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Background: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Methods: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Results: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 ( P =0.061) to 0.85 ( P =0.008) and the ACM HR from 0.86 ( P =0.016) to 0.81 ( P =0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. Conclusions: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01144338.

Background: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW’s effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. Methods: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. Results: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77–0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80–0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85–1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68–0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71–0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89–1.29]; interaction P =0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68–0.99]; P =0.038). Conclusions: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01144338.

Background: Recent trials have identified anti–diabetes mellitus agents that lower major adverse cardiovascular event (MACE) rates, although some increase rates of lower-extremity amputation (LEA). Patients with peripheral artery disease (PAD) have greater incidence of diabetes mellitus and risk for LEA, prompting this investigation of clinical outcomes in patients with diabetes mellitus and PAD in the EXSCEL trial (Exenatide Study of Cardiovascular Event Lowering). Methods: EXSCEL evaluated the effects of once-weekly exenatide (a GLP-1 [glucagon-like peptide-1] receptor agonist) versus placebo on the rates of the primary composite MACE end point (cardiovascular death, myocardial infarction, or stroke) among patients with type 2 diabetes mellitus. In this post hoc analysis, we assessed the association of baseline PAD with rates of MACE, LEA, and the effects of exenatide versus placebo in patients with and without PAD. Results: EXSCEL included 2800 patients with PAD (19% of the trial population). These individuals had higher unadjusted and adjusted rates of MACE compared with patients without PAD (13.6% versus 11.4%, respectively) as well as a higher adjusted hazard ratio (adjusted hazard ratio, 1.13 [95% CI, 1.00–1.27]; P =0.047). Patients with PAD had higher all-cause mortality (adjusted hazard ratio 1.38 [95% CI, 1.20–1.60]; P P Conclusions: EXSCEL participants with PAD had higher rates of all-cause mortality and LEA compared with those without PAD. There were no differences in MACE or LEA rates with exenatide versus placebo. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01144338.

One of the most important questions in diabetes management is whether long-term glycemic control can reduce the risk for micro- and macrovascular complications in diabetes. Dr. Hadler in this issue of the Clinical Journal of the American Society of Nephrology raises his concerns about the use of glycosylated hemoglobin (HbA1c) as a surrogate marker of diabetes control and questions whether lowering HbA1c with the currently available oral hypoglycemic agents makes a clinically important long-term outcome difference for patients with type 2 diabetes. He is particularly concerned about the lack of evidence of cardiovascular risk reduction with HbA1c reduction in patients with type 2 diabetes. He further comments that “we were blinded” by the results of Diabetes Control and Complications Trial (DCCT) that showed reduction in microvascular complications after meticulous blood glucose control. However, it took 17 yr before any discernible advantage in terms of macrovascular disease was documented and the results are “far from a dramatic advance” in patients with type 1 diabetes; hence, one should not expect any more benefit in the middle-aged population with insulin resistance. He further cited the United Kingdom Prospective Diabetes Study (UKPDS), in which, after several years of intervention, there was no significant improvement in macrovascular complications. He questions the validity of UKPDS secondary analysis and challenges the new screening guidelines for detection and treatment of diabetes. Dr. Hadler supports his argument of lack of beneficial effects of effectiveness of oral hypoglycemic agents by reviewing A Diabetes Outcomes Progression Trial (ADOPT) results that showed relatively modest overall beneficial effects and an unexpected finding of higher fracture rates in women. Finally, he admonishes that in our focus of bringing down HbA1c, we are exposing our patients to higher risk for adverse effects such as weight gain, hypoglycemia, and fractures: “…talk …

We present 3 cases of calciphylaxis, better termed calcific uremic arteriolopathy (CUA), which illustrate typical and atypical presentations of this disorder to discuss its classification, pathophysiology, and treatment based on a review of the literature. Of the 3 patients presenting with biopsy-proven CUA, 1 patient with proximal lesions expired in the setting of upper gastrointestinal bleeding and superinfection of ulcers, a second patient had an extensive distal ulcerative lesion that failed to heal and necessitated lower-extremity amputation, and a third patient with multiple small distal lesions experienced complete resolution of the ulcers. The classification, pathophysiology, and treatment of CUA are detailed here. CUA is a heterogeneous syndrome which typically follows a progressive course leading to loss of life or limb. Diagnosis requires a high index of suspicion and low threshold for biopsy in at-risk patients. Parathyroidectomy is appropriate to rapidly lower the calcium-phosphorus product in the setting of marked hyperparathyroidism; additional therapy includes the avoidance of purported precipitants, medical lowering of the serum calcium and phosphorus, and promotion of wound healing with hyperbaric oxygen therapy.

Hypertension (HTN) in Type 2 diabetes (T2D) is often treated with an ACEi/ARB + additional antihypertensives agents (AHTs). Dapagliflozin (DAPA) is an inhibitor of sodium glucose co-transporter 2, reducing hyperglycemia in T2D by increasing urinary glucose excretion. This is associated with weight reduction, osmotic diuresis and serum uric acid reduction, all of which may contribute to BP lowering. This Phase 3 study assessed 12 weeks of DAPA 10 mg (N=225) or placebo (PBO; N=224) in T2D patients (HbA1c 7.0-10.5%) with HTN (seated SBP / DBP 140

Objectives: Adipocyte-fatty acid binding protein (aP2) or FABP4 is expressed predominantly in adipose and macrophages. Its less abundant family member, FABP5 (Mal1), is more diffusely expressed but also found in adipocytes and macrophages. Gene deletion studies in rodents suggest that FABP4, to a greater extent than FABP5, modulates obesity and atherosclerosis. Preliminary clinical studies support a relationship of circulating FABP4 with obesity and the metabolic syndrome (MetSyn). However, there are no studies of circulating FABPs and atherosclerosis in humans. Methods: We evaluated the association of FABP4 and 5 (ELISA, Biovender) with cardiovascular risk factors, NCEP-defined MetSyn and Coronary Artery Calcification (CAC) in 846 asymptomatic, type 2 DM subjects (62.5% Caucasian, 32.5% African-American; 60% male; aged 58.6±9.2) recruited to the Penn Diabetes Heart Study. Findings : Levels [(median (IQ range)] of FABP4 [37.1 (23.0–55.2) vs 20.9 (14.0–31.0) ng/mL; p2 =29.8, p2 =36.2, p Conclusion: Both FABP 4 and 5 are biomarkers of adiposity and MetSyn. In the first study of its kind, plasma FABP4, but not FABP5, was associated with CAC in type 2 DM, but neither were independent predictors of this subclinical atherosclerosis measure.