2, n=13) at baseline. Renal function and circulating levels of renin-angiotensin-aldosterone system mediators and NO were measured under clamped euglycemic (4-6 mmol/l) and hyperglycemic (9-11 mmol/l) conditions at baseline and end of treatment. During clamped euglycemia, hyperfiltration was attenuated by −33 ml/min/1.73m 2 with empagliflozin in T1D-H, (GFR 172±23-139±25 ml/min/1.73 m 2 , P<0.01). This effect was accompanied by declines in plasma NO and effective renal plasma flow and an increase in renal vascular resistance (all P<0.01). Similar significant effects on GFR and renal function parameters were observed during clamped hyperglycemia. In T1D-N, GFR, other renal function parameters, and plasma NO were not altered by empagliflozin. Empagliflozin reduced hemoglobin A1c significantly in both groups, despite lower insulin doses in each group (P≤0.04). This distal tubular condition is sensed as a low effective circulating volume stimulus at the level of the juxtaglomerular apparatus, causing an afferent renal vasodilatory response ( Figure 1B). The consequence of this altered TGF results in supranormal glomerular filtration rate (GFR) values into the hyperfiltration range. Targeting TGF in renal hyperfiltration has shown promising results in experimental animal models by using phlorizin, a nonspecific inhibitor of the renal tubular glucose transporters SGlT1 and SGlT2. 13,14 The clinical relevance of these findings, however, could not be conclusively studied in humans, because of the poor tolerability of phlorizin resulting from its low selectivity for SGlT2, SGlT1 inhibition-related gastrointestinal side effects and very limited oral bioavailability. Conclusions-In14 Subsequent studies with selective SGlT2 inhibitors in animals have also shown similar significant effects on renal hyperfiltration. 15 More recently, several highly selective SGlT2 inhibitors have been developed for use in clinical trials in patients with type 2 diabetes mellitus (T2D). 16,17 These compounds generally do not affect SGlT1 at clinical doses and have pharmacological features that allow once daily oral dosing. In T2D, this class of drugs is well-tolerated and has consistently improved glycemic control, along with weight loss, and antihypertensive effects. 17,18 Available evidence for SGlT2 inhibitors in T1D is however limited, and is mainly derived from experimental animal models. Only 1 clinical pilot study has been conducted, which demonstrated that a single dose of remogliflozin improved postprandial glucose profiles. 19 Based on previous findings with phlorizin and other SGlT2 inhibitors in animals, the concept of altering renal hyperfiltration by blocking renal glucose absorption with SGlT2 inhibitors is intriguing, because reducing this surrogate marker of intraglomerular pressure is renal protective in experimental models of diabetes mellitus. 13,20,21 However, potential renal hemodynamic effects of these drugs in subjects with diabetes mellitus, including effects on renal hyperfiltration, remain unknown. Accordingly, the p...

IMPORTANCE Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. OBJECTIVE To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. DESIGN, SETTING, AND PARTICIPANTS Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A 1c of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200 mg/g), and high renal risk (reduced eGFR and micro-or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. INTERVENTIONS Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. MAIN OUTCOMES AND MEASURES Primary outcome was time to first occurrence of the composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. RESULTS Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73 m 2 ; 80.1% with UACR >30 mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI, −0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P < .001 for noninferiority). The kidney outcome occurred in 327 of 3494 (9.4%) and 306 of 3485 (8.8%), respectively (absolute incidence rate difference, 0.22 [95% CI, −0.52 to 0.97] per 100 person-years) (HR, 1.04; 95% CI, 0.89-1.22; P = .62). Adverse events occurred in 2697 (77.2%) and 2723 (78.1%) patients in the linagliptin and placebo groups; 1036 (29.7%) and 1024 (29.4%) had 1 or more episodes of hypoglycemia; and there were 9 (0.3%) vs 5 (0.1%) events of adjudication-confirmed acute pancreatitis. CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes and high CV and renal risk, linagliptin added to usual care compared with placebo added to usual care resulted in a noninferior risk of a composite CV outcome over a median 2.2 years.

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Renal GluconeogenesisIts importance in human glucose homeostasis R E V I E W A R T I C L EStudies conducted over the last 60 years in animals and in vitro have provided considerable evidence that the mammalian kidney can make glucose and release it under various conditions. Until quite recently, however, it was generally believed that the human kidney was not an important source of glucose except during acidosis and after prolonged fasting. This review will summarize early work in animals and humans, discuss methodological problems in assessing renal glucose release in vivo, and present results of recent human studies that provide evidence that the kidney may play a significant role in carbohydrate metabolism under both physiological and pathological conditions. R e v i e w s / C o m m e n t a r i e s / P o s i t i o n S t a t e m e n t s