Kalliopi Pafili

Abdominal aortic aneurysms and diabetes mellitus.

There is accumulating evidence that risk profiles differ between coronary artery disease and abdominal aortic aneurysms (AAAs). However, diabetes mellitus (DM) appears to be negatively associated with AAA formation. The underlying mechanisms for this negative relationship are far from defined, but may include: increased arterial wall matrix formation via advanced glycation end products; suppression of plasmin and reduction of levels and activity of matrix metalloproteinases (MMP)-2 and 9; diminished aortic wall macrophage infiltration, elastolysis and neovascularization. In addition, the effect of pharmacological agents used for the treatment of patients with DM on AAA formation has been studied with rather controversial results. Statins, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, fenofibrate, antibiotics and some hypoglycemic agents are beginning to be appreciated for a potential modest protection from AAAs, but further studies are needed.

The relationship between obstructive sleep apnoea and coronary heart disease.

Purpose of review Recent studies have provided evidence that severe obstructive sleep apnoea (OSA) may warrant inclusion in the list of coronary heart disease (CHD) equivalents. Recent findings Data within the past 12 months provide insight into complex issues. Specifically, OSA was shown to play an important role in the development of inflammation and atherosclerosis, but its effects on endothelial dysfunction were equivocal. Continuous positive airway pressure (CPAP) treatment was linked with significant improvements in heart function, blood pressure and total cholesterol, but the effect was not always the most significant. Summary At present, caution is warranted in the interpretation of results. In the future, data from randomized controlled trials with longer duration are expected to shed more light on the relationship between CHD and OSA and on what can be expected from CPAP regarding CHD risk factors.

Luseogliflozin and other sodium-glucose cotransporter 2 inhibitors: no enemy but time?

Glycosuria is being increasingly recognised as not only a symptom but also as a novel therapeutic approach in the management of type 2 diabetes mellitus (T2DM). This is accomplished through sodium glucose co-transporter 2 (SGLT2) inhibitors. Consequently, the safety and efficacy of these new agents have been thoroughly studied, both in randomised controlled trials and in systematic reviews and meta-analyses. More recently, a review on the mechanism of action, clinical efficacy and safety of luseogliflozin, a new highly selective SGLT2 inhibitor approved and launched in Japan for T2DM, has documented that this drug lowers plasma glucose concentration and body weight, and that it exhibits benefits in other metabolic parameters with a good safety profile. Despite the promising characteristics of this drug, important issues await consideration. These include the question as to when and to whom early use of SGLT2 inhibitors would be most suitable, as well as instructions on reduction of sulfonylurea dosage during add-on treatment. Further important questions are long-term safety concerns and cost-effectiveness of this new therapeutic class. Finally, we need to know more about the potential differences between the various SGLT2 inhibitors, as such differences might prove clinically useful in selection of hypoglycaemic agents.

Thermography in the follow up of the diabetic foot: best to weigh the enemy more mighty than he seems

Thermography is being increasingly appreciated as a further modality contributing to the early detection of incipient tissue damage predisposing to diabetic foot ulceration in selected high-risk patients. Among currently available modalities, liquid crystal thermography and infrared thermography have been most widely used. The former is effective, but its main limitation is low sensitivity. The latter permits non-contact measurements at different angles of the foot, independent of the quality of the camera used. It has been suggested that 5-year use of such techniques for daily self-examination among high-risk patients may contribute to the significant reduction of diabetic foot complications. Clearly, further experience with thermography in the real-life setting is now very welcome.

Gevokizumab in type 1 diabetes mellitus: extreme remedies for extreme diseases?

Introduction: Insulin is the cornerstone of type 1 diabetes mellitus (T1DM) therapy. However, it cannot achieve a delay in the onset or evolution of this condition, while cardiovascular morbidity remains an unquestionable threat. Areas covered: In this review, the authors discuss gevokizumab (XOMA 052), a recombinant monoclonal antibody that can neutralize human IL-1β by binding to it. This is relevant, because this IL has been associated with β-cell toxicity in both diabetes types. Moreover, gevokizumab presents two major advantages: it spares IL-1α and it exhibits favorable pharmacokinetic properties. Gevokizumab has already proven its safety and efficacy in improving glycemic control, β cell function and inflammation markers in clinical trials in diabetic patients. Expert opinion: Despite the very promising characteristics of gevokizumab, important questions remain to be answered. One important question is what to expect from a combination of this agent with insulin and if there is a subset of patients that might respond more favorably to treatment. We also need to know at what stage in the natural history of T1DM could gevokizumab be most efficacious, as well as its potential effects on cardiovascular outcomes.

The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes

ABSTRACT Introduction: There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion. Areas covered: In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM. Expert opinion: Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.

Evaluation of sural nerve automated nerve conduction study in the diagnosis of peripheral neuropathy in patients with type 2 diabetes mellitus

Introduction New tests for improved diagnosis of diabetic peripheral neuropathy (DPN) are useful. Material and methods We evaluated the utility of automated nerve conduction study (NCS) of the sural nerve with a new portable device for the diagnosis of DPN in patients with type 2 diabetes mellitus (T2DM). This study included 114 T2DM patients (58 men) with mean age 64.60 ±8.61 years. Exclusion criteria were B12 depletion, alcohol abuse and other causes of peripheral neuropathy. The reference method was the Neuropathy Disability Score (NDS) with a threshold NDS ≥ 3. Sural nerve automated NCS was carried out with the portable NC-stat DPNCheck device. Sensory nerve conduction velocity and sensory nerve action potential amplitude were measured bilaterally. Automated NCS was considered abnormal when ≥ 1 of the two aforementioned neurophysiological parameters was abnormal in at least one leg. Results Examination with NC-stat DPNCheck exhibited 90.48% sensitivity, 86.11% specificity, 79.17% positive predictive value (PPV) and 93.94% negative predictive value (NPV). The positive likelihood ratio (LR+) was 6.51 and the negative likelihood ratio (LR–) was 0.11. Conclusions Sural nerve automated NCS with the NC-stat DPNCheck device exhibits high sensitivity and specificity for the diagnosis of DPN in T2DM.

Charcot osteoarthropathy and coronary artery disease in diabetes: the twilight of innocence?

Sir, Traditionally, Charcot osteoarthropathy (COA) in diabetes was thought to occur in relatively younger patients, often free from macrovascular disease [1]. Indeed, the presence of peripheral arterial disease was considered to protect from the development of COA [1]. However, van Baal et al. [2] showed that patients presenting with acute COA had a marked and significant reduction in life expectancy. Importantly, patients with neuropathic foot ulceration had a comparable reduction in life expectancy [2]. However, the causes of premature death in this work could not be ascertained [2]. Interestingly, two studies recently published in this journal [3, 4] have demonstrated an association between COA and coronary artery disease (CAD), providing some insight into the possibility of increased mortality in patients with COA. Pitocco et al. [3] have reported that patients with COA exhibit a higher prevalence of severe coronary plaques, as compared with those having diabetic neuropathy but no COA. Bergis et al. [4] have identified CAD as an independent and the most important predictor of survival in patients with COA. Taken together, the data suggest that COA should no longer be deemed a relatively innocent local condition without increased cardiovascular morbidity. Conversely, it is linkedwith highermortality rates, possibly due toCAD [2–4]. Certainly, the mechanisms underlying the relationship between COA and CAD are far from clear. For instance, cytokines play a crucial role in the pathogenesis of COA [1], and so it is attractive to implicate them in the development of CAD [3], but this is merely a speculation. We also need to ascertain whether this excess mortality is observed in the acute versus chronic phase of COA [1], as well as to investigate the potential role of confounding factors. Meanwhile, the everyday clinician needs to become aware that patients with COA may be at increased risk of cardiovascular morbidity and need appropriate screening. In this context, they deserve to be taken as seriously as those with neuropathic foot ulceration, given the growing appreciation of increased atherosclerotic disease in the latter [5].

Treatment of diabetic complications: how can we learn by seeking and blundering?

Some of the clinical features of diabetes mellitus (DM) were first described in Egypt 3500 years ago. However, understanding the relevant pathophysiology and introduction of the first therapeutic principles were late in following, with slow progress between 1500 and 1990. In the latter part of the 20th century, it was realized that the prevalence of type 2 DM (T2DM) was rising, calling for improved management of DM and its complications. New insulin analogs, glucagon-like peptide 1 agonists, and valuable oral hypoglycemic agents have been introduced during the last 30 years. In 1993, the results of the Diabetes Control and Complications Trial (DCCT) were released, followed by the publication of the United Kingdom Prospective Diabetes Study (UKPDS) in 1998. These landmark trials concluded that tight glycemic control contributed to reduced incidence of some of diabetic complications in type 1 DM (T1DM) and T2DM, respectively. The next step was to explore the effect of rapidly attaining tight glycemic control in patients with T2DM and high cardiovascular risk. This was the aim of 3 trials, the Action to Control Cardiovascular Risk in Diabetes (ACCORD), the Veterans Administration Diabetes Trial (VADT), and the Action in Diabetes and Vascular Disease (ADVANCE), which showed that tight glycemic control conferred virtually no benefit in this setting. However, trials do not reflect everyday situations, and so a recent publication in the New England Journal of Medicine assessed the incidence of diabetic complications in the United States between 1990 and 2010. Data were obtained from the National Health Interview Survey, the National Hospital Discharge Survey, the US Renal Data System, and the US National Vital Statistics System. The rates of 5 major diabetic complications, namely acute myocardial infarction (AMI), stroke, end-stage renal disease (ESRD), amputations, and death from hyperglycemic crisis, were significantly reduced. Among these, ESRD exhibited the smallest relative decline, while the most marked decrease was seen for AMI. The reduction in the latter, accompanied by the increased absolute number of strokes, led to comparable rates between AMI and stroke. Furthermore, the greatest absolute decline was seen for AMI and the smallest for deaths from hyperglycemic crisis. Interestingly, the greatest reductions were observed in patients older than 75 years of age, with the exception of ESRD: as a result, amputation rates were comparable in younger and older patients, while deaths from hyperglycemic crisis were more frequent among younger patients. Importantly, rates of stroke, AMI, ESRD, and amputations showed a smaller reduction in the population without DM, suggesting that greater progress had been accomplished in the treatment of diabetic patients. The authors attributed their findings to improved (1) preventative health care, (2) treatment of acute complications, (3) availability of drugs and therapeutic procedures (eg, revascularization), and (4) earlier detection and management of diabetic complications. Even neuropathy, which remains a frequently overlooked complication, can now be diagnosed more reliably by new tests. Moreover, there appears to have been some improvement in lifestyle factors such as smoking and dietary habits as well as in self-monitoring of blood glucose. These achievements notwithstanding, the overall burden of diabetic complications has not been reduced, at least not to the extent that was set as a goal by the St Vincent declaration. This is primarily attributable to the growing diabetes epidemic, which is, in turn, due to urbanization, Westernized dietary habits, obesity, and prolonged life expectancy. Arguably, obesity and industrialization apply more to patients with T2DM, while prolonged survival after diagnosis, resulting in increased lifetime DM duration, applies more not only to patients with T1DM but also to patients with T2DM. The New England Journal of Medicine analysis has its limitations. These include the lack of data on microvascular diabetic complications and hypoglycemia, the failure to compare complication rates between the 2 DM types as well as the absence of more detailed ascertainment of the progress hitherto achieved in DM management and adherence to guidelines. Accordingly, further data are now desirable in an endeavor to increase our knowledge in these areas. In this context, some improvements are now highly welcome. First, it would be useful to obtain more data on less

Serum uric acid as a predictor of vascular complications in diabetes: an additional case for neuropathy.

We read with interest the excellent article by Bjornstad et al. [1]. Indeed, serum uric acid (SUA) as a predictor of vascular complications may have far-reaching clinical implications [2]. The authors concluded that baseline SUA independently predicted the development of certain diabetic complications over 6 years, namely diabetic nephropathy, diabetic retinopathy (including its more severe proliferative form) and coronary artery calcification in type 1 diabetic patients [1]. Furthermore, they provided the message that SUA may play an important role as an additional risk factor in risk-stratification for diabetes complications [1]. We have previously investigated the role of SUA in type 2 diabetic patients with peripheral neuropathy [3] and sudomotor dysfunction [4]. SUA levels were significantly higher in patients with peripheral neuropathy compared with patients without this complication, while there was also a significant correlation with the severity of neuropathy [3]. The same observations were made for sudomotor dysfunction, a less well known neuropathic feature [4]. In both studies, SUA exhibited a significant positive correlation with C-reactive protein [3, 4]. In patients with peripheral neuropathy, SUA also exhibited positive correlations with triglycerides, total cholesterol and low-density lipoprotein cholesterol, and a negative correlation with high-density lipoprotein cholesterol (HDL-C) [3]. In patients with sudomotor dysfunction, SUA exhibited a positive correlation with triglycerides, and a negative correlation with HDL-C [4]. Accordingly, in neuropathic patients SUA may be a marker of systemic inflammation and dyslipidaemia, both of which are known to contribute to the pathogenesis of this complication [3]. Overall, the data suggest that SUA may be an important risk factor for microand macrovascular diabetic complications. Importantly, this appears to hold true for both diabetes types [1, 3, 4]. We would like to add that this applies to diabetic neuropathy as well [3, 4]. Therefore, we strongly agree with the authors’ opinion that SUA needs to be addressed as an adjunctive risk factor for the prediction of diabetic complications [1]. However, it should be underlined that prospective clinical trials are now desirable to ascertain the actual relevance of SUA in predicting the risk of developing these complications, as well as the potential clinical benefit that may follow pharmacological lowering of SUA levels. Such evidence may influence the choice of many drugs that are not primarily prescribed to lower circulating SUA levels [5].