Genetics: Is LADA just late onset type 1 diabetes?

Background: There is a controversy regarding Latent Autoimmune Diabetes in Adults (LADA) classification and whether it should be considered a slowly progressing form of type 1 (T1) diabetes (DM) or a distinct type of DM altogether. Methods: This cross-sectional study assessed major genes associated with T1DM (class II HLA, PTPN22 [rs2476601] and INS [rs689]) in patients with LADA, as compared with participants with T1DM (stratified according to age of diagnosis before or after 30) and T2DM. HLA genotyping of the DRB1, DQA1 and DQB1 loci was performed by reverse PCR sequence-specific oligonucleotides. HLA haplotypes were assigned according to those most frequently described in the European population. INS and PTPN22 SNPs were genotyped by real-time PCR. Results: A total of 578 participants were included: 248 with T1DM (70 diagnosed after the age of 30), 256 with T2DM and 74 with LADA. High risk HLA alleles were significantly more frequent in LADA than in T2DM, whereas the opposite was true for protective alleles. We found a lower frequency of the high-risk DRB1*04-DQB1*03:02-DQA1*03:01 haplotype in LADA (21.1%) than in the overall T1DM (34.7%) (p<0.05), whereas no differences were found between these groups for DRB1*03-DQB1*02:01-DQA1*05:01 or for protective alleles. Only 12% the overall T1DM group had no risk alleles vs 30% of LADA (p<0.0005). However, HLA allele distribution was similar in LADA and T1DM diagnosed after the age of 30. A total of 506 individuals (195 with T1DM [21 diagnosed after age 30] 253 with T2DM and 58 with LADA) were genotyped for the PTPN22 and INS SNPs. The G/A genotype of the PTPN22 rs2476601 was more frequent and the T/T genotype of the INS SNP rs689 was less frequent in T1DM compared to LADA. We did not find any significant differences in the frequency of the mentioned SNPs between LADA and T2DM, or between LADA and T1DM diagnosed after the age of 30. Conclusion: In this relatively small cross-sectional study, the genetic profile of subjects with LADA showed a similar T1DM-related risk allele distribution as in participants with T1DM diagnosed after the age of 30, but fewer risk alleles than those diagnosed before 30. Differences were present for HLA, as well as PTPN22 and INS genes.

Kidney function and glucose metabolism in overweight and obese cats.

Background: In people, obesity and prediabetes mellitus might predispose to chronic kidney disease (CKD).Aims: To assess the association of overweight [Body condition score (BCS) >5] and glucose metabolism alterations, with established or potential markers of CKD. In addition, fructosamine and fasted blood glucose were compared as predictors of early abnormal glucose metabolism.Methods: 54 clinically healthy cats were included in a cross-sectional study comprising 25 neutered males and 29 (28 neutered) females aged 7.2 (5.5-9.4) years. Two potential markers of CKD, namely urinary free active transforming growth factor-ß1-creatinine ratio and urinary retinol binding protein-creatinine ratio were measured along with other parameters to assess CKD. A receiver operating curve was used to identify the best sensitivity and specificity of fructosamine to identify cats with fasting glucose >6.5 mmol/L.Results: No association was found between BCS and markers of CKD. Fructosamine was greater in cats with fasting glucose >6.5 mmol/L compared to those with fasting glucose ≤6.5 mmol/L. A fructosamine concentration ≥250 µmol/L was able to detect cats with hyperglycemia with a sensitivity of 77% and a specificity of 65%. Furthermore, fructosamine was more strongly correlated with fasting glucose than albumin-corrected fructosamine (r = 0.43, p = 0.002 vs r = 0.32, p = 0.026). Cats with higher fructosamine had lower serum symmetric dimethylarginine concentrations.Conclusion: The present study does not suggest an effect of obesity on renal function in domestic cats.Clinical relevance: Fructosamine might be of value for the diagnosis of prediabetes mellitus in cats.

Assessment of Alimentación Normal con Ajuste de Insulina (ANAIS), a Spanish version of the DAFNE programme, in people with Type 1 diabetes: a randomized controlled parallel trial.

AIM: To evaluate the effects of Alimentación Normal con Ajuste de Insulina (ANAIS), a group-based, therapeutic education programme for Type 1 diabetes based on a flexible insulin regimen adjusted to the individual's food intake. METHODS: Participants with Type 1 diabetes and HbA1c levels of 53-86 mmol/mol (7-10%) were recruited from outpatient clinics at a tertiary care centre. They were randomized (using opaque, sealed envelopes, with a 2:1 treatment allocation ratio) to attend the training course immediately (immediate ANAIS; intervention group) or a year later (delayed ANAIS; control group). The main outcome was HbA1c level at 1 year. Secondary outcomes included lipid levels, weight, hypoglycaemic events, insulin dose, treatment satisfaction, self-perceived dietary freedom, quality of life and participant-defined goals. RESULTS: A total of 48 participants were assigned to the intervention group and 32 to the control group. Twelve months after completing the training, adjusted HbA1c was not significantly different in the intervention group [64 ± 1.3 vs 68 ± 1.6 mmol/mol (8.0 ±0.1% vs 8.4 ±0.1%); P=0.081]. Treatment satisfaction was significantly higher in the intervention group, but no differences were found in hypoglycaemic events, weight, insulin dose or changes in dietary freedom. At 1 year after the intervention, 72% of the participants (vs 33% in the control group; P=0.046) reported exceeding their expectations regarding achievement of their main personal goal. CONCLUSION: Promoting dietary freedom and empowering people with Type 1 diabetes through structured education programmes, such as ANAIS, improves treatment satisfaction and self-defined goals. No significant improvement in HbA1c level was achieved.

Effect of liraglutide on physical performance in type 2 diabetes: Results of a randomized, double-blind, controlled trial (LIPER2).

AIMS: To assess the effect of the GLP-1 analogue liraglutide on measures of cardiac function and physical performance in patients with type 2 diabetes (T2D). METHODS: In this phase-IV randomized double-blind placebo-controlled parallel-group clinical trial at a tertiary hospital, T2D patients with HbA1c levels of 7-10% with oral agents and/or intermediate-/long-acting insulin were allocated (computer-generated randomization, ratio 1:1) to either liraglutide 1.8 mg/day or a placebo for 6 months. The primary endpoint was maximum oxygen consumption (VO2max) during cycle ergometry, while other procedures included a 6-min walk test, echocardiography, anthropometry and blood tests. Safety endpoints were also monitored, and an intention-to-treat analysis was performed. RESULTS: A total of 24 patients (15 women) aged 52 (11.7) years, with diabetes duration of 8.7 (5.8) years, BMI 34.98 (6.2) kg/m2 and HbA1c 8.2% (0.68%), were randomized to liraglutide 1.8 mg daily or placebo. There were no differences in VO2max [17.98 (4.8) vs. 15.90 (4.96) mL/kg/min; P > 0.10], VE/VCO2 slope [30.18 (4.8) vs. 32 (4.49)], left ventricular ejection fraction or 6-min walk test [530.7 (86) vs. 503.9 (84) m] at 6 months. HbA1c was lower (6.7% vs. 7.7%; P = 0.005), with a trend towards lower maximum systolic blood pressure during ergometry [171.7 (24.4) vs. 192.5 (25.6); P = 0.052] in the liraglutide group at the end of the study. There were no severe adverse events. CONCLUSION: In this trial, liraglutide improved glycaemic control in T2D, but had no significant effects on either physical performance or myocardial function.

ISO-based assessment of accuracy and precision of glucose meters in dogs.

BACKGROUND: Portable blood glucose meters (PBGMs) allow easy glucose measurements. As animal-specific PBGMs are not available everywhere, those for humans are widely used. OBJECTIVES: To assess the accuracy and precision of 9 PBGMs in canine whole blood (WB) and plasma, based on the ISO 15197:2013. ANIMALS: Fifty-nine client-owned dogs attending the Veterinary Teaching Hospital. METHODS: Analytical evaluation of 100 blood samples was performed for accuracy and 23 for precision (glucose 29-579 mg/dL) following ISO recommendations. A PBGM was considered accurate if 95% of the measurements were within ±15 mg/dL from the reference when glucose was <100 mg/dL and within ±15% when it was ≥100 mg/dL, and if 99% of them were within zones A and B in error grid analysis (EG). A hexokinase-based analyzer was used as reference. Ninety samples were assessed for hematocrit interferences. RESULTS: Accuracy requirements were not fulfilled by any PBGM in WB (74% of measurements within the limits for the most accurate) and by 1 only in plasma. However, the EG analysis in WB was passed by 6 PBGM and by all in plasma. The most accurate were also the most precise, with coefficients of variation <5% in WB and <3% in plasma. Hematocrit correlated with bias against the reference method in 4 PBGM (r = -0.243 - [-0.371]; P < .021). CONCLUSIONS AND CLINICAL IMPORTANCE: This disparity among PBGM suggests that meters approved for humans need to be evaluated before use in other species.

Insulin resistance explains the relationship between novel cardiovascular risk factors and hypertension. The Telde Study.

BACKGROUND: Most studies describing an association between hypertension and an inflammatory/pro-thrombotic state do not assess insulin resistance. AIM: To examine the association between hypertension and new cardiovascular risk factors when considering both classical risk factors and insulin resistance. METHODS: In a population-based sample of 1030 subjects, clinical information and blood samples were obtained. Subjects were classified according to the presence or absence of hypertension, and insulin resistance was estimated using the homeostasis model of assessment (HOMA). To identify variables independently associated with hypertension, a four-model multiple logistic regression was performed: model 1 included novel risk factors (Plasminogen Activator Inhibitor- 1 [PAI-1], fibrinogen, von Willebrand Factor [vWF], lipoprotein(a), homocysteine and C-reactive Protein [CRP]); model 2, novel risk factors plus HOMA; model 3 included both classical (smoking, triglycerides, HDL cholesterol, total cholesterol, waist circumference and diabetes) and novel risk factors and model 4, model 3 plus HOMA. All were adjusted for age, BMI and gender and compared using Akaike's Information Criterion (AIC). RESULTS: In model 1, only PAI-1, age and BMI showed association with hypertension.When HOMA and classical risk factors were also included, PAI-1 was replaced by triglyceride, smoking and diabetes. The lowest AIC value (best adjustment) was displayed by model 4, comprising all of the variables. Only age, BMI, HOMA and smoking remained significantly associated with hypertension. CONCLUSIONS: The novel cardiovascular risk factors assessed do not add information as markers of hypertension when classical risk factors or insulin resistance are included in the evaluation.

Differences in traditional and emerging cardiovascular risk factors of subjects discordantly classified by metabolic syndrome definitions of the International Diabetes Federation and the National Cholesterol Education Program.

BACKGROUND AND AIM: Several working definitions of metabolic syndrome have been proposed for clinical use. However, individuals can be discordantly classified as having or not having metabolic syndrome depending on the choice of one or another definition. This study compared the cardiovascular risk profile of subjects concordantly and discordantly diagnosed by the criteria of the National Cholesterol Education Program (NCEP) and the criteria of the International Diabetes Federation (IDF). METHODS AND RESULTS: Nine hundred and twenty-nine non-diabetic adult subjects belonging to a cross-sectional population-based study in Gran Canaria island (Spain) were assessed. Participants completed a questionnaire and underwent physical examination, fasting blood analyses, and a standardized oral glucose tolerance test. Two hundred and four subjects (22%) had metabolic syndrome according to both definitions, 31 (3.3%) only by the IDF criteria, and 5 (0.5%) only by the NCEP criteria. Participants fulfilling both proposals showed more adverse age and sex-adjusted measures of BMI, waist, HDL cholesterol, triglycerides, post-load glucose, HOMA-IR and plasminogen inhibitor activator-1 (PAI-1) than individuals exclusively satisfying the IDF criteria. Moreover, in contrast to subjects meeting both criteria, those that fulfilled only the IDF criteria had levels of BMI, waist, total and HDL cholesterol, post-load glucose, glycated HbA1c, C-reactive protein, PAI-1 and fibrinogen not significantly different from those observed in subjects without metabolic syndrome. CONCLUSION: The IDF definition identifies a surplus of individuals whose cardiovascular risk profile, particularly regarding to some non-traditional cardiovascular risk factors, is less adverse than that observed in subjects also diagnosed by the NCEP definition.

Gender dimorphism in body composition abnormalities in acromegaly: males are more affected than females.

BACKGROUND: Acromegaly changes body composition (BC), but long-term gender differences have not been reported. OBJECTIVE: To evaluate BC in active and controlled acromegalic patients. DESIGN AND METHODS: Clinical and biochemical variables and BC (by dual-energy X-ray absorptiometry) were evaluated in 60 acromegalic patients (19 active, 41 controlled) and 105 controls, matched for age and gender. RESULTS: Acromegalic males (n=24) had more total mass (89+/-13 vs 76.5+/-15.3 kg, P<0.001), lean body mass (LBM; 64.6+/-8.7 vs 56.4+/-5.8 kg, P<0.001), and bone mineral content (BMC; 2.9+/-0.5 vs 2.6+/-0.3 kg, P<0.05) than controls (n=33). Controlled male patients (n=14) had more total mass (89+/-14.7 vs 76.5+/-15.3 kg, P<0.05) and a trend to have more LBM (61.8+/-9.4 vs 56.4+/-5.8 kg, P=0.065) than controls. Only in active disease was a decrease in fat mass (FM) observed, compared with controlled patients and controls (males: 19.5+/-5.3 vs 27+/-6.2 and 25.9+/-4%, P<0.001; females: 30.3+/-6.7 vs 37.1+/-5.8 and 36.5+/-6.6%, P<0.01). In females, no further differences were observed. No differences in BMC were found between eugonadal and hypogonadal acromegalic patients, but in hypogonadal females, acromegaly appeared to prevent the BMC loss seen in hypogonadal postmenopausal controls. GH and IGF1 levels were negatively correlated with FM (males, P<0.05; females, P<0.001), but in the regression analysis GH was a predictor of FM only in women. CONCLUSIONS: Control of acromegaly reverts decreased FM in both genders; only in males more total mass and a trend for more LBM persist. The anabolic effect of GH on bone reverted in cured males, but persisted in females and appeared to override the bone loss of menopause.

Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase?

AIMS/HYPOTHESIS: Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. MATERIALS AND METHODS: Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 microg/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. RESULTS: A high level of PIMT protein was detected in beta cells. CGP3466B induced a two- to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokine-induced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6+/-9.0 vs 84.3+/-6.8 vs 106.6+/-13.5 days, respectively; p<0.01 for high-dose vs low-dose and control groups), the severity of the disease was reduced (glucose 22.2+/-3.2 vs 16.9+/-2.6 vs 15.8+/-2.7 mmol; p<0.01 for high- and low-dose groups vs control group) and residual beta cells were more frequently identified (43% vs 71% vs 86%; p<0.05 for high-dose vs control group) in the treated animals. CONCLUSIONS/INTERPRETATION: The results support a role for post-translational modifications and PIMT in the development of type 1 diabetes in the diabetes-prone BB rat, and perhaps also in humans.

Determinants of neurosurgical outcome in pituitary tumors.

OBJECTIVE: Neurosurgery is one of the main therapies for pituitary tumors; optimising outcome is highly desirable for the patient and the health system. We have analysed predictors of outcome in surgically treated pituitary adenomas operated in this centre. DESIGN AND PATIENTS: A total of 289 patients underwent neurosurgery for a pituitary tumor, by the same two neurosurgeons, between 1982 and 2001. Their records were examined to find predictors of post-surgical outcome. Thirty-eight percent were males, with a median age of 40.8 (8-82.7) yr; 51.9% had been operated since 1992, 92.2% by the transsphenoidal route. Most tumors (70.2%) were macroadenomas; 28.4% were non-functioning, 27.3% secreted PRL, 26.3% GH of which 14 (4.8%) also secreted PRL, 17.3% ACTH, 0.3% FSH and 0.3% TSH. RESULTS: A stepwise, forward logistic regression analysis revealed tumor size as the only significant predictor of radiological cure [odds ratio (OR) for macroadenoma 0.16 vs microadenoma, p=0.0005]. Hormonally, PRL-secretion by the tumor was a predictor of poor prognosis (OR 3.29 for cure of non-PRL-secreting tumors, p=0.005), as was tumor size (OR 0.45 for cure of macroadenomas, p=0.005). Considering simultaneous radiological and hormonal remission, tumor size (OR 0.35 for macroadenoma, p=0.0002), and operation date (OR 0.40 for up to 1991, p=0.0002) were the only significant predictors. CONCLUSIONS: PRL secretion, tumor size and operation date are the main predictors of neurosurgical outcome in pituitary tumors, the latter suggesting that neurosurgical experience plays an important role.

The inflammatory properties of electronegative low-density lipoprotein from type 1 diabetic patients are related to increased platelet-activating factor acetylhydrolase activity.

AIMS/HYPOTHESIS: Chemical and biological characteristics of LDL(-) from type 1 diabetic subjects were analysed. The diabetic patients were studied during poor and optimised glycaemic control. MATERIALS AND METHODS: Total LDL was subfractionated into electropositive LDL(+) and electronegative LDL(-) by anion exchange chromatography and the lipid and protein composition of the two determined. RESULTS: LDL(-) differed from LDL(+) in that it had higher triglyceride, non-esterified fatty acids, apoE, apoC-III and platelet-activating factor acetylhydrolase (PAF-AH), as well as lower apoB relative content. No evidence of increased oxidation was observed in LDL(-). LDL(-) increased two-fold the release of interleukin 8 (IL-8) and monocyte chemotactic protein 1 (MCP-1) in endothelial cells, suggesting an inflammatory role. Optimisation of glycaemic control after insulin therapy decreased the proportion of LDL(-), but did not modify the composition of LDL subfractions, except for a decrease in PAF-AH activity in LDL(-). The possibility that LDL(-) could be generated by non-enzymatic glycosylation was studied. Fructosamine and glycated LDL content in LDL subfractions from type 1 diabetic patients was greater than in LDL subfractions isolated from normoglycaemic subjects, and decreased after glycaemic optimisation in both subfractions. However, no difference was observed between LDL(+) and LDL(-) before and after insulin therapy. CONCLUSIONS/INTERPRETATION: These results provide evidence that LDL(-) is not produced by glycosylation. Nevertheless, LDL(-) from diabetic patients displays inflammatory potential reflected by the induction of chemokine release in endothelial cells. This proatherogenic effect could be related to the high PAF-AH activity in LDL(-).

Quantitative effect of glycaemic improvement on the components of diabetic dyslipidaemia: a longitudinal study.

In order to assess the effect of glycaemic improvement on lipoprotein concentrations, we studied 73 type 2 diabetic subjects before (HbA1c 10.1 (6.2-16)%) and after (HbA1c 6.6 (3.8-8.0)%) glycaemic improvement. Total triglyceride and cholesterol (c), LDLc, HDLc, non-HDLc and apolipoproteins AI (apoAI) and B (apoB) were measured. Bivariate correlations and step-wise, multivariate analysis were performed to find predictors of change in the different components of diabetic dyslipidaemia. Changes in HDLc (r = -0.358, P = 0.001), apoAI (r = -0.355, P = 0.003), apoAI/apoB ratio (r = -0.333, P = 0.005), weight (r = -0.245, P = 0.046) and BMI (r = -0.253, P = 0.039) correlated with that of HbA1c, but, in multivariate analysis, only changes in HDLc, apoAI and apoAI/apoB ratio were predicted by the decrease in HbA1c. For the median observed change in HbA1c (-3.3 percentage-points), the estimated changes were +0.14 mmol/l, +0.12 g/l and +0.20 for HDLc, apoAI and apoAI/apoB ratio, respectively, accounting for 81, 92 and 80% of the observed changes. In conclusion, for the component of diabetic dyslipidaemia for which less therapeutic tools are available, glycaemic improvement is most effective.

LDL-cholesterol/apolipoprotein B ratio is a good predictor of LDL phenotype B in type 2 diabetes.

LDL phenotype B is a component of diabetic dyslipidaemia, but its diagnosis is cumbersome. Our aim was to find easily available markers of phenotype B in a group of type 2 diabetic subjects. We studied 123 type 2 diabetic patients (67.5% male, aged 59.3+/-10.1 years, mean HbA1c 7.4%). Clinical features and fasting total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol (LDLc, using Friedewald's equation and an alternative formula), apolipoprotein B (apoB), lipoprotein (a) and LDL particle size (on gradient polyacrylamide gel electrophoresis) were assessed. Patients with phenotypes A (predominant LDL size > or =25.5 nm) and B (<25.5 nm) were compared, and regression analysis was performed to find the best markers of LDL particle. Cut-off points were obtained and evaluated as predictors of phenotype B (kappa index). Patients with phenotype B (36%) showed higher total cholesterol, triglyceride and apolipoprotein B, and lower HDL cholesterol and LDLc/apoB ratio. Triglyceride was the best predictor of LDL particle size (r=-0.632, p<0.01), but an LDLc/apoB ratio below 1.297 mmol/g detected phenotype B best (sensitivity 65.9%, specificity 92.4%, kappa=0.611). Although triglyceride concentration is the best predictor of LDL size in type 2 diabetes, LDLcholesterol/apolipoproteinB ratio is the best tool to detect phenotype B.

The effect of manual forestripping on milking performance of Holstein dairy cows.

The objective of this study was to evaluate the effects of forestripping as a premilking stimulation technique on milk yield, milking unit attachment time, and milk flow rates in Holstein dairy cattle. Multiparous Holstein cows (n = 24) were divided into two groups (HPE, high producing, early lactation; LPL, low producing, late lactation) based on prestudy milk yield and stage of lactation. Within the production group, cows were randomly assigned into treatment (n = 6) and control groups (n = 6) in a switchback design. Cows were milked twice daily and treatments were switched after 20 milkings. Premilking udder preparation for the treatment group was as follows: forestripping, predipping with 0.5% iodine, and drying with paper towels followed by unit attachment. Udder preparation for the control group was identical except forestripping was not performed. Data were analyzed by using the PROC Means and PROC Mixed models described by SAS. During the study, cows in the HPE group produced significantly more milk and had longer milking unit attachment times compared with cows in the LPL group. The milk flow rate was 0.36 kg/min faster for the HPE cows compared with the LPL cows. There was no significant effect of order of treatment administration on any outcome variable. There were no significant differences in milk yield, milk unit attachment time, or milk flow for animals that were forestripped compared with animals that were not forestripped. In this study, the addition of forestripping to an otherwise acceptable premilking udder preparation routine did not increase milking performance of multiparous Holstein dairy cows.

Diabetes mellitus and cardiovascular disease.

Diabetes is associated with a high incidence and poor prognosis of cardiovascular disease, and with high short- and long-term mortality. Adequate treatment of cardiovascular disorders and aggressive management of coexisting risk factors have proved to be at least as effective in diabetic as in nondiabetic patients in randomized, controlled studies. Indeed, treating diabetic patients with cardiovascular disease results in a larger absolute risk reduction than in nondiabetic subjects. Nevertheless, diabetic patients often receive inadequate therapy, which may, to a certain extent, explain their poor prognosis. Recommendations for the treatment of diabetic patients with acute myocardial infarction should include beta-blockers, aspirin, and ACE-inhibitors in all patients in whom no specific contraindications exist. Fibrinolysis should be administered when indicated, and the benefits of improving glycemic control should not be forgotten either. In patients with multi-vessel disease who need revascularization, when selecting the type of procedure, the superiority of surgical revascularization over angioplasty should be borne in mind. Even heart transplantation should be included as a therapeutic option since there are no data to support the exclusion of patients on account of their diabetes. Finally, coexisting risk factors should be intensively treated through lifestyle intervention, with or without drug therapy, in order to achieve secondary prevention goals.