Gabriel Coll-de-Tuero

Clinical inertia in the treatment of hyperglycemia in type 2 diabetes patients in primary care

Abstract Objective: To assess clinical inertia, defined as failure to intensify antidiabetic treatment of patients who have not achieved the HbA1c therapeutic goal (≤7%). Research design and methods: Multicenter cross-sectional study. Clinical inertia was assessed in a random sample of type 2 diabetes mellitus (T2DM) patients seen in primary care centers. Results: A total of 2783 patients (51.3% males; mean age: 68 [±11.5] years; diabetes duration: 7.1 [±5.6] years; mean HbA1c: 6.8 [±1.5]) were analyzed. Of those, 997 (35.8%) had HbA1c >7%. Treatment was intensified in 66.8% and consisted of: dose increase (40.5%); addition of oral antidiabetic (45.8%); or insulin treatment initiation (3.7%). Mean HbA1c values in patients for whom treatment was intensified vs. non-intensified were 8.4% (±1.2) vs. 8.2% (±1.2), p < 0.05. Clinical inertia was detected in 33.2% of patients and diminished along with treatment complexity: lifestyle changes only (38.8%), oral monotherapy (40.3%), combined oral antidiabetics (34.5%), insulin monotherapy (26.1%) and combination of insulin and oral antidiabetics (21.4%). Clinical inertia decreased as HbA1c increased: 37.3% for HbA1c values ranging between 7.1%–8%; 29.4% for the 8.1%–9% HbA1c range and 27.1% for HbA1c ≥9%. Multivariate analysis confirmed that diabetes duration, step of treatment and HbA1c were related to inertia. For each unit of HbA1c increase clinical inertia decreased 47% (OR: 0.53). Limitations: The retrospective design of the study precluded an accurate investigation about reasons for lack of intensification that could actually be justified by some patient conditions, especially patients’ lack of adherence. Conclusions: Clinical inertia affected one third of T2DM patients with poor glycemic control and was greater in patients treated with only lifestyle changes or oral monotherapy. Treatment changes were performed when mean HbA1c values were 1.4 points above therapeutic goals.

Chronic kidney disease in the type 2 diabetic patients: prevalence and associated variables in a random sample of 2642 patients of a Mediterranean area

BackgroundKidney disease is associated with an increased total mortality and cardiovascular morbimortality in the general population and in patients with Type 2 diabetes. The aim of this study is to determine the prevalence of kidney disease and different types of renal disease in patients with type 2 diabetes (T2DM).MethodsCross-sectional study in a random sample of 2,642 T2DM patients cared for in primary care during 2007. Studied variables: demographic and clinical characteristics, pharmacological treatments and T2DM complications (diabetic foot, retinopathy, coronary heart disease and stroke). Variables of renal function were defined as follows: 1) Microalbuminuria: albumin excretion rate & 30 mg/g or 3.5 mg/mmol, 2) Macroalbuminuria: albumin excretion rate & 300 mg/g or 35 mg/mmol, 3) Kidney disease (KD): glomerular filtration rate according to Modification of Diet in Renal Disease < 60 ml/min/1.73 m2 and/or the presence of albuminuria, 4) Renal impairment (RI): glomerular filtration rate < 60 ml/min/1.73 m2, 5) Nonalbuminuric RI: glomerular filtration rate < 60 ml/min/1.73 m2 without albuminuria and, 5) Diabetic nephropathy (DN): macroalbuminuria or microalbuminuria plus diabetic retinopathy.ResultsThe prevalence of different types of renal disease in patients was: 34.1% KD, 22.9% RI, 19.5% albuminuria and 16.4% diabetic nephropathy (DN). The prevalence of albuminuria without RI (13.5%) and nonalbuminuric RI (14.7%) was similar. After adjusting per age, BMI, cholesterol, blood pressure and macrovascular disease, RI was significantly associated with the female gender (OR 2.20; CI 95% 1.86–2.59), microvascular disease (OR 2.14; CI 95% 1.8–2.54) and insulin treatment (OR 1.82; CI 95% 1.39–2.38), and inversely associated with HbA1c (OR 0.85 for every 1% increase; CI 95% 0.80–0.91). Albuminuria without RI was inversely associated with the female gender (OR 0.27; CI 95% 0.21–0.35), duration of diabetes (OR 0.94 per year; CI 95% 0.91–0.97) and directly associated with HbA1c (OR 1.19 for every 1% increase; CI 95% 1.09–1.3).ConclusionsOne-third of the sample population in this study has KD. The presence or absence of albuminuria identifies two subgroups with different characteristics related to gender, the duration of diabetes and metabolic status of the patient. It is important to determine both albuminuria and GFR estimation to diagnose KD.

Treatment efficacy of anti-hypertensive drugs in monotherapy or combination: ATOM systematic review and meta-analysis of randomized clinical trials according to PRISMA statement.

Background:The relative efficacy of antihypertensive drugs/combinations is not well known. Identifying the most effective ones and the patients’ characteristics associated with best performance of the drugs will improve management of hypertensive patients. Objective:To assess the blood pressure (BP) reduction attributed to antihypertensive drugs and identify characteristics associated with BP decrease. Data sources:MEDLINE, Cochrane Central Register of Controlled Trials from inception through July 2012 and selected papers. Study eligibility criteria:Double-blind, randomized clinical trials whose main result was the reduction in BP by antihypertensive treatment, with study population ≥50 or ≥25 if the study was a crossover, follow-up of at least 8 weeks, and available required data. Study appraisal and synthesis methods:Study data were independently extracted by multiple observers and introduced in an electronic database. Inconsistencies were resolved by discussion and referral back to the original articles. Meta-analysis was performed according to PRISMA statement and using a Bayesian framework. Main Outcome(s) and Measure(s):Mean decrease in systolic (SBP) and diastolic blood pressure (DBP) achieved by each drug or combination. Results:Two hundred eight trials including 94,305 patients were identified. In monotherapy, most drugs achieved 10 to 15 mm Hg SBP and 8 to 10 mm Hg DBP decreases.Olmesartan/amlodipine, olmesartan/hydrochlorothiazide, felodipine/metoprolol, and valsartan/hydrochlorothiazide were the combinations leading to the greatest mean SBP reductions (>20 mm Hg). Female sex and body mass index >25 kg/m2 were associated with more pronounced SBP and DBP reductions, whereas Afro-American ethnicity was associated with BP reductions smaller than the median. Results were adjusted by study duration, cardiovascular disease, and diabetes mellitus. Still, the estimation was performed using the mean administered doses, which do not exactly match those of the available drug formats. Limitations:Data corresponded to those obtained in each of the included trials; the analysis of the combinations was limited to the most recent ones; estimations were performed using the mean administered doses. Conclusions and implications:Certain drug combinations achieve BP reductions ranging from 20 to 25/10 to 15 mm Hg. Sex, ethnicity, and obesity are associated with antihypertensive response. This information can contribute to better selection of the antihypertensive drug, depending on the magnitude of pretreatment BP elevation. Guidelines should be revised.

Metabolic control and cardiovascular risk factors in type 2 diabetes mellitus patients according to diabetes duration.

BACKGROUND Control of glycaemic levels as well as cardiovascular risk factors (CVRF) is essential to prevent the onset of complications associated with type 2 diabetes mellitus (T2DM). AIM To describe the degree of glycaemic control and CVRF in relation to diabetes duration. PATIENTS AND METHODS Multicentre cross-sectional study in T2DM patients seen in primary care centres during 2007. VARIABLES Demographical and clinical characteristics, antidiabetic treatments and development of disease complications. Diabetes duration classification: 0-5, 6-10, 11-20 and >20 years. Logistic regression models were used in the analysis. RESULTS A total of 3130 patients; 51.5% males; mean age: 68±11.7 years; mean diabetes duration:7.0 (±5.6) years, median: 5 (interquartile range:3-9) years; mean HbA1c: 6.84 (±1.5), were analyzed. There has been a progressive decline in HbA1c levels (HbA1c > 7% in 25.8% of patients during the first 5 years and 51.8% after 20 years). Blood pressure values remained relatively stable throughout disease duration. The mean value of low density lipoprotein (LDL) experienced a slight decline with the progression of the disease, but due to the significant increase of cardiovascular disease (CVD) after 20 years of duration, less patients reached the recommended target (LDL < 100mg/dl) in secondary prevention. Logistic regression model controlling for age, sex and CVD showed that diabetes duration was related to glycaemic control (odds ratio: 1.066, 95% confidence interval: 1.050-1.082 per year) but not to blood pressure or LDL control. CONCLUSIONS The degree of glycaemic control and the risk factors in relation to the duration of T2DM followed different patterns. Diabetes duration was associated with a poorer glycaemic control but in general had a limited role in blood pressure control or lipid profile.

Noninsulin Antidiabetic Drugs for Patients with Type 2 Diabetes Mellitus: Are We Respecting Their Contraindications?

Aim. To assess prescribing practices of noninsulin antidiabetic drugs (NIADs) in T2DM with several major contraindications according to prescribing information or clinical guidelines: renal failure, heart failure, liver dysfunction, or history of bladder cancer. Methods. Cross-sectional, descriptive, multicenter study. Electronic medical records were retrieved from all T2DM subjects who attended primary care centers pertaining to the Catalan Health Institute in Catalonia in 2013 and were pharmacologically treated with any NIAD alone or in combination. Results. Records were retrieved from a total of 255,499 pharmacologically treated patients. 78% of patients with some degree of renal impairment (glomerular filtration rate (GFR) < 60 mL/min) were treated with metformin and 31.2% with sulfonylureas. Even in the event of severe renal failure (GFR < 30 mL/min), 35.3% and 22.5% of patients were on metformin or sulfonylureas, respectively. Moreover, metformin was prescribed to more than 60% of patients with moderate or severe heart failure. Conclusion. Some NIADs, and in particular metformin, were frequently used in patients at high risk of complications when they were contraindicated. There is a need to increase awareness of potential inappropriate prescribing and to monitor the quality of prescribing patterns in order to help physicians and policymakers to yield better clinical outcomes in T2DM.

Could Uric Acid Be Considered a Cardiovascular Risk Factor

Since the 19th century, uric acid (UA) has been related to a higher prevalence of arterial hypertension and, during the past decades, an increasing number of studies have been published showing a relationship between UA and incident hypertension, heart failure, onset of chronic kidney disease, metabolic syndrome, obesity, and diabetes. However, UA is not accepted as a cardiovascular risk factor by the scientific community, although it has shown an independent and strong association with cardiovascular morbidity and mortality. Results from published studies state a weak to moderate association, but not strong in any case, defined as a risk inwhich theminimum interval value is>2.Moreover, UA level changes caused by pharmacologic treatment did not predict all-cause or cardiovascular mortality. However, it is with the physiopathologic mechanism that more questions arise. Under normal conditions, UA behaves as an antioxidant molecule that defends the organism against reactive oxygen species, but, for some reason, in select metabolic conditions, UA is responsible for oxidative activity in vascular, liver, and renal cells and adypocites. These specific conditions are related to adipocytes activity in the metabolic syndrome, wherein there is an interaction between UA and the immune system, with an increase in proinflammatory cytokines production, which inhibits nitric oxide production and interacts with peripheral vascular tone control and microvascular disturbances. Thus far, studies have established a relationship between UA, incident arterial hypertension, and cardiovascular morbidity and mortality. The study by C a glı and coworkers in this Journal takes a step forward in relating UA levels with blood pressure (BP) variability (BPV), in particular with short-term BPV. In their paper, UA levels presented on a logarithm scale showed a weak correlation with systolic BPV on ambulatory BP monitoring (ABPM) and a moderate correlation with diastolic BPV on ABPM expressed as the standard deviation. This correlation remained when the standard deviation was weighted by the nocturnal and diurnal period, a variable with better prognostic value than simple standard deviation. BPV showed a modest but significant association with the onset of target organ damage and cardiovascular complications. Both longand short-term BPV are independently associated with increased cardiovascular risk but even so are not useful for better stratification of cardiovascular risk compared with the values obtained from ABPM. Therefore, BPV could be considered a weak surrogate variable when it comes to prognostic value even if it is justified in studies in which the purpose is to discover the influence of different factors, allowing the creation of a new hypothesis. A possible explanation for the better correlation between UA and diastolic BPV can be found in the association between peripheral resistance and diastolic BP (DBP). It has been shown that in hypertensive individuals, higher UA levels are associated with higher resting forearm blood flow and lower reactive hyperemia, markers of microvascular function. High UA levels can increase DBP variability by means of a disturbance in vascular tone, partly depending on endothelial function and nitric oxide. Because of this we can theorize about the possible link between endothelial dysfunction, peripheral resistance, and UA, with the variability a clinical expression of this interaction. In addition, the authors presented a positive and independent correlation between waist circumference and systolic and diastolic nighttime BPV. Waist circumference is one of the most important components in the metabolic syndrome that is associated with the UA oxidative effect. However, night breathing alterations may play a role in nocturnal SBP and DBP variability. UA levels are also associated with hemoglobin levels, showing a possible link between the patterns found in the night breathing disorders and nocturnal hypoxemia. There are some limitations in the work by C a glı and coworkers. The most important of which is the crosssectional design of the study, which makes it impossible to establish a causality relationship, and, therefore, the hypothesis derived from this work should be confirmed in the future by other studies created for this purpose. As stated by the authors, AU levels follow a circadian rhythm, with higher UA levels during the night and the first hours in the morning, possibly caused by a decrease in urine production and renal excretion during this time. However, there was no information about any action to control for this fact, as a fixed hour to collect blood samples, and possibly prevent a potential bias. Finally, to show the relationship between UA and other short-term variability measures as the ABPM night-day ratio or the morning surge measure in addition to the simple standard deviation and weighted standard deviation could contribute to a better understanding of this fact. Address for correspondence: Gabriel Coll-de-Tuero, Department of Medical Sciences, University of Girona, Girona, Spain E-mail: gabriel.coll@ias.scs.es

Why is cardiovascular risk stratification important in hypertensive patients

Abstract Background. The aim is to evaluate whether cardiovascular (CV) risk stratification in newly diagnosed hypertensive patients according to the European Society of Hypertension (ESH) guidelines, can predict the evolution of target organ damage (TOD) using routine examinations in clinical practice during 1 year. Methods. Prospective study of recently diagnosed untreated hypertensives. At the moment of inclusion and 1 year later, urinary albumin excretion rate (UAER), blood analysis, electrocardiogram, retinography, self-monitored blood pressure (BP) and ambulatory BP measurement were performed. TOD was defined following the ESH guidelines and evaluated as having favorable or unfavorable evolution. Results. Four hundred and seventy-nine hypertensive patients were included (58.8 years; 43.4% women). The baseline prevalence of TOD was: high UAER (2.4%), left ventricular hypertrophy (LVH) (20.7%), advanced lesion of the fundus oculi (FO) (10.2%). After 1 year, no differences were found between the final systolic and diastolic BP neither in the high/very high nor in the low/moderate CV risk groups. Patients with low/moderate CV risk had less unfavorable TOD evolution, LVH (9.2% vs 41.7%; p <0.001), FO advanced damage (0.99% vs 14.3%; p <0.001), high UAER (0.3% vs 5.1%; p <0.005) and amount of TOD (9.2% vs 44.0%; 0<0.001) than those with high/very high CV risk. The odds ratios of favorable TOD evolution adjusted for BP change and antihypertensive drug treatment were (low/moderate vs high/very high CV risk); 5.14 (95% confidence interval, CI, 3.99–6.64) for LVH; 12.42 (6.67–23.14) FO advanced damage; 10.71 (3.67–31.22) high UAER and 13.99 (10.18–19.22) for amount of TOD. Conclusions. It is possible to detect variations in TOD in hypertensive patients with a 1-year follow-up using the examinations available in routine clinic practice. The risk determined by the ESH guidelines predicts the evolution of TOD at 1 year.

Duration and dosing of Proton Pump Inhibitors associated with high incidence of chronic kidney disease in population-based cohort

Background Proton Pump Inhibitors (PPIs) have been associated with chronic kidney disease (CKD). Our objective was to quantify the association between PPI use and incident CKD in a population-based cohort. Methods and findings We used a population-based retrospective cohort, including people aged 15 years or over, between January 1, 2005 and December 31, 2012. PPI use was measured in a follow-up session by recording prescriptions. Incident CKD was defined as an estimated glomerular filtration rate < 60 ml/ min/1.73 m2 and/or urinary albumin level to creatinine level ≥ 30 mg/g, in two or more determinations over a period of at least 3 months of the follow-up. Proton Pump Inhibitor use was associated with incident CKD in analysis adjusted for different clinical variables (Hazard Ratio (HR) 1.18; 95% CI 1.04–1.51) in individuals who used PPI in the basal visit (HR 1.37; 95% CI 1.25–1.50) and in those who started to use PPI during the follow-up. High doses of PPI increased the risk of incident CKD (HR 1.92; 95%CI 1.00–6.19) for any type of exposure to PPIs (HR 2.40; 95%CI 1.65–3.46) and for individuals who used high doses throughout the follow-up. This risk of incident CKD increased after three months’ exposure to PPIs, (HR1.78; 95% CI 1.39–2.25) between the third and sixth months and (HR 1.30; 95%CI 1.07–1.72) after the sixth month. Conclusions PPI use is associated with a higher risk of incident CKD. This association is greater for high doses and becomes apparent after three months’ exposure.

Is Persistent Office Hypertension in Treated Hypertensive Patients a Benign Condition

Arterial stiffness is a powerful and independent risk factor for cardiovascular (CV) disease. Its prognostic value is added to others including hypertension. The estimation of both stiffness and blood pressure (BP) can provide advantages in individual CV risk determination. “Out-of-office” BP has a better CV prognostic value than office BP in hypertensive patients. This is a common knowledge; however, it is unclear how clinicians use this information in their decision-making. In untreated hypertensive patients at baseline, some authors have shown that those with white-coat hypertension (WCH) according to ambulatory BP monitoring (ABPM) have similar CV risk to normotensive patients. However, other cohort studies with longer follow-up periods have shown that the CV risk of patients with WCH according to ABPM or home BP monitoring (HBPM) is intermediate between normotension and sustained hypertension or even higher. There are some factors to consider when discussing these discordant results. First is the rate of detection of subclinical vascular disease in patients diagnosed withWCH.When a patient has subclinical vascular disease, the diagnosis of WCH is not possible. For this reason, it is important to perform the appropriate search of subclinical vascular disease. If not, CV morbidity and mortality can be influenced. Second, patients identified as having WCH have a different profile according to out-of-office BP measurements (ABPM or HBPM). Patients with normal BP by bothmeasurements have a lower basal CV risk than those who have normal values according to only one measurement. According to the above, hypertensive patients in whom normal out-of-office BP required by both techniques, ABPM and HBPM, have an incidence of CV events similar to that of normotensive patients, while those with one of the two measures high and the other normal have an intermediate CV risk among normotensive and sustained hypertensive patients. When these out-of-office measurements apply to the monitoring of treated hypertensive patients, it seems that both are useful and reliable. When a patient has outof-office BP controlled according to any one of the measures, ABPM orHBPM, CV risk is independent of BP measurement in the office. The work by Barochiner and colleagues published in this issue of the Journal shows that hypertensive patients with persistent office hypertension (high BP in the office and normal HBPM) have greater arterial stiffness, measured by pulse wave velocity, than those with sustained normotension. Previously, Cuspidi and colleagues showed similar findings with both ABPM and HBPM in treated hypertensive patients in relation to left ventricular hypertrophy.The conclusion is that this condition (persistent office hypertension) is perhaps not so benign, as is the case ofWCH in untreated hypertensive patients. The study discussed has limitations that require caution in interpreting its results, particularly referring to the BP measurement types: office BP was obtained with only one determination; the inter-arm BP difference was not determined when it was known that one inter-arm BP difference exceeding 10 mm Hg was associated with greater CV risk; and this study used only HBPM for out-of-office BP measurement, not both ABPM and HBPM. Nevertheless, the relationship between rigidity and BP are physiological and conceptually complex. In the estimation of arterial stiffness and carotid-femoral pulse wave velocity, it is not possible to differentiate which part is directly attributable to BP level. Spronck and colleagues found that carotid tonometry builds pressure curves throughout the cardiac cycle to measure stiffness, as the average 10 mm Hg of systolic BP change resulted in a variation of 1 m/s of pulse wave velocity. Although Barochiner and colleagues compared HBPM vs office BP, and not the physiopathological role of BP in arterial stiffness, establishing the status of persistent office hypertension with only one BP office measurement may have caused misclassification of patients in this category. More longitudinal studies are needed to improve the usefulness of out-of-office BP in the management of treated hypertensive patients. There are several questions regarding this issue. First, is normal BP according to ABPM or HBPM while on treatment enough to consider the patient well controlled? Second, should both techniques be required or also the addition of office BP to consider the patient well controlled? Finally, are the currently accepted cutoff values the most appropriate for monitoring hypertensive patients? Pending further studies to answer these questions, the use of ABPM or HBPM has an important place in the management of hypertensive patients; however, decision-making in the treatment of hypertensive patients must be accompanied by appropriate monitoring of the development and Address for Correspondence: Gabriel Coll-de-Tuero, MD, PhD, USR Girona, dIAP, Maluquer Salvador, 11 17002 Girona, Spain E-mail: gabriel.coll@ias.scs.es

Are There Height-Dependent Differences in Subclinical Vascular Disease in Hypertensive Patients?

The aim of the study was to determine whether there are differences in subclinical vascular disease (SVD) in hypertensive patients in relation to height. A total of 922 hypertensive, newly diagnosed, treatment‐naive patients were included. Physical examination was conducted, with renal function, electrocardiography, and retinography. Patients were distributed according to quartiles of height and sex. Multivariate analysis adjusted for age, sex, and body mass index showed an association between height above the mean and fasting glucose (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.02–1.06), high‐density lipoprotein cholesterol (OR, 0.96; CI, 0.92–0.99), triglycerides (OR, 1.07; CI, 1.01–1.15), and left ventricular hypertrophy (LVH) (OR, 1.57; CI, 1.10–2.24). The authors found an inverse association between arteriole‐to‐venule ratio and height above the mean (OR, 0.97; CI, 0.94–0.99). There are differences in the SVD of hypertensive patients in relation to height. Tall stature is associated with LVH while short stature is associated with increased microvascular involvement. Detection of SVD in hypertensive patients should consider the height.