A phase 2a, randomized, double-blind, placebo-controlled, three-arm, parallel-group study to assess the efficacy, safety, tolerability and pharmacodynamics of PF-06835919 in patients with non-alcoholic fatty liver disease and type 2 diabetes.

AIM: To assess the safety, tolerability and pharmacodynamics (PD) of the ketohexokinase inhibitor PF-06835919 in participants with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). MATERIALS AND METHODS: This double-blind, placebo-controlled, parallel-group study enrolled adults with NAFLD (≥ 8% whole liver fat [WLF] using MRI proton density fat fraction [MRI-PDFF]) and T2D on stable doses of metformin (≥ 500 mg/day). Participants received once-daily placebo, PF-06835919 150 or 300 mg for 16 weeks. Randomization (1:1:1) was via an interactive response technology system. Endpoints included percentage change from baseline (CFB) in WLF using MRI-PDFF (primary endpoint) and CFB in HbA1c (co-primary endpoint) at 16 weeks, PD, safety and tolerability. RESULTS: Among 164 participants randomized and treated, 145 completed the treatment (placebo, n = 50; PF-06835919 150 mg, n = 46; PF-06835919 300 mg, n = 49). At week 16, least squares mean (90% confidence interval) percentage CFB in WLF was -5.26% (-12.86%, 2.99%), -17.05% (-24.01%, -9.46%) and -19.13% (-25.51%, -12.20%) in the placebo, PF-06835919 150-mg and 300-mg groups, respectively (PF-06835919 300-mg group vs. placebo, P = .0288). Modest numerical reductions in HbA1c were observed in all groups that did not reach statistical significance. Treatment-emergent adverse event incidence was similar across groups (40.7%, 45.5% and 32.7% in the placebo, PF-06835919 150-mg and 300-mg groups, respectively), with no apparent dose-related trend. CONCLUSIONS: PF-06835919 administration over 16 weeks was generally safe and well tolerated and resulted in reductions in WLF in participants with NAFLD and T2D.

Prognostic value of comorbidity indices and lung diseases in early rheumatoid arthritis: a UK population-based study.

OBJECTIVES: We assessed comorbidity burden in people with RA at diagnosis and early disease (3 years) and its association with early mortality and joint destruction. The association between lung disease and mortality in RA is not well studied; we also explored this relationship. METHODS: From a contemporary UK-based population (n = 1, 475 762) we identified a cohort with incident RA (n = 6591). The prevalence of comorbidities at diagnosis of RA and at 3 years was compared with age- and gender-matched controls (n = 6591). In individuals with RA we assessed the prognostic value of the Charlson Comorbidity Index and Rheumatic Disease Comorbidity Index calculated at diagnosis for all-cause mortality and joint destruction (with joint surgery as a surrogate marker). We separately evaluated the association between individual lung diseases [chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease] and mortality. RESULTS: Respiratory disease, cardiovascular disease, stroke, diabetes, previous fracture and depression were more common (P < 0.05) in patients with RA at diagnosis than controls. Comorbidity (assessed using RDCI) was associated with all-cause mortality in RA [adjusted hazard ratio (HR) 1.26, 95% CI 1.00-1.60]. There was no association with joint destruction. COPD, but not asthma, was associated with mortality (COPD HR 2.84, 95% CI 1.13-7.12). CONCLUSION: There is an excess burden of comorbidity at diagnosis of RA including COPD, asthma and interstitial lung disease. COPD is a major predictor of early mortality in early RA. Early assessment of comorbidity including lung disease should form part of the routine management of RA patients.

Haematological abnormalities in new-onset rheumatoid arthritis and risk of common infections: a population-based study.

OBJECTIVES: To describe the prevalence of haematological abnormalities in individuals with RA at the point of diagnosis in primary care and the associations between haematological abnormalities, vaccinations and subsequent risk of common infections. METHODS: We studied 6591 individuals with newly diagnosed RA between 2004 and 2016 inclusive using the UK Royal College of General Practitioners Research and Surveillance Centre primary care database. The prevalence of haematological abnormalities at diagnosis (anaemia, neutropenia and lymphopenia) was established. Cox proportional hazards models were used to evaluate the association between each haematological abnormality and time to common infections and the influence of vaccination status (influenza and pneumococcal vaccine) on time to common infections in individuals with RA compared with a matched cohort of individuals without RA. RESULTS: Anaemia was common at RA diagnosis (16.1% of individuals), with neutropenia (0.6%) and lymphopenia (1.4%) less so. Lymphopenia and anaemia were associated with increased infection risk [hazard ratio (HR) 1.18 (95% CI 1.08, 1.29) and HR 1.37 (95% CI 1.08, 1.73), respectively]. There was no evidence of an association between neutropenia and infection risk [HR 0.94 (95% CI 0.60, 1.47)]. Pneumonia was much more common in individuals with early RA compared with controls. Influenza vaccination was associated with reduced risk of influenza-like illness only for individuals with RA [HR 0.58 (95% CI 0.37, 0.90)]. CONCLUSION: At diagnosis, anaemia and lymphopenia, but not neutropenia, increase the risk of common infections in individuals with RA. Our data support the effectiveness of the influenza vaccination in individuals with RA.

Retinal arterial hypertrophy: the new LVH?

Prevention of target organ damage represents the El Dorado for clinicians who treat hypertension. Although many of the cardiovascular sequelae of chronic hypertension are due to large artery atherosclerosis, an equal number are due to small artery dysfunction. These microvascular complications include eye disease (retinopathy), kidney failure, diastolic dysfunction of the heart and small vessel brain disease leading to stroke syndromes, dementia and even depression. Examination of the retinal vasculature represents the only way to reliably derive information regarding small arteries responsible for these diverse pathologies. This review aims to summarise the rapidly accruing evidence indicating that easily observable abnormalities of retinal arteries reflect target organ damage elsewhere in the body of hypertensive patients. In tandem, we also present putative mechanisms by which hypertension and diabetes fundamentally change small artery structure and function and how these processes may lead to target organ damage.

Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study.

BACKGROUND: Preoperative anaemia is associated with adverse outcomes after cardiac surgery but outcomes after non-cardiac surgery are not well established. We aimed to assess the effect of preoperative anaemia on 30-day postoperative morbidity and mortality in patients undergoing major non-cardiac surgery. METHODS: We analysed data for patients undergoing major non-cardiac surgery in 2008 from The American College of Surgeons' National Surgical Quality Improvement Program database (a prospective validated outcomes registry from 211 hospitals worldwide in 2008). We obtained anonymised data for 30-day mortality and morbidity (cardiac, respiratory, CNS, urinary tract, wound, sepsis, and venous thromboembolism outcomes), demographics, and preoperative and perioperative risk factors. We used multivariate logistic regression to assess the adjusted and modified (nine predefined risk factor subgroups) effect of anaemia, which was defined as mild (haematocrit concentration >29-<39% in men and >29-<36% in women) or moderate-to-severe (≤29% in men and women) on postoperative outcomes. FINDINGS: We obtained data for 227,425 patients, of whom 69,229 (30·44%) had preoperative anaemia. After adjustment, postoperative mortality at 30 days was higher in patients with anaemia than in those without anaemia (odds ratio [OR] 1·42, 95% CI 1·31-1·54); this difference was consistent in mild anaemia (1·41, 1·30-1·53) and moderate-to-severe anaemia (1·44, 1·29-1·60). Composite postoperative morbidity at 30 days was also higher in patients with anaemia than in those without anaemia (adjusted OR 1·35, 1·30-1·40), again consistent in patients with mild anaemia (1·31, 1·26-1·36) and moderate-to-severe anaemia (1·56, 1·47-1·66). When compared with patients without anaemia or a defined risk factor, patients with anaemia and most risk factors had a higher adjusted OR for 30-day mortality and morbidity than did patients with either anaemia or the risk factor alone. INTERPRETATION: Preoperative anaemia, even to a mild degree, is independently associated with an increased risk of 30-day morbidity and mortality in patients undergoing major non-cardiac surgery. FUNDING: Vifor Pharma.

Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease.

BACKGROUND: Many physicians retain reservations regarding the routine prescription of renin-angiotensin blockade (RAB) in patients with atheromatous renovascular disease (ARVD). Conversely, these patients are in most need of the cardio- and renal protection offered by RAB. This reservation is mostly because of fear of precipitating acute renal deterioration. We aimed to study whether RAB can be used safely in ARVD patients and whether it altered their outcome. METHODS: Prospective observational study of all ARVD patients presenting to our tertiary referral centre from 1999-2009. Data capture included usage and tolerability of RAB, and correlation with endpoints of cardiovascular events, dialysis or death. RESULTS: Six hundred and twenty-one subjects were available for analysis. Mean age (SD) of the cohort was 71.3 (8.8) years, median (interquartile range) follow-up 3.1 (2.1, 4.8), range 0.2-10.61 years. Seventy-four patients had an intolerance to RAB at study entry. When utilized prospectively, RAB was tolerated in 357 of 378 patients (92%), and this was even seen in 54/69 (78.3%) patients with bilateral>60% renal artery stenosis (RAS) or occlusion. Patients (4/21) who were intolerant of RAB during follow-up (and 12 retrospectively intolerant), underwent renal revascularization which facilitated safe use of these medications post-procedure. On multivariate time-adjusted analysis, patients receiving RAB were significantly less likely to die (P=0.02). CONCLUSION: RAB is well tolerated even in patients with bilateral severe RAS and reduced mortality in a large group of ARVD patients. We recommend all ARVD patients be considered for RAB therapy unless an absolute contra-indication exists. Intolerance of these agents due to renal dysfunction should be considered an emerging indication for renal revascularization to facilitate their re-introduction.

Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients.

BACKGROUND: Inflammation in adipose tissue has been implicated in vascular dysfunction, but the local mechanisms by which this occurs are unknown. METHODS AND RESULTS: Small arteries with and without perivascular adipose tissue were taken from subcutaneous gluteal fat biopsy samples and studied with wire myography and immunohistochemistry. We established that healthy adipose tissue around human small arteries secretes factors that influence vasodilation by increasing nitric oxide bioavailability. However, in perivascular fat from obese subjects with metabolic syndrome (waist circumference 111+/-2.8 versus 91.1+/-3.5 cm in control subjects, P<0.001; insulin sensitivity 41+/-5.9% versus 121+/-18.6% in control subjects, P<0.001), the loss of this dilator effect was accompanied by an increase in adipocyte area (1786+/-346 versus 673+/-60 mum(2), P<0.01) and immunohistochemical evidence of inflammation (tumor necrosis factor receptor 1 12.4+/-1.1% versus 6.7+/-1%, P<0.001). Application of the cytokines tumor necrosis factor receptor-alpha and interleukin-6 to perivascular fat around healthy blood vessels reduced dilator activity, resulting in the obese phenotype. These effects could be reversed with free radical scavengers or cytokine antagonists. Similarly, induction of hypoxia stimulated inflammation and resulted in loss of anticontractile capacity, which could be rescued by catalase and superoxide dismutase or cytokine antagonists. Incubation with a soluble fragment of adiponectin type 1 receptor or inhibition of nitric oxide synthase blocked the vasodilator effect of healthy perivascular adipose tissue. CONCLUSIONS: We conclude that adipocytes secrete adiponectin and provide the first functional evidence that it is a physiological modulator of local vascular tone by increasing nitric oxide bioavailability. This capacity is lost in obesity by the development of adipocyte hypertrophy, leading to hypoxia, inflammation, and oxidative stress.

The benefit of renal artery stenting in patients with atheromatous renovascular disease and advanced chronic kidney disease.

BACKGROUND: Around 16% of all patients who present with atheromatous renovascular disease (ARVD) in the United States undergo revascularization. Historically, patients with advanced chronic kidney disease (CKD) have been considered least likely to show improvement in renal functional terms, or survival. We aimed to investigate whether differences in outcomes after revascularization compared to medical management might be observed in ARVD patients if stratified by their CKD classes. METHODS: Two prospective cohorts, a UK center with a traditionally conservative approach, and a German center who undertook a proactive revascularization approach, were compared. An improvement in renal function was defined as > 20% renal improvement at one year's follow-up. To improve validity and comparability, revascularized patients in the UK center were also used within analyses, RESULTS: 347 (UK conservative group), 89 (UK revascularized group), and 472 (German center) patients were included in the analysis. When subdivided by CKD stage, patient ages between the two centers were comparable. Improvements in renal function were observed in twice as many patients who underwent revascularization as compared to medical treatment, particularly in the latter CKD stages, 15.2 (German revascularization) vs. 0% in CKD 1-2, 12.2 (UK), and 32.8 (German) revascularization vs. 14.1% in CKD3, and 53.1 and 53.8 vs. 28.3 in patients with CKD 4-5. The improvements in eGFR were 10.2 (16) and 8.1 (12.5) ml/min/year in the German and UK revascularized groups, respectively, vs. -0.05 (6.8) ml/min/year in the medical cohort in CKD 4-5. Improvements in blood pressure control were noted at 1 year overall and within each CKD category. Multivariate analysis revealed that revascularization independently reduced the risk of death by 45% in all patients combined (RR 0.55, P = 0.013). CONCLUSIONS: Although this study has significant methodological limitations, it does shows that percutaneous renal revascularization can improve renal function in advanced CKD (stages 4-5), and that this can provide a survival advantage in prospective analysis.

Risk of venous thromboembolism in immune-mediated inflammatory diseases: a UK matched cohort study.

OBJECTIVES: To describe the risk of venous thromboembolism (VTE), and risk factors for VTE, in people with immune-mediated inflammatory diseases (IMID) (ulcerative colitis, Crohn's disease (CD), rheumatoid arthritis (RA) and psoriatic arthritis (PsA)), compared with a matched control population. METHODS: A total of 53 378 people with an IMID were identified over 1999-2019 in the UK Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database and were matched to 213 512 people without an IMID. The association between the presence of any IMID, and each IMID separately, and risk of VTE was estimated using unadjusted and multivariable-adjusted Cox proportional hazards models. The prevalence of VTE risk factors, and associations between VTE risk factors and risk of VTE, were estimated in people with and without an IMID. RESULTS: People with an IMID were at increased risk of VTE (adjusted HR [aHR] 1.46, 95% CI 1.36,1.56), compared with matched controls. When assessing individual diseases, risk was increased for CD (aHR 1.74, 95% CI 1.45 to 2.08), ulcerative colitis (aHR 1.27, 95% CI 1.10 to 1.45) and RA (aHR 1.54, 95% CI 1.40 to 1.70) but there was no evidence of an association for PsA (aHR 1.21, 95% CI 0.96 to 1.52). In people with an IMID, independent risk factors for VTE included male sex, overweight/obese body mass index, current smoking, history of fracture, and, across study follow-up, abnormal platelet count. CONCLUSIONS: VTE risk is increased in people with IMIDs. Routinely available clinical information may be helpful to identify individuals with an IMID at increased future risk of VTE. OBSERVATIONAL STUDY REGISTRATION NUMBER: Clinicaltrials.gov (NCT03835780).

Cardiovascular risk factors and outcomes in early rheumatoid arthritis: a population-based study.

OBJECTIVE: To assess the burden of cardiovascular disease (CVD) at and prior to diagnosis in people with early rheumatoid arthritis (RA) and subsequent CVD in these patients. METHODS: A retrospective case-control study using a large English primary care database. People with RA (n=6591) diagnosed between 2004 and 2016 (inclusive) were identified using a validated algorithm, matched 1:1 by age and gender to those without RA (n=6591) and followed for a median of 5.4 years. We assessed differences in CVD at, before and after diagnosis, and the impact of traditional and RA-related risk factors (C reactive protein, RA-related autoantibodies and medication use) on incident CVD (a composite of myocardial infarction (MI), stroke or heart failure). RESULTS: RA cases and their matched controls were both of mean age 58.7 (SD 15.5) at cohort entry, and 67.5% were female. Some CVD risk factors were more common at RA diagnosis including smoking and diabetes; however, total and low-density lipoprotein cholesterol were lower in patients with RA. CVD was more common in RA at cohort entry; stroke (3.9% vs 2.7%, p<0.001), heart failure (1.6% vs 1.0%, p=0.001), and non-significantly MI (3.1% vs 2.8%, p=0.092). Excess CVD developed in the 5 years preceding diagnosis. After adjustment for traditional and RA-related risk factors, RA was associated with greater risk of post-diagnosis CVD (HR 1.33, 95% CI 1.07 to 1.65, p=0.010). CONCLUSIONS: An excess of stroke and heart failure occurs before diagnosis of RA. There is excess risk for further cardiovascular events after diagnosis, which is not explained by differences in traditional CVD or RA-related risk factors at diagnosis.

Diabetic cardiomyopathy.

Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazolidinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy.

"A Step and a Ceiling": mechanical properties of Ca2+ spark vasoregulation in resistance arteries by pressure-induced oxidative activation of PKG.

We investigated the biomechanical relationship between intraluminal pressure within small mesenteric resistance arteries, oxidant activation of PKG, Ca2+ sparks, and BK channel vasoregulation. Mesenteric resistance arteries from wild type (WT) and genetically modified mice with PKG resistance to oxidative activation were studied using wire and pressure myography. Ca2+ sparks and Ca2+ transients within vascular smooth muscle cells of intact arteries were characterized using high-speed confocal microscopy of intact arteries. Arteries were studied under conditions of varying intraluminal pressure and oxidation. Intraluminal pressure specifically, rather than the generic stretch of the artery, was necessary to activate the oxidative pathway. We demonstrated a graded step activation profile for the generation of Ca2+ sparks and also a functional "ceiling" for this pressure --sensitive oxidative pathway. During steady state pressure - induced constriction, any additional Ca2+ sensitive-K+ channel functional availability was independent of oxidant activated PKG. There was an increase in the amplitude, but not the Area under the Curve (AUC) of the caffeine-induced Ca2+ transient in pressurized arteries from mice with oxidant-resistant PKG compared with wild type. Overall, we surmise that intraluminal pressure within resistance arteries controls Ca2+ spark vasoregulation through a tightly controlled pathway with a graded onset switch. The pathway, underpinned by oxidant activation of PKG, cannot be further boosted by additional pressure or oxidation once active. We propose that these restrictive characteristics of pressure-induced Ca2+ spark vasoregulation confer stability for the artery in order to provide a constant flow independent of additional pressure fluctuations or exogenous oxidants.

Abnormal Remodeling of Subcutaneous Small Arteries Is Associated With Early Diastolic Impairment in Metabolic Syndrome.

BACKGROUND: Small artery pathophysiology is frequently invoked as a cause of obesity-related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans. METHODS AND RESULTS: To address this, we studied human small artery structure and function in obesity and looked for correlations between vascular parameters and diastolic function. Seventeen obese patients with metabolic syndrome and 5 control participants underwent echocardiography and subcutaneous gluteal fat biopsy. Small arteries were isolated from the biopsy and pressure myography was used to study endothelial function and wall structure. In comparison with the control group, small arteries from obese participants exhibited significant endothelial dysfunction, assessed as the vasodilatory response to acetylcholine and also pathological growth of the wall. For the obese participants, multiple regression analysis revealed an association between left atrial volume and both the small artery wall thickness (ß=0.718, P=0.02) and wall-to-lumen ratio (ß=0.605, P=0.02). Furthermore, the E:E' ratio was associated with wall-to-lumen ratio (ß=0.596, P=0.02) and inversely associated with interleukin-6 (ß=-0.868, P=0.03). By contrast, endothelial function did not correlate with any of the echocardiographic parameters studied. CONCLUSIONS: Although the small arteries studied were not cardiac in origin, our results support a role for small artery remodeling in the development of diastolic dysfunction in humans. Further direct examination of the structure and function of the myocardial resistance vasculature is now warranted, to elucidate the temporal association between metabolic risk factors, small artery injury, and diastolic impairment.

Pressure-induced oxidative activation of PKG enables vasoregulation by Ca2+ sparks and BK channels.

Activation of Ca2+-sensitive, large-conductance potassium (BK) channels in vascular smooth muscle cells (VSMCs) by local, ryanodine receptor-mediated Ca2+ signals (Ca2+ sparks) acts as a brake on pressure-induced (myogenic) vasoconstriction-a fundamental mechanism that regulates blood flow in small resistance arteries. We report that physiological intraluminal pressure within resistance arteries activated cGMP-dependent protein kinase (PKG) in VSMCs through oxidant-induced formation of an intermolecular disulfide bond between cysteine residues. Oxidant-activated PKG was required to trigger Ca2+ sparks, BK channel activity, and vasodilation in response to pressure. VSMCs from arteries from mice expressing a form of PKG that could not be activated by oxidants showed reduced Ca2+ spark frequency, and arterial preparations from these mice had decreased pressure-induced activation of BK channels. Thus, the absence of oxidative activation of PKG disabled the BK channel-mediated negative feedback regulation of vasoconstriction. Our results support the concept of a negative feedback control mechanism that regulates arterial diameter through mechanosensitive production of oxidants to activate PKG and enhance Ca2+ sparks.

Oral anticoagulants for Asian patients with atrial fibrillation.

Anticoagulation is the most-important intervention to prevent stroke in patients with atrial fibrillation (AF). Despite a lower point prevalence of AF in Asian communities and Asian countries than in other populations, individuals of Asian ethnicity are at a disproportionately high risk of stroke and have greater consequent mortality. Warfarin and other vitamin K antagonists are conventionally used for anticoagulation, and demonstrably reduce the risk of stroke and all-cause mortality in patients with AF. The use of warfarin in Asian countries is suboptimal, primarily owing to the universal challenge of achieving controlled anticoagulation with an unpredictable drug as well as concerns about the particularly high-risk of haemorrhage in Asian patients. Instead, antiplatelet therapy has been favoured in Asian communities, this strategy is neither safe nor effective for stroke prevention in these individuals. The non-vitamin K antagonist, oral anticoagulant drugs offer a solution to this challenge. The direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have demonstrated noninferiority to warfarin in the prevention of stroke and systemic embolism in international, randomized, controlled trials. Importantly, some of these drugs are also associated with a significantly lower incidence of major haemorrhage, and all result in lower rates of intracranial haemorrhage and haemorrhagic stroke than warfarin. In this article, we review the use of the non-vitamin K antagonist anticoagulants in the management of AF in Asian populations.

DPP-IV inhibitors: Beyond glycaemic control?

Dipeptidyl-peptidase-IV (DPP-IV) inhibitors are a new class of oral hypoglycaemic agents recently approved for the management of type 2 diabetes mellitus. Early data suggested that they had a positive impact on the cardiovascular system: treatment appeared to result in improvements in cardiac performance, blood pressure and lipid levels. However, recent clinical findings bring this into question. Our understanding of the physiological actions of these agents is complicated by the fact that DPP-IV has a wide range of substrates in addition to glucagon-like peptide 1. Indeed, DPP-IV inhibition alters concentrations of a wide variety of cytokines and neuropeptides. A deeper understanding of the physiological effects of these drugs as well as their true impact on cardiovascular risk is needed before consideration can be given to extending their use beyond the treatment of diabetes.

Have we reached the limits for the treatment of diabetic nephropathy?

INTRODUCTION: The prevalence of diabetic nephropathy is increasing as a consequence of the global epidemic of diabetes, and the complications of diabetic nephropathy are unsurprisingly legion. Blockade of the renin-angiotensin-aldosterone system (RAAS) has formed the mainstay of management, but despite this, most individuals will suffer premature cardiovascular events, and many will progress to end-stage renal disease. Given the heterogeneity of pathologies, it is perhaps naïve to hope that blocking a single neurohormonal pathway will protect against the myriad of pathogenetic mechanisms that conspire to cause the injuries seen with diabetes. Chronic hyperglycaemia and resulting advanced glycation end products form a mechanistic axis, which appears central to many of the pathways that lead to diabetic nephropathy. Treatment with pyridoxamine (an inhibitor of advanced glycation end-products) may represent a strategy to counter these injurious pathways. AREAS COVERED: In this review, the authors explore pyridoxamine and other emerging therapeutic agents in the battle against diabetic nephropathy. The authors also provide their perspectives on the field and potential future directions. EXPERT OPINION: Although issues around validity of surrogate markers and clinical end points have complicated trial data in the field, currently available evidence is not persuasive as regards the clinical application of these agents. There remains a clear and growing need for emerging therapeutics to be used in combination with RAAS blocking agents.

Interrupting the natural history of diabetes mellitus: lifestyle, pharmacological and surgical strategies targeting disease progression.

In recent decades we have seen a surge in the incidence of diabetes in industrialized nations; a threat which has now extended to the developing world. Type 2 diabetes is associated with significant microvascular and macrovascular disease, with considerable impact on morbidity and mortality. Recent evidence has cast uncertainty on the benefits of very tight glycaemic goals in these individuals. The natural history of disease follows an insidious course from disordered glucose metabolism in a pre-diabetic state, often with metabolic syndrome and obesity, before proceeding to diabetes mellitus. In the research setting, lifestyle, pharmacological and surgical intervention targeted against obesity and glycaemia has shown that metabolic disturbances can be halted and indeed regressed if introduced at an early stage of disease. In addition to traditional anti-diabetic medications such as the glinides, sulphonylureas and the glitazones, novel therapies manipulating the endocannabinoid system, neurotransmitters, intestinal absorption and gut hormones have shown dual benefit in weight loss and glycaemic control normalisation. Whilst these treatments will not and should not replace lifestyle change, they will act as invaluable adjuncts for weight loss and aid in normalising the metabolic profile of individuals at risk of diabetes. Utilizing novel therapies to prevent diabetes should be the focus of future research, with the aim of preventing the challenging microvascular and macrovascular complications, and ultimately cardiovascular death.