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...

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor B (NF-B). Therefore, NF-B is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-B activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-B was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-B-controlled ␤-globin transgene were stressed by immobilization. Immobilization resulted in increased ␤-globin expression, which could be reduced in the presence of the ␣1-adrenergic inhibitor prazosin.

IMPORTANCE Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator. OBJECTIVE This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018. INTERVENTIONS Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need. MAIN OUTCOMES AND MEASURES The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3. RESULTS Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]). CONCLUSIONS AND RELEVANCE Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior ri...

BackgroundIndividuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.MethodsBlood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).ResultsIn response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.ConclusionsEmpagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.Trial registrationClinical trial registration: NCT01392560

No abstract

No abstract

URL: https://www.clinicaltrials.gov. Unique identifier: NCT01131676.

OBJECTIVEPreclinical data suggest that linagliptin, a dipeptidyl peptidase-4 inhibitor, may lower urinary albumin excretion. The ability of linagliptin to lower albuminuria on top of renin-angiotensin-aldosterone system (RAAS) inhibition in humans was analyzed by pooling data from four similarly designed, 24-week, randomized, double-blind, placebo-controlled, phase III trials.RESEARCH DESIGN AND METHODSA pooled analysis of four completed studies identified 217 subjects with type 2 diabetes and prevalent albuminuria (defined as a urinary albumin-to-creatinine ratio [UACR] of 30−3,000 mg/g creatinine) while receiving stable doses of RAAS inhibitors. Participants were randomized to either linagliptin 5 mg/day (n = 162) or placebo (n= 55). The primary end point was the percentage change in geometric mean UACR from baseline to week 24.RESULTSUACR at week 24 was reduced by 32% (95% CI −42 to −21; P < 0.05) with linagliptin compared with 6% (95% CI −27 to +23) with placebo, with a between-group difference of 28% (95% CI −47 to −2; P = 0.0357). The between-group difference in the change in HbA1c from baseline to week 24 was −0.61% (−6.7 mmol/mol) in favor of linagliptin (95% CI −0.88 to −0.34% [−9.6 to −3.7 mmol/mol]; P < 0.0001). The albuminuria-lowering effect of linagliptin, however, was not influenced by race or HbA1c and systolic blood pressure (SBP) values at baseline or after treatment.CONCLUSIONSLinagliptin administered in addition to stable RAAS inhibitors led to a significant reduction in albuminuria in patients with type 2 diabetes and renal dysfunction. This observation was independent of changes in glucose level or SBP. Further research to prospectively investigate the renal effects of linagliptin is underway.