Controlling Blood Glucose Levels in Patients with Type 2 Diabetes Mellitus An Evidence-Based Policy Statement by the American Academy of Family Physicians and American Diabetes Association

Peripheral Neuropathy in Patients with Type 2 Diabetes. Some trials suggest that lowering blood glucose improves isolated electrophysiologic measures.^10,16,19 A Japanese RCT¹⁶ reported an increase in median nerve conduction velocity and a reduction in arm vibration threshold, but other physiologic measures were unaffected. Neurologic symptoms were not measured. The UKPDS¹⁰ showed no effect on the incidence of absent ankle and knee reflexes, but abnormal biothesiometery data (for toes) occurred less frequently with intensive treatment. Impotence and heart rate responses to deep breathing and standing occurred with equal frequency.

Peripheral Neuropathy in Patients with Type 1 Diabetes. The DCCT showed a 69% reduction (9.8 vs 3.1/100 patient-years) in newly “confirmed clinical neuropathy” (abnormal neurologic history or physical examination combined with abnormal nerve conduction or autonomic nervous system studies), but the incidence of neurologic symptoms was not reported.^9,28 Progression of clinical neuropathy in patients with preexisting disease was reduced by 57%, from 16.1 to 7.0/100 patient-years. A Swedish RCT reported a lower incidence of neuropathic symptoms at 10-year follow-up (14% vs 32%) and higher pin-prick sensitivity.²⁹

Nephropathy in Patients with Type 2 Diabetes. Intensive insulin treatment does appear to reduce the incidence of albuminuria.^10,16,19 The UKPDS observed a lower incidence of microalbuminuria within 3 years and a lower incidence of gross proteinuria and increased plasma creatinine within 9 years of follow-up (relative risk reduction=17%, 33%, and 60%, respectively).¹⁰ The incidence rates of renal failure and death from renal disease did not differ significantly between the groups, but the absolute number of cases was small.

Nephropathy in Patients with Type 1 Diabetes. In the DCCT, among patients who lacked microalbuminuria at baseline, the incidence of new cases over 6.5 years was reduced by 34% (3.4 vs 2.2/100,000 patient-years), but the incidence of sustained microalbuminuria, macroalbuminuria, or abnormal creatinine clearance did not differ. In the secondary prevention group, the incidence of microalbuminuria was reduced from 5.7 to 3.6/100,000 patient-years, a 43% relative reduction, and the incidence of sustained microalbuminuria and of macroalbuminuria was also reduced.^9,30

Macrovascular Outcomes

Observational Studies. Some cross-sectional studies in type 2 diabetes report that elevated FPG concentrations or glycated hemoglobin levels are more common in people with coronary artery disease, an abnormal electrocardiogram, or cardiovascular disease.^31,32 Longitudinal studies show that patients with elevated blood glucose, glycated hemoglobin, or postprandial glucose levels at baseline are more likely to develop coronary artery disease or an abnormal electrocardiogram or to die of coronary artery or cardiovascular disease.^33-36 An association between blood glucose concentration and stroke or peripheral vascular disease (eg, incidence of amputation and foot ulcers) has also been demonstrated in such studies^{31,33,34,37,38} but less consistently.

Clinical Trials of Patients with Type 2 Diabetes. The UKPDS showed a 16% reduction in the 10-year incidence of myocardial infarction with intensive treatment, a difference of borderline statistical significance (P=.05, 95% confidence interval for relative risk=0.71-1.00).¹⁰ Statistically significant differences were noted in certain subgroups.³⁹ Sudden death was less common (relative risk reduction=46%, P=.05), but the incidence of fatal myocardial infarction, heart failure, angina, stroke, amputation, and death from peripheral vascular disease was unchanged.¹⁰ The authors noted that the study lacked statistical power to exclude an effect on fatal outcomes.

Another RCT reported no significant effect on cardiovascular events or mortality with intensive treatment, but the mean follow-up period was only 27 months.⁴⁰ A British trial involving patients with moderate hyperglycemia reported that cardiovascular events occurred less frequently in a group given high-dose tolbutamide and a recommended diet than in the control group, but the patient population, type of diabetes, and outcome measures were defined imprecisely.⁴¹

Clinical Trials of Patients with Type 1 Diabetes. The incidence of major cardiovascular and peripheral vascular events in most trials did not differ significantly with intensive treatment,^9,42 but the number of cases and length of follow-up were generally too small to detect a difference.

All-Cause Mortality

Observational Studies. Some observational studies report an association between poor glycemic control and all-cause mortality or overall survival rates in type 2 diabetes.^35,36,43-45 However, other cohort studies report that death rates are not reliably predicted by FPG concentrations or glycated hemoglobin levels.^46,47

Clinical Trials of Patients with Type 2 Diabetes. A Swedish RCT found that patients with diabetes admitted to coronary care units for recent myocardial infarction achieved better glycemic control and experienced significantly lower all-cause mortality (33% vs 44%) if they received intensive insulin therapy (insulin-glucose infusion for the first 24 hours and subcutaneous insulin 4 times daily for 3 months).⁴⁸ The UKPDS showed no significant effect on either all-cause or diabetes-related mortality but lacked statistical power to exclude an effect.¹⁰