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Severe Hypoglycemia in Type 2 Diabetes Linked to Progression of Coronary Artery Disease

Patients treated with standard therapy for blood glucose control show link between serious hypoglycemia and CAC progression, increasing risk of heart attack and stroke.

The objective of the study was to determine whether a link exists between serious hypoglycemia and progression of atherosclerosis in a substudy of the Veterans Affairs Diabetes Trial (VADT) and to examine whether glycemic control during the VADT modified the association between serious hypoglycemia and coronary artery calcium (CAC) progression. The study was conducted by the Phoenix VA Health Care System.

Serious hypoglycemia was defined as severe episodes with loss of consciousness, or requiring assistance, or documented glucose <50 mg/dL. Progression of CAC was determined in 197 participants with baseline and follow-up computed tomography scans.

The results showed that during an average follow-up of 4.5 years between scans, 97 participants reported severe hypoglycemia (n = 23) or glucose <50 mg/dL (n = 74). Serious hypoglycemia occurred more frequently in the intensive therapy group than in the standard treatment group (74% vs. 21%, P < 0.01). Serious hypoglycemia was not associated with progression of CAC in the entire cohort, but the interaction between serious hypoglycemia and treatment was significant (P < 0.01). Participants with serious hypoglycemia in the standard therapy group, but not in the intensive therapy group, had ∼50% greater progression of CAC than those without serious hypoglycemia (median 11.15 vs. 5.4 mm3, P = 0.02). Adjustment for all baseline differences, including CAC, or time-varying risk factors during the trial, did not change the results. Examining the effect of serious hypoglycemia by on-trial HbA1c levels (cutoff 7.5%) yielded similar results. In addition, a dose-response relationship was found between serious hypoglycemia and CAC progression in the standard therapy group only.

The progression of CAC was determined in patients using computed tomography scans. Scans were conducted before the study and during follow-up – the average follow-up time between the scans was 4.6 years.

Patients were assigned either standard or intensive treatment for glycemic control. The standard group was treated with 500mg of metformin, 4mg of rosiglitazone, 2mg of glimepiride and one unit of insulin per nine pounds of body weight. Their aim was to maintain HbA1c between 8-9 percent (64-75 mmol/mol). The intensive treatment group had to aim to keep their HbA1c lower than 6.0 percent (42 mmol/mol) and were treated with 500mg of metformin (up to 2000mg), 4mg of rosiglitazone, 8mg of glimepiride and one unit of insulin per nine pounds of body weight.

97 participants experienced one of more severe hypos; occurring in 74 percent in the intensive treatment group and 21 percent of the standard therapy group. The authors defined severe hypoglycemia “as severe episodes with loss of consciousness or requiring assistance or documented glucose <50 mg/dL (2.8 mmol/l).”

Severe hypos were not linked to CAC progression, but an interaction was observed between severe hypos and treatment type. Patients treated with standard therapy who had a severe hypo had greater CAC progression compared to those who didn’t have a severe hypo. This relationship remained after adjustments for differences between patients with and without severe hypos.

In both treatment groups, greater CAC progression was found in participants with a mean HbA1c of 7.5 percent (58.5 mmol/mol ) or over who had experienced severe hypoglycemia. Higher HbA1c was associated with CAC progression among severe hypo patients, but not in those who did not experience a severe hypo. In the standard therapy group, CAC progression increased with increasing incidences of severe hypoglycemia.

The researchers concluded: “This study shows that serious hypoglycemia is associated with increased progression of [coronary artery calcium] in patients undergoing standard therapy for glycemic control and in those with higher HbA1c (> 7.5%) during the VADT, despite a nearly threefold higher frequency of serious hypoglycemia with intensive therapy.”

The results may provide additional insights into long-term cardiovascular benefits of intensive glycemic control and support the importance of avoiding hypoglycemia, particularly in elderly patients with long-standing, poorly controlled type 2 diabetes.

The results show that those at greatest risk of CAC, and therefore heart disease and stroke, were those with relatively poorly controlled diabetes despite being on strong medication, glimepiride and insulin, which can induce hypos.

“The study did not look into how the risk of heart disease and stroke could best be prevented, but it is likely that a stronger focus on improving diet and physical activity, with close review of medication doses, would help lower the heart and stroke risk.”

In conclusion, the results showed that, despite a higher frequency of serious hypoglycemia in the intensive therapy group, serious hypoglycemia was associated with progression of CAC in only the standard therapy group.

Practice Pearls:

  • Those at greatest risk of CAC, and therefore heart disease and stroke, were those with relatively poorly controlled diabetes despite being on strong medication.
  • A stronger focus on improving diet and physical activity, with close review of medication doses, would help lower the heart and stroke risk.
  • Serious hypoglycemia is associated with increased progression of coronary artery calcium in patients undergoing standard therapy for glycemic control and in those with higher HbA1c (> 7.5%).

Researched and prepared by Steve Freed, BPharm, Diabetes Educator, Publisher and reviewed by Dave Joffe, BSPharm, CDE

 

Diabetes Care March 2016 vol. 39 no. 3 448-454