Impact of the individual components of the metabolic syndrome and their different combinations on the prevalence of atherosclerotic vascular disease in type 2 diabetes: the Diabetes in Germany (DIG) study

<p>Abstract</p> <p>Background</p> <p>One of the major controversies surrounding the metabolic syndrome (MetS) in type 2 diabetes is whether its single components act synergistically as risk factors for atherosclerotic vascular disease (AVD). We aimed to answer this by evaluating the relationship, and its various combinations to AVD in comparison to single traits in a population-based study with type 2 diabetes in Germany.</p> <p>Methods and results</p> <p>4020 unselected patients with type 2 diabetes aged 35 – 80 years. MetS was: diabetes plus ≥ 2 traits of the MetS by AHA/NHBLI definition.</p> <p>AVD was: history of myocardial infarction and/or coronary revascularization and/or stroke. The occurrence of AVD in relation to overall MetS/single traits/combinations was presented as OR (95% CI). Multiple logistic regression, including established cardiovascular risk factors, modeled their associations.</p> <p>The prevalence of overall MetS was 74.4% and the OR for AVD was 1.41 (1.12–1.78), which however was higher for hypertension as single trait (OR 4.76). Different combinations of MetS presented a wide range of ORs (0.47 to 10.90) and strong sex differences. Some clusters of MetS including hypertension and low HDL-cholesterol presented a higher risk factor than single traits or their sum, whereas the others out of 11 possible carried no increased AVD risk. Multiple logistic regression showed independent association between AVD and overall MetS.</p> <p>Conclusion</p> <p>The overall MetS in type 2 diabetes comprises 11 heterogenous clusters of traits. Overall MetS increases the risk of AVD in type 2 diabetes and individual traits in some clusters with hypertension and low HDL-cholesterol may act synergistically as risk factors particularly in women.</p

Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of Pioglitazone, Metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study

<p>Abstract</p> <p>Background</p> <p>We analyzed specific effects of an add-on therapy with pioglitazone compared to metformin and their combination in patients with basal insulin treatment on biomarkers of CV risk.</p> <p>Methods</p> <p>In this double-blind, randomized, multicentre, active comparator controlled trial, 121 patients with type 2 diabetes were enrolled. Inclusions: treatment with basal insulin, HbA_1C6.5% - 8.5%, age 30 - 75 years. After glargine therapy over 2 weeks for titration towards FBG ≤ 7.8 mmol/L, patients received either (A) bid 850 mg metformin (n = 42), (B) bid 15 mg pioglitazone (n = 40), or (C) 30 mg pioglitazone plus 1.7 g metformin (n = 39) over 6 months. Matrix Metal Proteinase 9 (MMP-9) was primary objective, together with biomarkers of CV risk.</p> <p>Results</p> <p>Pioglitazone (B) reduced MMP-9 versus baseline by 54.1 + 187.1 ng/mL, with metformin (A) it was increased by 49.6 + 336.2 ng/mL (p = 0.0345; B vs. A), and with the combination of both (C) it was decreased by 67.8 + 231.4 ng/mL (A vs. C: p = 0.0416; B vs. C: p = 0.8695). After logarithmic transformation due to high variances the exploratory results showed significance for A vs. B (p = 0.0043) and for A vs. C (p = 0.0289).</p> <p>Insulin dosage was reduced by 7.3 units in group B (p < 0.0001), by 6.0 units in C (p = 0.0004), but was increased by 2.5 units (p = 0.1539) in A at follow up. Reduction in hs-CRP was significant within treatment groups for B (p = 0.0098) and C (p < 0.0001), and between the groups for A vs. C (p = 0.0124). All three single regimens reduced PAI-1. Adiponectin was significantly elevated in B and C (p < 0.0001) and between-groups. HbA_1Cwas only significantly decreased in the combination group. No significant effects were observed for NFkB and PGFα. peripheral edema were seen in 11.9% vs. 40.0% vs. 20.5%, and weight change was -0.7 kg vs. +4.3 kg vs. +2.7 kg (A vs. B vs. C).</p> <p>Conclusions</p> <p>Addition of pioglitazone but not of metformin reduces MMP-9, hs-CRP and increased insulin sensitivity and adiponectin in this study. The combination of both had no additional effect on inflammation. Pioglitazone is suggested to be a rational add-on therapy to basal insulin in patients with high CV risk.</p

The metabolic vascular syndrome - guide to an individualized treatment

In ancient Greek medicine the concept of a distinct syndrome (going together) was used to label 'a group of signs and symptoms' that occur together and 'characterize a particular abnormality and condition'. The (dys)metabolic syndrome is a common cluster of five pre-morbid metabolic-vascular risk factors or diseases associated with increased cardiovascular morbidity, fatty liver disease and risk of cancer. The risk for major complications such as cardiovascular diseases, NASH and some cancers develops along a continuum of risk factors into clinical diseases. Therefore we still include hyperglycemia, visceral obesity, dyslipidemia and hypertension as diagnostic traits in the definition according to the term 'deadly quartet'. From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease. Thus metabolic and vascular abnormalities are in extricable linked. Therefore it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity. This has important implications for integrated diagnostics and therapeutic approach. According to the definition of a syndrome the rapid global rise in the prevalence of all traits and comorbidities of the MVS is mainly caused by rapid changes in life-style and sociocultural transition resp. with over- and malnutrition, low physical activity and social stress as a common soil

The role of co-morbidity in the selection of antidiabetic pharmacotherapy in type-2 diabetes

Metformin is, if not contraindicated and if tolerated, usually preferred over other antidiabetic drugs for the first line treatment of type-2 diabetes. The particular decision on which antidiabetic agent to use is based on variables such as efficacy, cost, potential side effects, effects on weight, comorbidities, hypoglycemia, risk, and patient preferences. However, there is no guidance how to consider these in the selection of antidiabetic drug treatment. In this work, we aimed to summarize available evidence and tried to give pragmatic treatment recommendations from a clinical practice perspective. There are clear contraindications for some drugs in those with impaired renal and liver function and precautions in those with heart failure for the use of metformin (NYHA III-IV) and glitazones. On the other hand, GLP-1 analogs, DPP-4 inhibitors and acarbose are generally less critical and can be used in the majority of patients. We identified the following gaps with respect to the selection of antidiabetic drug treatment in patients with co-morbid disease conditions: 1) Guidelines fail to give advice on the use of specific antidiabetic drugs in patients with co-morbidity. 2) The literature is deficient in studies documenting antidiabetic drug use in patients with severely impaired renal function, diabetic retinopathy, cerebrovascular disease and systolic heart failure. 3) Further there are no specific data on patients with multiple of these co-morbid disease conditions. We postulate that differential use of antidiabetic drugs in patients with co-morbid disease constellations will help to reduce treatment related complications and might improve prognosis

Sudomotor Testing of Diabetes Polyneuropathy

Objective: The performance of the Sudoscan technology for diagnosing diabetic polyneuropathy (DPN) was evaluated against the quantitative sudomotor axon reflex test (QSART). Furthermore, the association of Sudoscan with two clinical neuropathy scoring systems was evaluated.Methods: Forty-seven patients with type 2 diabetes (20 without DPN, 27 with DPN) and 16 matched controls were examined for neuropathic symptoms and for the extent of sensory deficits. Sweat latency and volume by QSART and the skin electrochemical conductance (ESC) by Sudoscan were measured.Results: The feet and hand ESC was significantly lower in patients with DPN as compared to controls. Patients with DPN had also lower hand ESC than patients without DPN. Sensitivity and specificity of feet and hand ESC for detecting DPN were 70/85% and 53/50% respectively. QSART could not differentiate between the three groups. ESC was inversely related to neuropathic symptoms and sensory impairment. ESC was significantly correlated with sensory impairment and pain.Conclusions: Sudoscan shows a good performance in detecting subjects with DPN and it correlates well with clinical signs and symptoms of neuropathy.Significance: This study provides evidence that Sudoscan has high potential to be used as screening tool for DPN and possibly also for small fiber neuropathy in diabetic patients.HIGHLIGHTS- The sudomotor function test Sudoscan shows a good performance to detect diabetes peripheral neuropathy.- Sudoscan measures significantly correlate with clinical signs and symptoms of neuropathy.- The Sudoscan technology may help to secure clinical diagnosis of small fiber neuropathy

Effect of the addition of rosiglitazone to metformin or sulfonylureas versus metformin/sulfonylurea combination therapy on ambulatory blood pressure in people with type 2 diabetes: A randomized controlled trial (the RECORD study)

BACKGROUND: Hypertension and type 2 diabetes are common co-morbidities. Preliminary studies suggest that thiazolidinediones reduce blood pressure (BP). We therefore used ambulatory BP to quantify BP lowering at 6-12 months with rosiglitazone used in combination with metformin or sulfonylureas compared to metformin and sulfonylureas in people with type 2 diabetes. METHODS: Participants (n = 759) in the multicentre RECORD study were studied. Those taking metformin were randomized (open label) to add-on rosiglitazone or sulfonylureas, and those on sulfonylurea to add-on rosiglitazone or metformin. RESULTS: 24-Hour ambulatory BP was measured at baseline, 6 months and 12 months. At 6 and 12 months, reductions in 24-hour ambulatory systolic BP (sBP) were greater with rosiglitazone versus metformin (difference at 6 months 2.7 [95% CI 0.5-4.9] mmHg, p = 0.015; 12 months 2.5 [95% CI 0.2-4.8] mmHg, p = 0.031). Corresponding changes for ambulatory diastolic BP (dBP) were comparable (6 months 2.7 [95% CI 1.4-4.0] mmHg, p < 0.001; 12 months 3.1 [95% CI 1.8-4.5] mmHg, p < 0.001). Similar differences were observed for rosiglitazone versus sulfonylureas at 12 months (sBP 2.7 [95% CI 0.5-4.9] mmHg, p = 0.016; dBP 2.1 [95% CI 0.7-3.4] mmHg, p = 0.003), but differences were smaller and/or not statistically significant at 6 months (sBP 1.5 [95% CI -0.6 to 3.6] mmHg, p = NS; dBP 1.3 [95% CI 0.0-2.5] mmHg, p = 0.049). Changes in BP were not accompanied by compensatory increases in heart rate, did not correlate with basal insulin sensitivity estimates and were not explained by changes in antihypertensive therapy between the various strata. CONCLUSION: When added to metformin or a sulfonylurea, 12-month treatment with rosiglitazone reduces ambulatory BP to a greater extent than when metformin and a sulfonylurea are combined. TRIAL REGISTRATION: NCT00379769 http://clinicaltrials.gov

Structured health care for subjects with diabetic foot ulcers results in a reduction of major amputation rates

OBJECTIVE: We tested the effects of structured health care for the diabetic foot in one region in Germany aiming to reduce the number of major amputations. RESEARCH DESIGN AND METHODS: In a prospective study we investigated patients with diabetic foot in a structured system of outpatient, in-patient and rehabilitative treatment. Subjects were recruited between January 1(st), 2000 and December 31, 2007. All participants underwent a two-year follow-up. The modified University of Texas Wound Classification System (UT) was the basis for documentation and data analysis. We evaluated numbers of major amputations, rates of ulcer healing and mortality. In order to compare the effect of the structured health care program with usual care in patients with diabetic foot we evaluated the same parameters at another regional hospital without interdisciplinary care of diabetic foot (controls). RESULTS: 684 patients with diabetic foot and 508 controls were investigated. At discharge from hospital 28.3% (structured health care program, SHC) vs. 23.0% (controls) of all ulcers had healed completely. 51.5% (SHC) vs. 49.8% (controls) were in UT grade 1. Major amputations were performed in 32 subjects of the structured health care program group (4.7%) vs. 110 (21.7%) in controls (p<0.0001). Mortality during hospitalization was 2.5% (SHC) vs. 9.4% in controls (p<0.001). CONCLUSIONS: With the structured health care program we achieved a significant reduction of major amputation rates by more than 75% as compared to standard care

Identification of the UBP1 Locus as a Critical Blood Pressure Determinant Using a Combination of Mouse and Human Genetics

Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27 recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897 G/A, located within the UBP1 locus, with systolic and diastolic BP (rs17030583: 1.3±0.4 mmHg p<0.001, 0.8±0.3 mmHg p = 0.006, respectively and rs2291897: 1.5±0.4 mmHg p<0.001, 0.8±0.3 mmHg p = 0.003, respectively) in three separate studies. Our study, which underscores the marked complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest that UBP1 and its functional partners are components of a network controlling blood pressure