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Objective: To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL)., Research Design and Methods: Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria)., Results: EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m 2 [95% CI -0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70-1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74-0.98]). Retinopathy rates did not differ by treatment group or in the HbA 1c -lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m 2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m 2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58-0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85-1.38]; P for interaction = 0.031)., Conclusions: EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m 2 in analyses unadjusted for multiplicity., (© 2019 by the American Diabetes Association.)

Objective: Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in exenatide-treated and placebo-administered participants and MTC incidence in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring., Research Design and Methods: EXSCEL participants were randomized 1:1 to once-weekly exenatide 2 mg or placebo. Serum calcitonin was measured at baseline (with trial medication discontinued if >40 ng/L) and annually thereafter (with trial medication discontinued if ≥50 ng/L). Median calcitonin concentrations were calculated at each time point, and thyroid malignancies were collected prospectively. Data regarding follow-up after an elevated calcitonin were collected retrospectively., Results: At baseline, 52 (30 exenatide and 22 placebo) participants had calcitonin >40 ng/L, and during follow-up an additional 23 participants (15 exenatide and 8 placebo) had calcitonin ≥50 ng/L in the intention-to-treat population. Median calcitonin concentrations were similar between treatment groups at baseline with no increase over time. Confirmed MTC occurred in three participants (2 exenatide and 1 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, and 655 ng/L)., Conclusions: During a median 3.2 years' follow-up, no change in serum calcitonin was seen with exenatide therapy. The three confirmed cases of MTC all occurred in participants with markedly elevated baseline calcitonin levels, measured prior to trial medication administration. Regular calcitonin monitoring identified no additional cases of MTC, suggesting no benefit of routine calcitonin monitoring during exenatide treatment., (© 2019 by the American Diabetes Association.)

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: To analyze the impact of adding saxagliptin versus placebo on the risk for hypoglycemia and to identify predictors of any and major hypoglycemia in patients with type 2 diabetes included in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) study., Research Design and Methods: Patients with type 2 diabetes (n = 16,492) were randomized to saxagliptin or placebo and followed for a median of 2.1 years. Associations between any hypoglycemia (symptomatic or glucose measurement <54 mg/dL) or major hypoglycemia (requiring extended assistance) and patient characteristics overall and by treatment allocation were studied., Results: At least one hypoglycemic event was reported in 16.6% of patients, and 1.9% reported at least one major event. Patients allocated to saxagliptin versus placebo experienced higher rates of any (hazard ratio [HR] 1.16 [95% CI 1.08, 1.25]; P < 0.001) or major (HR 1.26 [1.01, 1.58]; P = 0.038) hypoglycemia. Hypoglycemia rates (any or major) were increased with saxagliptin in patients taking sulfonylureas (SURs) but not in those taking insulin. Rates were increased with saxagliptin in those with baseline HbA1c ≤7.0% and not in those with baseline HbA1c >7.0%. Multivariate analysis of the overall population revealed that independent predictors of any hypoglycemia were as follows: allocation to saxagliptin, long duration of diabetes, increased updated HbA1c, macroalbuminuria, moderate renal failure, SUR use, and insulin use. Predictors of major hypoglycemia were allocation to saxagliptin, advanced age, black race, reduced BMI, long duration of diabetes, declining renal function, microalbuminuria, and use of short-acting insulin. Among SURs, glibenclamide was associated with increased risk of major but not any hypoglycemia., Conclusions: The identification of patients at risk for hypoglycemia can guide physicians to better tailor antidiabetic therapy., (© 2016 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.)

Objective: The objective of this study was to assess the efficacy and safety of triple therapy with saxagliptin add-on versus placebo add-on to dapagliflozin plus metformin in adults with type 2 diabetes., Research Design and Methods: Patients on stable metformin (≥1,500 mg/day) for ≥8 weeks with glycated hemoglobin (HbA1c) 8.0-11.5% (64-102 mmol/mol) at screening received open-label dapagliflozin (10 mg/day) plus metformin immediate release (IR) for 16 weeks. Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were then randomized to receive placebo (n = 153) or saxagliptin 5 mg/day (n = 162) in addition to background dapagliflozin plus metformin IR. The primary efficacy end point was change in HbA1c from baseline to week 24., Results: There was a significantly greater reduction in HbA1c at 24 weeks with saxagliptin add-on (-0.51% [-5.6 mmol/mol]) versus placebo (-0.16% [-1.7 mmol/mol]) add-on to dapagliflozin plus metformin (difference, -0.35% [95% CI -0.52% to -0.18%] and -3.8 [-5.7 to -2.0 mmol/mol], respectively; P < 0.0001). Reductions in fasting plasma glucose and 2-h postprandial glucose were similar between treatment arms. A larger proportion of patients achieved HbA1c <7% (53 mmol/mol) with saxagliptin add-on (35.3%) versus placebo add-on (23.1%) to dapagliflozin plus metformin. Adverse events were similar between treatment groups. Episodes of hypoglycemia were infrequent in both treatment arms, and there were no episodes of major hypoglycemia., Conclusions: Triple therapy with the addition of saxagliptin to dapagliflozin plus metformin was well tolerated and produced significant improvements in HbA1c in patients with type 2 diabetes inadequately controlled with dapagliflozin plus metformin., (© 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.)

Objective: To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment., Research Design and Methods: Patients receiving treatment with stable metformin (stratum A) (screening HbA1c level 8.0-11.5% [64-102 mmol/mol]) or stable metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor (stratum B) (HbA1c 7.5-10.5% [58-91 mmol/mol]) for ≥8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks (stratum A) or 8 weeks (stratum B) (saxagliptin replaced any DPP-4 inhibitor). Patients with inadequate glycemic control (HbA1c 7-10.5% [53-91 mmol/mol]) were randomized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin. The primary end point was the change in HbA1c from baseline to week 24. Secondary end points included fasting plasma glucose (FPG) level, 2-h postprandial glucose (PPG) level, body weight, and proportion of patients achieving an HbA1c level of <7% (53 mmol/mol)., Results: Treatment with dapagliflozin add-on to saxagliptin plus metformin resulted in a greater mean HbA1c reduction than placebo (-0.82 vs. -0.10% [-9 vs. -1.1 mmol/mol], P < 0.0001). Significantly greater reductions in FPG level, 2-h PPG level, and body weight were observed, and more patients achieved an HbA1c level of <7% (53 mmol/mol) with treatment with dapagliflozin versus placebo. Adverse events were similar across treatment groups, with a low overall risk of hypoglycemia (∼1%). Genital infections developed in more patients with dapagliflozin treatment (5%) than with placebo (0.6%)., Conclusions: Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy., (© 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.)

Objective: This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin., Research Design and Methods: This was a double-blind trial in adults with HbA1c ≥8.0% and ≤12.0% (64-108 mmol/mol), randomized to saxagliptin (SAXA) (5 mg/day) plus dapagliflozin (DAPA) (10 mg/day; n = 179), or SAXA (5 mg/day) and placebo (n = 176), or DAPA (10 mg/day) and placebo (n = 179) on background metformin extended release (MET) ≥1,500 mg/day. Primary objective compared changes from baseline in HbA1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET., Results: Patients had a mean baseline HbA1c of 8.9% (74 mmol/mol), diabetes duration of 7.6 years, and a BMI of 32 kg/m(2). At week 24, the adjusted mean change from the baseline HbA1c was -1.5% (-16.1 mmol/mol) with SAXA+DAPA+MET versus -0.9% (-9.6 mmol/mol) with SAXA+MET (difference -0.59% [-6.4 mmol/mol], P < 0.0001) and -1.2% (-13.1 mmol/mol) with DAPA+MET (difference -0.27% [3.0 mmol/mol], P < 0.02). The proportion of patients achieving HbA1c <7% (53 mmol/mol) was 41% with SAXA+DAPA+MET versus 18% with SAXA+MET and 22% with DAPA+MET. Urinary and genital infections occurred in ≤1% of patients receiving SAXA+DAPA+MET. Hypoglycemia was infrequent, with no episodes of major hypoglycemia., Conclusions: In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin, greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone., (© 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.)

Objective: Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes. The primary objective of this study was to assess short-term safety of dapagliflozin in combination with insulin; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters., Research Design and Methods: A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons., Results: Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55 to 121) with dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with placebo. Changes from baseline with dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24-h daily average blood glucose; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percent change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo., Conclusions: This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes., (© 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.)

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.)

Objective: Fetuin-A is an inhibitor of vascular calcification and a mediator of insulin resistance. This study evaluated the association of plasma fetuin-A and peripheral arterial disease (PAD)., Research Design and Methods: A total of 738 individuals with type 2 diabetes (mean age 58.7 years, 37.1% female) without known cardiovascular or kidney disease were included in this cross-sectional analysis., Results: Subjects with PAD had a significantly lower fetuin-A (264.3 vs. 293.4 ng/dl, P < 0.001). In multivariable analysis, a 1-SD decrease in fetuin-A increased the odds of PAD (odds ratio 1.6, P = 0.02). Subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate >80 (odds ratio 1.9, P = 0.05) or high-sensitivity C-reactive protein <3 mg/dl (odds ratio 2.7, P = 0.002)., Conclusions: Lower circulating fetuin-A is associated with PAD in type 2 diabetes beyond traditional and novel cardiovascular risk factors. Our findings suggest a potentially unique role for fetuin-A deficiency as a biomarker of PAD in patients with type 2 diabetes.