By Jeff Unger, MD
Medical Director, Unger Primary Care Medicine Group, Rancho Cucamonga, CA
Dr. Unger reports no financial relationships relevant to this field of study.
SYNOPSIS:A nationwide Swedish observational study of 33,915 patients with type 1 diabetes and 169,249 age and sex-matched controls demonstrated that patients with targeted A1C levels at or below 6.9% had a two-fold increase in cardiovascular mortality. A1C levels above 9.7% increased cardiovascular mortality 8- to 10-fold.
SOURCE: Lind M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 2014;371:1972-1982.
Type 1 diabetes is associated with an increased risk of mortality, secondary to microvascular (neuropathy, nephropathy) and macrovascular (coronary artery disease, stroke, peripheral vascular disease) complications. Mortality in patients younger than age 30 is most often explained by acute complications such as diabetic ketoacidosis and hypoglycemia, whereas cardiovascular disease is responsible for death later in the lives of those with type I diabetes. The American Diabetes Association (ADA) recommends targeting the A1C level in "most patients" to <7 %. Patients with hypoglycemia unawareness, with limited life span, in nursing homes, with advanced complications, or with known cardiovascular disease should be treated to less stringent A1C levels of 7.5-8%. This study suggests that mortality rates in patients with type 1 diabetes is almost entirely secondary to cardiovascular disease, even among those individuals who are achieving their recommended levels of glycemic control. The authors noted that "unlike patients with type 2 diabetes, those with type 1 diabetes generally do not have excess rates of obesity, hypertension, or hypercholesterolemia; thus, the increased risks of death from … cardiovascular causes in those who have good glycemic control is unexplained."
One possible cause of the increased cardiovascular mortality in patients with diabetes achieving their targeted A1C levels involves the induction of oxidative stress. Vascular endothelial cells form physical and biological barriers between the vessel wall and circulating blood cells, with the endothelium playing an important role in the maintenance of vascular homeostasis. Central to this role is the endothelial production of nitric oxide (NO). Daily fluctuations in glucose levels result in oxidative stress, which impairs NO bioactivity. Endothelial cells exposed to oxidative stress generate reactive oxygen species, which, in turn, activate biochemical pathways, favoring microvascular and macrovascular complications. Patients in whom the hexosamine pathway has been activated will likely develop cardiovascular disease.
Although A1C remains the standard by which clinicians determine the efficacy of various antidiabetes regimens, we should now evaluate the means by which postprandial excursions might be mitigated in patients with type 1 diabetes. Off-label use of GLP-1 receptor agonists in combination with SGLT2 inhibitors might prove to be an intriguing means by which glycemic variability may be improved, saving the lives of our patients with type 1 diabetes.
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