Published in UAB Insight, Summer 2006
Tight Glycemic Control Cuts Cardiovascular Risk in Type 1 Diabetes
ABSTRACT: Intensive near normalization of glucose in people with type 1 diabetes significantly cuts risks of cardiovascular events compared with standard treatment.
CME OBJECTIVE: The reader will understand the benefits and risks of tight glycemic control in patients with type 1 diabetes.
Fernando Ovalle, MD, no conflicts of interest
Cardiovascular disease is 10 times more prevalent among people with type 1 or type 2 diabetes mellitus than among those who do not suffer from the conditions, which affect nearly 21 million Americans. According to a landmark observational study published in The New England Journal of Medicine, achieving near normoglycemia significantly decreases microvascular and macrovascular disease for patients with type 1 diabetes (2005;353:2643-2653).
The Epidemiology of Diabetes Interventions and Complications (EDIC) trial found during a mean of 17 years, intensive glucose control significantly reduces risk of cardiovascular (CV) events, including stroke, nonfatal myocardial infarction (MI), the need for coronary-artery revascularization, and death from CV disease compared with conventional treatment. Cardioprotective benefits of intensive control persisted for more than a decade, despite a gradual rise in glycosylated hemoglobin (HbA1c) levels.
“Studies confirm the critical importance of early intervention with tight glucose control in individuals diagnosed with type 1 diabetes,” says UAB endocrinologist and diabetes expert Fernando Ovalle, MD. “We know patients with microvascular complications of diabetes have an increased risk of macrovascular complications. This critical study also confirms tight glycemic control significantly reduces the degree of atherosclerosis underlying CV disease, just as it decreases damage to eyes, nerves, and kidneys in people with type 1 diabetes.”
DCCT/EDIC Trials
EDIC’s latest findings compare the effects of conventional versus intensive treatment for type 1 diabetes on development and progression of CV disease. EDIC followed 1394 of 1422 patients with type 1 diabetes who participated for 13 years (1980-1993) in the Diabetes Control and Complications Trial (DCCT). At baseline, patients had no or minimal microvascular or macrovascular disease.
DCCT established hyperglycemia as a predictor of microvascular complications. Early intensive glycemic control reduced development and progression of retinopathy, nephropathy, and neuropathy by 35% to 90% compared with conventional therapy (JAMA. 2002;287[19]:2563-2569). Conventional therapy consisted of one to two insulin injections a day with daily urine or blood glucose testing, and no glucose goals beyond control of hyperglycemia and hypoglycemia.
The goal for patients assigned to intensive control was an HbA1c value of ≤6.5% with at least three insulin doses daily or use of an insulin pump and frequent blood glucose self-monitoring. Patients in the intensively treated group had mean HbA1c readings of 7.2%, while those treated conventionally had mean values of 9%. Most of the latter group adopted intensive control at the end of DCCT.
In 1994, the EDIC study picked up where DCCT left off, evaluating the influence of prior conventional or intensive diabetes treatment as well as tight control of blood pressure, lipid levels, and other factors on subsequent development and progression of macrovascular, neuropathic, and CV complications. Premeal daily glucose goals were maintained in the range of 70 to 120 mg/dL and peak post-meal goals were ≤180 mg/dL.
Investigators measured HbA1c quarterly and serum creatinine values, fasting lipid levels, and other CV risk factors annually. The benefits of the first 6 years of tight control persisted though HbA1c levels gradually rose. As in DCCT, microalbuminuria (urinary albumin excretion of at least 40 mg per 24-hour period) and albuminuria (at least 300 mg per 24-hour period) were more prevalent in the conventional treatment group, and serum creatinine values were significantly higher.
“Albuminuria is a marker of kidney disease and also may be a marker of endothelial dysfunction,” says Ovalle. “It is possible that by some unknown mechanism, these microvascular complications predispose people with renal disease and neuropathy to CV disease, rather than glucose alone being the culprit.”
A potential explanation for prolonged beneficial effects of early intensive intervention, or “metabolic memory,” Ovalle says, is its prevention of the formation of advanced glycation end products that result eventually in microvascular and macrovascular complications.
“Lowering glucose, therefore, lowers the risk of atherosclerosis in some people,” Ovalle says. Early intervention also helps preserve vital function of pancreatic β-cells responsible for insulin formation and secretion. “It is far easier to control hypoglycemia and reduce complications in diabetic patients with preserved β-cell function,” he says.
Intensive vs Conventional Therapy
Most type 1 diabetes patients are managed according to standard American Diabetes Association (ADA) goals, which currently recommend conventional therapy to achieve HbA1c levels of <7%. Other groups such as the American College of Endocrinology recommend tighter HbA1c values of ≤6.5% to minimize risk of microvascular and macrovascular complications. (Available at: http://www.aace.com/pub/pdf/guidelines/diabetes_2002.pdf. Accessed June 12, 2006.)
An editorial accompanying EDIC results suggests reassessing goals for glycemic control and CV disease in light of DCCT and EDIC findings (N Engl J Med. 2005;353:2707-2709).
Unfortunately, maintaining these glycosylated hemoglobin values is still difficult, says Ovalle. “It is like walking a tightrope. In some diabetic patients the rope is wider; in others — with renal disease, for example — it is very thin.”
Because of the risk for severe episodes of hypoglycemia, intensive therapy is not recommended for children younger than 13 years, individuals with advanced CV disease, older adults, and people with history of frequent severe hypoglycemia.
Cardiovascular Implications
EDIC’s primary endpoint was a first CV event with clinical findings of nonfatal myocardial infarction or stroke; death due to CV disease; subclinical MI identified on an annual electrocardiogram; angina confirmed by stress test or angiography; or the need for revascularization with angioplasty or coronary artery bypass.
Baseline characteristics associated with development of CV disease were older age; longer diabetes duration; retinopathy; smoking; assignment to conventional treatment; and higher body-mass index, low-density lipoprotein cholesterol, HbA1c levels, and albumin excretion rate. There were no significant differences in conventional CV risk factors between the groups.
There were 46 cardiac events among 31 patients assigned to intensive glucose treatment and 98 among 52 patients assigned to conventional treatment. Intensive treatment was associated with a 42% reduction in risk for a first CV event.
Atherosclerosis, measured by prevalence of coronary artery calcification and carotid intima-media thickness, progressed more slowly in the intensively treated group, Ovalle says. Decreased progression of atherosclerosis in the intensively treated group was reported up to 6 years after the DCCT trial ended (N Engl J Med. 2003;348:2294-2303). Assessed by a decrease in HbA1c values, improved glycemic control also seemed to account for much of the cardiovascular benefit.
The authors acknowledge that, because of limited sample size, the number of CV events was small. “Even so, the difference between the groups is as large, or even larger, than what we see from use of statins, beta blockers, or ACE inhibitors,” says Ovalle. “These other treatment modalities will still be necessary until we better understand the physiology of this disease, or specifically how diabetes leads to atherosclerosis.”
Currently, ADA guidelines for glycemic control remain an HbA1c test twice a year in patients meeting glycemic goals, and quarterly for patients who do not. The ADA recommends taking a thorough medical history and physical exam and a family history of diabetes or other endocrine disorders; performing a cardiac evaluation; assessing diet and medications that may affect glucose levels; measuring HbA1c levels, fasting lipid profile, albumin levels in the urine, and serum creatinine in children in the presence of proteinuria; and performing urinalysis for ketones, protein, and sediment. Complete 2006 Clinical Practice Recommendations are available on the Web. (Available at: http://care.diabetesjournals.org/content/vol29/suppl_1/.
Accessed June 12, 2006.)
For more information:
Dr. Fernando Ovalle
1.800.UAB.MIST
mist@uabmc.edu