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Aim: To demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups., Methods: PubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years)., Results: For SGLT-2is, five CVOTs (46,969 patients, 45-50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85-0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73-0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79-0.93]) with no difference in subgroups <65 or ≥65 years. For GLP-1RAs, nine CVOTs (n = 64,236, 34-75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83-0.95]), stroke (RR; 0.86 [CI, 0.76-0.97]) and ACM (RR; 0.90 [CI, 0.83-0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years. Four CVOTs (n = 33,063; 35-58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups., Conclusion: The overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals., Competing Interests: Declaration of competing interest REP reports speaker fees from Merck and Novo Nordisk; consulting fees from Bayer AG, Endogenex, Inc., Gasherbrum Bio, Inc., Hengrui (USA) Ltd., Intas Pharmaceuticals, Inc., Lilly, Novo Nordisk, Pfizer, Rivus Pharmaceuticals Inc., and Sun Pharmaceutical Industries; and grants from Dompe and Novo Nordisk. All funds are paid directly to Dr. Pratley's employer, AdventHealth, a nonprofit organization that supports education and research. TKT reports consulting fees from Novo Nordisk and Lilly, research support from Novo Nordisk and Bayer. She is on the speaker bureau for Bayer and Lilly. CTR received research grant through institution from Anthos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis; Honoraria for scientific advisory boards and consulting fees from Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer. CTR and KI are members of the TIMI Study Group, which has received institutional research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc., AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc., Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Softcell Medical Limited, The Medicines Company, Zora Biosciences. All other authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events., Methods: TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed., Results: After re-adjudication of potential HHF events in the intent-to-treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person-years) and 239 patients in the placebo arm (1.13/100 person-years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78-1.13, p = .49). Concordance between the outcome of the original adjudication and the re-adjudication for HHF events was 82.7%. The meta-analysis of CV outcomes trials with DPP-4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83-1.39), with moderate heterogeneity (p = .45, I 2  = 62.07%)., Conclusion: The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) injected periodically have been shown to not increase and, for some members of this class, decrease the risk of cardiovascular events. The cardiovascular safety of delivering a continuous subcutaneous infusion of the GLP-1RA exenatide (ITCA 650) is unknown. Here, we randomly assigned patients with type 2 diabetes with, or at risk for, atherosclerotic cardiovascular disease (ASCVD) to receive ITCA 650 or placebo to assess cardiovascular safety in a pre-approval trial ( NCT01455896 ). The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina. On the basis of 2008 guidance from the US Food and Drug Administration, a non-inferiority margin of 1.8 for the upper bound of the 95% confidence interval (CI) of the hazard ratio (HR) was used. We randomized 4,156 patients (2,075 assigned to receive ITCA 650 and 2,081 assigned to receive placebo) who were followed for a median of 16 months. The primary outcome occurred in 4.6% (95/2,075) of patients in the ITCA 650 group and 3.8% (79/2,081) of patients in the placebo group, meeting the pre-specified non-inferiority criterion (HR = 1.21, 95% CI, 0.90-1.63, P non-inferiority  = 0.004). Serious adverse events were similar between the two groups. Adverse events were more frequent in the ITCA 650 group (72%, 1,491/2,074) than in the placebo group (63.9%, 1,325/2,070), mainly due to an increase in gastrointestinal events and disorders while on ITCA 650. In patients with type 2 diabetes with, or at risk for, ASCVD, ITCA 650 was non-inferior to placebo. A larger and longer-duration cardiovascular outcomes trial is needed to define more precisely the cardiovascular effects of ITCA 650 in this population., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown., Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR)., Design, Setting, and Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018., Interventions: Dapagliflozin vs placebo., Main Outcomes and Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF., Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher., Conclusions and Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria., Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.

Background: Metformin is first-line therapy for type 2 diabetes mellitus, although its effects on the cardiovascular system are unproved., Methods: In this post hoc analysis, patients in SAVOR-TIMI 53 (Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus) with baseline biomarker samples (n=12 156) were classified as ever versus never taking metformin during the trial period. Associations between metformin exposure and outcomes were estimated with inverse probability of treatment weighting Cox modeling for the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke, as well as cardiovascular death and all-cause mortality, with biomarkers included as covariates. Additional sensitivity analyses included propensity score matching and Cox multivariable models., Results: Of the 12 156 patients with baseline biomarker samples, 8971 (74%) had metformin exposure, 1611 (13%) had prior heart failure, and 1332 (11%) had at least moderate chronic kidney disease (estimated glomerular filtration rate ≤45 mL·min -1 ·1.73 m -2 ). Metformin use was associated with no difference in risk for the composite end point (hazard ratio for inverse probability of treatment weighting, 0.92 [95% CI, 0.76-1.11]) but lower risk of all-cause mortality (hazard ratio for inverse probability of treatment weighting, 0.75 [95% CI, 0.59-0.95]). There was no significant relationship between metformin use and these end points in patients with prior heart failure or moderate to severe chronic kidney disease., Conclusions: In a cohort of 12 156 patients with type 2 diabetes mellitus and high cardiovascular risk, metformin use was associated with lower rates of all-cause mortality, including after adjustment for clinical variables and biomarkers, but not lower rates of the composite end point of cardiovascular death, myocardial infarction, or ischemic stroke. This association was most apparent in patients without prior heart failure or moderate to severe chronic kidney disease., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01107886.

Background: Cardiac and renal diseases commonly occur with bidirectional interactions. We hypothesized that cardiac and inflammatory biomarkers may assist in identification of patients with type 2 diabetes mellitus (T2DM) at high risk of worsening renal function., Methods: In this exploratory analysis from SAVOR-TIMI 53, concentrations of high-sensitivity cardiac troponin T (hs-TnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP) were measured in baseline serum samples of 12310 patients. The primary end point for this analysis was a ≥40% decrease in estimated glomerular filtration rate (eGFR) at end of treatment (EOT) at a median of 2.1 years. The relationships between biomarkers and the end point were modeled using adjusted logistic and Cox regression., Results: After multivariable adjustment including baseline renal function, each biomarker was independently associated with an increased risk of ≥40% decrease in eGFR at EOT [Quartile (Q) Q4 vs Q1: hs-TnT adjusted odds ratio (OR), 5.63 (3.49-9.10); NT-proBNP adjusted OR, 3.53 (2.29-5.45); hs-CRP adjusted OR, 1.84 (95% CI, 1.27-2.68); all P values ≤0.001]. Furthermore, each biomarker was independently associated with higher risk of worsening of urinary albumin-to-creatinine ratio (UACR) category (all P values ≤0.002). Sensitivity analyses in patients without heart failure and eGFR >60 mL/min provided similar results. In an adjusted multimarker model, hs-TnT and NT-proBNP remained significantly associated with both renal outcomes (all P values <0.01)., Conclusions: hs-TnT, NT-proBNP, and hs-CRP were each associated with worsening of renal function [reduction in eGFR (≥40%) and deterioration in UACR class] in high-risk patients with T2DM. Patients with high cardiac or inflammatory biomarkers should be treated not only for their risk of cardiovascular outcomes but also followed for renal deterioration., (© 2019 American Association for Clinical Chemistry.)

Background: Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined., Methods: We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease., Results: In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001)., Conclusions: In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.

Background: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined., Methods: We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function., Findings: We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline., Interpretation: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure., Funding: None., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

We sought to assess the prevalence of polyvascular disease in patients with type 2 diabetes mellitus (T2DM) and its impact on ischemic events. Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53, a large contemporary, randomized trial, evaluated the effect of saxagliptin versus placebo in 16,492 patients with T2DM and a history of or at risk for cardiovascular (CV) events. Polyvascular disease was defined as a history of clinical events involving 2 or more vascular beds (coronary, peripheral, or cerebrovascular system) at the time of randomization. The primary composite endpoint of CV death, myocardial infarction, or ischemic stroke was compared according to the number of diseased arterial beds. At the time of randomization, 3,667 (22.2%) patients had risk factors for CV events; 11,423 (69.3%) had established 1 arterial bed disease; 1,298 (7.9%) had 2 bed disease; and 104 (0.6%) had 3 bed disease. Compared with diabetic patients with no established atherosclerosis, the adjusted hazard ratio for the composite primary end point in 1, 2, or 3 diseased beds was 1.95, 3.54, and 4.64, respectively (trend p < 0.0001). The adjusted risk for overall mortality increased in a similar stepwise fashion from 1.47 to 2.33 to 3.12, respectively (trend p = 0.0001) with each additional diseased arterial territory. In conclusion, in patients with confirmed atherosclerosis enrolled in SAVOR-TIMI 53, 11% had polyvascular disease; and compared with diabetic patients with single bed disease, the risk of ischemic events and overall mortality was substantially higher in patients with T2DM and polyvascular disease., (Copyright © 2018. Published by Elsevier Inc.)

Importance: An elevated level of urinary albumin to creatinine ratio (UACR) is a marker of renal dysfunction and predictor of kidney failure/death in patients with type 2 diabetes. The prognostic use of UACR in established cardiac biomarkers is not well described., Objective: To evaluate whether UACR offers incremental prognostic benefit beyond risk factors and established plasma cardiovascular biomarkers., Design, Setting, and Participants: The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 study was performed from May 2010 to May 2013 and evaluated the safety of saxagliptin vs placebo in patients with type 2 diabetes with overt cardiovascular disease or multiple risk factors. Median follow-up was 2.1 years (interquartile range, 1.8-2.3 years)., Interventions: Patients were randomized to saxagliptin vs placebo plus standard care., Main Outcomes and Measures: Baseline UACR was measured in 15 760 patients (95.6% of the trial population) and categorized into thresholds., Results: Of 15 760 patients, 5205 were female (33.0%). The distribution of UARC categories were: 5805 patients (36.8%) less than 10 mg/g, 3891 patients (24.7%) at 10 to 30 mg/g, 4426 patients (28.1%) at 30 to 300 mg/g, and 1638 patients (10.4%) at more than 300 mg/g. When evaluated without cardiac biomarkers, there was a stepwise increase with each higher UACR category in the incidence of the primary composite end point (cardiovascular death, myocardial infarction, or ischemic stroke) (3.9%, 6.9%, 9.2%, and 14.3%); cardiovascular death (1.4%, 2.6%, 4.1%, and 6.9%); and hospitalization for heart failure (1.5%, 2.5%, 4.0%, and 8.3%) (adjusted P < .001 for trend). The net reclassification improvement at the event rate for each end point was 0.081 (95% CI, 0.025 to 0.161), 0.129 (95% CI, 0.029 to 0.202), and 0.056 (95% CI, -0.005 to 0.141), respectively. The stepwise increased cardiovascular risk associated with a UACR of more than 10 mg/g was also present within each chronic kidney disease category. The UACR was associated with outcomes after including cardiac biomarkers. However, the improvement in discrimination and reclassification was attenuated; net reclassification improvement at the event rate was 0.022 (95% CI, -0.022 to 0.067), -0.008 (-0.034 to 0.053), and 0.043 (-0.030 to 0.052) for the primary end point, cardiovascular death, and hospitalization for heart failure, respectively., Conclusions and Relevance: In patients with type 2 diabetes, UACR was independently associated with increased risk for a spectrum of adverse cardiovascular outcomes. However, the incremental cardiovascular prognostic value of UACR was minimal when evaluated together with contemporary cardiac biomarkers., Trial Registration: clinicaltrials.gov Identifier: NCT01107886.

Hypoglycaemia is a well-known risk associated with the use of sulphonylureas and insulin, often limiting achievement of glycaemic goals. Recognizing the precipitants and recurrence patterns of hypoglycaemic events, particularly major events, is therefore clinically important. The SAVOR-TIMI-53 trial was a cardiovascular outcome study of 16 492 patients allocated to saxagliptin vs placebo added to conventional care for a median of 2.1 years. Hypoglycaemic events were a prespecified outcome in the study and were defined as a symptomatic episode that recovered with carbohydrates or any recorded blood glucose <3.0 mmol/l (<54 mg/dL). A major event was defined as one that required third-party assistance. Analysis of the features of the first hypoglycaemic event for each patient showed that a precipitant for the event was recognized by fewer than half of the patients, with the precipitant most often being a missed meal. In 40% of patients reporting major hypoglycaemic events, no precipitating factor was recognized, and in >60%, no previous hypoglycaemic event was reported during the timespan of the study, underscoring the lack of predictability of such an event., (© 2017 John Wiley & Sons Ltd.)

Objective: Dipeptidyl peptidase 4 inhibitors may have a protective effect in diabetic nephropathy., Research Design and Methods: We studied renal outcomes of 16,492 patients with type 2 diabetes, randomized to saxagliptin versus placebo and followed for a median of 2.1 years in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial., Results: At baseline, 9,696 (58.8%) subjects had normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g), 4,426 (26.8%) had microalbuminuria (ACR 30-300 mg/g), and 1,638 (9.9%) had macroalbuminuria (ACR >300 mg/g). Treatment with saxagliptin was associated with improvement in and/or less deterioration in ACR categories from baseline to end of trial (EOT) (P = 0.021, P < 0.001, and P = 0.049 for individuals with baseline normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). At 2 years, the difference in mean ACR change between saxagliptin and placebo arms was -19.3 mg/g (P = 0.033) for estimated glomerular filtration rate (eGFR) >50 mL/min/body surface area per 1.73 m 2 (BSA), -105 mg/g (P = 0.011) for 50 ≥ eGFR ≥ 30 mL/min/BSA, and -245.2 mg/g (P = 0.086) for eGFR <30 mL/min/BSA. Analyzing ACR as a continuous variable showed reduction in ACR with saxagliptin (1 year, P < 0.0001; 2 years, P = 0.0143; and EOT, P = 0.0158). The change in ACR did not correlate with that in HbA 1c (r = 0.041, 0.052, and 0.036; 1 year, 2 years, and EOT, respectively). The change in eGFR was similar in the saxagliptin and placebo groups. Safety renal outcomes, including doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar as well., Conclusions: Treatment with saxagliptin improved ACR, even in the normoalbuminuric range, without affecting eGFR. The beneficial effect of saxagliptin on albuminuria could not be explained by its effect on glycemic control., (© 2017 by the American Diabetes Association.)

Objective: The glycemic management of patients with type 2 diabetes mellitus (T2DM) and renal impairment is challenging, with few treatment options. We investigated the effect of saxagliptin in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)-Thrombolysis in Myocardial Infarction (TIMI) 53 trial according to baseline renal function., Research Design and Methods: Patients with T2DM at risk for cardiovascular events were stratified as having normal or mildly impaired renal function (estimated glomerular filtration rate [eGFR] >50 mL/min/1.73 m(2); n = 13,916), moderate renal impairment (eGFR 30-50 mL/min/1.73 m(2); n = 2,240), or severe renal impairment (eGFR <30 mL/min/1.73 m(2); n = 336) and randomized to receive saxagliptin or placebo. The primary end point was cardiovascular death, myocardial infarction, or ischemic stroke., Results: After a median duration of 2 years, saxagliptin neither increased nor decreased the risk of the primary and secondary composite end points compared with placebo, irrespective of renal function (all P for interactions ≥ 0.19). Overall, the risk of hospitalization for heart failure among the three eGFR groups of patients was 2.2% (referent), 7.4% (adjusted hazard ratio [HR] 2.38 [95% CI 1.95-2.91], P < 0.001), and 13.0% (adjusted HR 4.59 [95% CI 3.28-6.28], P < 0.001), respectively. The relative risk of hospitalization for heart failure with saxagliptin was similar (P for interaction = 0.43) in patients with eGFR >50 mL/min/1.73 m(2) (HR 1.23 [95% CI 0.99-1.55]), eGFR 30-50 mL/min/1.73 m(2) (HR 1.46 [95% CI 1.07-2.00]), and in patients with eGFR <30 (HR 0.94 [95% CI 0.52-1.71]). Patients with renal impairment achieved reductions in microalbuminuria with saxagliptin (P = 0.041) that were similar to those of the overall trial population., Conclusions: Saxagliptin did not affect the risk of ischemic cardiovascular events, increased the risk of heart failure hospitalization, and reduced progressive albuminuria, irrespective of baseline renal function., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: Diabetes mellitus and heart failure frequently coexist. However, few diabetes mellitus trials have prospectively evaluated and adjudicated heart failure as an end point., Methods and Results: A total of 16 492 patients with type 2 diabetes mellitus and a history of, or at risk of, cardiovascular events were randomized to saxagliptin or placebo (mean follow-up, 2.1 years). The primary end point was the composite of cardiovascular death, myocardial infarction, or ischemic stroke. Hospitalization for heart failure was a predefined component of the secondary end point. Baseline N-terminal pro B-type natriuretic peptide was measured in 12 301 patients. More patients treated with saxagliptin (289, 3.5%) were hospitalized for heart failure compared with placebo (228, 2.8%; hazard ratio, 1.27; 95% confidence intercal, 1.07-1.51; P=0.007). Corresponding rates at 12 months were 1.9% versus 1.3% (hazard ratio, 1.46; 95% confidence interval, 1.15-1.88; P=0.002), with no significant difference thereafter (time-varying interaction, P=0.017). Subjects at greatest risk of hospitalization for heart failure had previous heart failure, an estimated glomerular filtration rate ≤60 mL/min, or elevated baseline levels of N-terminal pro B-type natriuretic peptide. There was no evidence of heterogeneity between N-terminal pro B-type natriuretic peptide and saxagliptin (P for interaction=0.46), although the absolute risk excess for heart failure with saxagliptin was greatest in the highest N-terminal pro B-type natriuretic peptide quartile (2.1%). Even in patients at high risk of hospitalization for heart failure, the risk of the primary and secondary end points were similar between treatment groups., Conclusions: In the context of balanced primary and secondary end points, saxagliptin treatment was associated with an increased risk or hospitalization for heart failure. This increase in risk was highest among patients with elevated levels of natriuretic peptides, previous heart failure, or chronic kidney disease., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT01107886., (© 2014 American Heart Association, Inc.)

Objective: To determine the incidence of pancreatitis and pancreatic cancer in the SAVOR-TIMI 53 trial., Research Design and Methods: A total of 16,492 type 2 diabetic patients ≥40 years old with established cardiovascular (CV) disease or CV risk factors were randomized to saxagliptin or placebo and followed for 2.1 years. Outcome measures were investigator reported with blinded expert adjudication of total pancreatitis (acute and chronic) and reported cases of pancreatic cancer., Results: Trial investigators reported 35 events of pancreatitis in each treatment arm in 63 patients (33 [0.40%] in the saxagliptin arm and 30 [0.37%] in control arm), with a hazard ratio (HR) of 1.09 (95% CI 0.66-1.79, P = 0.80). Adjudication confirmed pancreatitis in 24 patients (26 events) in the saxagliptin arm (0.29%) and 21 patients (25 events) in placebo arm (0.26%), with an HR of 1.13 (0.63-2.06, P = 0.77). Cases of definite acute pancreatitis were confirmed in 17 (0.2%) vs. 9 (0.1%) (HR 1.88 [0.86-4.41], P = 0.17), definite plus possible pancreatitis in 22 vs. 16 (HR 1.36 [0.72-2.64], P = 0.42), and chronic pancreatitis in 2 vs. 6 (HR 0.33 [0.05-1.44], P = 0.18) in the saxagliptin and placebo arms, respectively. No differences in time to event onset, concomitant risk factors for pancreatitis, investigator-reported causality from study medication or disease severity, and outcome were found between treatment arms. The investigators reported 5 and 12 cases of pancreatic cancer in the saxagliptin and placebo arms, respectively (HR 0.42 [0.13-1.12], P = 0.09)., Conclusions: In the SAVOR-TIMI 53 trial, within 2.1 years of follow-up, risk for pancreatitis in type 2 diabetic patients treated with saxagliptin was low and apparently similar to placebo, with no sign of increased risk for pancreatic cancer. Further studies are needed to completely resolve the pancreatic safety issues with incretin-based therapy., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)