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Insulin Dose, Cardiovascular Disease Risk and Outcomes

Apr 2, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Dahlia Elimairi, Pharm D Student, UC Denver Skaggs School of Pharmacy

Intensive diabetes therapy can be associated with excess weight gain, central obesity, and dyslipidemia with increased heart disease risk.

In the Diabetes Control and Complications Trial (DCCT), a total of 1,441 participants were randomly assigned to intensive or conventional diabetes therapy. After an average of 6.5 years of follow-up, 96% of the surviving cohort enrolled in the Epidemiology of Diabetes Interventions and Complications (EDIC) observational study, which included annual visits with detailed medical history, physical examination, and laboratory testing.

The DCCT demonstrated that intensive therapy reduces diabetes mellitus complications

but was associated with weight gain and obesity.

An analysis of the DCCT and EDIC study done by J.Q. Purnell et al and published in 2013 aimed to determine if excessive weight gain with diabetes therapy is prospectively associated with atherosclerotic disease.

The study found that excessive weight gain with intensive therapy is sustained during 6 years of EDIC follow-up and remains associated with central obesity, insulin resistance, a progressive rise in blood pressure, and dyslipidemia as well as more extensive atherosclerosis during EDIC. Regardless of the treatment group assigned, subjects with the greatest weight gain had the greatest intima-media thickness (IMT) and highest coronary artery calcium (CAC) scores.

They concluded that whether or not  the atherogenic changes associated with weight gain will reduce the long-term benefit of intensive therapy on major cardiovascular events needs to be examined with future follow-up. However, based on the results of this study, efforts should be made to limit excess weight gain that accompanies intensive glucose treatment.

In a recent study, the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study was analyzed to evaluate the relationship between longitudinal changes in insulin dose and CVD risk factors and outcomes.

Cardiovascular disease events were adjudicated by a review committee. Generalized linear mixed models and Cox proportional hazards regression models were used to assess the association between insulin dose, cardiometabolic risk factors and CVD risk, respectively, over a total of 30 years.

The study found that higher insulin doses were significantly associated with a less favorable cardiometabolic risk profile (higher BMI, pulse rate, triglycerides, and lower HDL cholesterol) except for lower diastolic blood pressure and lower LDL cholesterol. In a minimally adjusted model, a 0.1 unit/kg body weight/day increase in insulin dose was associated with a 6% increased risk of any CVD. However, the association with insulin dose was no longer significant after adjustment for other CVD risk factors.

The study concluded that higher insulin doses were associated with adverse trends in several cardiometabolic risk factors, even after multivariable adjustment, but not with incident CVD outcomes.

They suggested that efforts to intensify insulin therapy should continue in order to reduce the risk for microvascular and cardiovascular complications in type 1 diabetes. Intensive insulin therapy, with higher doses, was associated with 50% reduction in the incidence of CVD events in the DCCT/EDIC. However, given the adverse impact of weight gain with insulin therapy, lifestyle counseling for prevention of weight gain is recommended. Adjunctive lifestyle regimens that minimize weight gain would be advisable for patients receiving insulin therapy.

Practice Pearls:

  • Higher insulin doses were associated with adverse cardiometabolic risk factors, including excess weight gain, central obesity, higher heart rate and dyslipidemia but not with incident cardiovascular disease outcomes.
  • The studies suggested that for now efforts to intensify insulin therapy should continue to reduce the risk for microvascular and cardiovascular complications in people who have type 1 diabetes.
  • There should be more effort made to limit excess weight gain that accompanies intensive glucose treatment through adjunctive lifestyle regimens.

References:

Braffett BH, Dagogo-Jack S, Bebu I, Sivitz WI, Larkin M, Kolterman O, Lachin JM; DCCT/EDIC Research Group. Association of Insulin Dose, Cardiometabolic Risk Factors, and Cardiovascular Disease in Type 1 Diabetes During 30 Years of Follow-up in the DCCT/EDIC Study. Diabetes Care. 2019 Feb 6.

Purnell JQ, Zinman B, Brunzell JD; DCCT/EDIC Research Group. The effect of excess weight gain with intensive diabetes mellitus treatment on cardiovascular disease risk factors and atherosclerosis in type 1 diabetes mellitus: results from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complicatios Study (DCCT/EDIC) study. Circulation. 2013 Jan 15;127(2):180-7.

Dahlia Elimairi, Pharm D student UC Denver Skaggs School of Pharmacy