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By Jeff Unger, MD, ABFP, FACE
Medical Director, Unger Primary Care Medicine Group, Rancho Cucamonga, CA
Dr. Unger is on the speaker’s bureau for Janssen Pharmaceuticals, Novo Nordisk and Valeritas; is an advisory board member for Janssen, Sanofi-Aventis, Novo Nordisk, Halozyme, and Abbott; is a consultant for Novo Nordisk, Sanofi-Aventis, Valeritas, and Dance Pharmaceuticals. He also received research grants from Boehringer Ingelheim, Novo Nordisk, GSK, Eli Lilly, Johnson and Johnson, Pfizer, Sanofi-Aventis, Takeda, and Merck.
Synopsis: Sixty-one patients with type 2 diabetes discontinued their prescribed antihyperglycemic agents and underwent 4 weeks of intensive insulin therapy. A total of 56% of patients demonstrated a reduction in glycemic variability and improvement in beta-cell function.
Source: Kramer CK, et al. Glycemic variability in patients with early type 2 diabetes: The impact of improvement in beta-cell function. Diabetes Care 2014;37:1116-1123.
In this study, 61 patients with type 2 diabetes for an average dura-tion of 3 years began intensive insulin therapy using basal insulin detemir and prandial insulin aspart. The initial total daily dose of insulin was 0.2-0.4 units/kg with 60% provided at mealtime and 40% injected as a basal dose. Patients were asked to perform self blood glucose monitoring at least four times daily with two additional 2-hour postprandial checks at least four times each week. All blood glucose values were sent to a study coordinator who titrated the insulin doses to a target fasting level of 72-108 mg/dL and a 2-hour postprandial level < 144 mg/dL. Prior to and at the conclusion of the study, researchers assessed pancreatic beta-cell function using the insulin secretion-sensitivity index-2 (ISSI-2) and determined the coefficient of variability based on the changes in 6-point glucose testing. Between the first and last week of the study, 55.7% of patients demonstrated a reduction in their glucose variability. Patients demonstrating a ≥ 25% increase in ISSI-2 experienced the highest reduction in glycemic variability compared with other subjects in the trial. Therefore, treatments that minimize glycemic variability in patients with type 2 diabetes may preserve beta-cell function, thereby reducing the risk of long-term diabetes-related complications.1,2
Although A1C has become the standard by which clinicians target their treatment strategies for all patients with diabetes, other therapeutic parameters have been found to have significance for predicting outcomes. In the Diabetes Control and Complication Trial (DCCT), the A1C and the duration of diabetes (glycemic exposure) explained only 11% of the variation in retinopathy risk for the entire DCCT cohort. Thus, 89% of the risk for vision loss appeared to originate from sources other than glycemic control. In 2008, Kilpatrick et al noted that the long-term variability in A1C levels over months or years, rather than the diurnal glycemic changes, may be more predictive of complications.4 Glycemic variability induces oxidative stress, which activates microvascular and macrovascular complication pathways. Variability also increases one’s risk of hypoglycemia and tends to have a deleterious effect on residual beta-cell function.
Patients with diabetes who remain C-peptide positive are less likely to develop microvascular complications and experience episodes of severe hypoglycemia. Therefore, anything we as clinicians can do to support the beta-cell appears to be in the patient’s best interest.
We have many tools that may be used to minimize glycemic variability in patients with both type 1 and type 2 diabetes. The safety and efficacy of liraglutide is currently being tested in patients with type 1 diabetes in a series of Phase 3 clinical trials (ADJUNCT-ONE and ADJUNCT-TWO). By reducing postprandial glucagon levels, patients with type 1 diabetes may be able to minimize their glycemic excursions using liraglutide. Liraglutide does not appear to have a negative influence on glucose counterregulation in patients with type 1 diabetes and may promote weight reduction in this patient population.
Mitigation of glycemic variability is important for all patients with diabetes. Early and ambitious intervention to salvage remaining beta-cells will perhaps allow intensively managed individuals to minimize their risk of hypoglycemia while avoiding many long-term complications.