Valdis Pirags

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial

BACKGROUNDnPatients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.nnnMETHODSnWe did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993.nnnFINDINGSnTwo patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups.nnnINTERPRETATIONnPioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Effects of Pioglitazone in Patients With Type 2 Diabetes With or Without Previous Stroke: Results From PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04)

Background and Purpose— Diabetes is an important risk factor for stroke. We conducted analyses in patients who had entered the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) with a history of stroke or without stroke. Methods— The prospective, double-blind PROactive (mean duration, 34.5 months) randomized 5238 patients with type 2 diabetes and a history of macrovascular disease to pioglitazone (titrated to 45 mg) or placebo, in addition to current diabetes and cardiovascular medications. Cardiovascular end-point events were independently adjudicated. This analysis evaluated the risk of stroke and other cardiovascular outcomes in patients with (n=984) and without (n=4254) prior stroke. Results— In patients with previous stroke (n=486 in the pioglitazone group and n=498 in the placebo group), there was a trend of benefit with pioglitazone for the primary end point of all-cause death, nonfatal myocardial infarction, acute coronary syndrome, and cardiac intervention (including coronary artery bypass graft or percutaneous coronary intervention), stroke, major leg amputation, or bypass surgery or leg revascularization (hazard ratio[HR]=0.78, event rate=20.2% pioglitazone vs 25.3% placebo; 95% CI=0.60–1.02; P=0.0670) and for the main secondary end point of all-cause death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.78, event rate=15.6% pioglitazone vs 19.7% placebo; 95% CI=0.58–1.06; P=0.1095). Pioglitazone reduced fatal or nonfatal stroke (HR=0.53, event rate=5.6% pioglitazone vs 10.2% placebo; 95% CI=0.34–0.85; P=0.0085) and cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (HR=0.72, event rate=13.0% pioglitazone vs 17.7% placebo; 95% CI=0.52–1.00; P=0.0467). Higher event rates were observed in patients with prior stroke compared with those without prior stroke. In patients without prior stroke, no treatment effect was observed for a first stroke. Conclusions— In a subgroup analysis from PROactive, pioglitazone reduced the risk of recurrent stroke significantly in high-risk patients with type 2 diabetes.

Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

This study establishes a mechanism for metabolic hyperalgesia based on the glycolytic metabolite methylglyoxal. We found that concentrations of plasma methylglyoxal above 600 nM discriminate between diabetes-affected individuals with pain and those without pain. Methylglyoxal depolarizes sensory neurons and induces post-translational modifications of the voltage-gated sodium channel Nav1.8, which are associated with increased electrical excitability and facilitated firing of nociceptive neurons, whereas it promotes the slow inactivation of Nav1.7. In mice, treatment with methylglyoxal reduces nerve conduction velocity, facilitates neurosecretion of calcitonin gene-related peptide, increases cyclooxygenase-2 (COX-2) expression and evokes thermal and mechanical hyperalgesia. This hyperalgesia is reflected by increased blood flow in brain regions that are involved in pain processing. We also found similar changes in streptozotocin-induced and genetic mouse models of diabetes but not in Nav1.8 knockout (Scn10−/−) mice. Several strategies that include a methylglyoxal scavenger are effective in reducing methylglyoxal- and diabetes-induced hyperalgesia. This previously undescribed concept of metabolically driven hyperalgesia provides a new basis for the design of therapeutic interventions for painful diabetic neuropathy.

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options.

Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients

AIMSnThe present study was undertaken to investigate the relationship between glyoxalase 1 (Glo1) enzyme activity and painful diabetic neuropathy (DN) in patients with diabetes mellitus.nnnMETHODSnGlo1 activity and biochemical markers were determined in blood samples from 108 patients with type 1 diabetes, 109 patients with type 2 diabetes, and 132 individuals without diabetes as a control. Painful and painless peripheral DN was assessed and multivariate regression analysis was used to determine independent association of Glo1 activity with occurrence of painful DN.nnnRESULTSnIn patients with type 1 and type 2 diabetes mellitus and painful DN compared to patients with painless DN, Glo1 activity was significantly reduced by 12 and 14%, respectively. The increase in Glo1 activity was significantly associated with reduced occurrence of painful DN after adjusting for confounders by multivariate analysis.nnnCONCLUSIONSnOur results demonstrate for the first time that Glo1 activity is lower in patients with both types of diabetes mellitus who were diagnosed with painful DN. These data support the hypothesis that Glo1 activity modulates the phenotype of DN and warrant further investigation into the role of Glo1 in DN.

Association of microsatellite polymorphisms of the human 14q13.2 region with type 2 diabetes mellitus in latvian and finnish populations

A polymorphic microsatellite in intron 6 of the human proteasome core particle PSMA6 gene (HSMS006), and four other microsatellites localized upstream on human chromosome 14q13.2 (HSMS801, HSMS702, HSMS701, HSMS602), were genotyped in 104 type 2 diabetic patients and 129 age‐matched control subjects from Latvia and replicated in 91 type 2 diabetic patients and 88 age‐matched healthy control subjects from the Botnia Study in Finland. In type 2 diabetic patients from both populations the HSMS006 (TG)22 allele was two times more frequent compared to the control group. In the Latvian population the (CAA)8 allele of the HSMS602 marker was less frequent in the diabetic group, as was the (AC)24 allele of microsatellite HSMS801. Allele frequencies of the HSMS701 and 702 repeats were similar in healthy controls and type 2 diabetic patients. In conclusion, our data suggest that variants in the PSMA6 gene on chromosome 14q13.2 are associated with type 2 diabetes.

Microsatellite genotyping of Chromosome 14q13.2-14q13 in the vicinity of proteasomal gene PSMA6 and association with Graves’ disease in the Latvian population

The 270-kb Chromosome 14q13.2-14q13 region harboring the proteasomal alpha subunitxa06 gene PSMA6 was analyzed for polymorphism of five microsatellite repeats in cases/controls and association with Graves’ disease. Four novel microsatellite markers were localized to the 14q13.2 region upstream of PSMA6. Dinucleotide repeats HSMS801, HSMS702, HSMS701 were identified in two introns of the gene KIAA0391; the most upstream trinucleotide HSMS602 marker was found in an intron of the C14orf24 gene. A polymorphism study performed on the Latvian population revealed 13 and 14 alleles for HSMS801 and HSMS702, respectively, seven alleles for HSMS701, and four alleles for HSMS602. Heterozygosity analysis revealed that all the four markers obey Hardy-Weinberg distribution. The previously described HSMS006 marker, represented by 12 alleles, is localized in intronxa06 of the PSMA6 gene. No significant differences were observed between patients and controls in allele distribution of the HSMS702 and HSMS701 microsatellite repeats. However, the allele frequencies of HSMS006 and HSMS801 were significantly different between Graves’ disease and control subjects. The 181- and 185-bp alleles of HSMS006 and the 133-, 143-, and 149-bp alleles of HSMS801 were found more often, but the 189- and 191-bp alleles of HSMS006 were much less frequent in Graves’ disease patients compared with the controls. An additional 174-bp allele of the HSMS602 marker, absent in healthy subjects, was found in Graves’ disease patients.

A comparison of efficacy and safety of an ezetimibe/simvastatin combination compared with other intensified lipid-lowering treatment strategies in diabetic patients with symptomatic cardiovascular disease

The low-density lipoprotein cholesterol (LDL-C) lowering efficacy of switching to ezetimibe/simvastatin (EZ/S) 10/20 mg versus doubling the run-in statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg in subjects with cardiovascular disease (CVD) and diabetes was assessed. Endpoints included percentage change in LDL-C and percentage of patients achieving LDL-C <70 mg/dL. Significantly greater reductions in LDL-C occurred when switching to EZ/S versus statin doubling in the overall population and in subjects treated with simvastatin 20 mg or atorvastatin 10 mg (all p < 0.001). The LDL-C reduction was numerically greater when switching to EZ/S versus switching to rosuvastatin (p = 0.060). Significantly more subjects reached LDL-C <70 mg/dL with EZ/S (54.5%) versus statin doubling (27.0%) or rosuvastatin (42.5%) in the overall population (all p < 0.001) and within each stratum (all p < 0.001). Switching to EZ/S provided significantly greater reductions in LDL-C versus statin doubling and significantly greater achievement of LDL-C targets versus statin doubling or switching to rosuvastatin.

SNPs of the PSMA6 gene: Investigation of possible association with myocardial infarction and type 2 diabetes mellitus

In our preceding studies, we have identified microsatellite polymorphisms inside the PSMA6 gene and in its 5′ upstream region. Following the observed associations of microsatellite polymorphisms with non-insulin dependent diabetes mellitus and Graves’ disease, we extended the evaluation of PSMA6 genetic variations to cardiovascular disorders and non-insulin dependent diabetes mellitus. New polymorphisms in the promoter region and exon 6 of the gene were identified by direct sequencing of the promoter region and all seven exons of the gene in 30 individuals of the European descent. Two SNPs at positions −110 and −8 from the translation start, in the promoter region and 5′ UTR, respectively, were analyzed. Neither polymorphism was associated with the risk of myocardial infarction. No significant association of the polymorphisms with plasma lipid levels or BMI was observed. A borderline association of both polymorphisms with diastolic blood pressure was observed in the control group. Genotype −8CG was significantly more frequent in type 2 diabetes patients, and haplotype C−110/G−8, compared to C−110/G−8 was associated with a higher risk of NIDDM.

Identification of glyoxalase 1 polymorphisms associated with enzyme activity

The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glycation end products (AGEs), such as methylglyoxal (MG) and other reactive dicarbonyls, the formation of which is increased in diabetes patients as a result of excessive glycolysis. MG is partly responsible for harmful protein alterations in living cells, notably in neurons, leading to their dysfunction, and recent studies have shown a negative correlation between GLO1 expression and tissue damage. Neuronal dysfunction is a common diabetes complication due to elevated blood sugar levels, leading to high levels of AGEs. The aim of our study was to determine whether single nucleotide polymorphisms (SNPs) in the GLO1 gene influence activity of the enzyme. In total, 125 healthy controls, 101 type 1 diabetes, and 100 type 2 diabetes patients were genotyped for three common SNPs, rs2736654 (A111E), rs1130534 (G124G), and rs1049346 (5-UTR), in GLO1. GLO1 activity was determined in whole blood lysates for all participants of the study. Our results showed a significant association between the minor alleles rs1130534 and rs1049346 and decreased enzyme activity (P=0.001 and P=2.61×10(-5), respectively). Increased allelic counts of the risk alleles were strongly associated with decreased GLO1 activity (standardised β=-0.24, P=2.15×10(-5)), indicating independent actions of these variants on GLO1 activity, as supported by the haplotype analysis. We showed for the first time an association between genetic variants with GLO1 enzyme activity in humans. SNPs in GLO1 can be used to predict enzyme activity and detoxifying capabilities, but further studies are needed to link these SNPs with common complications in diabetes.