The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D ...who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Oral Treatment With α-Lipoic Acid Improves Symptomatic Diabetic Polyneuropathy
The SYDNEY 2 trial
Dan Ziegler , MD, FRCPE 1 ,
Alexander Ametov , MD 2 ,
Alexey Barinov , MD 3 ,
Peter J. Dyck , MD 4 ,
...Irina Gurieva , MD 5 ,
Phillip A. Low , MD 4 ,
Ullrich Munzel , PHD 6 ,
Nikolai Yakhno , MD 3 ,
Itamar Raz , MD 7 ,
Maria Novosadova , MD 5 ,
Joachim Maus , MD 6 and
Rustem Samigullin , MD 6
1 German Diabetes Clinic, German Diabetes Center, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany
2 Russian Medical Academy for Advanced Studies, Moscow, Russia
3 Neurology Clinic, Moscow Medical Academy, Moscow, Russia
4 Department of Neurology, Mayo Clinic, Rochester, Minnesota
5 Federal Center for Diabetic Foot, Moscow, Russia
6 MEDA Pharma, Bad Homburg, Germany
7 Hadassah University, Jerusalem, Israel
Address correspondence and reprint requests to Prof. Dan Ziegler, MD, FRCPE, Deutsche Diabetes-Klinik, Deutsches Diabetes-Zentrum,
Leibniz-Institut an der Heinrich-Heine-Universität, Auf’m Hennekamp 65, 40225 Düsseldorf, Germany. E-mail: dan.ziegler{at}ddz.uni-duesseldorf.de
Abstract
OBJECTIVE —The aim of this trial was to evaluate the effects of α-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits
in diabetic patients with distal symmetric polyneuropathy (DSP).
RESEARCH DESIGN AND METHODS —In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received
once-daily oral doses of 600 mg ( n = 45) (ALA600), 1,200 mg ( n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA ( n = 46) or placebo ( n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total
Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points
included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients’
global assessment of efficacy.
RESULTS —Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%)
in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (≥50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant
improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients’
global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea,
vomiting, and vertigo.
CONCLUSIONS —Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600
mg once daily appears to provide the optimum risk-to-benefit ratio.
ALA, α-lipoic acid
DSP, distal symmetric polyneuropathy
NIS, Neuropathy Impairment Score
NSC, Neuropathy Symptoms and Change
TSS, Total Symptom Score
Footnotes
D. Z., A.A., A.B., P.J.D., I.G., P.A.L., N.Y., I.R., and M.N. received honoraria for speaking activities and research grants
from MEDA.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Accepted July 26, 2006.
Received June 12, 2006.
DIABETES CARE
Impaired glucose tolerance (IGT) is a common carbohydrate metabolism disorder world-wide. To evaluate the efficacy and safety of 12-week Subetta therapy in correcting 2-h plasma glucose in patients ...with IGT, a multicenter, double-blind, placebo-controlled, randomized clinical trial was performed. Derived by technological treatment of antibodies to insulin receptor β-subunit and endothelial NO synthase, Subetta increases the sensitivity of insulin receptors by activating the insulin signaling pathway. Oral glucose tolerance test (OGTT), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were examined at screening, after 4 and 12 weeks. In Per Protocol population, 2-h plasma glucose in the Subetta group decreased by 2.05 ± 2.11 mmol/L (versus 0.56 ± 2.55 mmol/L in the Placebo group) after 12 weeks. The difference between the two groups was 1.49 ± 2.33 mmol/L (p < 0.0001). After 12 weeks, 65.2% of patients had 2-h plasma glucose <7.8 mmol/L. FPG remained almost unchanged. HbA1c tended to decrease. The number of adverse events did not differ in both groups. Subetta treatment is beneficial for patients with IGT; it also prevents progression of carbohydrate metabolism disorders.
EMPA-REG OUTCOME is recognised by international guidelines as a landmark study that showed a significant cardioprotective benefit with empagliflozin in patients with type 2 diabetes (T2D) and ...cardiovascular disease. To assess the impact of empagliflozin in routine clinical practice, the ongoing EMPRISE study is collecting real-world evidence to compare effectiveness, safety and health economic outcomes between empagliflozin and DPP-4 inhibitors. A planned interim analysis of EMPRISE was recently published, confirming a substantial reduction in hospitalisation for heart failure with empagliflozin across a diverse patient population. In this commentary article, we discuss the new data in the context of current evidence and clinical guidelines, as clinicians experienced in managing cardiovascular risk in patients with T2D. We also look forward to what future insights EMPRISE may offer, as evidence is accumulated over the next years to complement the important findings of EMPA-REG OUTCOME.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Because alpha-lipoic acid (ALA), a potent antioxidant, prevents or improves nerve conduction attributes, endoneurial blood flow, and nerve (Na(+) K(+) ATPase activity in experimental diabetes and in ...humans and may improve positive neuropathic sensory symptoms, in this report we further assess the safety and efficacy of ALA on the Total Symptom Score (TSS), a measure of positive neuropathic sensory symptoms.
Metabolically stable diabetic patients with symptomatic (stage 2) diabetic sensorimotor polyneuropathy (DSPN) were randomized to a parallel, double-blind study of ALA (600 mg) (n = 60) or placebo (n = 60) infused daily intravenously for 5 days/week for 14 treatments. The primary end point was change of the sum score of daily assessments of severity and duration of TSS. Secondary end points were sum scores of neuropathy signs (NIS), symptoms (NSC), attributes of nerve conduction, quantitative sensation tests (QSTs), and an autonomic test.
At randomization, the groups were not significantly different by the criteria of metabolic control or neuropathic end points. After 14 treatments, the TSS of the ALA group had improved from baseline by an average of 5.7 points and the placebo group by an average of 1.8 points (P < 0.001). Statistically significant improvement from baseline of the ALA, as compared with the placebo group, was also found for each item of the TSS (lancinating and burning pain, asleep numbness and prickling), NIS, one attribute of nerve conduction, and global assessment of efficacy.
Intravenous racemic ALA, a potent antioxidant, rapidly and to a significant and meaningful degree, improved such positive neuropathic sensory symptoms as pain and several other neuropathic end points. This improvement of symptoms was attributed to improved nerve pathophysiology, not to increased nerve fiber degeneration. Because of its safety profile and its effect on positive neuropathic sensory symptoms and other neuropathic end points, this drug appears to be a useful ancillary treatment for the symptoms of diabetic polyneuropathy.
Objective: To evaluate the influence of combined therapy of sitagliptin and metformin on fat metabolism in patients with type 2 diabetes mellitus.
Methods: The study included 82 patients (age, ...55.3±9.1 years) with obesity and lipid metabolism disorders. None of the patients had reached their target glycated haemoglobin levels after metformin and diet therapy. Patients in gr1 (n=42) received 1.5-2-g metformin daily before the study and were switched to a formulation of 100-mg sitagliptin and 2-g metformin once a day. Patients in gr 2 (n=40) were on a diet therapy before inclusion and were started on 2-g metformin/day. The following were evaluated at baseline and after 6 months of therapy: fasting glucose levels, postprandial glucose levels, HbA1c, weight, waist circumference and lipid profile; insulin, proinsulin, leptin and adiponectin levels; HOMA IR and HOMA-β. In addition, magnetic resonance imaging was performed to assess the amount of visceral fat for the total cohort.
Results: After 6 months, HbA1c decreased by 18.52% (p <0.001) in gr 1 and by 8.17% (p <0.001) in gr 2. FPGl and PPG levels in gr 1 were reduced by 21% (p <0.001) and 26.35% (p <0.001), respectively; the corresponding reductions in gr 2 were 1.45% (p >0.05) and 5.31% (p <0.05), respectively. HOMA-β increased by 33% in gr1 (p <0.001) and by 11% in gr 2 (p >0.05). Adiponectin levels increased by 27.06% (p <0.001) in gr 1 and by 7.16% in gr 2 (p <0.001). Leptin levels were reduced by 30.47% (p <0.001) in gr 1 and by 5.41% in gr 2 (p <0.001). MRI showed a 7.52% reduction in visceral fat for gr 1 (p <0.001) and a 1.76% reduction for gr2 (p <0.01). The comparison of subcutaneous fat dynamics did not show statistically significant differences between the groups.
Conclusion: Compared with metformin monotherapy, sitagliptin and metformin combination therapy had a prominent effect on nonglycaemic parameters, with more marked decreases in visceral fat and leptin and increases in adiponectin levels.
Disclosure
A. Ametov: None. D. Gusenbekova: None.
Incretin hormones are important for normal pancreatic islet function and glucose homeostasis. Sensitivity to glucose of the α- and β-cells of the pancreas is diminished in type 2 diabetes mellitus ...(T2DM), leading to impaired insulin secretion, insulin resistance due to elevated glucagon levels in hyperglycaemia and impaired glucagon counterregulation in hypoglycaemia. In addition, T2DM is associated with increased lipotoxicity-induced insulin resistance. This article is a comprehensive review of the safety and efficacy of vildagliptin in patients with T2DM and evaluates the extra-pancreatic effects of incretin-based therapies. Clinical evidence has proven that vildagliptin effectively decreases HbA1c with a low risk of hypoglycaemia and is weight neutral. Vildagliptin also suppresses postprandial triglyceride (TG)-rich lipoprotein levels after ingestion of fat-rich meals and reduces fasting lipolysis, suggesting inhibition of fat absorption and reduced TG stores in non-fat tissues.
Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones initially discovered in the 1960s. GIP and GLP-1 have gained great scientific interest due ...to their properties in increasing insulin secretion and lowering blood glucose levels. The study of these incretin hormones has progressed substantially in recent decades, in that their systemic effects has begun to be actively discussed. In particular, incretins are involved in the pathogenesis of obesity and non-alcoholic fatty liver disease. Moreover, incretins are able to improve cognitive function, suppress the formation of -amyloid plaques and provide an oncoprotective effect. Recent data show promising oncoprotective effect of GLP-1 agonists on prostate and breast cancer.
This review provides systematisation of recent data on the role and mechanisms of action of incretin hormones on carbohydrate metabolism, as well as effects not related to glucose homeostasis, which contributes to a better understanding of potential vectors for the development of incretinotropic therapy. In addition, this review offers insight into pathogenic prerequisites and highlights the current issues in creating innovative polyagonists for treatment of type 2 diabetes mellitus.
Background. The indication for radiotherapy in oncological practice are metastases of differentiated thyroid cancer after thyroidectomy, the presence of distant metastases, or stage N1b, or negative ...dynamics of blood thyroglobulin levels after thyroidectomy for thyroid cancer. The mechanism of action of radiotherapy is based on provoking double-stranded DNA breaks. It is important to study the role of polymorphisms of NFKB1, ATM, ATG16L2 and ATG10 genes, products of which are involved in the processes of DNA damage response pathway and autophagy, in the formation of resistance to radioiodine therapy of thyroid cancer patients.
Aim. To examine the association between NFKB1, ATM, ATG16L2 and ATG10 polymorphisms and resistance to radioiodine therapy in thyroid cancer patients.
Materials and methods. The study included 181 patients (37 men, 144 women; mean age 53.515.7 years) with histologically confirmed thyroid cancer and a history of thyroidectomy who received radioiodine therapy. Carriage of single-nucleotide polymorphisms (rs230493) NFKB1, (rs11212570) ATM, (rs10898880) ATG16L2 and (rs10514231, rs1864183, rs4703533) ATG10 was determined by real-time PCR using TaqMan kits.
Results. Among 181 patients, resistance to radioiodine therapy was observed in 11 (6.1%) cases. No significant associations between the individual polymorphisms and resistance to radioiodine therapy were obtained, p0.05. Haplotype analysis showed that carriage of the C-C ATG10 rs10514231-rs1864183 haplotype was associated with an increased risk of developing resistance to radioiodine therapy, p=0.04.
Conclusion. Further studies on large samples of radioiodine therapy-resistant patients using whole-genome sequencing methods are required to specify the role of genetic factors in the response to 131I therapy.
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