Clinical trial NCT02910271: Clinical Features and Prevalence of Asymptomatic Peripheral Artery Disease in Patients With Type 1 Diabetes Mellitus
Official title: Clinical Features and Prevalence of Asymptomatic Peripheral Artery Disease in Patients With Type 1 Diabetes Mellitus
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Type 1 Diabetes Mellitus
Peripheral Artery Disease
Lead sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Sponsor class: OTHER
First posted: 2016-09-22
Enrollment: 299
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with prior diagnosis of T1DM ≥ 18 years old, consecutively selected from T1DM and Insulin Pump clinics of a tertiary Hospital in Madrid.

Brief summary: AIMS: Determining the clinical features and prevalence of peripheral artery disease (PAD) in asymptomatics patients with type 1 diabetes mellitus (T1DM) and checking the validity of the current recommendations regarding for PAD screening in T1DM.

METHODOLOGY: An observational and cross-sectional prevalence study. The whole group of patients (sample size calculated: 299 patients) will make the Edinburgh Questionnaire for detecting classic symptoms of intermittent claudication, and after verifying the absence of symptoms and exclusion criteria, they will be included in the study. All patients will undergo assessment of clinical parameters related to T1DM and classic cardiovascular risk factors, as well as, an analytical assessment of the lipid profile, HbA1c level, proinflammatory profile and oxidative stress status. They will also undergo a comprehensive anthropometric assessment including office blood pressure (BP) monitoring and ambulatory 24-hours BP monitoring in patients with an indication as routine clinical practice, assessment of cardioautonomic function, and lastly an ankle-brachial index (ABI) by Doppler ultrasound, in the context of routine clinical practice in patients with clinical indication, or as an extraordinary procedure for participating in the study in patients who do not meet criteria for screening according to current recommendations.

Detailed description: INTRODUCTION:

PAD is a condition characterized by atherosclerotic occlusive disease of the lower extremities. While PAD is a major risk factor for lower-extremity amputation, it is also accompanied by a high likelihood for symptomatic cardiovascular and cerebrovascular disease.

PAD is often more subtle in its presentation in patients with diabetes than in those without diabetes. In contrast to the focal and proximal atherosclerotic lesions of PAD found typically in other high-risk patients, in diabetic patients the lesions are more likely to be more diffuse and distal. Importantly, PAD in individuals with diabetes is usually accompanied by peripheral neuropathy with impaired sensory feedback, thus a classic history of claudication may be less common. Data from Framingham Heart Study revealed that 20% of PAD symptomatic patients had diabetes mellitus, but probably, this data greatly underestimates PAD prevalence. As well, it has been reported that of those with PAD, over one-half of patients are asymptomatic or have atypical symptoms, about one-third have claudication, and the rest have more severe disease. Also, patients with diabetes who have been identified with PAD are more prone to sudden ischemia secondary to arterial thrombosis or to have a pivotal event leading to neuroischemic ulceration or infection that rapidly results in an acute presentation with critical limb ischemia and risk of amputation.

However, is important to note, that most clinical data about PAD and diabetes, are becoming from population studies and randomized clinical trials, made up exclusively with type 2 patients, or more frequently, after analyzing all patients with diabetes diagnosis, without distinction between T1 to T2 subtypes. Thus, although much is known regarding PAD in the general population, the assessment and management of PAD in those with diabetes is less clear, especially in patients with T1DM diagnosis.

In 2003, a Consensus Development Conference was held regarding PAD in diabetes. After a series of lectures by experts in the field of endocrinology, cardiology, vascular surgery, orthopedic surgery, podiatry, and nursing, a vascular medicine panel was asked to answer questions about the epidemiology and impact of PAD in people with diabetes, diagnosis and treatment of PAD, but always generalizing the management of T1 and T2 diabetes, under the unique same term of "diabetes".

PAD diagnosing in patients with diabetes is of clinical importance for two reasons:

i) to identify patients at high risk of subsequent cardiovascular and cerebrovascular disease ii) to diagnose and treat PAD, which may be associated with functional disability and limb loss.

Preventive measures in a patient with subclinical disease will make possible to avoid acute and chronic complications. Therefore, the knowledge about the true prevalence of PAD in T1DM is relevant for setting the screening indication in this patients, given that this is frequently asymptomatic and it might be clinically different at presentation compared to type 2 diabetes patients.

AIMS:

The main objective of this works is determine the clinical features and prevalence of PAD in asymptomatics patients with T1DM and check the validity of the current recommendations regarding for PAD screening in T1DM.

METHODOLOGY:

Observational and cross-sectional prevalence study will be conducted. A consecutive population of type 1 patients from our clinics (sample size calculated: 299 patients) will be screened by the Edinburgh Questionnaire (Leng \& Fowkes 1992) for detecting classic symptoms of intermittent claudication, and after verifying the absence of symptoms and exclusion criteria, they will be included in the study.

* All patients will undergo assessment of clinical parameters related to T1DM (years of the initial diagnosis, insulin treatment, metabolic control, microvascular chronic complications), cardiovascular risk factors (hypertension, dyslipidemia, chronic smoking), prior cardiovascular disease (coronary and cerebrovascular disease), as well as, an analytical assessment including a lipid profile, HbA1c level, proinflammatory markers (C-reactive protein, homocysteine) and oxidative stress status.
* They will undergo a comprehensive anthropometric evaluation: weight, height, body mass index \[BMI (kg / m2)\], abdominal and hip circumference, and body fat percentage to total body weight by bioelectrical impedance.
* Office BP and ambulatory 24-hours BP monitoring in patients with an indication as routine clinical practice (Mancia G. et al 2013).
* Assessment of cardiovascular autonomic dysfunction: orthostatism systolic and diastolic BP, orthostatism heart rate, heart rate variability to expiration / inspiration, Valsalva and orthostatic.
* Diabetic foot exploration (including bilateral peripheral pulses, Neuropathy Symptoms Score questionnaire, monofilament exploration, and calibrated tuning fork).
* The ABI will be performed by Doppler ultrasound (HADECO® Minidop 8 Mhz), in the context of routine clinical practice in patients with clinical indication, or an extraordinary procedure for participating in the study in patients who do not meet criteria for screening according to current recommendations.

The ABI will be measured in both posterior tibial and pedia arteries. Interpretation of ABI wil be as follows: Average: 0.90 to 1.20; mild arterial obstruction: 0.70 to 0.89; moderate arterial obstruction: 0.40 to 0.69; severe arterial obstruction \< 0.40; poorly compressible arteries \> 1.20.

In patients with ABI \> 1.20 or \< 0.9, the examination will be completed as recommended guidelines about asymptomatic PAD diagnosis by assessing the graphic recording blood flow and assessment index finger-arm.

Eligibility criteria: Inclusion Criteria:

* Previous diagnosis of T1DM before 30 years of age.

DM diagnostic criteria:

* DM cardinal symptoms (polyuria, polydipsia, unexplained weight loss) with plasma glucose ≥ 200 mg / dl, or diagnosis as diabetic ketoacidosis (DKA).
* fasting plasma glucose (≥ 8 h) ≥ 126 mg / dl.
* plasma glucose at 2 h in testing oral glucose tolerance test (75 g glucose) ≥ 200 mg / dl.
* glycosylated hemoglobin (HbA1c) ≥ 6.5% \[as certified by the National method Glycohemoglobin Standardized Program (NGSP) and standardized according to the Diabetes Control and Complication Trial trial (DCCT)\].

The criteria b, c and d require confirmation, except in cases of hyperglycemia with acute decompensation (criteria a).

* Positive determination of a autoantibody serum markers of immune destruction against antigens cytoplasm of the islet cells (ICA), anti-insulin (AAI), and / or anti protein glutamate decarboxylase (GADA) at initial diagnosis time or during the course of the disease.

Acceptance of participation in the study and sign the informed consent.

Exclusion Criteria:

* Prior diagnosis of PAD, diabetic foot, leg amputation or symptoms in line with PAD according to the Edinburgh questionnaire for intermittent claudication.
* Diagnosis of type 2 diabetes, gestational diabetes, latent autoimmune diabetes in adults (LADA) or maturity-onset diabetes of youth (MODY) diabetes.
* Current pregnancy, institutionalized or terminal illness subjects.
* Refusal to participate in the study or to sign the informed consent.

Primary outcomes:
measure: Prevalence of PAD in asymptomatic patients with T1DM assessed by ankle-branchial index.
timeFrame: 2 years
Secondary outcomes:
measure: Association between anthropometric parameters and asymptomatic peripheral artery disease in patients with type 1 diabetes mellitus.
timeFrame: 2 years
measure: Association between lipid profile and asymptomatic artery disease in patients with type 1 diabetes mellitus.
timeFrame: 2 years
measure: Association between glycemic control and asymptomatic artery disease in patients with type 1 diabetes mellitus.
timeFrame: 2 years
measure: Association between C-reactive protein and asymptomatic artery disease in patients with type 1 diabetes mellitus.
timeFrame: 2 years
measure: Association between homocysteine and asymptomatic artery disease in patients with type 1 diabetes mellitus.
timeFrame: 2 years
measure: Number and percentage of patients with pathological ankle-branchial index without screening criteria according to the current recommendations for subjects with type 1 diabetes mellitus.
timeFrame: 2 years
measure: Number and percentage of patients with type 1 diabetes mellitus, cardiovascular autonomic dysfunction and asymptomatic PAD.
timeFrame: 2 years
measure: Number and percentage of patients with type 1 diabetes mellitus, cardiovascular autonomic dysfunction and asymptomatic PAD.
timeFrame: 2 years
measure: Number and percentage of patients with type 1 diabetes mellitus, cardiovascular autonomic dysfunction and asymptomatic PAD.
timeFrame: 2 years
measure: Prevalence of asymptomatic atherosclerotic carotid disease in patients with asymptomatic PAD.
timeFrame: 2 years
Other outcomes:
Locations:
city: Madrid
country: Spain
facility: Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
Study officials:
affiliation: Diabetes, Obesity and Human Reproduction Research Group, Department of Endocrinology and Nutrition, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)
name: María Lía Nattero Chávez
role: PRINCIPAL_INVESTIGATOR
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