Classes Of Glucose-lowering Medications Research Articles

Association of Thiazide Diuretics With Diabetes Progression, Kidney Disease Progression, Cardiovascular Outcomes, and Death Among Patients With Diabetes Who Initiate Statins

Statins have been associated with diabetes mellitus (DM) progression but their cardiovascular benefit in patients with DM outweigh the harm. However, the effects of concurrent use of other medications that similarly increase blood glucose level, such as thiazide diuretics, are not well studied. This study aimed to evaluate the association of concurrent use of thiazide diuretics and statins on DM progression, cardiovascular and renal outcomes, and death in patients with DM. This is a retrospective cohort study of Veterans with DM who initiated statins between 2003 and 2015. The cohort comprised thiazide users (concomitantly used thiazides and statins for ≥6months) and active comparators (concomitantly used calciun channel blockers [CCB] but not thiazides and statins for ≥6months). We excluded patients who were <18 years old, with chronic kidney disease stage 4 or worse, or used loop diuretics. We propensity-score-matched comparison groups on 99 baseline characteristics including demographics, healthcare utilization, co-morbidities, cardiovascular and co-morbidity scores, vital signs, laboratory data, and medication class usage. Outcomes were: (1) DM progression (new insulin initiation, increase in the number of glucose-lowering medication classes, and hyperglycemic episodes); (2) kidney disease progression (doubling of serum creatinine, incidence of chronic kidney disease stage 5, initiation of renal replacement therapy, and incidence of diabetic nephropathy); (3) cardiovascular outcomes (acute myocardial infarction, stroke, cardiac arrest); and (4) total mortality. From 297,967 statin users (228,509 Thiazide-statin users and 69,458 active comparators), we successfully matched 67,614 pairs. In comparison to active comparators, thiazide-statin users had increased risk of DM progression (65.6% in CCB group vs 68.1% in thiazide group; odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.09 to 1.15), decreased risk of kidney progression (16.9% in CCB group vs 16.5 in thiazide group; OR: 0.97, 95% CI: 0.94 to 0.99), decreased risk of cardiovascular outcomes (15.7% in CCB group vs 14.6% in thiazide group; OR: 0.92, 95% CI: 0.89 to 0.95), and similar risk of total mortality (19.7% in each group; OR: 1.00, 95% CI: 0.98 to 1.03). This study attempted to answer an important clinical question whether thiazide diuretics should be discontinued or substituted upon statin initiation. Our results showed that concurrent use of statin and thiazides in patients with DM was associated with DM progression but with less kidney progression and cardiovascular outcomes and no difference in mortality. Clinicians should closely monitor DM control when thiazides and statins are used concurrently.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes

Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. ClinicalTrials.gov Identifier: NCT01794143.

Hierarchical network meta-analysis models for synthesis of evidence from randomised and non-randomised studies

BackgroundWith the increased interest in the inclusion of non-randomised data in network meta-analyses (NMAs) of randomised controlled trials (RCTs), analysts need to consider the implications of the differences in study designs as such data can be prone to increased bias due to the lack of randomisation and unmeasured confounding. This study aims to explore and extend a number of NMA models that account for the differences in the study designs, assessing their impact on the effect estimates and uncertainty.MethodsBayesian random-effects meta-analytic models, including naïve pooling and hierarchical models differentiating between the study designs, were extended to allow for the treatment class effect and accounting for bias, with further extensions allowing for bias terms to vary depending on the treatment class. Models were applied to an illustrative example in type 2 diabetes; using data from a systematic review of RCTs and non-randomised studies of two classes of glucose-lowering medications: sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists.ResultsAcross all methods, the estimated mean differences in glycated haemoglobin after 24 and 52 weeks remained similar with the inclusion of observational data. The uncertainty around these estimates reduced when conducting naïve pooling, compared to NMA of RCT data alone, and remained similar when applying hierarchical model allowing for class effect. However, the uncertainty around these effect estimates increased when fitting hierarchical models allowing for the differences in study design. The impact on uncertainty varied between treatments when applying the bias adjustment models. Hierarchical models and bias adjustment models all provided a better fit in comparison to the naïve-pooling method.ConclusionsHierarchical and bias adjustment NMA models accounting for study design may be more appropriate when conducting a NMA of RCTs and observational studies. The degree of uncertainty around the effectiveness estimates varied depending on the method but use of hierarchical models accounting for the study design resulted in increased uncertainty. Inclusion of non-randomised data may, however, result in inferences that are more generalisable and the models accounting for the differences in the study design allow for more detailed and appropriate modelling of complex data, preventing overly optimistic conclusions.

Association of Medication Adherence With HbA1c Control Among American Indian Adults With Type 2 Diabetes Using Tribal Health Services.

To examine HbA1c levels and adherence to oral glucose-lowering medications and their association with future HbA1c levels among American Indian adults with type 2 diabetes (T2D) receiving medications at no cost from a tribal health care system. Tribal citizens with T2D who used Choctaw Nation Health Services Authority (CNHSA) and Pharmacies and had HbA1c data during 2017-2018 were included in this study. Medication adherence (proportion of days covered [PDC] ≥0.80) was calculated using 2017 CNHSA electronic health record data. Of the 74,000 tribal citizens living on tribal lands, 4,560 were eligible; 32% had HbA1c at or below target (≤7%), 36% were above target (>7 to ≤9%), and 32% were uncontrolled (>9%) in 2017. The percentage of patients with PDC ≥0.80 was 66% for those using biguanides, 72% for sulfonylureas, 75% for dipeptidyl peptidase 4 inhibitors, and 83% for sodium-glucose cotransporter 2 inhibitors. The proportion of patients with HbA1c at or below target increased slightly from 32% in 2017 to 42% in 2018. Higher average PDC in 2017 was associated with lower HbA1c levels in 2018 (β = -1.143; P < 0.001). Medication adherence was higher than that found in previous studies using self-report methods in American Indian populations, although a smaller proportion of patients had HbA1c at or below target relative to U.S. adults with T2D. Medication adherence was associated with improved HbA1c levels for most oral glucose-lowering medication classes. Future studies of American Indians should use both longitudinal prescription data from both electronic health records and pharmacy refills.

Remission as an Emerging Therapeutic Target in Type 2 Diabetes in the Era of New Glucose-Lowering Agents: Benefits, Challenges, and Treatment Approaches.

Type 2 diabetes mellitus (T2DM) is a progressive disease with a growing prevalence, associated with an increased risk of complications. The introduction of new classes of antidiabetic drugs into clinical practice has dramatically changed the landscape of diabetes therapy. However, despite the progress made in the pharmacotherapy of T2DM, mitigating the burden of the disease on individuals, societies and health care systems remains a challenge. Remission has recently emerged as a therapeutic target in T2DM, achievable through a wide range of interventions. Recent studies have shown that extensive lifestyle changes, such as weight reduction, bariatric surgery, and intensive glucose lowering therapy, can prompt the remission of diabetes, but some unanswered questions remain regarding its long-term effects on diabetic complications. Metabolic surgery and novel classes of glucose-lowering medications are currently the most effective interventions to induce weight loss and by extension remission in patients with diabetes; however, the ideal strategy to achieve the long-term maintenance of remission remains doubtful. In this narrative review, we discuss the available therapeutic approaches to target the remission of diabetes through personalized multimodal care, based on the latest evidence.

864-P: Glycemic Control across eGFR Categories with the Dual SGLT1 and 2 Inhibitor Sotagliflozin in SCORED

In cardiovascular (CV) outcome trials (OT) of glucose-lowering medications (GLM) , glycated hemoglobin (A1c) is typically treated according to local standard of care, with aim of glycemic equipoise between the randomized groups. However, in SGLT inhibitor CVOTs, larger A1c reductions are consistently seen in the active therapy vs. placebo (PBO) groups, since the former has access to an additional class of GLM. SCORED was a multicenter, double-blind, placebo-controlled CVOT of the dual SGLT1 and 2 inhibitor sotagliflozin (SOTA) , which may have preserved antihyperglycemic effects even in those with advanced chronic kidney disease (CKD.) We assessed the association between A1c lowering and assignment to SOTA vs. PBO in the overall trial population and across various pre-specified subgroups, including CKD categories. 10,584 type 2 diabetes (T2D) (A1c ≥7%) patients with CKD (eGFR 25-60 mL/min/1.73 m2) and increased CV risk were randomized to SOTA vs. PBO and followed for a median of 15.9 months. We previously reported that the risk for the primary composite outcome of total CV deaths and hospitalizations or urgent visits for heart failure was reduced by 26% in the SOTA group (p&amp;lt;0.001) . In the overall population, from a baseline A1c of 8.7%, the least-squares mean change in A1c was -0.60% with SOTA and -0.17% with placebo (mean difference [95% CI] = -0.42% [-0.47, -0.38]; p&amp;lt;0.0001) . Differences were larger with increasing baseline A1C: &amp;lt;8%: -0.31%; 8-&amp;lt;9%: -0.40%; and ≥9%: -0.57% (all p&amp;lt;0.0001) . The association between SOTA use and A1c lowering vs. placebo was consistent across strata of baseline eGFR, including those with CKD stage 4 (eGFR&amp;gt;45, 30-&amp;lt;45, and &amp;lt;30: -0.47%. -0.38%, and -0.31%, respectively [all p&amp;lt;0.001]) . These results were similarly consistent across age, sex, race/ethnicity, age, and BMI subgroups. In SCORED, SOTA consistently reduced A1c across all pre-specified subgroups, including patients with the lowest baseline eGFR, possibly reflecting SOTA’s dual mechanism of action. Disclosure S.E.Inzucchi: Advisory Panel; Abbott Diagnostics, ESPERION Therapeutics, Inc., vTv Therapeutics, Consultant; Merck &amp; Co., Inc., Pfizer Inc., Other Relationship; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk. J.P.Dwyer: Consultant; Akebia Therapeutics, Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Cincor, Inc, CSL Behring, FibroGen, Inc., Reata Pharmaceuticals, Inc., Sanofi, Tricida, Inc. B.M.Scirica: Consultant; Allergan, Boehringer Ingelheim International GmbH, ESPERION Therapeutics, Inc., Hanmi Pharm. Co., Ltd., Novo Nordisk, Research Support; Better Therapeutics, Eisai Co., Ltd., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc., Stock/Shareholder; Heath At Scale. C.J.Bailey: None. P.L.Banks: Employee; Lexicon Pharmaceuticals, Inc. R.Diaz: None. K.K.Ray: Consultant; Abbott, AstraZeneca, Cargene, CSL Behring, Daiichi Sankyo, Eli Lilly and Company, ESPERION Therapeutics, Inc., GlaxoSmithKline plc., Kaleido, Kowa Company, Ltd., New Amsterdam Pharma, Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Pharmaceuticals Inc., Roche Diagnostics, The Medicines Company, Research Support; Amgen Inc., Daiichi Sankyo, Regeneron Pharmaceuticals Inc., Sanofi, Speaker's Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Medscape, Novartis Pharmaceuticals Corporation, Novo Nordisk, Sanofi, Viatris Inc., Stock/Shareholder; Cargene, PEMI31. J.A.Udell: Consultant; Boehringer Ingelheim International GmbH, Novartis AG, Sanofi, Other Relationship; GlaxoSmithKline plc., Sanofi, Research Support; Amgen Inc., Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research &amp; Development, LLC. R.D.Lopes: Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, GlaxoSmithKline plc., Medtronic, Pfizer Inc., Portola Pharmaceuticals, Inc., Other Relationship; Bristol-Myers Squibb Company, Sanofi, Research Support; Medtronic, Pfizer Inc. L.A.Leiter: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi, Research Support; AstraZeneca, Bayer AG, Lexicon Pharmaceuticals, Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Servier Laboratories. P.G.Steg: Advisory Panel; AstraZeneca, Bristol-Myers Squibb Company, Board Member; Novartis AG, Consultant; Amarin Corporation, Amgen Inc., Bayer AG, Idorsia Pharmaceuticals Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., Sanofi. D.L.Bhatt: Research Support; Afimmune Limited, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi USA, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Novartis AG, Sanofi. Scored investigators: n/a. B.Pitt: Advisory Panel; Merck &amp; Co., Inc., Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Vifor Pharma Funding Sanofi/Lexicon

Association of Statin Therapy Initiation With Diabetes Progression

Statin therapy has been associated with increased insulin resistance; however, its clinical implications for diabetes control among patients with diabetes is unknown. To assess diabetes progression after initiation of statin use in patients with diabetes. This was a retrospective matched-cohort study using new-user and active-comparator designs to assess associations between statin initiation and diabetes progression in a national cohort of patients covered by the US Department of Veterans Affairs from fiscal years 2003-2015. Patients included were 30 years or older; had been diagnosed with diabetes during the study period; and were regular users of the Veterans Affairs health system, with records of demographic information, clinical encounters, vital signs, laboratory data, and medication usage. Treatment initiation with statins (statin users) or with H2-blockers or proton pump inhibitors (active comparators). Diabetes progression composite outcome comprised the following: new insulin initiation, increase in the number of glucose-lowering medication classes, incidence of 5 or more measurements of blood glucose of 200 mg/dL or greater, or a new diagnosis of ketoacidosis or uncontrolled diabetes. From the 705 774 eligible patients, we matched 83 022 pairs of statin users and active comparators; the matched cohort had a mean (SD) age of 60.1 (11.6) years; 78 712 (94.9%) were men; 1715 (2.1%) were American Indian/Pacific Islander/Alaska Native, 570 (0.8%) were Asian, 17 890 (21.5%) were Black, and 56 633 (68.2 %) were White individuals. Diabetes progression outcome occurred in 55.9% of statin users vs 48.0% of active comparators (odds ratio, 1.37; 95% CI, 1.35-1.40; P < .001). Each individual component of the composite outcome was significantly higher among statin users. Secondary analysis demonstrated a dose-response relationship with a higher intensity of low-density lipoprotein-cholesterol lowering associated with greater diabetes progression. This retrospective matched-cohort study found that statin use was associated with diabetes progression, including greater likelihood of insulin treatment initiation, significant hyperglycemia, acute glycemic complications, and an increased number of prescriptions for glucose-lowering medication classes. The risk-benefit ratio of statin use in patients with diabetes should take into consideration its metabolic effects.

Delivering joined-up care for people with type 2 diabetes: rationale, challenges and examples

Approximately 3.8 million people in the UK have type 2 diabetes mellitus (T2DM) and are, as a consequence, at risk of developing micro- and macrovascular disease. The rapid increase in T2DM prevalence places a considerable burden on secondary healthcare. New classes of glucose-lowering medications (sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists) can improve macrovascular outcomes for people with T2DM; however, these options have brought another layer of complexity to managing this disease. In combination, these factors are calling into question the suitability of the primary–secondary care healthcare model and prompting healthcare professionals to investigate alternative solutions. Bringing high-quality care to people with diabetes and meeting their complex needs requires integrated multidisciplinary expertise in the community. However, setting up such systems within the National Health Service (NHS) can be challenging. The complexities of the internal market (in NHS England), lack of training and expertise, inadequate information technology systems and resistance to change on a systemic and individual level all constitute significant barriers to establishing easy-to-access integrated care. When barriers are removed, successful integrated care systems can be established, which improve care for people with diabetes and alleviate pressure on secondary care centres.

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors in heart transplant patients with type 2 diabetes: Initial report from a cardiometabolic center of excellence

Type 2 diabetes mellitus (T2D) is a common comorbidity among patients who have undergone heart transplantation. Recently two classes of glucose-lowering medications (sodium-glucose cotransporter type-2 inhibitors [SGLT-2Is] and glucagon-like-peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes. There is a paucity of data regarding their use in immunosuppressed patients, with many studies specifically excluding this population. We retrospectively evaluated the safety and efficacy of GLP-1RAs and SGLT-2Is in patients who had undergone orthotopic heart transplant at a high-volume center. Among 21 patients, we found significant weight loss, reductions in insulin use, hemoglobin A1c, and low-density lipoprotein-cholesterol. Moreover, both SGLT-2Is and GLP-1RAs were well tolerated with no adverse events leading to discontinuation of either therapy. While larger studies of patients after solid organ transplant are needed, this small hypothesis-generating study demonstrates that SGLT-2Is and GLP-1RAs appear safe and effective therapies among patients with T2D after heart transplant.

Prescribing in Type 2 Diabetes Patients With and Without Cardiovascular Disease History: A Descriptive Analysis in the UK CPRD

PurposeSome classes of glucose-lowering medications, including sodium-glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1-receptor agonists (GLP1-RAs) have cardio-protective benefit, but it is unclear whether this influences prescribing in the United Kingdom (UK). This study aims to describe class-level prescribing in adults with type 2 diabetes mellitus (T2DM) by cardiovascular disease (CVD) history using the Clinical Practice Research Datalink (CPRD). MethodsFour cross-sections of people with T2DM aged 18–90 and registered with their general practice for >1 year on 1st January 2017 (n = 166,012), 1st January 2018 (n = 155,290), 1st January 2019 (n = 152,602) and 31st December 2019 (n = 143,373) were identified. Age-standardised proportions for class use through time were calculated separately in those with and without CVD history and by total number of medications prescribed (one, two, three, four+). An analysis by UK country was also performed. FindingsAround 31% of patients had CVD history at each cross-section. Metformin was the most common treatment (>70% of those with and without CVD had prescriptions across all treatment lines). Overall use of SGLT2is and GLP1-RAs was low, with slightly less use in patients with CVD (SGLT2i: 9.8% and 13.8% in those with and without CVD respectively; GLP1-RA: 4.3% and 4.9%, December 2019). Use of SGLT2is as part of dual therapy was low but rose throughout the study. In January 2017, estimated use was 8.0% (95% CI 6.9–9.1%) and 8.9% (8.6–9.3%) in those with and without CVD. By December 2019 this reached 18.3% (17.0–19.5%) and 21.2% (20.6–21.7%) for those with and without CVD respectively. SGLT2i use as triple therapy increased: 22.7% (21.0–24.4%) and 25.9% (25.2–26.6%) in January 2017 to 41.3% (39.5–43.0%) and 45.5% (44.7–46.3%) in December 2019. GLP1-RA use also increased, but observed usage remained lower than SGLT2 inhibitors. Insulin use remained stable throughout, with higher use observed in those with CVD (16% vs 9.7% Dec 2019). Time trends in England, Wales, Scotland and Northern Ireland were similar, although class prevalence varied. ImplicationsAlthough use of SGLT2is and GLP1-RAs has increased, overall usage remains low with slightly lower use in those with CVD history, suggesting there is opportunity to optimise use of these medicines in T2DM patients to manage CVD risk. Insulin use was substantially more prevalent in those with CVD despite no evidence of CVD benefit. Further investigation of factors influencing this finding may highlight strategies to improve patient access to the most appropriate treatments, including those with evidence of cardiovascular benefit.

Glucose-Lowering Medication Use in CKD: Analysis of US Medicare Beneficiaries Between 2007 and 2016

BackgroundInformation regarding the use of glucose-lowering medications in patients with chronic kidney disease (CKD) is limited.Study DesignRetrospective cohort study.Setting & ParticipantsMedicare 5% random sample of patients with CKD with type 2 diabetes, 2007 to 2016.PredictorsStudy year, CKD stage, low-income subsidy status, and demographic characteristics (age, sex, and race/ethnicity).OutcomesTrends in use of glucose-lowering medications.Analytical ApproachYearly cohorts of patients with CKD and type 2 diabetes were created. Descriptive statistics were used to report proportions of patients using glucose-lowering medications. To test overall trends in glucose-lowering medication classes, linear probability models with adjustment for age, sex, race/ethnicity, CKD stage, and low-income subsidy status were used.ResultsMetformin use increased significantly from 32.7% in 2007 to 48.7% in 2016. Use of newer classes of glucose-lowering medications increased significantly, including dipeptidyl peptidase 4 inhibitors (5.6%, 2007; 21.7%, 2016), glucagon-like peptide 1 receptor agonists (2.3%, 2007; 6.1%, 2016), and sodium-glucose cotransporter 2 inhibitors (0.2%, 2013; 3.3%, 2016). Newer insulin analogue use increased from 37.2% in 2007 to 46.3% in 2013 and then remained steady. Use of sulfonylureas, thiazolidinediones, older insulins (human regular and neutral protamine Hagedorn), α-glucosidase inhibitors, amylin mimetics, and meglitinides decreased significantly. Insulin was the most highly used single medication class. Insulin use was higher among low-income subsidy than among non–low-income subsidy patients. Combination therapy was less common as CKD stage increased.LimitationsPatients with CKD and type 2 diabetes and the CKD stages were identified with diagnosis codes and could not be verified through medical record review. Our results may not be generalizable to younger patients with CKD with type 2 diabetes.ConclusionsUse of metformin and newer glucose-lowering medication classes is increasing in patients with CKD with type 2 diabetes. We anticipate that percentages of patients with CKD using these newer agents will increase.

Order of discontinuation of glucose-lowering medications following bariatric surgery

AimsTo assess the order of glucose-lowering medication (GLM) discontinuation following bariatric surgery among patients taking ≥2 GLMs. MethodsPatients with diabetes mellitus taking ≥2 GLM classes who underwent bariatric surgery were identified using health claims data from the United States. The order of discontinuation was assessed in patients taking ≥2 GLM classes by comparing each GLM class to the other classes in aggregate. Descriptive statistics and Poisson regression were used to assess the order of discontinuation and changes in trends in the order of discontinuation. ResultsOverall, 12,244 of 26,651 patients with type 2 diabetes who underwent bariatric surgery were taking ≥2 GLM classes. When each GLM class was assessed separately, fewer than 50% of patients had metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, glucosidase inhibitor, or insulin discontinued first when compared to the other classes in aggregate. Between 2008 and 2014, thiazolidinediones were increasingly more likely to be the first GLM discontinued (p = 0.0432). Slightly more than 50% of patients whose GLM regimen included a sulfonylurea discontinued the sulfonylurea first despite clinical recommendations. ConclusionsFrom a population level, there was no consistent approach in the order of discontinuation of GLM classes in patients following bariatric surgery.

Trends in diabetes medications in Canada, England, Scotland and Australia: a repeated cross-sectional analysis (2012-2017)

BackgroundWe studied the uptake of new classes of glucose lowering medications, such as Dipeptidyl peptidase-4 inhibitors (DPP4s) and Sodium-glucose cotransporter 2 inhibitors (SGLT2s) amongst patients living with type 2 diabetes. We compared this in Australia, Canada, England and Scotland, and explored whether these new drugs are supplementing or replacing older classes of medications.&#x0D; Research Design and MethodsWe used primary care Electronic Medical Data on prescriptions (Canada, UK) and dispensing data (Australia) from 2012 to 2017. We included persons aged 40 years or over on at least one glucose lowering medication in each year of interest; we excluded those on insulin only. We determined proportions of patients in each nation on each class of medication, as well as on combinations of classes.&#x0D; ResultsIn 2017, data from 28,063 patients in Canada, 106,000 in Australia, 88,953 in England and 15,603 in Scotland were included. The proportion of patients on metformin increased by 3.4% in Australia (95% CI: 3.24% to 3.55%) and decreased in the other nations. Canada had the greatest decrease, at 4.7% (95% CI: -5.05% to -4.34%). Sulfonylurea use decreased in most nations, while DPP4s increased in all. By 2017, between 10.1% and 15.3% of patients were on a SGLT2 and the use of either a DPP4 or SGLT2 combined with metformin approached or exceeded the use of sulfonylureas with metformin.&#x0D; ConclusionsNewer, more expensive medications are replacing sulfonylureas and, to a lesser degree, metformin. The effects of these trends on health outcomes and overall costs should be examined.

Trends in diabetes medication use in Australia, Canada, England, and Scotland: a repeated cross-sectional analysis in primary care.

BackgroundSeveral new classes of glucose-lowering medications have been introduced in the past two decades. Some, such as sodium-glucose cotransporter 2 inhibitors (SGLT2s), have evidence of improved cardiovascular outcomes, while others, such as dipeptidyl peptidase-4 inhibitors (DPP4s), do not. It is therefore important to identify their uptake in order to find ways to support the use of more effective treatments.AimTo analyse the uptake of these new classes among patients with type 2 diabetes.Design and settingThis was a retrospective repeated cross-sectional analysis in primary care. Rates of medication uptake in Australia, Canada, England, and Scotland were compared.MethodPrimary care Electronic Medical Data on prescriptions (Canada, UK) and dispensing data (Australia) from 2012 to 2017 were used. Individuals aged ≥40 years on at least one glucose-lowering drug class in each year of interest were included, excluding those on insulin only. Proportions of patients in each nation, for each year, on each class of medication, and on combinations of classes were determined.ResultsData from 238 619 patients were included in 2017. The proportion of patients on sulfonylureas (SUs) decreased in three out of four nations, while metformin decreased in Canada. Use of combinations of metformin and new drug classes increased in all nations, replacing combinations involving SUs. In 2017, more patients were on DPP4s (between 19.1% and 27.6%) than on SGLT2s (between 10.1% and 15.3%).ConclusionNew drugs are displacing SUs. However, despite evidence of better outcomes, the adoption of SGLT2s lagged behind DPP4s.

Long-Acting Injectable GLP-1 Receptor Agonists for the Treatment of Adults with Type 2 Diabetes: Perspectives from Clinical Practice.

Randomized controlled trials (RCTs) have consistently shown glycemic and extra-glycemic benefits of long-acting injectable glucagon-like-peptide-1 receptor agonists (GLP-1RAs, liraglutide, albiglutide, exenatide once-weekly, dulaglutide, and semaglutide) in terms of reduction in the rates of cardiovascular events and mortality among patients with type 2 diabetes. Recently, the analyses of large datasets collecting routinely-accumulated data from clinical practice (ie, real-world studies, RWS) have provided new opportunities to complement the information obtained from RCTs. In this narrative review, we addressed clinically relevant questions that might be answered by well-conducted RWS: are subjects treated with GLP-1RAs in the “real-world” similar to those included in RCTs? Is the performance of GLP-1RA observed in the RWS (effectiveness) similar to that described in RCTs (efficacy)? Is the effectiveness similar in population of patients generally under-represented in RCTs? Are the cardiovascular benefits of GLP-1RAs confirmed in RWS? We also describe a few comparisons currently un-explored by specific RCTs, such as direct comparison between different administration strategies (eg, fixed- versus flexible-combination with basal-insulin) or between GLP-1RAs versus dipeptidyl-peptidase-4 inhibitor (DDP4i) or versus sodium/glucose cotransporter-2 inhibitors (SGLT-2i) on hard cardio-renal outcomes. Altogether, RWS provide highly informative information on treatment with GLP-1RAs. On the one side, RWS showed different clinical characteristics between subjects enrolled in RCTs versus those attending real-world clinics and receiving a GLP-1RA. On the other hand, RWS showed that GLP-1RA effectiveness is overall consistent in subgroups of patients less represented in RCTs. In addition, RWS allowed the identification of modifiable factors (eg, titration or adherence) that might guide physicians towards better GLP-1RAs use. Finally, multiple RWS reported better cardio-renal outcomes with GLP-1RAs than with DPP-4i, while initial findings from RWS described a weaker cardiovascular protection compared to SGLT-2i. Therefore, there is the need for further RWS and RCTs comparing these different classes of glucose lowering medications.

1112-P: Does Background T2D Therapy Modify the Benefits of Dapagliflozin in Heart Failure? Analysis of the DAPA-HF Trial

Background: At present, dapagliflozin (dapa) is typically used as a 2nd-line glucose-lowering medication (GLM) in T2D, often added to metformin. In DAPA-HF, dapa improved clinical outcomes vs. placebo in patients (pts) with HF and reduced ejection fraction (HFrEF), with or without T2D. We examined whether these benefits varied by background GLM in the T2D cohort, including in drug naïve pts and in pts not on metformin. Methods: The primary outcome was a composite of worsening HF (hospitalization or urgent visit requiring IV therapy) or cardiovascular death. The effect of dapa vs. placebo was examined using Cox proportional hazards models. Results: Of the 2139 T2D pts, 1596 (75%) were treated with GLM: metformin (48%), insulin (25%), sulfonylurea (21%), DPP-4 inhibitor (14%) and GLP-1 agonist (1%). Drug-naïve pts had a lower A1c (6.9%±1.2 vs. 7.5%±1.6; P&amp;lt;0.001) and shorter T2D duration (median 5.5 vs. 103 months; P&amp;lt;0.001). Those not using metformin had a lower eGFR (61 vs. 66; P&amp;lt;0.001). The effect of dapa on the primary outcome was consistent in the drug-naïve vs. pts receiving GLM (HR 0.86 [95%CI 0.60-1.23] vs. 0.72 [0.58-0.88]; P-interaction=0.39) and across GLM classes, including those using vs. not using metformin (HR 0.67 [0.51-0.88] vs. 0.81 [0.64-1.03]; P-interaction=0.30). Conclusion: In DAPA-HF, dapa improved outcomes irrespective of use/no use of GLM or by type of GLM used in pts with T2D and HFrEF. Disclosure K. Docherty: Speaker’s Bureau; Self; Eli Lilly and Company. Other Relationship; Self; AstraZeneca. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck &amp; Co., Inc., vTv Therapeutics. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. L. Kober: Speaker’s Bureau; Self; AstraZeneca, Novartis AG. Other Relationship; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. F. Martinez: Board Member; Self; AstraZeneca, Novartis Pharmaceuticals Corporation. O. Bengtsson: Employee; Self; AstraZeneca. D.L. DeMets: Consultant; Self; Actelion Pharmaceuticals US, Inc., AstraZeneca, Boston Scientific, Bristol-Myers Squibb, DalCor Pharmaceuticals, Intercept Pharmaceuticals, Inc., Medtronic. M. Sjöstrand: Employee; Self; AstraZeneca. M.S. Sabatine: Consultant; Self; Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor Pharmaceuticals, Dyrnamix Inc., Esperion Therapeutics, Inc., IFM Therapeutics, Intarcia Therapeutics, Ionis Pharmaceuticals, Inc., Medicines Company, MedImmune, Merck &amp; Co., Inc. Research Support; Self; Amgen, AstraZeneca, Bayer U.S., Daiichi Sankyo, Eisai Inc., Intarcia Therapeutics, Janssen Research and Development, Medicines Company, MedImmune, Merck &amp; Co., Inc., Novartis AG, Pfizer Inc., Quark Pharmaceuticals. S. Solomon: Consultant; Self; AstraZeneca, Theracos, Inc. Research Support; Self; AstraZeneca, Theracos, Inc. P. Jhund: Advisory Panel; Self; Cytokinetics Inc. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Novartis AG. Other Relationship; Self; AstraZeneca. J.J. McMurray: Other Relationship; Self; AbbVie Inc., Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Bristol-Myers Squibb, Cardurion, GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Theracos, Inc.

The effect of various classes of glucose-lowering medications on the blood vessel elasticity in patients with type 2 diabetes

Aim. To study the effect of various classes of glucose-lowering agents (dipeptidyl peptidase-4 (DPP-4) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors) on the vascular stiffness in patients with type 2 diabetes (T2D) and high cardiovascular risk.Material and methods. The open-label, prospective 24-week study included 120 patients with T2D and high cardiovascular risk. We evaluated the effect of modern glucose-lowering medications, empagliflozin at a dose of 25 mg/day (SGLT-2 inhibitor) and sitagliptin at a dose of 100 mg/day (DPP-4 inhibitor), on vascular elasticity, central hemodynamic and laboratory parameters.Results. After 24-week therapy, the target glycated hemoglobin level reached 71% and 80% of patients in the sitagliptin and empagliflozin groups, respectively. In both groups, vascular stiffness and central hemodynamic parameters were improved. However, significant changes were recorded only in the empagliflozin (carotid-femoral pulse wave velocity decreased by 14,4%, augmentation index — by 6%, central pulse pressure — by 7,8%) (p&lt;0,05). Use of sitagliptin was associated with significant improvements in the lipid profile (total cholesterol decreased by 9,5%, triglycerides — by 21%, low density lipoproteins — by 15,1%; high density lipoproteins increased by 15,7%) (p&lt;0,05). In the empagliflozin group, anthropometric parameters were improved (body mass index decreased by 9,1%, waist circumference — by 4,1%) (p&lt;0,05). Patients in both groups had a significant decrease in HOMA-IR index and highly sensitive C-reactive protein: by 34% and 51,6% in the empagliflozin group and by 31,8% and 22,1% in the sitagliptin group, respectively (p&lt;0,05).Conclusion. The use of empagliflozin is more associated with arterial stiffness decrease in T2D patients with high cardiovascular risk compared with sitagliptin.

Glucokinase Activators for Type 2 Diabetes: Challenges and Future Developments.

Increased hepatic glucose output, the primary liver dysregulation associated with Type 2 diabetes mellitus (T2DM), is not directly or effectively targeted by the currently available classes of glucose-lowering medications except metformin. This unmet need might be addressed through activation of a specific enzyme-member of the hexokinase family, namely glucokinase (GK). GK serves as a "glucose-sensor" or "glucose receptor" in pancreatic cells, eliciting glucose-stimulated insulin secretion, and as glucose "gate-keeper" in hepatocytes, promoting hepatic glucose uptake and glycogen synthesis and storage. GK activation by small molecules present an alternative approach to restore/improve glycaemic control in patients with T2DM. GK activators (GKAs)may increase insulin secretionfromthe pancreas and promoteglycogen synthesisin the liver, and hence reduce hepatic glucose output. Despite several setbacks in their development, interest in the GKA class has been renewed, particularly since the introduction of a novel, dual-acting full GKA, dorzagliatin, and anovel hepatoselective molecule, TTP399. In this article we provide an overview of the role, efficacy, safety and future developments of GKAs in the management of T2DM.

Metformin and cardiorenal outcomes in diabetes: A reappraisal.

The guidance issued to the pharmaceutical industry by the US Food and Drug Administration in 2008 has led to the publication of a series of randomized, controlled cardiovascular outcomes trials with newer therapeutic classes of glucose‐lowering medications. Several of these trials, which evaluated the newer therapeutic classes of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists, have reported a reduced incidence of major adverse cardiovascular and/or renal outcomes, usually relative to placebo and standard of care. Metformin was the first glucose‐lowering agent reported to improve cardiovascular outcomes in the UK Prospective Diabetes Study (UKPDS) and thus became the foundation of standard care. However, as this clinical trial reported more than 20 years ago, differences from current standards of trial design and evaluation complicate comparison of the cardiovascular profiles of older and newer agents. Our article revisits the evidence for cardiovascular protection with metformin and reviews its effects on the kidney.

Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Classes of Glucose-Lowering Medications on Renal Outcome in Type 2 Diabetes

ObjectiveTo assess whether sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy is associated with a favorable renal prognosis for patients with type 2 diabetes melllitus (T2DM) outside the clinical trials setting. Participants and MethodsThis retrospective study analyzed routinely collected health care records of ∼160 medical institutions in Japan from April 1, 2014, to December 31, 2017/2018 (varying at the institutional level). Adults with T2DM but without end-stage renal disease who initiated either SGLT2i or other classes of glucose-lowering medications (o-GLM) were matched using propensity score. The primary outcome was the time course of estimated glomerular filtration rate (eGFR) displayed in spline curve. The composite of renal worsening (>40% decline in eGFR) and the development of eGFR<30 mL/1.73 m2 per minute was evaluated as a secondary outcome. Two sensitivity analyses were conducted to determine the robustness of results. ResultsWe compared a matched cohort of 1433 SGLT2i users and 2739 o-GLM users (mean age: 61 years). The eGFR declined over time in both groups during the observation period (median: 17 months; maximum: 54 months), with a slower eGFR slope observed in SGLT2i users. This slower decline was consistently observed across different SGLT2i agents and different baseline eGFR groups. The cumulative incidence of composite renal endpoints was lower in the SGLT2i group with a hazard ratio of 0.70 (95% CI, 0.50-0.98; P=.039). Those findings were consistent in sensitivity analyses limited to the period adherent to the initial drug regimen and with a different approach for propensity score calculation. ConclusionIn a matched cohort of T2DM patients, SGLT2i use was associated with preserved renal function relative to o-GLM use over 2 to 4 years.