By Jeff Unger, MD, FACE
Director, Unger Primary Care Concierge Medical Group, Rancho Cucamonga, CA
Dr. Unger reports no financial relationships relevant to this field of study.
The authors conducted a retrospective cohort study from 2004 to 2013. A total of 101 patients with type 2 diabetes with a history of severe hypoglycemia were studied. A random sample of 101 patients with type 2 diabetes without any hypoglycemia was selected by matching values of baseline blood creatinine, age, sex, and diabetic duration.
Over 14 months, baseline serum creatinine (1.42 ± 0.75 mg/dL) significantly increased to 1.77 ± 1.26 mg/dL while eGFR decreased from 44.37 ± 26.1 to 41.28 ± 27.7 mL/min/1.73 m2 in the severe hypoglycemia cohort. No changes in eGFR or serum creatinine were noted in the patients without a history of severe hypoglycemia. The deterioration in renal function begins with the onset of the initial episode of hypoglycemia and continues to decline for a period of 8 months.
Fifty-nine percent of insulin-requiring patients with type 2 diabetes experience hypoglycemia. Continuous glucose monitoring studies suggest the majority of hypoglycemic events are nocturnal and undetected by the patients. Hypoglycemia results in dysregulation of glucose counterregulation, thereby increasing the likelihood of prolonged or repeated events within a 24 hour period. Chow et al, using a combination of Holter monitors and continuous glucose sensors, demonstrated that glucose values of 45 mg/dL result in prolonged bradyarrythmias, QT prolongation, and flattening of T waves.2 All these effects can have disastrous consequences for an individual with known coronary artery disease. A post hoc analysis of the ACCORD and ADVANCE trials by Garg et al noted alarming associations between hypoglycemia and mortality and between hypoglycemia and cardiovascular disease in intensive care-managed patients.3 A study by Zhao et al demonstrated that all-cause mortality tends to occur within 16 months of a single episode of severe hypoglycemia.4 In this study, severe hypoglycemia results in a rapid deterioration of renal function. Patients with a higher baseline creatinine are more vulnerable to chronic kidney disease progression.
Hypoglycemia can induce several physiologic changes, which can induce vascular compromise, including sympathoadrenal activation, vasoconstriction, inflammation, ischemia, abnormal cardiac repolarization, sepsis, and impaired autonomic nerve function. Hypoglycemia increases clot formation while decreasing thrombolysis, the effects of which persist for 2 days after hypoglycemia recovery.
Clinicians should adjust their glycemic targets in older patients with long-duration type 2 diabetes who have eGFRs < 45 mL/min/1.73 m2. These patients are at high risk of severe hypoglycemia, which can increase the likelihood of renal impairment, fatal cardiac arrhythmias, and all-cause mortality. Drugs that favor hypoglycemia, such as sulfonylureas and insulin, should be monitored carefully and discontinued in high-risk patients.
Pazos-Couselo M, et al. High incidence of hypoglycemia in stable insulin-treated type 2 diabetes mellitus: Continuous glucose monitoring vs self-monitored blood glucose. Observational Prospective Study. Can J Diabetes 2015 Aug 5.pii: S1499-2671(15)00468-2.doi:10.1016/j.jcjd.2015.05.007.
Chow E, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014;63:1738-1747.
Garg R, et al. Hypoglycemia with or without insulin therapy, is associated with increased mortality among hospitalized patients. Diabetes Care 2013;36:1107-1110.
Zhao Y, et al. Impact of hypoglycemia associated with antihyperglycemic medications on vascular risks in veterans with type 2 diabetes. Diabetes Care 2012;35:1126-1132.