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Intensive Glucose Control and Macrovascular Complications 

Feb 1, 2020
Editor: Steve Freed, R.PH., CDE

Author: Alessa Grieff, PharmD candidate, University of South Florida College of Pharmacy

Intensive glucose control and macrovascular complications: results from a 15-year observational study. 

Past studies have shown conflicting evidence regarding the benefits of intensive glucose lowering on cardiovascular events. There is clear evidence in the benefits of reducing the incidence of microvascular complications, but not for cardiovascular events. The ACCORD, ADVANCE, and VADT trials showed modest and nonsignificant reductions in CV events over 3-6 years, but a 10-year follow up of the VADT showed emerging benefits. 

The VADT follow up study examined long-term consequences of intensive glycemic control on cardiovascular disease outcomes, quality of life, mortality, and legacy effects. The results of this 15-year trial are analyzed here. The trial included 6-year intensive glucose lowering treatment with a 10-year observational follow up; it included 1791 military veterans with type 2 diabetes who were randomly assigned to receive either intensive glucose control or standard treatment. The goal in the intensive group was to achieve a hemoglobin A1C 1.5% lower than the standard therapy (standard-therapy goal was 8%-9%). Central VA medical files, CMS claims, VA death files, and the National Death Index were the registries utilized to collect data about the outcomes. Some participants also completed surveys (survey cohort) for additional data collection. These surveys included questions for significant events in the past year, and they were completed annually. The primary outcome was the first major cardiovascular event (nonfatal MI, nonfatal stroke, new or worsening CHF, amputation for ischemic gangrene, or death from CV causes) in a time-to-event manner. The additional analysis included death from CV causes, death from any purpose, any primary diabetes outcome, and health-related quality of life. Cos proportional hazards were used to estimate hazard ratios and to examine the effects of the glycated hemoglobin level on the primary outcome and on the observed treatment effects. Post hoc sensitivity analysis to compare the role of glucose control at different intervals was also conducted. Duration of diabetes, baseline CV risk, a history of CV disease were three variables that were prespecified to be analyzed for heterogeneity within the treatment effects for the primary outcome and any significant diabetes outcome.  

In the VADT, most participants were male, overweight, or obese, and had a mean duration of diabetes of 12 years. The mean glycated hemoglobin level for the intensive-therapy group was 6.9%, and the median separation of the glycated hemoglobin curves was 1.5% which gradually diminished to 0.2-0.3% in the three years after trial completion, and then stabilized at a median of 8% in both groups. Medications for diabetes management were similar between the groups, with slightly higher doses in the intensive-therapy group during the VADT, but the use of medications was almost identical during the VADT-F. The intensive therapy group had more weight gain which remained higher (by BMI 1.3; 95% CI 1.1-1.5) through the follow-up study. The use of statins and medications for hypertension were similar between the groups. The study found that, at the median follow-up of 13.6 years, the primary composite outcome was non-significantly lower in the intensive therapy group by 9% (HR 0.91; 95% CI 0.78-1.06; p=0.23) and also non-significantly lower for any major diabetes event and death from any causes (hazard ratio 0.90 95% CI, 0.78-1.04 and hazard ratio 0.94; 95% CI, 0.78 to 1.03, respectively). There was also no evidence of shorter time to death or improved quality of life. Analysis of the three specified risk variables also found similar results. Results did show that during the ten years of separation of the glycated hemoglobin curve, there was a significant reduction of nearly 17% in the risk of the primary outcome. Results also did not show glucose-control legacy effects. 

The results of this study highlighted that intensive glucose control did not yield significantly lower risk of major cardiovascular events versus standard therapy. The results that did show a considerable difference suggest that there are modest, long-term CV benefits of intensive glucoselowering treatment in patients with more advanced diabetes and that long-term maintenance may be necessary to maintain these improvements. This trial was limited in that the patients may have already been at high risk for CVD, and they were mainly male and approximately 60 years old.  The study was also a follow-up based on 5.6 years of intensive therapy that was not continued after the study completed and thus, more sustained efforts could have yielded more significant long-term benefits.  

Practice Pearls: 

  • Past studies have shown conflicting evidence regarding the benefits of intensive glucose lowering concerning cardiovascular events. 
  • Intensive glucose control did not yield significantly lower risk of major cardiovascular events versus standard therapy. 
  • There are modest, long-term CV benefits of intensive glucoselowering therapy in patients with more advanced diabetes. 

Reference for “Intensive Glucose Control and Macrovascular Complications”:
 PD, Emanuele NV, Wiitala WL, Bahn GD, Reda DJ, McCarren M, DuckworthWC, Hayward RA; VADT Investigators. Intensive Glucose Control in Patients with Type 2 Diabetes – 15-Year Follow-up. N Engl J Med. 2019 Jun 6;380(23):2215 2224. doi: 10.1056/NEJMoa1806802.

Alessa Grieff, PharmD candidate, University of South Florida College of Pharmacy 


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