Francisco J. Nóvoa

Differences in cardiovascular risk profile of diabetic subjects discordantly classified by diagnostic criteria based on glycated hemoglobin and oral glucose tolerance test

OBJECTIVE To characterize the cardiovascular risk profile of subjects categorized differently by A1C- and oral glucose tolerance test (OGTT)-based diagnostic criteria for diabetes according to the recommendations of the American Diabetes Association (ADA). RESEARCH DESIGN AND METHODS An OGTT, A1C, and several cardiovascular risk factors were assessed in 964 individuals without known diabetes participating in a cross-sectional epidemiological survey in Gran Canaria, Spain. RESULTS Taking the OGTT as the gold standard, the sensitivity and specificity of an A1C value ≥6.5% were 38.7 and 99.6%, respectively. Subjects who fulfilled A1C-based criterion presented greater measures of BMI and waist circumference, lower values for HDL cholesterol, and higher values for fasting plasma glucose, homeostasis model assessment of insulin resistance, and fibrinogen than subjects with diabetic OGTT but A1C <6.5%. CONCLUSIONS Newly diagnosed diabetic individuals who fulfill A1C-based diagnostic criterion for the disease display a more unfavorable cardiovascular risk profile than individuals who only meet the glucose-based criteria.

Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship

Background— Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor ( LDLR ), apolipoprotein B ( APOB ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), and LDL protein receptor adaptor 1 ( LDLRAP1 ). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results— Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB , 5 for LDLRAP1 , and 41 for LDLR ), 45 compound heterozygous for LDLR , 3 double heterozygous for LDLR and PSCK9 , and 2 double heterozygous for LDLR and APOB . No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions— HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.Background—Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and extremely high risk of premature atherosclerotic cardiovascular disease. HoFH is caused by mutations in several genes, including LDL receptor (LDLR), apolipoprotein B (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL protein receptor adaptor 1 (LDLRAP1). No epidemiological studies have assessed HoFH prevalence or the clinical and molecular characteristics of this condition. Here, we aimed to characterize HoFH in Spain. Methods and Results—Data were collected from the Spanish Dyslipidemia Registry of the Spanish Atherosclerosis Society and from all molecular diagnoses performed for familial hypercholesterolemia in Spain between 1996 and 2015 (n=16 751). Clinical data included baseline lipid levels and atherosclerotic cardiovascular disease events. A total of 97 subjects were identified as having HoFH—of whom, 47 were true homozygous (1 for APOB, 5 for LDLRAP1, and 41 for LDLR), 45 compound heterozygous for LDLR, 3 double heterozygous for LDLR and PSCK9, and 2 double heterozygous for LDLR and APOB. No PSCK9 homozygous cases were identified. Two variants in LDLR were identified in 4.8% of the molecular studies. Over 50% of patients did not meet the classical HoFH diagnosis criteria. The estimated HoFH prevalence was 1:450 000. Compared with compound heterozygous cases, true homozygous cases showed more aggressive phenotypes with higher LDL-C and more atherosclerotic cardiovascular disease events. Conclusions—HoFH frequency in Spain was higher than expected. Clinical criteria would underestimate the actual prevalence of individuals with genetic HoFH, highlighting the importance of genetic analysis to improve familial hypercholesterolemia diagnosis accuracy.

Successful outcome of pregnancy in a patient with Cushing's disease under treatment with ketoconazole during the first trimester of gestation

Background. Ketoconazole is the most widely used medical treatment for Cushings syndrome, but, because of its potential to cause birth defects, it is not recommended during pregnancy. Specifically, due to its antiandrogenic effects, ketoconazole entails theoretical risks of interfering with the development of external genitalia in male fetuses. Case. A pregnancy was diagnosed at 13 weeks of gestation in a 26-year-old woman with Cushings disease under treatment with ketoconazole. The drug was withdrawn and the patient underwent transsphenoidal surgery at 16 weeks of pregnancy. She did not develop postsurgical adrenal insufficiency and was treated with metyrapone during the second and third trimesters of gestation. Partum was induced at 34 weeks of pregnancy. The patient delivered a healthy male infant with normal external genitalia. Conclusion. Treatment with ketoconazole during the critical period of organogenesis did not cause congenital birth defects to the male fetus of a woman with Cushings disease. This report should be taken into account for future cases of unplanned pregnancies in women with Cushings syndrome treated with ketoconazole, as well in those cases in which other therapeutic options are not feasible.

Disproportionately high incidence of diabetes-related end-stage renal disease in the Canary Islands. An analysis based on estimated population at risk

BACKGROUND An exceptionally high incidence of diabetes-related end-stage renal disease (DM-ESRD) has been reported in the Canary Islands. This phenomenon was attributed to an increased prevalence of diabetes in this community. We compared the incidence of DM-ESRD in the Canary Islands with the rest of Spain among the estimated number of individuals at risk (people with diabetes in the population). METHODS The population-at-risk was calculated using census population figures and estimates of self-reported diabetes prevalence from the Spanish National Health Survey in the years 2003 and 2006. The incidence of DM-ESRD for the same years was obtained through Spanish regional registries. The independent effect of age, community of residence and calendar year was estimated with a Poisson regression model. Age-standardized acceptance rate ratios were calculated for each community. RESULTS Overall DM-ESRD incidence in the Canary Islands population-at-risk was 1209.9 per million population (pmp) in 2003 and 1477.3 pmp in 2006. Rates for the remaining Spanish regions ranged from 177.3-984.9 pmp. The incidence was higher in the Canary Islands across all age groups, but was most striking for patients > or =75 years. Diabetes prevalence in the general population was greater in the two youngest age strata and diminished from 75 years on in the Canary Islands, in comparison with other areas of Spain. Using a cluster of three communities with the lowest incidence as a reference, the relative risk of DM-ESRD in the Canary Islands population-at-risk was 3.88 [95% confidence interval (CI): 3.07-4.89]. Age-standardized acceptance ratios (95% CI) in the Canary Islands were 2.21 (1.85-2.61) in 2003 and 2.73 (2.34-3.17) in 2006. CONCLUSIONS Individuals with diabetes in the Canary Islands present a disproportionately high incidence of ESRD. Diabetic Canary inhabitants are exposed to the disease for a longer time and therefore, may be more vulnerable to the development of chronic diabetes complications, including ESRD.

Mumps Orchitis in the Post-vaccine Era (1967-2009): A Single-center Series of 67 Patients and Review of Clinical Outcome and Trends

Since the introduction of the mumps vaccine, the age of appearance of mumps infection has shifted from children to adolescents and young adults, groups with a higher incidence of disease complications and sequelae. During the years 2000-2001, the Gran Canaria Island was part of an epidemic of mumps. In that period, our institution attended 67 cases of serologically confirmed acute mumps orchitis, the most serious complication of mumps infection in young postpubertal males. We conducted a descriptive and prospective study of this cohort and extensively reviewed the literature from 1967 (the year the first mumps vaccine was introduced) to 2009. Fifty-six patients were admitted because of general impairment and were treated with alpha-interferon. Sixty-six patients presented parotitis previous to orchitis (interval from parotitis to orchitis, 4.9 d). Orchitis was unilateral in 89.5% and bilateral in 10.4% of cases. More than 98% of patients had orchitis-associated fever. Nine patients had clinical and biochemical data showing acute mumps meningitis, and 11 had subclinical pancreatitis. The mean duration of symptoms was 4.6 days (range, 1-9). During the acute phase, more than 41% of the evaluated testes had a volume >25 mL. Acute hormonal disturbances were highly prevalent. These included decreased levels of testosterone and inhibin B with low or normal levels of gonadotropins in 35% of subjects, and, to our knowledge not previously reported, an atypical hormonal pattern consisting of low levels of free testosterone and inhibin B, along with increased measures of luteinizing hormone but low or normal follicle-stimulating hormone levels (11% of cases). During the follow-up period (mean, 331 d) a high incidence of sperm disturbance was found. Abbreviations: CRP = C-reactive protein, CSF = cerebrospinal fluid, ESR = erythrocyte sedimentation rate, FSH = follicle-stimulating hormone, LH = luteinizing hormone, MMR = measles, mumps, and rubella triple vaccine, NSAID = nonsteroidal antiinflammatory drugs, WHO = World Health Organization.

Serum glucose and lipid levels in adult congenital heart disease patients.

Atherosclerosis has been correlated with known cardiovascular risk factors such as serum glucose or lipid levels. Because congenital heart disease patients tend to survive until adulthood, atherosclerosis has also become a matter of concern in these patients. One hundred fifty-eight congenital heart disease patients and 152 patients selected at random from the population were studied and compared to determine serum glucose, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein cholesterol, and triglycerides levels. Both groups had similar socioeconomic status levels and the same environmental influences. Significant differences were seen between congenital heart disease patients and the control group, after sex, age, and body mass index adjustment, in fasting plasma glucose (97.7 [94.2-101.2] vs 86.9 [83.2-90.7], P < .001), total cholesterol (171.5 [165.7-177.3] vs 199.8 [90.7-206.0], P < .001), LDL cholesterol (103.9 [98.8-108.8] vs 123.8 [118.5-129.1], P < .001), and high-density lipoprotein cholesterol (48.1 [46.2-50.0] vs 54.2 [52.1-56.2], P < .001) levels. Nonsignificant differences were seen in triglycerides concentrations. Those patients with ventricular septal defect, coarctation of the aorta, and cyanosis had the lowest total cholesterol and LDL cholesterol concentrations. Congenital heart disease patients have lower plasma cholesterol concentrations and higher serum glucose levels than noncongenital ones.

High levels of lipoprotein(a) are associated with a lower prevalence of diabetes with advancing age: Results of a cross-sectional epidemiological survey in Gran Canaria, Spain

BackgroundRecent data suggest that concentrations of lipoprotein(a) [Lp(a)] may be inversely associated with the risk of diabetes. This study analyzed the relationships between Lp(a) and both diabetes and insulin resistance in an adult cohort from the island of Gran Canaria, Spain.MethodsLp(a), homeostasis model assessment for insulin resistance (HOMA-IR) and conventional risk factors for diabetes were assessed in a sample of 1,030 adult individuals participating in a cross-sectional population-based epidemiological survey in the city of Telde. Diabetes was defined according to the WHO 1999 criteria, or as a previous diagnosis of diabetes. To identify patients at risk for diabetes, an Lp(a) cutoff level of 46 mg/dl was selected previously using classification and regression tree analysis. A multivariate logistic regression model with L2-regularization was used to assess the independent effect of Lp(a) on diabetes and its interactions with variables traditionally linked to the disease. Additionally, to investigate the effect of Lp(a) on insulin resistance, a parametric model was developed to describe the relationship between age and HOMA-IR values in subjects with levels of Lp(a) ≤46 or >46 mg/dl.ResultsAlong with variables known to be associated with diabetes, including age, mean blood pressure, serum triglycerides, and an interaction term between age and low HDL cholesterol, the logistic model identified a significant inverse association for diabetes and the interaction term between age and Lp(a) levels >46 mg/dl. According to the proposed parametric model, HOMA-IR was significantly lower in subjects of all ages who had Lp(a) levels >46 mg/dl.ConclusionsThese results suggest that the age-related increase in the probability of having diabetes is significantly lower in subjects with Lp(a) levels >46 mg/dl. This could be explained in part by a lower insulin resistance in this subset of the population.

Severe deterioration of metabolic control caused by malfunction of a disposable insulin pen device.

This report describes the case of a 68-yr-old diabetic woman with severe deterioration of glycemic control caused by the use of a malfunctioning insulin pen device.

design, construction, and implementation of an online platform for patients with type 1 diabetes: Encodiab

Purpose The purpose of this study was to develop, build, and implement a virtual platform equipped with practical tools, relevant contents, and communication rooms, with the aim of facilitating patients’ self-management of type 1 diabetes mellitus (T1DM). Materials and methods The design of the platform was based on the suggestions of T1DM patients who were being managed at two reference hospitals. Patients’ needs and preferences were identified in group discussion sessions. Before having access to the platform, patients underwent a baseline assessment, which included physical examination and the administration of validated questionnaires for evaluation of clinical background, quality of life, treatment satisfaction, and well-being. Results A total of 33 patients were included in the study; 54.5% of them were men, their median age was 34 (18–50) years, the median duration of diabetes was 15 (1–38) years, and the median A1C was 7.4% (6%–12.6%). Based on their suggestions and requests, the online platform EncoDiab was built and organized into four domains: a personal domain, two domains shared by the patients and the staff of each of the two participating hospitals, and one domain that was accessible to all participants. The platform included practical tools (a body mass index calculator, a carbohydrate counting tool, and an insulin-dose calculator), a library with relevant information (documents on prevention and treatment of acute complications, nutrition, exercise, etc), and a chat room. Conclusion Although the study is still ongoing, our current results demonstrate the feasibility of building and implementing an online platform for helping T1DM patients in the self-management of their disease in the public health setting.

Suspension of basal insulin to avoid hypoglycemia in type 1 diabetes treated with insulin pump

Summary Treatment with continuous s.c. insulin infusion (CSII) provides better glycemic control and lower risk of hypoglycemia than conventional therapy with multiple daily insulin injections. These benefits have been related to a more reliable absorption and an improved pharmacokinetic profile of insulin delivered through CSII therapy. However, even for patients treated with CSII, exaggerated postmeal hyperglycemic excursions and late postabsorptive hypoglycemia can still constitute a therapeutic challenge. Two female patients with type 1 diabetes who began treatment with CSII required to increase their previous breakfast insulin-to-carbohydrate ratio in order to achieve postprandial glycemic goals. However, they simultaneously presented recurrent episodes of late hypoglycemia several hours after breakfast bolus. Advancing the timing of the bolus was ineffective and bothersome for patients. In both cases, the best therapeutic option was to set a basal insulin rate of zero units per hour during 6 h after breakfast. Even so, they need to routinely take a midmorning snack with 10–20 g of carbohydrates to avoid late postabsorptive hypoglycemia. They have been using this insulin schedule for about 3 years without complications. The action of prandial insulin delivered through insulin pumps can be inappropriately delayed for the requirements of some patients. Although suspension of basal rate can be an acceptable therapeutic alternative for them, these cases demonstrate that new strategies to improve the bioavailability of prandial insulin infused through CSII are still needed. Learning points CSII remains the most physiologically suitable system of insulin delivery available today. Additionally, the duration of action of prandial insulin delivered through insulin pumps can be excessively prolonged in some patients with type 1 diabetes. These patients can present recurrent late episodes of hypoglycemia several hours after the administration of insulin boluses. The routine suspension of basal insulin for several hours, leaving meal bolus to cover both prandial and basal insulin requirements, can be a therapeutic option for these subjects.