Blood Sugar Control for Diabetes: Asking the Heart Questions

Posted on June 16, 2015 by Dr. Francis Collins

Credit: Thinkstock

When most people think about risk factors for cardiovascular disease, they likely think of blood pressure readings or cholesterol levels. But here’s something else that should be high on that list: diabetes. That’s because people with diabetes are roughly twice as likely to die of heart disease than other folks [1]. Yet the issue of how best to help such people lower their cardiovascular risks remains a matter of intense debate. Some studies have suggested that part of the answer may lie in tightly controlling blood sugar (glucose) levels with a strict regimen of medications and monitoring [2]. Other research has shown that the intense effort needed to keep blood glucose levels under tight control might not be worth it and may even make things worse for certain individuals [3].

Now, a follow up of a large, clinical trial involving nearly 1,800 U.S. military veterans with type 2 diabetes—the most common form of diabetes—provides further evidence that tight blood glucose control may indeed protect the cardiovascular system. Reporting in The New England Journal of Medicine [4], researchers found a significant reduction in a composite measure of heart attacks, strokes, heart failure, and circulation-related amputations among the vets who maintained tight glucose control for about five and a half years on average. What’s particularly encouraging is most of the cardiovascular-protective benefit appears to be achievable through relatively modest, rather than super strict, reductions in blood glucose levels.

To assess blood glucose control, the Veterans Affairs Diabetes Trial (VADT) used a common laboratory blood test for glycosylated hemoglobin A1C, often simply referred to as A1C. This test, which measures the amount of glucose attached to hemoglobin in red blood cells, reflects a person’s average blood glucose level over the preceding two to three months. A normal A1C level is below 5.7 percent, while levels between 5.7 and 6.4 percent indicate an increased risk of diabetes. People with frank diabetes usually have A1C levels above 6.5 percent.

When they enrolled in the VADT study, all of the veterans had long-standing type 2 diabetes; had cardiovascular disease or were at high risk for cardiovascular disease; and had poorly controlled blood glucose levels (their A1C readings averaged 9.4 percent). Half were assigned to an intensive therapy regimen, while the others remained on standard treatment for an average of 5.6 years.

The primary difference between the two treatment approaches were the doses of glucose-lowering oral medications (metformin, rosiglitazone, and/or glimepiride) and when insulin therapy was initiated. Patients in the intensive therapy group were prescribed doses of oral medication that were twice as high as standard. In addition, they received insulin when their A1C levels rose above 6 percent, compared to 9 percent for the standard therapy group. All participants also received aspirin and a cholesterol-lowering statin drug to control other cardiovascular risk factors.

During the clinical trial, the vets in the intensive therapy group lowered their A1C levels to 6.9 percent on average, compared to 8.4 percent in the standard care group—a significant difference. However, follow-up work, led by Rodney Hayward at the University of Michigan and the Ann Arbor VA Healthcare System, found that the effect did not persist: three years after the trial ended, both groups’ A1C levels hovered around 8 percent, separated by just 0.2 to 0.3 percentage points.

Still, nearly 10 years after the vets signed up for VADT, those who received intensive therapy were 17 percent less likely to suffer major cardiovascular events than their standard therapy counterparts. However, no differences were seen in cardiovascular-related deaths. According to the researchers, this may be partially due to recent life-saving improvements in the way the public, emergency personnel, and health-care professionals respond to heart attacks and strokes.

When the VADT results are considered along with those from three previous major clinical trials of blood glucose control, the researchers say the data underscore the importance of encouraging everyone with diabetes to strive for at least a moderate level of blood glucose control. They concluded that an average long-term A1C level of 8 percent was sufficient to reap most of the cardiovascular benefits. While a 7 percent A1C level can be safely attained in many people, the intense therapy needed to maintain such tight blood glucose control may not always be worth it in terms of cardiovascular protection.

One thing is clear: the number of Americans with type 2 diabetes continues to rise, and more research is needed into this major public health challenge. For example, the VADT study included only 47 females, so further work is needed to confirm its findings in larger groups of women with type 2 diabetes. Hayward and his colleagues also plan to continue to follow the VADT participants to see whether the cardiovascular benefits of better blood glucose control hold up over time.

Another important take-home message is that each individual with diabetes needs to work closely with his or her physician to weigh the benefits and risks of tight blood glucose control and develop a personalized diabetes management plan that takes into account cardiovascular risk, age, and a variety of other factors. Keep in mind that very low blood glucose levels (hypoglycemia) from too much insulin can also cause serious health problems, including fainting, seizures, and even death.

The new Precision Medicine Initiative stands ready to provide some help in this area. In a population of 1 million American volunteer participants, there will be tens of thousands of people with type 2 diabetes. This will provide an unprecedented opportunity to test new methods of disease management. Currently, most people with diabetes have to rely on a regular routine of finger pricks, test strips, and hand-held monitors to track their blood glucose levels between A1C lab tests. Among the many goals of the Precision Medicine Initiative is to support research aimed at developing and testing ways of gathering such biological data in real-time using a variety of innovative wireless technologies. In the case of blood glucose, researchers are already exploring ideas ranging from a needle-free “tattoo” that uses a mild electrical current to measure glucose levels in the skin to a “smart” contact lens that gets its glucose readings from a person’s tears.

References:

[1] This National Diabetes Month, take steps to improve diabetes outcomes. National Institute of Diabetes and Digestive and Kidney Diseases. November 3, 2014.

[2] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65.

[3] Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. Zoungas S, Chalmers J, Neal B, Billot L, Li Q, Hirakawa Y, Arima H, Monaghan H, Joshi R, Colagiuri S, Cooper ME, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Lisheng L, Mancia G, Marre M, Matthews DR, Mogensen CE, Perkovic V, Poulter N, Rodgers A, Williams B, MacMahon S, Patel A, Woodward M; ADVANCE-ON Collaborative Group. N Engl J Med. 2014 Oct 9;371(15):1392-406.

[4] Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, Duckworth WC, Emanuele NV; VADT Investigators. N Engl J Med. 2015 Jun 4;372(23):2197-206.

Links:

What is Diabetic Heart Disease? (National Heart, Lung, and Blood Institute/NIH)

The A1C Test and Diabetes (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Glycemic Control and Complications in Diabetes Mellitus Type 2 (VADT) (Clinicaltrials.gov)

Precision Medicine Initiative (NIH)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute