In control human IAPP transgenic islets, amyloid formation was associated with increased beta cell apoptosis and beta cell loss. Increasing human IAPP release with exendin-4 or KCl increased amyloid deposition. However, while KCl further increased beta cell apoptosis and beta cell loss, exendin-4 did not. Conversely, decreasing human IAPP release with diazoxide or somatostatin limited amyloid formation and its toxic effects. Treatment with exendin-4 was associated with an increase in AKT phosphorylation compared with control and KCl-treated islets. IAPP release is necessary for islet amyloid formation and its toxic effects. Thus, use of insulin secretagogues to treat type 2 diabetes may result in increased islet amyloidogenesis and beta cell death. However, the AKT-associated anti-apoptotic effects of GLP-1 receptor agonists such as exendin-4 may limit the toxic effects of increased islet amyloid.

Antidiabetic Therapies Affect Risk of Pancreatic Cancer

Antidiabetic drugs have been found to have various effects on cancer in experimental systems and in epidemiologic studies, although the association between these therapeutics and the risk of human pancreatic cancer has not been explored. We investigated the effect of antidiabetic therapies on the risk of pancreatic cancer. A hospital-based case-control study was conducted at M. D. Anderson Cancer Center from 2004 to 2008 involving 973 patients with pancreatic adenocarcinoma (including 259 diabetic patients) and 863 controls (including 109 diabetic patients). Information on diabetes history and other risk factors was collected by personal interview. The frequencies of use of insulin, insulin secretagogues, metformin, and other antidiabetic medications among diabetic patients were compared between cases and controls. The risk of pancreatic cancer was estimated using unconditional logistic regression analysis. Diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin (odds ratio, 0.38; 95% confidence interval, 0.22-0.69; P = .001), with adjustments for potential confounders. This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes >2 years or those who never used insulin. In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk of pancreatic cancer compared with diabetic patients who had not taken these drugs. Metformin use was associated with reduced risk, and insulin or insulin secretagogue use was associated with increased risk of pancreatic cancer in diabetic patients.