Diabetes and Cardiovascular Disease: Does Lowering Hemoglobin A1c Help or Harm?

Diabetes and Cardiovascular Disease: Does Lowering Hemoglobin A1c Help or Harm?

Key words: diabetes mellitus, hemoglobin A1c, cardiovascular disease

Case 1: Mr A. is a 55-year-old man who comes to your office for a routine physical examination. He is a traveling salesman and has recently gained weight. He does not exercise much and is a frequent visitor to fastfood establishments. His father had “a touch of diabetes” and died of a myocardial infarction (MI) at age 59. The patient says he feels fine and is able to work 60 hours a week without any difficulty. His body mass index (BMI) is 32, and blood pressure is 148/88 mm Hg (measured 3 times); there are no other significant physical findings. Laboratory studies reveal the following values: fasting blood glucose (FBG), 136 mg/dL; hemoglobin A1c (HbA1c), 6.8%; low-density lipoprotein (LDL) cholesterol, 155 mg/dL; high-density lipoprotein (HDL) cholesterol, 32 mg/dL; and triglycerides, 233 mg/dL.

Case 2: Mrs B. is a 77-year-old woman with a 25-year history of type 2 diabetes mellitus. She is new to your practice. She recently moved to town to live with her daughter after her husband died 8 months earlier. You provide care to the daughter and her family. The patient has osteoarthritis and retinopathy and had an MI 7 years earlier. Her daughter thinks her mother is having some memory problems. Medications include metformin, 1000 mg bid; glipizide, extended release, 10 mg/d; atorvastatin, 10 mg/d; lisinopril, 10 mg/d; aspirin, 81 mg/d; and acetaminophen as needed. BMI is 26, and blood pressure is 127/64 mm Hg; diminished pedal pulses and sensory loss above the ankles bilaterally are noted. Laboratory studies reveal the following values: FBG, 176 mg/dL; HbA1c, 7.8%; LDL-cholesterol, 145 mg/dL; HDL-cholesterol, 45 mg/dL; and triglycerides, 283 mg/dL. Serum creatinine level is 1.1 mg/dL. Glomerular filtration rate is higher than 60 mL/min/1.73 m2, and the urine microalbumin/creatinine ratio is 120 μg/mg.

In the United States, diabetes is the sixth leading cause of death; the most common cause of blindness, end-stage renal disease, and nontraumatic limb amputations; and a major contributor to cardiovascular disease (CVD).1-4 Cardiovascular events are responsible for 70% of the mortality and morbidity in persons with diabetes, and these patients have a 2- to 4-fold higher risk of CVD.5,6 Prevention of these complications is the major goal of diabetes care.

The risk of complications can be reduced by controlling the hyperglycemia, hyperlipidemia, and hypertension associated with diabetes. Two landmark studies, the Diabetes Control and Complications Trial (DCCT)7 and the United Kingdom Prospective Diabetes Study (UKPDS),8 provide excellent evidence that lowering HbA1c levels to 7% or less reduces the incidence of retinopathy, neuropathy, and nephropathy (microvascular complications). For every 1% drop in HbA1c, a 33% to 37% reduction in each of these microvascular complications occurs. In the initial UKPDS, a reduction in the incidence of CVD (macrovascular complications) was observed, but it was not statistically significant.

Benefits of intensive therapy. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, the original patients in the DCCT were followed for an average of 17 years. The patients in the intensive therapy group were no longer treated intensively, but they demonstrated a 42% reduction in risk of any cardiovascular event. The authors concluded that the initial 6.5 years of intensive treatment created a “metabolic memory” that provided some protection against CVD.9

The patients in the UKPDS were followed up for an additional 5 years after the initial data analysis, and no attempt was made to continue the initial intensive therapy. Within 1 year, HbA1c levels were similar in the intensive and conventional treatment groups.

In the sulfonylurea-insulin arm of the UKPDS, reductions in risk of any diabetes-related end point (9%) and microvascular disease (24%) persisted after 10 years; risk reductions for MI (15%) and death from any cause (13%) emerged over time. In the metformin group, risk reductions persisted for any diabetes-related end point (21%), MI (33%), and death from any cause (27%). All of these end points reached statistical significance. The protective effect of early intensive therapy was called the “legacy effect” by the study authors.10 This study demonstrated the extended effects of improved glycemic control in patients with newly diagnosed type 2 diabetes, some of whom were followed up for up to 30 years.


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