Research Article: Hypoglycemia does not affect the progression of preclinical atherosclerosis in subjects with type 2 diabetes

Date Published: March 5, 2019

Publisher: Public Library of Science

Author(s): Concetta Irace, Antonio Cutruzzolà, Delia Francesca Carbotti, Simona Mastroianni, Michela Cavallo, Agostino Gnasso, Rosa Corcoy.


Intensive treatment aimed at achieving optimal metabolic control to prevent the development of chronic diabetic complications is often associated with an increased rate of hypoglycemic events. Hypoglycemia is believed to be responsible for acute fatal and nonfatal cardiovascular events likely as a consequence of the activation of pro-inflammatory and pro-atherothrombotic pathways. Hypoglycemia has been reported to influence the development of preclinical atherosclerosis. The present study was designed to prospectively evaluate whether hypoglycemia influences the function and the morphology of the arteries in subjects with type 2 diabetes without complications and uncontrolled diabetes.

Seventy-six subjects underwent a noninvasive evaluation of carotid wall thickness and brachial artery function at baseline and after one year of treatment with the intent of obtaining optimal glycemic control. At the end of the observation time, subjects were divided in two groups: with hypoglycemia (H-group) or without hypoglycemia (C-group).

Baseline characteristic were comparable between groups. HbA1c significantly decreased in both groups, and fasting plasma glucose was only significant in the H-group. Subjects with hypoglycemia showed a significant reduction of carotid wall thickness after one-year of treatment (H-groups: right baseline 834±141 vs. 1-year 770±132 μ p<0.05; C-group: 757±162 vs. 767±135 μ p = ns). Endothelial function remained unchanged during the study for both groups. The present findings demonstrate that hypoglycemia does not affect endothelial function. Furthermore, subjects who experience more hypoglycemia show significant reduction of carotid wall thickness. Optimal metabolic control should be pursued as soon as possible.

Partial Text

Diabetes is a progressive disease with a significant risk for long-term complications, which can be delayed or prevented by early and stable glycemic control. Large clinical trials have shown that microvascular complications are responsive to intensive treatment in both type 1 and type 2 diabetes. The progression of macrovascular complications seems to be influenced by intensive treatment in type 1 diabetes at any stage of the disease (DCCT/EDIC) and in type 2 when an early and adequate blood glucose control is achieved (UKPDS follow-up) [1,2]. The intensification of treatment is often associated with an increased incidence of hypoglycemia as described in three large clinical studies ACCORD, VADT, and ADVANCE published in the last decade [3–5]. These trials examined the effect of intensive glycemic treatment on cardiovascular morbidity and mortality in subjects with type 2 diabetes. In particular, ACCORD reported an increased risk of mortality among subjects randomized into the intensive compared with the conventional arm. The greater number of hypoglycemic events recorded in intensive treatment subjects has been hypothesized to be responsible for the increased rate of acute vascular events. However, a retrospective analysis of the ACCORD study reported increased mortality in subjects experiencing symptomatic severe hypoglycemia independent of the assignment in the intensive or standard arm treatment. Furthermore, subjects in the intensive arm with severe hypoglycemia requiring medical assistance had a lower risk of death compared with subjects in the standard arm. Even if limited by the design of the study, this retrospective analysis reveals the complex relationship between mortality and hypoglycemia [6,7]. Hypoglycemia causes pathophysiological effects on the cardiovascular system as increases in heart rate, peripheral blood pressure, and myocardial contractility and decreases in central blood pressure. In addition, hypoglycemia also has harmful effects on cardiac electrophysiology revealed as flattening or inversion of T wave, QT prolongation, and ST depression [8]. Hypoglycemia is the other unavoidable side of the coin of glucose-lowering therapy, mainly in insulin-treated patients. The rate of hypoglycemia in real life ranges from 35 to 70 per 100 patients per year, and the major determinants are sex, age, disease duration, and type of treatment [9]. In type 1 diabetes, the rate is definitely higher and strictly dependent on the intensity of treatment [10]. The fear of hypoglycemia gives rise to inadequate metabolic control. Indeed, both patients and physicians keep fasting plasma glucose at higher levels to minimize the risk of hypoglycemia. Hypoglycemia modulates the levels of cytokines, coagulation molecules and fibrinolysis factors, promoting the development of early atherosclerotic lesions [11]. Furthermore, hypoglycemia seems to influence the morphology and function of the artery. Two papers published to date have reported reduced brachial artery dilation and increased thickness of the carotid artery wall in adult subjects with type 1 and type 2 diabetes and frequent hypoglycemia [12,13].

This is a cohort prospective study including adult type 2 diabetes subjects regularly attending an outpatient clinic. Exclusion criteria were previous cardiovascular events or revascularization, carotid artery stenosis >50%, peripheral artery disease, history of micro- and macroalbuminuria or CKD (chronic kidney disease), retinopathy, neuropathy, and history of severe hypoglycemia defined as an event characterized by profound neuroglycopenia requiring the assistance of another person for recovery. Longstanding uncontrolled hyperglycemia defined as three consecutive HbA1c measurements >8.5% was also considered exclusion criteria. Study subjects were recruited in a six-month period. Before enrollment, subjects were instructed about the aim of the research, and those who gave their signed informed consent and met inclusion and exclusion criteria were enrolled. Per routine practice, subjects attending the outpatient clinic undergo annual screening for micro- and macrovascular complications. Therefore, the presence of exclusion criteria was evaluated by examining clinical records.

Seventy-six subjects were enrolled and completed the study. In total, 66% were men, and the overall age range and mean±SD were 46–75 and 60±7 years, respectively. Only 5 subjects were current smokers: 3 in the C-group and 2 in the H-group.

The main results of the present study suggest that hypoglycemic events do not cause deterioration of endothelial function, and they can even lead to a reduction of the intima media thickness of the common carotid artery in 60-year-old patients with T2DM and without longstanding uncontrolled hyperglycemia.




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