EBDM March 2019: Clinical Updates

New Look at VA Diabetes Trial Links Severe Hypoglycemia, Cardiovascular Events

A decade ago, the New England Journal of Medicine published findings from the Veterans Affairs Diabetes Trial (VADT), which compared standard glucose control with intensive control on 2 groups of patients with longstanding type 2 diabetes (T2D).¹ Already, 40% had suffered a cardiovascular event. The study found no significant difference between the 2 groups in cardiovascular outcomes or most microvascular complications. This was important at the time, because the results differed from the ACCORD trial, which had stopped early because deaths had spiked among the intensive therapy group.

The VADT was significant because it looked specifically at the impact of glycemic control¹ rather than the effect of a specific agent. Now, with cardiovascular outcomes in T2D front and center among researchers, the VADT investigators have published a post hoc analysis in Diabetes Care, this time looking at differences among veterans who suffered severe hypoglycemia—and this group did see worse outcomes.²

The original trial involved 1791 veterans, almost all men but with good geographic and racial diversity. Their average age was 60.5 years, and they had lived with T2D and for an average of 11.5 years. Their condition was poorly controlled, with an average glycated hemoglobin (A1C) of 9.4% ± 2.0%. According to a 2015 interview with Peter Reaven, MD, a VADT lead investigator (and author on the new study), the treatment goal for the standard group was just below 7.0% for the intensive group and just below 8.4% for those receiving standard care—consistent with published findings that stated the 2 groups’ targeted A1C goals were 1.5% apart.

During the study reported in Diabetes Care, veterans were seen every 3 months, and doctors recorded the number of severe hypoglycemia events, defined as a “self-reported episode of a low blood glucose value accompanied by confusion requiring assistance from another person or loss of consciousness.” Those data were missing for less than 0.5% of the participants (35 of 1791), who were excluded from the post hoc analysis.

Investigators found that the rate of severe hypoglycemia was higher in the intensive treatment group: 10.3 per 100 patient-years compared with 3.7 per 100 patient-years in the standard treatment group (P <.001). Severe hypoglycemia within the past 3 months was associated with an increased risk of serious cardiovascular events (P = .032), cardiovascular mortality (P = .012), and total mortality (P = .024).

However, the analysis found a relatively greater increased risk of total mortality in the group that was treated to the standard goal compared with the group treated to the more intensive goal (P = 0.019). The association between severe hypoglycemia and cardiovascular events increased significantly as overall cardiovascular risk increased, based on the UK Prospective Diabetes Study risk score (P = .012).

Also, there were several independent predictors of severe hypoglycemia: insulin use at baseline (P = .02), protein in the urine (P = .009), and autonomic neuropathy, which can affect the cardiovascular system (P = .01). A higher body mass index had a protective effect (P = .017), a paradox observed in other studies. “Perhaps [this was] because of the associated insulin resistance providing some protection against the glucose-lowering effects of insulin or insulin secretagogues,” the VADT investigators wrote.

The new analysis shows the need to customize treatment to individual requirements, especially in older patients, according to the VADT investigators. “The serious consequences of these hypoglycemia-associated outcomes (cardiovascular events and mortality) emphasize the importance of careful selection of patients and medications when initiating intensification of therapy and close monitoring of patients for evidence of these events,” they wrote.

REFERENCES:

1. Duckworth W, Abraira C, Moritz T, et al; VADT investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139. doi: 10.1056/NEJMoa0808431.
2. Davis SN, Duckworth W, Emanuele N; Investigators of the Veterans Affairs Diabetes Trial. Effects of severe hypoglycemia on cardiovascular outcomes and death in the Veterans Affairs Diabetes Trial. Diabetes Care. 2019;42(1):157-163. doi: 10.2337/dc18-1144.

Alzheimer's Association Funds Extension of Study on Blood Pressure, Dementia Connection

More than 3 years ago, the National Institutes of Health ordered an early halt to the landmark SPRINT study (Systolic Blood Pressure Intervention Trial),¹ which found that aggressively lowering systolic blood pressure to 120 mm Hg instead of 140 mm Hg for patients with high blood pressure and another health risk led to fewer heart attacks, strokes, and cardiac deaths.

Investigators had good reason to take that step. The results were so clear that it would have been unethical to continue the trial; in fact, they have already prompted the American College of Cardiology and the American Heart Association to revise their definition² of what constitutes high blood pressure.

But stopping the study had an unintended consequence. The SPRINT MIND segment would end early, too, possibly leaving it underpowered to answer a different question: Does aggressively controlling blood pressure in certain patients with cardiac risks help prevent dementia?

Results from that truncated trial were published recently in JAMA. The findings suggest a connection but did not reach the level of significance.³ The authors stated that stopping the trial early meant there were simply fewer cases of dementia than expected. For that reason, the Alzheimer’s Association announced that it will take the extraordinary step of awarding $800,000 to fund SPRINT MIND 2.0, which will reengage the original participants and add 2 years of follow-up “to try to allow for a more definitive statement on reducing dementia risk,” according to a statement⁴ from the group.

The possible connection between cardiovascular disease (CVD) and dementia or Alzheimer disease has been studied for some time. An accompanying editorial in JAMA stated, “The mechanisms by which CVD risk factors and the risk of developing [Alzheimer disease] are most likely related to the important role in vascular health for β-amyloid and other neurodegenerative protein deposition, and observational studies have suggested that hypertension is associated with an increased risk of all-cause dementia.”⁵

What set SPRINT MIND apart was a plan for lengthy follow-up and a specific plan to look for both dementia and mild cognitive impairment, a separate state between normal aging and full-blown dementia. When the follow-up period was cut short, the planned year 4 cognitive assessments were done after primary care physicians again provided medications. The results showed that this difference rose to the level of significance, but the primary outcome of dementia did not.

Of the more than 9300 participants in the overall trial, 149 were in the SPRINT MIND intensive treatment group versus 176 in the standard treatment group. The latest data gathered in the SPRINT MIND trial showed that aggressively controlling blood pressure did result in a significant difference in these cases of mild cognitive impairment (14.6 cases per 1000 person-years in the treatment group vs 18.3 cases per 1000 person-years in the standard group, HR, 0.81; 95% CI, 0.69-0.95). When the trial ended with more than a year to go, the dementia cases were far fewer: 7.2 cases per 1000 person-years in the treatment group vs 8.6 per 1000 person-years in the standard group (HR, 0.83; 95% CI, 0.67-1.04).

The Alzheimer’s Association said in its statement that the group found the data “compelling.” Maria C. Carrillo, PhD, the group’s chief science officer, said in the statement that, mild cognitive impairment (MCI) “is a known risk factor for dementia, and everyone who experiences dementia passes through MCI. When you prevent new cases of MCI, you are preventing new cases of dementia.”

The group, she said, “is committed to getting clarity and certainty on the dementia outcome by following participants for a longer period of time.”

SPRINT MIND 2.0 will begin early this year.

REFERENCES:

1. Caffrey M. 5 things to know about the SPRINT study. The American Journal of Managed Care^® website. ajmc.com/ newsroom/5-things-to-know-about-the-sprint-study. Published November 13, 2015. Accessed January 28, 2019.
2. Caffrey M. High blood pressure starts at 130/80, new guidelines say. The American Journal of Managed Care^® website. ajmc.com/conferences/aha-2017/80-new-guidelines-say. Published November 13, 2017. Accessed January 28, 2019.
3. Williamson JD, Pajewski NM, Auchus AP, et al; SPRINT MIND Investigators for the SPRINT Research Group. Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321(6)553-561. doi: 10.1001/jama.2018.21442.
4. Alzheimer’s Association funds two-year extension of the SPRINT MIND study [press release]. Chicago, IL: Alzheimer’s Association; January 28, 2019. prnewswire.com/news-releases/alzheimers-association-funds-two-year-extension-of-the-sprint-mind-study-300784755.html. Accessed January 28, 2019.
5. Yaffe K. Prevention of cognitive impairment with intensive systolic blood pressure control. JAMA. 2019;321(6):548-549. doi: 10.1001/jama.2019.0008.

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