Non-insulin Glucose-lowering Drugs Research Articles

Non-adherence to non-insulin glucose-lowering drugs: Prevalence, predictors and impact on glycemic control and insulin initiation. A longitudinal cohort study in a large primary care database in Spain

BackgroundA better understanding of patient non-adherence to type 2 diabetes medication is needed to design effective interventions to address this issue.Objectives(1) To estimate the prevalence of non-adherence to diabetes medication; (2) to examine its impact on glycemic control and insulin initiation; (3) to develop and validate a prediction model of non-adherence.MethodsWe conducted a longitudinal cohort study based on data from electronic health records. We included adult patients registered within the Health Service of the Balearic Islands (Spain) starting a new prescription of a non-insulin glucose-lowering drug between January 2016 and December 2018. We calculated non-adherence at 12 months follow-up, defined as medication possession ratio (MPR) ≤ 80%. We fitted multivariable regression models to examine the association between non-adherence and glycemic control and insulin initiation and identified predictors of non-adherence.ResultsOf 18,119 patients identified, after 12 months follow-up, 5,740 (31.68%) were non-adherent. Compared with non-adherent, adherent patients presented lower HbA1c levels (mean difference = −0.32%; 95%CI = −0.38%; −0.27%) and were less likely to initiate insulin (aOR = 0.77; 95%CI = 0.63; 0.94). A predictive model explained 22.3% of the variation and presented a satisfactory performance (AUC = 0.721; Brier score = 0.177). The most important predictors of non-adherence were: non-Spanish nationality, currently working, low adherence to previous drugs, taking biguanides, smoker and absence of hypertension.ConclusionAround one-third of the patients do not adhere to their non-insulin glucose-lowering drugs. More research is needed to optimise the performance of the predicting model before considering its implementation in routine clinical practice.

Variations in Use of Diabetes Drugs With Cardiovascular Benefits Among Medicaid Patients

Cardiovascular death remains the leading cause of mortality in patients with type 2 diabetes (T2D). A better understanding of the current use and adoption of glucose-lowering drugs with cardiovascular benefit can inform state policies to ensure their appropriate use in patients with T2D. To characterize the use of glucose-lowering agents with known cardiovascular benefit over time and across states. This cross-sectional pharmacoepidemiological study of Medicaid prescription rates of glucose-lowering agents with known cardiovascular benefit vs those with less well-established cardiovascular benefit was conducted between 2014 and 2019. In 50 states and the District of Columbia, the study focused on nonmetformin, noninsulin glucose-lowering drugs divided into 3 cohorts: (1) sodium-glucose cotransporter 2 (SGLT2) inhibitors, (2) glucagon-like peptide 1 (GLP1) receptor agonists, and (3) all other classes of glucose-lowering drugs. Data were analyzed from January 2014 to December 2019. Number of days supplied of each cohort, use ratios between the aggregated days supplied of glucose-lowering agents with known cardiovascular benefit vs those with less well-established cardiovascular benefit, and the mean change in use ratios per quarter. Across the 50 states and the District of Columbia, the use ratio of glucose-lowering agents with known cardiovascular benefit ranged from 1.58 to 0.14 (mean [SD], 0.48 [0.27]) in 2019. A lower use ratio was seen in states with a higher prevalence of diabetes (β = -0.049; 95% CI, -0.086 to -0.012; P = .01), a larger total population (β = -0.013; 95% CI, -0.023 to -0.003; P = .01), a greater number of Medicaid enrollees (β = -0.054; 95% CI, -0.096 to -0.014; P = .01), a greater proportion of people enrolled in Medicaid (β = -0.018; 95% CI, -0.030 to -0.007; P = .002), and a greater proportion of Medicaid patients enrolled in managed care organizations (β = -0.0032; 95% CI, -0.0051 to -0.0013; P = .002). Higher Medicaid expenditures per enrollee (β = 0.047; 95% CI, 0.007 to 0.089; P = .03) were associated with a higher use ratio of these agents. The relative use of glucose-lowering agents with known cardiovascular benefit by Medicaid enrollees increased 7.4% per year from 2014 to 2019, with wide variations across state Medicaid programs. In this cross-sectional study, glucose-lowering agents with cardiovascular benefit increased in use during the study period, but also demonstrated considerable variation among states in their relative use. Medicaid programs should try to clarify which factors may be contributing to relative underuse of these potentially life-saving drugs.

Classification of Non-Insulin Glucose Lowering Drugs.

The ever-changing scenario of diabetes care, especially pharmacotherapy, calls for a framework to help classify non-insulin glucose drugs. Such a taxonomic structure should be of contemporary relevance as well as futuristic in vision; scholarly in intent but easy to understand; and based on pathophysiologic principles while being useful for the clinician. We propose a rubric which lists four classes of non-insulin glucose lowering drugs; insulin secretagogues, insulin sensitizers, calorie restriction mimetics, and calorie restrictors. This classification serves the need of students and teachers as well as pharmacologists and clinicians alike.

Incidence and risk factors for mortality and end-stage renal disease in people with type 2 diabetes and diabetic kidney disease: a population-based cohort study in the UK

IntroductionWe aimed to determine the incidence of, and risk factors for all-cause/cardiovascular disease (CVD) mortality, and end-stage renal disease (ESRD) among people with type 2 diabetes with/without diabetic kidney disease...

Improving the Estimation of Subgroup Effects for Clinical Trial Participants with Multimorbidity by Incorporating Drug Class-Level Information in Bayesian Hierarchical Models: A Simulation Study

BackgroundThere is limited guidance for using common drug therapies in the context of multimorbidity. In part, this is because their effectiveness for patients with specific comorbidities cannot easily be established using subgroup analyses in clinical trials. Here, we use simulations to explore the feasibility and implications of concurrently estimating effects of related drug treatments in patients with multimorbidity by partially pooling subgroup efficacy estimates across trials.MethodsWe performed simulations based on the characteristics of 161 real clinical trials of noninsulin glucose-lowering drugs for diabetes, estimating subgroup effects for patients with a hypothetical comorbidity across related trials in different scenarios using Bayesian hierarchical generalized linear models. We structured models according to an established ontology—the World Health Organization Anatomic Chemical Therapeutic Classifications—allowing us to nest all trials within drugs and all drugs within anatomic chemical therapeutic classes, with effects partially pooled at each level of the hierarchy. In a range of scenarios, we compared the performance of this model to random effects meta-analyses of all drugs individually.ResultsHierarchical, ontology-based Bayesian models were unbiased and accurately recovered simulated comorbidity-drug interactions. Compared with single-drug meta-analyses, they offered a relative increase in precision of up to 250% in some scenarios because of information sharing across the hierarchy. Because of the relative precision of the approaches, a large proportion of small subgroup effects was detectable only using the hierarchical model.ConclusionsBy assuming that similar drugs may have similar subgroup effects, Bayesian hierarchical models based on structures defined by existing ontologies can be used to improve the precision of treatment efficacy estimates in patients with multimorbidity, with potential implications for clinical decision making.

Trends in Total and Out-of-pocket Payments for Noninsulin Glucose-Lowering Drugs Among U.S. Adults With Large-Employer Private Health Insurance From 2005 to 2018.

To estimate trends in total payment and patients' out-of-pocket (OOP) payments of noninsulin glucose-lowering drugs by class from 2005 to 2018. We analyzed data for 53 million prescriptions from adults aged >18 years with type 2 diabetes under fee-for-service plans from the 2005-2018 IBM MarketScan Commercial Databases. The total payment was measured as the amount that the pharmacy received, and the OOP payment was the sum of copay, coinsurance, and deductible paid by the beneficiaries. We applied a joinpoint regression to evaluate nonlinear trends in cost between 2005 and 2018. We further conducted a decomposition analysis to explore the drivers for total payment change. Total annual payments for older drug classes, including metformin, sulfonylurea, meglitinide, α-glucosidase inhibitors, and thiazolidinedione, declined during 2005-2018, ranging from -$271 (-53.8%) for metformin to -$2,406 (-92.2%) for thiazolidinedione. OOP payments for these drug classes also reduced. In the same period, the total annual payments for the newer drug classes, including dipeptidyl peptidase-4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors, increased by $2,181 (88.4%), $3,721 (77.6%), and $1,374 (37.0%), respectively. OOP payment for these newer classes remained relatively unchanged. Our study findings indicate that switching toward the newer classes for noninsulin glucose-lowering drugs was the main driver that explained the total payment increase. Average annual payments and OOP payment for noninsulin glucose-lowering drugs increased significantly from 2005 to 2018. The uptake of newer drug classes was the main driver.

Impact of Age, Frailty, and Dementia on Prescribing for Type 2 Diabetes at Hospital Discharge 2012-2016

The risks of intensive blood glucose lowering may outweigh the benefits in vulnerable older people. Our primary aim was to determine whether age, frailty, or dementia predict discharge treatment types for patients with type 2 diabetes (T2D) and related complications. Secondly, we aimed to determine the association between prior hypoglycemia and discharge treatment types. We conducted a cohort study involving 3,067 patients aged 65-99 years with T2D and related complications, discharged from Melbourne's Eastern Health Hospital Network between 2012 and 2016. Multinomial logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CI) for the association between age, frailty, dementia and hypoglycemia, and being prescribed insulin-only, non-insulin glucose-lowering drugs (GLDs) or combined insulin and non-insulin GLDs compared to no GLD. International Classification of Diseases-10 codes were used to identify dementia status and prior hypoglycemia; frailty was quantified using the Hospital Frailty Risk Score. Insulin-only, non-insulin GLDs, combined insulin and non-insulin GLDs, and no GLDs were prescribed to 19%, 39%, 20%, and 23% of patients, respectively. Patients >80 years were less likely than patients aged 65-80 to be prescribed any of the GLD therapies, (eg. non-insulin GLDs [OR 0.67; 95%CI 0.55-0.82]), compared to no GLD. Similarly, high vs. low frailty scores were associated with not being prescribed any of the three GLD therapies, (eg. non-insulin GLDs [OR 0.63; 95%CI 0.45-0.87]). However, dementia was not associated with discharge prescribing of GLD therapies. Patients with a hypoglycemia-related admission were more likely than those not hospitalized with hypoglycemia to receive insulin-only (OR 4.28; 95%CI 2.89-6.31). Clinicians consider age and frailty when tailoring diabetes treatment regimens for patients discharged from hospital with T2D and related complications. There is scope to optimize prescribing for patients with dementia and for those admitted with hypoglycemia.

Use of professional-mode flash glucose monitoring, at 3-month intervals, in adults with type 2 diabetes in general practice (GP-OSMOTIC): a pragmatic, open-label, 12-month, randomised controlled trial

Continuous glucose monitoring, either real-time (personal) or retrospective (professional mode), can identify day-to-day glucose profiles to guide management decisions for people with type 2 diabetes. We aimed to examine the effects of professional-mode flash glucose monitoring, done at 3-month intervals, in adults with type 2 diabetes in general practice. We did a pragmatic, two-arm, open label, 12-month, individually randomised controlled trial (GP-OSMOTIC) in 25 general practices in Victoria, Australia. Eligible participants were adults aged 18-80 years, with type 2 diabetes diagnosed for at least 1 year and HbA1c at least 5·5 mmol/mol (0·5%) above their target in the past month despite being prescribed at least two non-insulin glucose-lowering drugs, insulin, or both (with therapy stable for at least 4 months). We randomly assigned participants (1:1) to either use of a professional-mode flash glucose monitoring system or usual clinical care (control). All participants wore the flash glucose monitoring sensor at baseline, and electronic randomisation (using permuted block sizes of four and six, and stratified by clinic) was done after the sensor was attached. Masking of participants and treating clinicians to group allocation was not possible, but the study statistician was masked to allocation when analysing the data. At baseline, and 3, 6, 9, and 12 months, participants in the flash glucose monitoring group wore the professional-mode flash glucose monitoring sensor for 5-14 days before their general practice visit. The sensor recorded interstitial glucose concentrations every 15 min, but the glucose data were not available to the participant until their general practice visit, where the sensor output would be uploaded to a computer by the health professional and discussed. Control group participants wore the sensor at baseline and at 12 months for data analysis only, and had usual care visits every 3 months. The primary outcome was the between-group difference in mean HbA1c at 12 months. Secondary outcomes were the between-group differences in: mean percentage time in target glucose range (4-10 mmol/L), based on ambulatory glucose profile data at 12 months; mean diabetes-specific distress (assessed with the Problem Areas In Diabetes [PAID] scale) at 12 months; and mean HbA1c at 6 months. Analysis was done by intention to treat. This trial is registered at the Australian and New Zealand Clinical Trials Registry, ACTRN12616001372471. Between Oct 4, 2016, and Nov 17, 2017, we randomly assigned 299 adults: 149 to flash glucose monitoring and 150 to usual care. At 6 months, HbA1c was lower in the flash glucose monitoring group than in the usual care group (difference -0·5%, 95% CI -0·8% to -0·3%; p=0·0001). However, at 12 months (primary outcome), there was no significant between-group difference in estimated mean HbA1c (8·2% [95% CI 8·0 to 8·4] for flash glucose monitoring vs 8·5% [8·3 to 8·7] for usual care; between-group difference -0·3%, 95% CI -0·5 to 0·01; [66 mmol/mol, 95% CI 64 to 68 vs 69 mmol/mol, 67 to 72; between-group difference -3·0, 95% CI -5·0 to 0·1]; p=0·059). Mean percentage time spent in target glucose range at 12 months was 7·9% (95% CI 2·3 to 13·5) higher in the flash glucose monitoring group than in the usual care group (p=0·0060). Diabetes-specific distress PAID scores were unchanged at 12 months (between-group difference -0·7, 95% CI -3·3 to 1·9; p=0·61). No episodes of severe hypoglycaemia or treatment-related deaths were reported. One participant died during the study from causes unrelated to the intervention (following complications post-myocardial infarction with multiple comorbidities). Professional-mode flash glucose monitoring in adults with type 2 diabetes in general practice did not improve the primary outcome of HbA1c at 12 months or diabetes-specific distress compared with usual care, but did improve time in target glucose range at 12 months and HbA1c at 6 months. Our findings suggest that professional-mode flash glucose monitoring can be implemented in a pragmatic primary care environment. Although there was no change in HbA1c at 12 months, the improved time in target range might reflect the potential of the technology to support personalised clinical care by providing insights into glycaemic profiles for some people with type 2 diabetes. National Health and Medical Research Council of Australia, Sanofi Australia, and Abbott Diabetes Care.

FRAILTY AND THE EFFECTIVENESS AND SAFETY OF NEW GLUCOSE-LOWERING DRUGS IN OLDER ADULTS WITH TYPE 2 DIABETES

Recently, several classes of non-insulin glucose-lowering drugs, such as dipeptidyl peptidase-4 inhibitors (DPP4i), glucagon-like peptide-1 receptor agonists (GLP1-RA), and sodium glucose co-transporter-2 inhibitors (SGLT2i), have been approved to treat type 2 diabetes. Clinical trials have shown that GLP1RA and SGLT2i confer cardiovascular benefit, while DPP4i do not have such benefit; these drugs do not seem to increase the risk of hypoglycemia. However, due to underrepresentation of older adults with frailty and lack of frailty assessment in clinical trials, little is known about how the effectiveness and safety of these drugs change across different levels of frailty. In this symposium, we present the real-world evidence from Medicare data April 2013-December 2016 on the utilization trends of newly approved diabetes drugs (Dr. Dave) and comparative effectiveness and safety of SGLT2i vs sulfonylurea (Dr. Pawar), SGLT2i vs DPP4i (Dr. Kim), and SGLT2i vs GLP1-RA (Dr. Patorno). The outcomes were 1) composite cardiovascular endpoint of mortality, myocardial infarction, stroke, or heart failure; and 2) severe hypoglycemia, defined as emergency department visits or hospitalizations due to hypoglycemia. We applied a validated claims-based frailty index (CFI) to estimate the treatment effectiveness and safety in non-frail (CFI<0.10), pre-frail (CFI 0.10-0.19), or frail individuals (CFI≥0.20). Following individual presentations, Dr. Munshi and presenters will lead an interactive discussion about clinical implications and methodological challenges in conducting geriatric pharmacoepidemiologic studies using Medicare data. This symposium will demonstrate the utility of CFI in claims-based pharmacoepidemiologic studies and provide health care providers with new evidence to tailor diabetes pharmacotherapy based on frailty.

The glucose-lowering therapy structure in special groups of type 2 diabetes mellitus patients based on data from the Moscow region register

BACKGROUND : Data of real clinical practice in diabetes mellitus (DM) register allow to evaluate features and trends in structure of glucose-lowering therapy (GLT). AIM : Тo analyze of structure of GLT received by patients with type 2 diabetes mellitus (T2DM) in Moscow region for 2018 and to evaluate its dynamics over 15 years. METHODS : Analysis of GLT structure was carried out on basis of data from register of patients with DM in Moscow region, which is part of National register of diabetes mellitus in Russian Federation. In March 2018 it contained data on 211,792 T2DM patients of Moscow region. Structure of GLT administration was evaluated according T2DM duration, patient’s age and presence of cardiovascular diseases (CVD). Dynamics of GLT is analyzed from 2004 to 2018 yrs. RESULTS : In 2018 non-insulin glucose-lowering drugs (NIGD) prescription prevailed (78.3%), insulin therapy was prescribed in 18.5% of patients, 3.2% of patients did not receive drug therapy. Most commonly prescribed NIGD were metformin (69.3%) and sulfonylurea (51.3%). Older patients more often than younger did not use GLT at all and less frequently received insulin therapy and iDPP-4. Insulin therapy was prescribed twice as often in patients with CVD compared with patients without CVD (29.6% and 15.5%). NIGD monotherapy has been less commonly used in patients with CVD (67.3% and 81.2%). Glucagon-like peptide-1 receptor agonists (GLP-1 RA) were prescribed to patients with CVD GLP-1 RA – in 0.1% of cases, without CVD in 0.3% of cases, and sodium-glucose cotransporter 2 (SGLT2) inhibitors in 1.1% and 0.6%. correspondently. CONCLUSION : Metformin was most commonly prescribed drug in GLT structure for T2DM patients in the Moscow region in 2018 yr. Percentage of new drugs in the structure of GLT increased mainly due to iDPP-4, and secondly due to SGLT2 inhibitors. New classes of GLT were more often prescribed to patients of younger age, with diabetes duration up to 10 years, overweight or obese. Administration of NIGD with proven cardiovascular protection in presence of CVD is almost two times less than for those without CVD.

The glucose-lowering therapy structure in special groups of type 2 diabetes mellitus patients based on data from the Moscow region register

BACKGROUND: Data of real clinical practice in diabetes mellitus (DM) register allow to evaluate features and trends in structure of glucose-lowering therapy (GLT).&#x0D; AIM: Тo analyze of structure of GLT received by patients with type 2 diabetes mellitus (T2DM) in Moscow region for 2018 and to evaluate its dynamics over 15 years.&#x0D; METHODS: Analysis of GLT structure was carried out on basis of data from register of patients with DM in Moscow region, which is part of National register of diabetes mellitus in Russian Federation. In March 2018 it contained data on 211,792 T2DM patients of Moscow region. Structure of GLT administration was evaluated according T2DM duration, patients age and presence of cardiovascular diseases (CVD). Dynamics of GLT is analyzed from 2004 to 2018 yrs.&#x0D; RESULTS: In 2018 non-insulin glucose-lowering drugs (NIGD) prescription prevailed (78.3%), insulin therapy was prescribed in 18.5% of patients, 3.2% of patients did not receive drug therapy. Most commonly prescribed NIGD were metformin (69.3%) and sulfonylurea (51.3%). Older patients more often than younger did not use GLT at all and less frequently received insulin therapy and iDPP-4. Insulin therapy was prescribed twice as often in patients with CVD compared with patients without CVD (29.6% and 15.5%). NIGD monotherapy has been less commonly used in patients with CVD (67.3% and 81.2%). Glucagon-like peptide-1 receptor agonists (GLP-1 RA) were prescribed to patients with CVD GLP-1 RA in 0.1% of cases, without CVD in 0.3% of cases, and sodium-glucose cotransporter 2 (SGLT2) inhibitors in 1.1% and 0.6%. correspondently.&#x0D; CONCLUSION: Metformin was most commonly prescribed drug in GLT structure for T2DM patients in the Moscow region in 2018 yr. Percentage of new drugs in the structure of GLT increased mainly due to iDPP-4, and secondly due to SGLT2 inhibitors. New classes of GLT were more often prescribed to patients of younger age, with diabetes duration up to 10 years, overweight or obese. Administration of NIGD with proven cardiovascular protection in presence of CVD is almost two times less than for those without CVD.

Prevalence and correlates of diabetes distress, perceived stress and depressive symptoms among adults with early-onset Type 2 diabetes: cross-sectional survey results from the Danish DD2 study.

To establish the prevalence of diabetes distress, perceived stress and depressive symptoms among adults with early-onset Type 2 diabetes, and to examine their association with socio-demographic and clinical characteristics. A cross-sectional survey was performed among individuals with Type 2 diabetes aged 20-45 years who were included in the Danish nationwide Danish Center for Strategic Research in Type 2 Diabetes cohort between 2010 and 2016. The survey assessed diabetes distress (20-item Problem Areas in Diabetes Scale), perceived stress (10-item Perceived Stress Scale) and depressive symptoms (10-item short form of the Center for Epidemiological Studies Depression Scale Revised), as well as socio-demographic characteristics. Clinical data were collected from national health registers. In total, 216/460 (47%) individuals (48% women) with Type 2 diabetes completed the survey. The median (IQR) age was 42 (38-44) years and the diabetes duration was 5 (3-7) years. In total, 24% of respondents reported high diabetes distress (Problem Areas in Diabetes Scale ≥ 40), 46% reported high perceived stress (Perceived Stress Scale ≥ 18) and 41% reported elevated symptoms of depression (Center for Epidemiological Studies Depression Scale Revised ≥ 10). The prevalence of emotional problems was higher among women than men. Diabetes distress was higher among those prescribed non-insulin glucose-lowering drugs (vs. no glucose-lowering drugs), but was not associated with other clinical or socio-demographic characteristics. High perceived stress was associated with being unemployed and using antidepressant medication, and elevated depressive symptoms were associated with low education level, unemployment, living alone, having a psychiatric disorder and using antidepressant medication. We found a high prevalence of emotional problems among adults with early-onset Type 2 diabetes in Denmark. Health care for this group should focus on both physical health and psychosocial circumstances and should also address general as well as diabetes-specific emotional problems.

Prospective Study on Incidence of Cardiovascular-Renal Diseases, Severe Hypoglycaemia, and Death in Chinese with Latent Autoimmune Diabetes in Adults

Objectives: Few studies have examined the progression to chronic complications in patients with latent autoimmune diabetes in adults (LADA). We compared incidence of cardiovascular-renal diseases, severe hypoglycaemia and death in patients with LADA and type 2 diabetes. Methods: Between 1995-2012, 1569 Chinese with young-onset (age of diagnosis &amp;lt;40 years) non-type 1 diabetes underwent comprehensive disease assessment at Prince of Wales Hospital, Hong Kong. LADA (n=124 [7.9%]) was identified by positive anti-glutamic acid decarboxylase antibodies measured from stored serum. Patients were followed for new events of cardiovascular disease (CVD), end-stage renal disease (ESRD), severe hypoglycaemia and all-cause death until June 2017. Results: At baseline, patients with LADA (mean age: 43.4 years, median diabetes duration: 6.0 years) had lower serum C-peptide, BMI and triglyceride but higher HbA1c than patients with type 2 diabetes (mean age: 41.7 years, median diabetes duration: 8.0 years). Use of insulin was more frequent in those with LADA whilst use of non-insulin glucose lowering drugs was comparable. Over follow-up period of 10 years, incidence (in 1000 person-year) of CVD, ESRD, severe hypoglycaemia and death were 4.1, 8.0, 20.2 and 5.5 in LADA, and 10.4, 9.5, 10.8 and 8.8 in type 2 diabetes, respectively. Using Cox regression, patients with LADA had lower hazard to have CVD (hazard ratio [HR] 0.41 [95% CI 0.19-0.89], p=0.024), higher hazard to have severe hypoglycaemia (HR 1.74 [95% CI 1.15-2.62], p=0.008) and similar risks for ESRD and mortality compared with type 2 diabetes, adjusted for age, gender, disease duration, smoking, glycaemic and metabolic indices, and baseline insulin use. Conclusions: Patients with LADA had lower risks of CVD but higher risks of severe hypoglycaemia than type 2 diabetes. Disclosure A. Luk: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Sanofi. E.S. Lau: None. C.K.P. Lim: None. E. Chow: Research Support; Self; Sanofi. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp &amp; Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd. A.P. Kong: Research Support; Self; AstraZeneca. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck &amp; Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp &amp; Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company.

Mortality Risk of Noninsulin Glucose-Lowering Drugs in Type 2 Diabetes—A Network Meta-analysis of Observational Trials

Given the short-comings of randomized controlled trials, such as low numbers of patients and events, we aimed to perform a network meta-analysis of observational trials on the effects of non-insulin glucose-lowering drugs on all-cause and cardiovascular mortality in type 2 diabetes. We searched MEDLINE and EMBASE through August 2017. From the 38 eligible studies, we extracted patient characteristics, exposure, outcome, confounder-adjusted effect measures, and risk of bias. All-cause and cardiovascular mortality risk were assessed with random-effects network meta-analysis. In 32 studies reporting on all-cause mortality (1,661,945 persons) and in 11 studies on cardiovascular mortality (358,784 persons), 119,591 (7.2%) and 9,221 (2.6%) persons, respectively, died during follow-up. Compared to metformin, sulfonylurea drugs (SU) increased all-cause mortality risk (HR: 1.42 (95% CI: 1.29-1.56)). Dipeptidyl peptidase-4 inhibitors (DDP4i) added to metformin significantly decreased all-cause mortality risk compared to metformin monotherapy (HR: 0.76 (0.63-0.93)), any other drug class as monotherapy, and SU + metformin dual therapy (HR: 0.69 (0.60-0.79)). DPP-4i + metformin dual therapy was associated with even larger reductions in risk of cardiovascular mortality; HR: 0.40 (0.21-0.79) when compared to metformin monotherapy, and HR: 0.41 (0.23-0.74) when compared to SU + metformin dual therapy. Glucagon-like-peptide-1 receptor agonists + metformin dual therapy tended to, but did not significantly, decrease mortality risk when compared to metformin monotherapy (all-cause mortality, HR: 0.88 (0.53-1.47); cardiovascular mortality, HR: 0.74 (0.30-1.82)). In conclusion, this large network meta-analysis evidently confirmed that SU, compared to metformin, increased all-cause mortality risk. DPP-4i + metformin dual therapy, compared to other treatments, resulted in a consistent risk reduction of both all-cause and cardiovascular mortality. Disclosure B. Bongaerts: None. L.M. Lindner: None. A. Hoyer: None. O. Kuss: None. C. Herder: Other Relationship; Self; Sanofi, Eli Lilly and Company. H. Al-Hasani: None. K. Müssig: None. M. Roden: Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Research Support; Self; Boehringer Ingelheim GmbH. Consultant; Self; Poxel SA. Research Support; Self; Danone Nutricia Early Life Nutrition, GlaxoSmithKline plc., Nutricia Advanced Medical Nutrition, Sanofi. W. Rathmann: Advisory Panel; Self; AstraZeneca. Research Support; Self; Novo Nordisk A/S.

Impact of sex and glucose-lowering treatments on hypoglycaemic symptoms in people with type 2 diabetes and chronic kidney disease. The French Chronic Kidney Disease – Renal Epidemiology and Information Network (CKD-REIN) Study

AimTo describe current practices of glucose-lowering treatments in people with diabetes and chronic kidney disease (CKD), the associated glucose control and hypoglycaemic symptoms, with an emphasis on sex differences. MethodsAmong the 3033 patients with CKD stages 3–5 recruited into the French CKD-REIN study, 645 men and 288 women had type 2 diabetes and were treated by glucose-lowering drugs. ResultsOverall, 31% were treated only with insulin, 28% with combinations of insulin and another drug, 42% with non-insulin glucose-lowering drugs. In CKD stage 3, 40% of patients used metformin, 12% at stages 4&5, similar for men and women; in CKD stage 3, 53% used insulin, similar for men and women, but at stages 4&5, 59% of men and 77% of women used insulin. Patients were reasonably well controlled, with a median HbA1c of 7.1% (54mmol/mol) in men, 7.4% (57mmol/mol) in women (P=0.0003). Hypoglycaemic symptoms were reported by 40% of men and 59% of women; they were not associated with the estimated glomerular filtration rate, nor with albuminuria or with HbA1c in multivariable analyses, but they were more frequent in people treated with insulin, particularly with fast-acting and pre-mixed insulins. ConclusionGlucose-lowering treatment, HbA1c and hypoglycaemic symptoms were sex dependent. Metformin use was similar in men and women, but unexpectedly low in CKD stage 3; its use could be encouraged rather than resorting to insulin. Hypoglycaemic symptoms were frequent and need to be more closely monitored, with appropriate patient-education, especially in women.

Heart failure risk and major cardiovascular events in diabetes: an overview of within-group differences in non-insulin antidiabetic treatment.

Recently, great attention is paid to cardiovascular impact of non-insulin glucose-lowering drugs, particularly in terms of major cardiovascular events and risk of heart failure. In this regard, a surprising diversity among different molecules within the same pharmacological class has been noticed, yielding to an intra-class discrepancy which has no analogous in other cardiovascular fields. The aim of this paper is to review the literature, giving an insight of the heterogeneous effects among groups and within group shown by oral antidiabetic drugs, with a special concern to fragile patients, such as those with or at risk of heart failure.

Rates of glycaemic deterioration in a real-world population with type 2 diabetes

Aims/hypothesisThere is considerable variability in how diabetes progresses after diagnosis. Progression modelling has largely focused on ‘time to failure’ methods, yet determining a ‘coefficient of failure’ has many advantages. We derived a rate of glycaemic deterioration in type 2 diabetes, using a large real-world cohort, and aimed to investigate the clinical, biochemical, pharmacological and immunological variables associated with fast and slow rates of glycaemic deterioration.MethodsAn observational cohort study was performed using the electronic medical records from participants in the Genetics of Diabetes Audit and Research in Tayside Study (GoDARTS). A model was derived based on an individual’s observed HbA1c measures from the first eligible HbA1c after the diagnosis of diabetes through to the study end (defined as insulin initiation, death, leaving the area or end of follow-up). Each HbA1c measure was time-dependently adjusted for the effects of non-insulin glucose-lowering drugs, changes in BMI and corticosteroid use. GAD antibody (GADA) positivity was defined as GAD titres above the 97.5th centile of the population distribution.ResultsThe mean (95% CI) glycaemic deterioration for type 2 diabetes and GADA-positive individuals was 1.4 (1.3, 1.4) and 2.8 (2.4, 3.3) mmol/mol HbA1c per year, respectively. A younger age of diagnosis, lower HDL-cholesterol concentration, higher BMI and earlier calendar year of diabetes diagnosis were independently associated with higher rates of glycaemic deterioration in individuals with type 2 diabetes. The rate of deterioration in those diagnosed at over 70 years of age was very low, with 66% having a rate of deterioration of less than 1.1 mmol/mol HbA1c per year, and only 1.5% progressing more rapidly than 4.4 mmol/mol HbA1c per year.Conclusions/interpretationWe have developed a novel approach for modelling the progression of diabetes in observational data across multiple drug combinations. This approach highlights how glycaemic deterioration in those diagnosed at over 70 years of age is minimal, supporting a stratified approach to diabetes management.

An Automated System Combining Safety Signal Detection and Prioritization from Healthcare Databases: A Pilot Study.

Signal detection from healthcare databases is possible, but is not yet used for routine surveillance of drug safety. One challenge is to develop methods for selecting signals that should be assessed with priority. The aim of this study was to develop an automated system combining safety signal detection and prioritization from healthcare databases and applicable to drugs used in chronic diseases. Patients present in the French EGB healthcare database for at least 1year between 2005 and 2015 were considered. Noninsulin glucose-lowering drugs (NIGLDs) were selected as a case study, and hospitalization data were used to select important medical events (IME). Signal detection was performed quarterly from 2008 to 2015 using sequence symmetry analysis. NIGLD/IME associations were screened if one or more exposed case was identified in the quarter, and three or more exposed cases were identified in the population at the date of screening. Detected signals were prioritized using the Longitudinal-SNIP (L-SNIP) algorithm based on strength (S), novelty (N), and potential impact of signal (I), and pattern of drug use (P). Signals scored in the top 10% were identified as of high priority. A reference set was built based on NIGLD summaries of product characteristics (SPCs) to compute the performance of the developed system. A total of 815 associations were screened and 241 (29.6%) were detected as signals; among these, 58 (24.1%) were prioritized. The performance for signal detection was sensitivity=47%; specificity=80%; positive predictive value (PPV) 33%; negative predictive value=82%. The use of the L-SNIP algorithm increased the early identification of positive controls, restricted to those mentioned in the SPCs after 2008: PPV=100% versus PPV=14% with its non-use. The system revealed a strong new signal with dipeptidylpeptidase-4 inhibitors and venous thromboembolism. The developed system seems promising for the routine use of healthcare data for safety surveillance of drugs used in chronic diseases.

Trends in the incidence of use of noninsulin glucose-lowering drugs between 2006 and 2013 in France.

This study aimed at describing trends in the incidence of use of noninsulin glucose-lowering drugs (NIGLDs) between 2006 and 2013 in France. Repeated cross-sectional studies on NIGLD new users were performed annually from 2006 to 2013 within the Echantillon Généraliste des Bénéficiaires (EGB) database, a 1/97th representative sample of the population covered by the French healthcare insurance system. NIGLD included metformin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, dipeptidylpeptidase-4 (DPP-4) inhibitors, glinides and glucagon-like peptide-1 analogues. New users were defined as patients with no delivery of any NIGLD (first-line new users) or no delivery of a NIGLD of the same class (add-on/switch new users) in the preceding year. Incidence rates of use and corresponding 95% confidence intervals (95% CI) were estimated per 1000 persons. Among the 507 043 persons included in the EGB in 2006, 2036 were identified as NIGLD first-line new users and 2192 as add-on/switch new users, which corresponded to an incidence of use of 4.0‰ (95%CI 3.8-4.2) and 4.3‰ (4.1-4.5), respectively. First-line incidence increased to 5.3‰ (5.1-5.5) in 2010 and then decreased to 4.2‰ (4.0-4.4) in 2013; add-on/switch incidence increased to 8.0‰ (7.8-8.2) in 2010 and then decreased to 5.3‰ (5.1-5.5) in 2013. This reduction was mainly related to DPP-4 inhibitors, whose use as add-on/switch NIGLDs was roughly halved between 2010 and 2013. Concomitantly, the use of sulfonylureas and glinides increased. In conclusion, after reaching a peak in 2010, the incidence of use of NIGLDs has markedly decreased in France. Since then, prescribers seem to have reverted to older and well-known therapies.

Diabetes medication pharmacology

Diabetes medication pharmacology