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

An estimated 16 million people in the United States have diabetes.¹ Its microvascular complications (retinopathy, nephropathy, neuropathy) are a leading cause of blindness among adults,² end-stage renal disease,³ and lower-extremity amputations.⁴ Its macrovascular complications pose an even greater public health burden, increasing the risk of coronary artery disease, stroke, and peripheral vascular disease.⁵ Each year diabetes costs the country an estimated $90 billion to $99 billion.^6,7

Type 2 diabetes, which accounts for 90% to 95% of diabetes cases,⁸ differs from type 1 disease in average age of onset and etiology. In both forms, however, the underlying cause of microvascular (and possibly macrovascular) complications appears to be chronic elevations in blood glucose concentrations. The overriding factors in predicting microvascular pathogenesis have less to do with the type of diabetes than with the number of years the patient has had hyperglycemia and the magnitude of the glucose elevation.

In recent years, 2 major randomized controlled trials (RCTs), the Diabetes Control and Complications Trial⁹ (DCCT) in patients with type 1 disease and the United Kingdom Prospective Diabetes Study¹⁰ (UKPDS) in patients with type 2 diabetes, have shown that microvascular complications can be reduced significantly in patients who achieve normal or near-normal blood glucose levels. There is now agreement in the medical community about the importance of lowering markedly elevated blood glucose levels.

The incremental benefit of tight glycemic control (as opposed to less intensive therapy) varies across patient groups, however. Years are required for microvascular complications to progress to symptomatic disease. Patients with type 1 diabetes, who are generally younger, are more likely to live long enough to benefit from tight glycemic control than patients with type 2 disease, who face a shorter life expectancy because of their age and risk of cardiovascular disease. For patients with coexistent diseases, the delayed benefits of glycemic control may be offset by the more immediate inconvenience, complications, and costs of intensive treatment and by the health effects of comorbid conditions.

These generalizations do not apply to all patients. The older age of onset of type 2 diabetes is a population average with a wide distribution. Many patients with type 2 diabetes live long enough to experience significant microvascular disease and may benefit from glycemic control. Also, interventions that extend life expectancy (eg, smoking cessation, blood pressure control, and lipid control) give patients more time to encounter advanced microvascular disease and an opportunity to benefit from treatment.

In 1996, the American Academy of Family Physicians convened a panel to conduct a systematic review of the evidence of the benefits and harms of glycemic control in type 2 diabetes and to develop evidence-based recommendations. The 9-member panel included family physicians, general internists, endocrinologists, and a practice guidelines methodologist. Four members were appointed by the American Diabetes Association and the American College of Physicians. We summarize the panel’s findings, which are available in a full report.*

Methods

Systematic Review

The review methods are provided in detail in the full report. The literature search retrieved published evidence on the effects of glycemic control on microvascular and macrovascular complications in type 1 and type 2 diabetes and on adverse effects. RCT evidence for type 1 diabetes was considered relevant in evaluating the effects of glycemic control in type 2 disease. A total of 798 citations met initial inclusion criteria. All articles underwent structured abstraction. We closed the search with the publication of the UKPDS results in September 1998.

In reviewing the evidence, the panel gave greater weight to RCTs than to observational studies and emphasized data on health outcomes perceptible to patients (eg, visual acuity) over those for intermediate or surrogate end points (eg, retinopathy) that precede or are associated with such outcomes. Most trials did not designate health outcomes as primary end points and therefore lacked the statistical power and duration to prove an effect. Panel recommendations were evidence-based and did not reflect expert opinion. Fourteen outside diabetologists and family physicians externally reviewed the full report, and revisions consistent with the evidence were adopted. The American Academy of Family Physicians and the American Diabetes Association endorsed the full report in March 1999 and this policy statement in October 1999.

We focused the review on the benefits of glycemic control in general and not on specific agents (eg, sulfonylureas, metformin). Interventions not associated with glycemic control (eg, laser phototherapy, angiotensin-converting enzyme inhibitors), which also mitigate the effects of microvascular disease, were not examined in our review.

Results

Microvascular Outcomes

Evidence from Observational Studies. Many cross-sectional studies indicate that people with type 2 diabetes who have higher plasma glucose or glycated hemoglobin (e.g., hemoglobin A1c) levels are more likely to have evidence of retinopathy, neuropathy, or albuminuria.¹¹ Numerous prospective longitudinal studies also show that an elevated fasting plasma glucose (FPG) concentration or glycated hemoglobin level at baseline or over time increases the chances that type 2 patients will develop new or worsened retinopathy, abnormal electrophysiologic findings, or renal dysfunction.^12-15 However, observational data, unlike evidence from RCTs, does not prove that lowering blood glucose levels reduces the incidence of these complications.

Evidence from RCTs. Ten RCTs do provide this evidence.^9,10,16-24 Three trials involved patients with type 2 diabetes: the very large UKPDS¹⁰ (approximately 4200 patients) and 2 small Japanese studies.^16,19 The largest of the 7 trials of patients with type 1 diabetes was the DCCT (1441 patients).⁹ In most trials, patients were randomly allocated to an intensive treatment group that received multiple or continuous insulin administrations or to a control group that received conventional insulin therapy. Most studies confirmed (through mean glycated hemoglobin levels) better glycemic control with intensive treatment. For example, mean hemoglobin A1c levels in the intensive/conservative treatment groups of the DCCT and UKPDS were 7.2%/9.1% and 7.0%/7.9%, respectively.^9,10 An old RCT (University Group Diabetes Program) that did not produce significant differences in glucose control in some treatment arms and lacked statistical power was excluded from our review.²⁵ Average lengths of follow-up in the RCTs ranged from 2 to 12.5 years (6.5 and 10 years, respectively, in the DCCT and UKPDS).

Retinopathy in Patients with Type 2 Diabetes. RCTs provide good evidence that glycemic control reduces the incidence of retinopathy. In a Japanese trial, among patients with no retinopathy at baseline, the 6-year incidence of new disease (progression Ž2 steps on the Early Treatment Diabetic Retinopathy Study [ETDRS] scale²⁶) in the intensive and conservative treatment groups was 6% and 36%, respectively, a relative reduction of 83%. In patients with retinopathy at baseline (secondary prevention group), the incidence rates for intensive and conservative treatment groups were 17% and 44%, respectively.¹⁶

The authors of the UKPDS results, who reported a 25% relative reduction in the incidence of microvascular complications (11.4 vs 8.6 events/1000 patient-years) attributed much of the benefit to reduced retinopathy.¹⁰ The need for laser therapy was lowered from 11.0 to 7.9 events/1000-patient years, a 29% relative reduction. Within 6 years, the incidence of a 2-step progression on the ETDRS scale was lowered from 28% to 23%. The relative reduction in cataract extraction was 24%. The incidence of decreased visual acuity, blindness, and vitreous hemorrhage was not lowered significantly. The extent to which the latter resulted from treatment for early complications is not known.

Retinopathy in Patients with Type 1 Diabetes. Among patients with no baseline retinopathy in the DCCT (primary prevention group), the 6.5-year incidence of a sustained 3-step change on the ETDRS scale was reduced by 76% (from 4.7 to 1.2/100 patient-years).⁹ In the secondary prevention group, the rate of progression was lowered by 54% (from 7.8 to 3.7/100 patient-years). In this group intensive treatment was also associated with a lower incidence of severe retinopathy, need for laser treatment, and sustained progression worsening for at least 6 months (adjusted relative risk reduction=47%, 56%, and 65%, respectively).^9,27 A Swedish trial reported improved ETDRS scales and a lower prevalence of visual impairment (14% vs 35%) at 7.8 years median follow-up.¹⁷

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

Clinical Trials of Patients with Type 1 Diabetes. There are few data on all-cause mortality in patients with type 1 diabetes because of the low event rate.^9,42

Discussion

Potential Harms of Intensive Glycemic Control

Specific complications can occur with each of the agents used to treat type 2 diabetes: Insulin has potential adverse effects, and oral glucose-lowering drugs carry some risk of undesirable side effects and uncommon but serious complications (eg, lactic acidosis, hepatotoxicity).

Attempts to achieve euglycemia can increase the risk of hypoglycemia, and some medications are associated with weight gain. The risk of severe hypoglycemia is greatest for patients with type 1 diabetes. In the subjects with type 2 diabetes in the UKPDS, the incidence of major hypoglycemic episodes was higher among the intensively treated than conventionally treated patients, but the rate was low (1% to 2%).¹⁰ More typically in type 2 disease, a more substantial risk exists for minor hypoglycemic episodes, which are usually inconsequential.^10,40 An association between intensive treatment and weight gain has been reported (mean=3.1 kg and 4.6 kg in the UKPDS and DCCT, respectively),^9,10 but there is no evidence that this amount of weight gain affects outcomes.

Intensive treatment requires that patients perform home glucose monitoring; follow diet and physical activity regimens; tolerate minor side effects and the risk of more serious complications from medications; regularly attend physician visits for testing and examinations; and absorb costs not covered by insurance for physicians and medical supplies, lost work (or school), and transportation. In many cases these inconveniences, discomforts, and costs are borne over a number of years, often a lifetime. RCTs have shown no adverse association between these efforts and quality of life,⁴⁹ however, and one study suggested that glycemic control might improve quality of life and work productivity.⁵⁰

Modeling Estimates

Mathematical models, largely based on the DCCT, have attempted to estimate the magnitude of benefits and harms from glycemic control. One model estimated that patients with type 2 diabetes who maintained a glycated hemoglobin level of 7.2% would reduce their cumulative lifetime risk of blindness, end-stage renal disease, and lower-extremity amputation by 72% (from 19% to 5%), 87% (from 17% to 2%), and 67% (from 15% to 5%), respectively.⁵¹ Life expectancy would increase by 1.39 years. A Markov model estimated that reducing glycated hemoglobin from 9% to 7% in a patient in whom diabetes developed at age 45 years would lower the lifetime risk of blindness from 2.6% to 0.3%.⁵² The same change in a patient who developed diabetes at age 65 years would decrease the risk of blindness from only 0.5% to <0.1%.

In theory, such projections could be useful to clinicians and patients to estimate the benefits and harms of different levels of glycemic control in individual situations. Since there are different designs and assumptions, however, available models offer discrepant predictions about the same types of patients. For example, the lifetime risk of blindness in a white patient aged 55 years who lowers his glycated hemoglobin level from 9% to 7% would, according to one model, be reduced by 5.6% (from 9% to 3.4%)⁵¹ and, according to another model by 1.1% (from 1.2% to 0.1%).⁵² These discrepancies must be reconciled before reliable outcome estimates can be introduced with confidence in practice.

Weighing the Magnitude of Benefit

The evidence demonstrates a continuous and curvilinear relationship between hyperglycemia and the microvascular and neuropathic complications of diabetes, with risk rising progressively as mean blood glucose concentrations increase. RCTs confirm that for both type 1 and type 2 diabetes glycemic control significantly reduces the incidence of microvascular complications. The following points should be considered when applying this evidence to routine practice:

1. The intensity of treatment in RCTs may be difficult to replicate to the same degree in community practice. In the DCCT, for example, patients received insulin by injection 3 times daily or by external pump, self-monitored blood glucose at least 4 times per day, underwent weekly nocturnal blood glucose measurements, visited their study center monthly, and received frequent telephone calls. The target glycated hemoglobin value was less than 6.1%.⁹ More typical treatment practices were followed in the UKPDS. Although some practices and health care systems have successfully achieved satisfactory blood glucose levels through aggressive programs that assist clinicians and patients, other constraints and the inability or reluctance of patients to adhere to treatment protocols remain problems in other settings.⁵³
2. The microvascular end points in most RCTs were primarily intermediate (eg, ETDRS scales, nerve conduction velocity, urinary albumin excretion) or surrogate (eg, laser phototherapy) outcomes rather than health outcomes. Few trials were designed to measure health outcomes, providing limited data on the extent to which the symptoms that patients experience (eg, visual impairment, paresthesias, complications of renal failure) are reduced by intensive treatment. Such complaints generally do not occur until the patient has end-stage disease and are often forestalled by early treatment (eg, laser phototherapy). It is reasonable to infer that long-term benefits result from glycemic control-the intermediate end points affected are known risk factors for clinical disease-but one cannot assume that the observed magnitude of risk reduction for intermediate outcomes applies also to symptomatic disease.
3. Relative risk reductions are greater than absolute risk reductions. The 25% relative reduction in microvascular complications reported by the UKPDS represents an absolute reduction of only 2%: 8%, rather than 10%, of patients had complications during 10 years of treatment.¹⁰ Also, relative risk reductions generally refer to intermediate outcomes. The 76% reduction in the risk of retinopathy reported by the DCCT refers to a 3-step change on the ETDRS scale, not to improved vision.⁹ The number needed to treat to affect outcomes perceptible to patients is necessarily higher than that for retinopathy, delayed nerve conduction, or elevated urinary albumin excretion, because only a subset of patients with these intermediate outcomes go on to develop symptomatic disease.¹⁵ According to the UKPDS, 37 patients would require intensive treatment for 10 years to prevent one patient from undergoing laser treatment; 208 would require treatment to prevent one case of blindness.¹⁰ The observed 16% difference in the incidence of blindness in the UKPDS was not statistically significant.On the other hand, when examined at the population level, even modest absolute risk reductions can translate into large numbers of persons in society for whom clinical benefit is achievable. Given the millions of people in the United States with type 2 diabetes, even a 2% absolute reduction in the risk of microvascular complications represents many thousands of people who would benefit from glycemic control.
4. Because of the average time required for glycemic control to affect outcomes, some patients with diabetes may not live long enough to benefit, because of the competing risks of death of macrovascular complications and other comorbid diseases. Although elevated blood glucose levels are a likely risk factor for cardiovascular disease, glycemic control has not been shown to enhance life expectancy or prevent heart disease. The 16% reduction in myocardial infarction reported by the UKPDS was of borderline statistical significance.¹⁰ Another RCT did find that improved glycemic control reduced the incidence of ischemic cardiac events, stroke, and cardiovascular deaths in patients with acute myocardial infarction.⁴⁸ Two other trials that failed to show a benefit may have lacked adequate duration and sample size.^16,40
5. For any given patient, the absolute magnitude of risk reduction is a continuous variable that is a function of the patient’s current glycated hemoglobin level, the duration and magnitude of previous hyperglycemia, and the extent of preexisting microvascular complications. The probability that the patient will live long enough to experience the benefits of reduced complications depends on cardiovascular risk factors other than blood glucose (eg, smoking, hypertension, lipid levels, physical inactivity, obesity, preexisting coronary artery disease) and other determinants of life expectancy (eg, age, coexisting diseases, health status). Of these, the most critical variable is the patient’s current glycated hemoglobin level. Because of their increased risk of complications, individuals with marked elevations generally benefit more (in absolute terms) from the same absolute reduction in glycated hemoglobin levels than do individuals with mild to moderate elevations.⁵³ Although it is obviously important for clinicians to keep patients from progressing from mild (eg, hemoglobin A1c levels of 6% to 8%) to marked hyperglycemia (eg, hemoglobin A1c levels >9.5%), in those patients who have already developed marked hyperglycemia, efforts directed at achieving even moderate control (eg, hemoglobin A1c levels of 8% to 9.5%) will yield greater health benefits than pursuing euglycemia in patients with moderate elevations.

Recommendations for clinical practice

For any patient with type 2 diabetes, the better the glycemic control, the lower the probability of chronic microvascular, neuropathic, and possibly cardiovascular complications. However, because of differences in patients’ life expectancies, comorbidities, and preferences, it is inappropriate to set a uniform target glycated hemoglobin level for all patients. Individuals with long life expectancies and few comorbidities may wish to pursue euglycemia, but less vigorous goals may be appropriate for others, such as patients with multiple comorbid conditions or with limited life expectancies.

Whether the magnitude of benefit of a given treatment goal justifies the potential inconvenience, harms, and costs involves value judgments that must be tailored to the individual patient. Patients’ personal risk profiles and capabilities and the relative importance they assign to the potential outcomes and supporting evidence are integral in determining how intensively to treat.

Cardiovascular disease is the most likely cause of death in patients with type 2 diabetes, and attention to glycemic control should not distract clinicians and patients from other interventions that may be more effective in preventing coronary artery disease and stroke. These include smoking cessation, serum lipid management, control of blood pressure, diet, physical activity, and weight management. Guidelines for the control of these risk factors appear elsewhere.^54-56 Clinicians should also pursue treatments other than glycemic control for preventing microvascular complications (eg, blood pressure control, angiotensin-converting enzyme inhibitors for diabetic nephropathy, laser treatment for diabetic retinopathy).

Whatever the desired goals and intensity of treatment, patients face considerable barriers in implementing recommendations. Modifying diet and other personal habits; complying with self-monitoring, medication, and home care; and returning for follow-up visits are difficult. Physicians should work with patients to overcome remediable barriers and should use recommended techniques for patient education and counseling to offer the necessary information and motivation for meaningful change.⁵⁷

Acknowledgments

The systematic review on which this guideline is based was supported in part by funding from the Health Care Financing Administration. We thank Richard D. Kahn, PhD, (American Diabetes Association), and Herbert F. Young, MD, and Bellinda Schoof (American Academy of Family Physicians) for their assistance, as well as the expert panel that externally reviewed the full report: Eugene Barrett, MD; John A. Colwell, MD; Richard C. Eastman, MD; Saul Genuth, MD; Ronald Klein, MD, MPH; Martin Mahoney, MD; James W. Mold, MD; David M. Nathan, MD; Jonathan E. Rodnick, MD; Jeffrey L. Susman, MD; Sandeep Vijan, MD, MS; and Bruce Zimmerman, MD. Their participation in the review process does not necessarily imply endorsement of the report or its recommendations.

An estimated 16 million people in the United States have diabetes.¹ Its microvascular complications (retinopathy, nephropathy, neuropathy) are a leading cause of blindness among adults,² end-stage renal disease,³ and lower-extremity amputations.⁴ Its macrovascular complications pose an even greater public health burden, increasing the risk of coronary artery disease, stroke, and peripheral vascular disease.⁵ Each year diabetes costs the country an estimated $90 billion to $99 billion.^6,7

Type 2 diabetes, which accounts for 90% to 95% of diabetes cases,⁸ differs from type 1 disease in average age of onset and etiology. In both forms, however, the underlying cause of microvascular (and possibly macrovascular) complications appears to be chronic elevations in blood glucose concentrations. The overriding factors in predicting microvascular pathogenesis have less to do with the type of diabetes than with the number of years the patient has had hyperglycemia and the magnitude of the glucose elevation.

In recent years, 2 major randomized controlled trials (RCTs), the Diabetes Control and Complications Trial⁹ (DCCT) in patients with type 1 disease and the United Kingdom Prospective Diabetes Study¹⁰ (UKPDS) in patients with type 2 diabetes, have shown that microvascular complications can be reduced significantly in patients who achieve normal or near-normal blood glucose levels. There is now agreement in the medical community about the importance of lowering markedly elevated blood glucose levels.

The incremental benefit of tight glycemic control (as opposed to less intensive therapy) varies across patient groups, however. Years are required for microvascular complications to progress to symptomatic disease. Patients with type 1 diabetes, who are generally younger, are more likely to live long enough to benefit from tight glycemic control than patients with type 2 disease, who face a shorter life expectancy because of their age and risk of cardiovascular disease. For patients with coexistent diseases, the delayed benefits of glycemic control may be offset by the more immediate inconvenience, complications, and costs of intensive treatment and by the health effects of comorbid conditions.

These generalizations do not apply to all patients. The older age of onset of type 2 diabetes is a population average with a wide distribution. Many patients with type 2 diabetes live long enough to experience significant microvascular disease and may benefit from glycemic control. Also, interventions that extend life expectancy (eg, smoking cessation, blood pressure control, and lipid control) give patients more time to encounter advanced microvascular disease and an opportunity to benefit from treatment.

In 1996, the American Academy of Family Physicians convened a panel to conduct a systematic review of the evidence of the benefits and harms of glycemic control in type 2 diabetes and to develop evidence-based recommendations. The 9-member panel included family physicians, general internists, endocrinologists, and a practice guidelines methodologist. Four members were appointed by the American Diabetes Association and the American College of Physicians. We summarize the panel’s findings, which are available in a full report.*

Methods

Systematic Review

The review methods are provided in detail in the full report. The literature search retrieved published evidence on the effects of glycemic control on microvascular and macrovascular complications in type 1 and type 2 diabetes and on adverse effects. RCT evidence for type 1 diabetes was considered relevant in evaluating the effects of glycemic control in type 2 disease. A total of 798 citations met initial inclusion criteria. All articles underwent structured abstraction. We closed the search with the publication of the UKPDS results in September 1998.

In reviewing the evidence, the panel gave greater weight to RCTs than to observational studies and emphasized data on health outcomes perceptible to patients (eg, visual acuity) over those for intermediate or surrogate end points (eg, retinopathy) that precede or are associated with such outcomes. Most trials did not designate health outcomes as primary end points and therefore lacked the statistical power and duration to prove an effect. Panel recommendations were evidence-based and did not reflect expert opinion. Fourteen outside diabetologists and family physicians externally reviewed the full report, and revisions consistent with the evidence were adopted. The American Academy of Family Physicians and the American Diabetes Association endorsed the full report in March 1999 and this policy statement in October 1999.

We focused the review on the benefits of glycemic control in general and not on specific agents (eg, sulfonylureas, metformin). Interventions not associated with glycemic control (eg, laser phototherapy, angiotensin-converting enzyme inhibitors), which also mitigate the effects of microvascular disease, were not examined in our review.

Results

Microvascular Outcomes

Evidence from Observational Studies. Many cross-sectional studies indicate that people with type 2 diabetes who have higher plasma glucose or glycated hemoglobin (e.g., hemoglobin A1c) levels are more likely to have evidence of retinopathy, neuropathy, or albuminuria.¹¹ Numerous prospective longitudinal studies also show that an elevated fasting plasma glucose (FPG) concentration or glycated hemoglobin level at baseline or over time increases the chances that type 2 patients will develop new or worsened retinopathy, abnormal electrophysiologic findings, or renal dysfunction.^12-15 However, observational data, unlike evidence from RCTs, does not prove that lowering blood glucose levels reduces the incidence of these complications.

Evidence from RCTs. Ten RCTs do provide this evidence.^9,10,16-24 Three trials involved patients with type 2 diabetes: the very large UKPDS¹⁰ (approximately 4200 patients) and 2 small Japanese studies.^16,19 The largest of the 7 trials of patients with type 1 diabetes was the DCCT (1441 patients).⁹ In most trials, patients were randomly allocated to an intensive treatment group that received multiple or continuous insulin administrations or to a control group that received conventional insulin therapy. Most studies confirmed (through mean glycated hemoglobin levels) better glycemic control with intensive treatment. For example, mean hemoglobin A1c levels in the intensive/conservative treatment groups of the DCCT and UKPDS were 7.2%/9.1% and 7.0%/7.9%, respectively.^9,10 An old RCT (University Group Diabetes Program) that did not produce significant differences in glucose control in some treatment arms and lacked statistical power was excluded from our review.²⁵ Average lengths of follow-up in the RCTs ranged from 2 to 12.5 years (6.5 and 10 years, respectively, in the DCCT and UKPDS).

Retinopathy in Patients with Type 2 Diabetes. RCTs provide good evidence that glycemic control reduces the incidence of retinopathy. In a Japanese trial, among patients with no retinopathy at baseline, the 6-year incidence of new disease (progression Ž2 steps on the Early Treatment Diabetic Retinopathy Study [ETDRS] scale²⁶) in the intensive and conservative treatment groups was 6% and 36%, respectively, a relative reduction of 83%. In patients with retinopathy at baseline (secondary prevention group), the incidence rates for intensive and conservative treatment groups were 17% and 44%, respectively.¹⁶

The authors of the UKPDS results, who reported a 25% relative reduction in the incidence of microvascular complications (11.4 vs 8.6 events/1000 patient-years) attributed much of the benefit to reduced retinopathy.¹⁰ The need for laser therapy was lowered from 11.0 to 7.9 events/1000-patient years, a 29% relative reduction. Within 6 years, the incidence of a 2-step progression on the ETDRS scale was lowered from 28% to 23%. The relative reduction in cataract extraction was 24%. The incidence of decreased visual acuity, blindness, and vitreous hemorrhage was not lowered significantly. The extent to which the latter resulted from treatment for early complications is not known.

Retinopathy in Patients with Type 1 Diabetes. Among patients with no baseline retinopathy in the DCCT (primary prevention group), the 6.5-year incidence of a sustained 3-step change on the ETDRS scale was reduced by 76% (from 4.7 to 1.2/100 patient-years).⁹ In the secondary prevention group, the rate of progression was lowered by 54% (from 7.8 to 3.7/100 patient-years). In this group intensive treatment was also associated with a lower incidence of severe retinopathy, need for laser treatment, and sustained progression worsening for at least 6 months (adjusted relative risk reduction=47%, 56%, and 65%, respectively).^9,27 A Swedish trial reported improved ETDRS scales and a lower prevalence of visual impairment (14% vs 35%) at 7.8 years median follow-up.¹⁷

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

Clinical Trials of Patients with Type 1 Diabetes. There are few data on all-cause mortality in patients with type 1 diabetes because of the low event rate.^9,42

Discussion

Potential Harms of Intensive Glycemic Control

Specific complications can occur with each of the agents used to treat type 2 diabetes: Insulin has potential adverse effects, and oral glucose-lowering drugs carry some risk of undesirable side effects and uncommon but serious complications (eg, lactic acidosis, hepatotoxicity).

Attempts to achieve euglycemia can increase the risk of hypoglycemia, and some medications are associated with weight gain. The risk of severe hypoglycemia is greatest for patients with type 1 diabetes. In the subjects with type 2 diabetes in the UKPDS, the incidence of major hypoglycemic episodes was higher among the intensively treated than conventionally treated patients, but the rate was low (1% to 2%).¹⁰ More typically in type 2 disease, a more substantial risk exists for minor hypoglycemic episodes, which are usually inconsequential.^10,40 An association between intensive treatment and weight gain has been reported (mean=3.1 kg and 4.6 kg in the UKPDS and DCCT, respectively),^9,10 but there is no evidence that this amount of weight gain affects outcomes.

Intensive treatment requires that patients perform home glucose monitoring; follow diet and physical activity regimens; tolerate minor side effects and the risk of more serious complications from medications; regularly attend physician visits for testing and examinations; and absorb costs not covered by insurance for physicians and medical supplies, lost work (or school), and transportation. In many cases these inconveniences, discomforts, and costs are borne over a number of years, often a lifetime. RCTs have shown no adverse association between these efforts and quality of life,⁴⁹ however, and one study suggested that glycemic control might improve quality of life and work productivity.⁵⁰

Modeling Estimates

Mathematical models, largely based on the DCCT, have attempted to estimate the magnitude of benefits and harms from glycemic control. One model estimated that patients with type 2 diabetes who maintained a glycated hemoglobin level of 7.2% would reduce their cumulative lifetime risk of blindness, end-stage renal disease, and lower-extremity amputation by 72% (from 19% to 5%), 87% (from 17% to 2%), and 67% (from 15% to 5%), respectively.⁵¹ Life expectancy would increase by 1.39 years. A Markov model estimated that reducing glycated hemoglobin from 9% to 7% in a patient in whom diabetes developed at age 45 years would lower the lifetime risk of blindness from 2.6% to 0.3%.⁵² The same change in a patient who developed diabetes at age 65 years would decrease the risk of blindness from only 0.5% to <0.1%.

In theory, such projections could be useful to clinicians and patients to estimate the benefits and harms of different levels of glycemic control in individual situations. Since there are different designs and assumptions, however, available models offer discrepant predictions about the same types of patients. For example, the lifetime risk of blindness in a white patient aged 55 years who lowers his glycated hemoglobin level from 9% to 7% would, according to one model, be reduced by 5.6% (from 9% to 3.4%)⁵¹ and, according to another model by 1.1% (from 1.2% to 0.1%).⁵² These discrepancies must be reconciled before reliable outcome estimates can be introduced with confidence in practice.

Weighing the Magnitude of Benefit

The evidence demonstrates a continuous and curvilinear relationship between hyperglycemia and the microvascular and neuropathic complications of diabetes, with risk rising progressively as mean blood glucose concentrations increase. RCTs confirm that for both type 1 and type 2 diabetes glycemic control significantly reduces the incidence of microvascular complications. The following points should be considered when applying this evidence to routine practice:

1. The intensity of treatment in RCTs may be difficult to replicate to the same degree in community practice. In the DCCT, for example, patients received insulin by injection 3 times daily or by external pump, self-monitored blood glucose at least 4 times per day, underwent weekly nocturnal blood glucose measurements, visited their study center monthly, and received frequent telephone calls. The target glycated hemoglobin value was less than 6.1%.⁹ More typical treatment practices were followed in the UKPDS. Although some practices and health care systems have successfully achieved satisfactory blood glucose levels through aggressive programs that assist clinicians and patients, other constraints and the inability or reluctance of patients to adhere to treatment protocols remain problems in other settings.⁵³
2. The microvascular end points in most RCTs were primarily intermediate (eg, ETDRS scales, nerve conduction velocity, urinary albumin excretion) or surrogate (eg, laser phototherapy) outcomes rather than health outcomes. Few trials were designed to measure health outcomes, providing limited data on the extent to which the symptoms that patients experience (eg, visual impairment, paresthesias, complications of renal failure) are reduced by intensive treatment. Such complaints generally do not occur until the patient has end-stage disease and are often forestalled by early treatment (eg, laser phototherapy). It is reasonable to infer that long-term benefits result from glycemic control-the intermediate end points affected are known risk factors for clinical disease-but one cannot assume that the observed magnitude of risk reduction for intermediate outcomes applies also to symptomatic disease.
3. Relative risk reductions are greater than absolute risk reductions. The 25% relative reduction in microvascular complications reported by the UKPDS represents an absolute reduction of only 2%: 8%, rather than 10%, of patients had complications during 10 years of treatment.¹⁰ Also, relative risk reductions generally refer to intermediate outcomes. The 76% reduction in the risk of retinopathy reported by the DCCT refers to a 3-step change on the ETDRS scale, not to improved vision.⁹ The number needed to treat to affect outcomes perceptible to patients is necessarily higher than that for retinopathy, delayed nerve conduction, or elevated urinary albumin excretion, because only a subset of patients with these intermediate outcomes go on to develop symptomatic disease.¹⁵ According to the UKPDS, 37 patients would require intensive treatment for 10 years to prevent one patient from undergoing laser treatment; 208 would require treatment to prevent one case of blindness.¹⁰ The observed 16% difference in the incidence of blindness in the UKPDS was not statistically significant.On the other hand, when examined at the population level, even modest absolute risk reductions can translate into large numbers of persons in society for whom clinical benefit is achievable. Given the millions of people in the United States with type 2 diabetes, even a 2% absolute reduction in the risk of microvascular complications represents many thousands of people who would benefit from glycemic control.
4. Because of the average time required for glycemic control to affect outcomes, some patients with diabetes may not live long enough to benefit, because of the competing risks of death of macrovascular complications and other comorbid diseases. Although elevated blood glucose levels are a likely risk factor for cardiovascular disease, glycemic control has not been shown to enhance life expectancy or prevent heart disease. The 16% reduction in myocardial infarction reported by the UKPDS was of borderline statistical significance.¹⁰ Another RCT did find that improved glycemic control reduced the incidence of ischemic cardiac events, stroke, and cardiovascular deaths in patients with acute myocardial infarction.⁴⁸ Two other trials that failed to show a benefit may have lacked adequate duration and sample size.^16,40
5. For any given patient, the absolute magnitude of risk reduction is a continuous variable that is a function of the patient’s current glycated hemoglobin level, the duration and magnitude of previous hyperglycemia, and the extent of preexisting microvascular complications. The probability that the patient will live long enough to experience the benefits of reduced complications depends on cardiovascular risk factors other than blood glucose (eg, smoking, hypertension, lipid levels, physical inactivity, obesity, preexisting coronary artery disease) and other determinants of life expectancy (eg, age, coexisting diseases, health status). Of these, the most critical variable is the patient’s current glycated hemoglobin level. Because of their increased risk of complications, individuals with marked elevations generally benefit more (in absolute terms) from the same absolute reduction in glycated hemoglobin levels than do individuals with mild to moderate elevations.⁵³ Although it is obviously important for clinicians to keep patients from progressing from mild (eg, hemoglobin A1c levels of 6% to 8%) to marked hyperglycemia (eg, hemoglobin A1c levels >9.5%), in those patients who have already developed marked hyperglycemia, efforts directed at achieving even moderate control (eg, hemoglobin A1c levels of 8% to 9.5%) will yield greater health benefits than pursuing euglycemia in patients with moderate elevations.

Recommendations for clinical practice

For any patient with type 2 diabetes, the better the glycemic control, the lower the probability of chronic microvascular, neuropathic, and possibly cardiovascular complications. However, because of differences in patients’ life expectancies, comorbidities, and preferences, it is inappropriate to set a uniform target glycated hemoglobin level for all patients. Individuals with long life expectancies and few comorbidities may wish to pursue euglycemia, but less vigorous goals may be appropriate for others, such as patients with multiple comorbid conditions or with limited life expectancies.

Whether the magnitude of benefit of a given treatment goal justifies the potential inconvenience, harms, and costs involves value judgments that must be tailored to the individual patient. Patients’ personal risk profiles and capabilities and the relative importance they assign to the potential outcomes and supporting evidence are integral in determining how intensively to treat.

Cardiovascular disease is the most likely cause of death in patients with type 2 diabetes, and attention to glycemic control should not distract clinicians and patients from other interventions that may be more effective in preventing coronary artery disease and stroke. These include smoking cessation, serum lipid management, control of blood pressure, diet, physical activity, and weight management. Guidelines for the control of these risk factors appear elsewhere.^54-56 Clinicians should also pursue treatments other than glycemic control for preventing microvascular complications (eg, blood pressure control, angiotensin-converting enzyme inhibitors for diabetic nephropathy, laser treatment for diabetic retinopathy).

Whatever the desired goals and intensity of treatment, patients face considerable barriers in implementing recommendations. Modifying diet and other personal habits; complying with self-monitoring, medication, and home care; and returning for follow-up visits are difficult. Physicians should work with patients to overcome remediable barriers and should use recommended techniques for patient education and counseling to offer the necessary information and motivation for meaningful change.⁵⁷

Acknowledgments

The systematic review on which this guideline is based was supported in part by funding from the Health Care Financing Administration. We thank Richard D. Kahn, PhD, (American Diabetes Association), and Herbert F. Young, MD, and Bellinda Schoof (American Academy of Family Physicians) for their assistance, as well as the expert panel that externally reviewed the full report: Eugene Barrett, MD; John A. Colwell, MD; Richard C. Eastman, MD; Saul Genuth, MD; Ronald Klein, MD, MPH; Martin Mahoney, MD; James W. Mold, MD; David M. Nathan, MD; Jonathan E. Rodnick, MD; Jeffrey L. Susman, MD; Sandeep Vijan, MD, MS; and Bruce Zimmerman, MD. Their participation in the review process does not necessarily imply endorsement of the report or its recommendations.

An estimated 16 million people in the United States have diabetes.¹ Its microvascular complications (retinopathy, nephropathy, neuropathy) are a leading cause of blindness among adults,² end-stage renal disease,³ and lower-extremity amputations.⁴ Its macrovascular complications pose an even greater public health burden, increasing the risk of coronary artery disease, stroke, and peripheral vascular disease.⁵ Each year diabetes costs the country an estimated $90 billion to $99 billion.^6,7

Type 2 diabetes, which accounts for 90% to 95% of diabetes cases,⁸ differs from type 1 disease in average age of onset and etiology. In both forms, however, the underlying cause of microvascular (and possibly macrovascular) complications appears to be chronic elevations in blood glucose concentrations. The overriding factors in predicting microvascular pathogenesis have less to do with the type of diabetes than with the number of years the patient has had hyperglycemia and the magnitude of the glucose elevation.

In recent years, 2 major randomized controlled trials (RCTs), the Diabetes Control and Complications Trial⁹ (DCCT) in patients with type 1 disease and the United Kingdom Prospective Diabetes Study¹⁰ (UKPDS) in patients with type 2 diabetes, have shown that microvascular complications can be reduced significantly in patients who achieve normal or near-normal blood glucose levels. There is now agreement in the medical community about the importance of lowering markedly elevated blood glucose levels.

The incremental benefit of tight glycemic control (as opposed to less intensive therapy) varies across patient groups, however. Years are required for microvascular complications to progress to symptomatic disease. Patients with type 1 diabetes, who are generally younger, are more likely to live long enough to benefit from tight glycemic control than patients with type 2 disease, who face a shorter life expectancy because of their age and risk of cardiovascular disease. For patients with coexistent diseases, the delayed benefits of glycemic control may be offset by the more immediate inconvenience, complications, and costs of intensive treatment and by the health effects of comorbid conditions.

These generalizations do not apply to all patients. The older age of onset of type 2 diabetes is a population average with a wide distribution. Many patients with type 2 diabetes live long enough to experience significant microvascular disease and may benefit from glycemic control. Also, interventions that extend life expectancy (eg, smoking cessation, blood pressure control, and lipid control) give patients more time to encounter advanced microvascular disease and an opportunity to benefit from treatment.

In 1996, the American Academy of Family Physicians convened a panel to conduct a systematic review of the evidence of the benefits and harms of glycemic control in type 2 diabetes and to develop evidence-based recommendations. The 9-member panel included family physicians, general internists, endocrinologists, and a practice guidelines methodologist. Four members were appointed by the American Diabetes Association and the American College of Physicians. We summarize the panel’s findings, which are available in a full report.*

Methods

Systematic Review

The review methods are provided in detail in the full report. The literature search retrieved published evidence on the effects of glycemic control on microvascular and macrovascular complications in type 1 and type 2 diabetes and on adverse effects. RCT evidence for type 1 diabetes was considered relevant in evaluating the effects of glycemic control in type 2 disease. A total of 798 citations met initial inclusion criteria. All articles underwent structured abstraction. We closed the search with the publication of the UKPDS results in September 1998.

In reviewing the evidence, the panel gave greater weight to RCTs than to observational studies and emphasized data on health outcomes perceptible to patients (eg, visual acuity) over those for intermediate or surrogate end points (eg, retinopathy) that precede or are associated with such outcomes. Most trials did not designate health outcomes as primary end points and therefore lacked the statistical power and duration to prove an effect. Panel recommendations were evidence-based and did not reflect expert opinion. Fourteen outside diabetologists and family physicians externally reviewed the full report, and revisions consistent with the evidence were adopted. The American Academy of Family Physicians and the American Diabetes Association endorsed the full report in March 1999 and this policy statement in October 1999.

We focused the review on the benefits of glycemic control in general and not on specific agents (eg, sulfonylureas, metformin). Interventions not associated with glycemic control (eg, laser phototherapy, angiotensin-converting enzyme inhibitors), which also mitigate the effects of microvascular disease, were not examined in our review.

Results

Microvascular Outcomes

Evidence from Observational Studies. Many cross-sectional studies indicate that people with type 2 diabetes who have higher plasma glucose or glycated hemoglobin (e.g., hemoglobin A1c) levels are more likely to have evidence of retinopathy, neuropathy, or albuminuria.¹¹ Numerous prospective longitudinal studies also show that an elevated fasting plasma glucose (FPG) concentration or glycated hemoglobin level at baseline or over time increases the chances that type 2 patients will develop new or worsened retinopathy, abnormal electrophysiologic findings, or renal dysfunction.^12-15 However, observational data, unlike evidence from RCTs, does not prove that lowering blood glucose levels reduces the incidence of these complications.

Evidence from RCTs. Ten RCTs do provide this evidence.^9,10,16-24 Three trials involved patients with type 2 diabetes: the very large UKPDS¹⁰ (approximately 4200 patients) and 2 small Japanese studies.^16,19 The largest of the 7 trials of patients with type 1 diabetes was the DCCT (1441 patients).⁹ In most trials, patients were randomly allocated to an intensive treatment group that received multiple or continuous insulin administrations or to a control group that received conventional insulin therapy. Most studies confirmed (through mean glycated hemoglobin levels) better glycemic control with intensive treatment. For example, mean hemoglobin A1c levels in the intensive/conservative treatment groups of the DCCT and UKPDS were 7.2%/9.1% and 7.0%/7.9%, respectively.^9,10 An old RCT (University Group Diabetes Program) that did not produce significant differences in glucose control in some treatment arms and lacked statistical power was excluded from our review.²⁵ Average lengths of follow-up in the RCTs ranged from 2 to 12.5 years (6.5 and 10 years, respectively, in the DCCT and UKPDS).

Retinopathy in Patients with Type 2 Diabetes. RCTs provide good evidence that glycemic control reduces the incidence of retinopathy. In a Japanese trial, among patients with no retinopathy at baseline, the 6-year incidence of new disease (progression Ž2 steps on the Early Treatment Diabetic Retinopathy Study [ETDRS] scale²⁶) in the intensive and conservative treatment groups was 6% and 36%, respectively, a relative reduction of 83%. In patients with retinopathy at baseline (secondary prevention group), the incidence rates for intensive and conservative treatment groups were 17% and 44%, respectively.¹⁶

The authors of the UKPDS results, who reported a 25% relative reduction in the incidence of microvascular complications (11.4 vs 8.6 events/1000 patient-years) attributed much of the benefit to reduced retinopathy.¹⁰ The need for laser therapy was lowered from 11.0 to 7.9 events/1000-patient years, a 29% relative reduction. Within 6 years, the incidence of a 2-step progression on the ETDRS scale was lowered from 28% to 23%. The relative reduction in cataract extraction was 24%. The incidence of decreased visual acuity, blindness, and vitreous hemorrhage was not lowered significantly. The extent to which the latter resulted from treatment for early complications is not known.

Retinopathy in Patients with Type 1 Diabetes. Among patients with no baseline retinopathy in the DCCT (primary prevention group), the 6.5-year incidence of a sustained 3-step change on the ETDRS scale was reduced by 76% (from 4.7 to 1.2/100 patient-years).⁹ In the secondary prevention group, the rate of progression was lowered by 54% (from 7.8 to 3.7/100 patient-years). In this group intensive treatment was also associated with a lower incidence of severe retinopathy, need for laser treatment, and sustained progression worsening for at least 6 months (adjusted relative risk reduction=47%, 56%, and 65%, respectively).^9,27 A Swedish trial reported improved ETDRS scales and a lower prevalence of visual impairment (14% vs 35%) at 7.8 years median follow-up.¹⁷

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

Clinical Trials of Patients with Type 1 Diabetes. There are few data on all-cause mortality in patients with type 1 diabetes because of the low event rate.^9,42

Discussion

Potential Harms of Intensive Glycemic Control

Specific complications can occur with each of the agents used to treat type 2 diabetes: Insulin has potential adverse effects, and oral glucose-lowering drugs carry some risk of undesirable side effects and uncommon but serious complications (eg, lactic acidosis, hepatotoxicity).

Attempts to achieve euglycemia can increase the risk of hypoglycemia, and some medications are associated with weight gain. The risk of severe hypoglycemia is greatest for patients with type 1 diabetes. In the subjects with type 2 diabetes in the UKPDS, the incidence of major hypoglycemic episodes was higher among the intensively treated than conventionally treated patients, but the rate was low (1% to 2%).¹⁰ More typically in type 2 disease, a more substantial risk exists for minor hypoglycemic episodes, which are usually inconsequential.^10,40 An association between intensive treatment and weight gain has been reported (mean=3.1 kg and 4.6 kg in the UKPDS and DCCT, respectively),^9,10 but there is no evidence that this amount of weight gain affects outcomes.

Intensive treatment requires that patients perform home glucose monitoring; follow diet and physical activity regimens; tolerate minor side effects and the risk of more serious complications from medications; regularly attend physician visits for testing and examinations; and absorb costs not covered by insurance for physicians and medical supplies, lost work (or school), and transportation. In many cases these inconveniences, discomforts, and costs are borne over a number of years, often a lifetime. RCTs have shown no adverse association between these efforts and quality of life,⁴⁹ however, and one study suggested that glycemic control might improve quality of life and work productivity.⁵⁰

Modeling Estimates

Mathematical models, largely based on the DCCT, have attempted to estimate the magnitude of benefits and harms from glycemic control. One model estimated that patients with type 2 diabetes who maintained a glycated hemoglobin level of 7.2% would reduce their cumulative lifetime risk of blindness, end-stage renal disease, and lower-extremity amputation by 72% (from 19% to 5%), 87% (from 17% to 2%), and 67% (from 15% to 5%), respectively.⁵¹ Life expectancy would increase by 1.39 years. A Markov model estimated that reducing glycated hemoglobin from 9% to 7% in a patient in whom diabetes developed at age 45 years would lower the lifetime risk of blindness from 2.6% to 0.3%.⁵² The same change in a patient who developed diabetes at age 65 years would decrease the risk of blindness from only 0.5% to <0.1%.

In theory, such projections could be useful to clinicians and patients to estimate the benefits and harms of different levels of glycemic control in individual situations. Since there are different designs and assumptions, however, available models offer discrepant predictions about the same types of patients. For example, the lifetime risk of blindness in a white patient aged 55 years who lowers his glycated hemoglobin level from 9% to 7% would, according to one model, be reduced by 5.6% (from 9% to 3.4%)⁵¹ and, according to another model by 1.1% (from 1.2% to 0.1%).⁵² These discrepancies must be reconciled before reliable outcome estimates can be introduced with confidence in practice.

Weighing the Magnitude of Benefit

The evidence demonstrates a continuous and curvilinear relationship between hyperglycemia and the microvascular and neuropathic complications of diabetes, with risk rising progressively as mean blood glucose concentrations increase. RCTs confirm that for both type 1 and type 2 diabetes glycemic control significantly reduces the incidence of microvascular complications. The following points should be considered when applying this evidence to routine practice:

1. The intensity of treatment in RCTs may be difficult to replicate to the same degree in community practice. In the DCCT, for example, patients received insulin by injection 3 times daily or by external pump, self-monitored blood glucose at least 4 times per day, underwent weekly nocturnal blood glucose measurements, visited their study center monthly, and received frequent telephone calls. The target glycated hemoglobin value was less than 6.1%.⁹ More typical treatment practices were followed in the UKPDS. Although some practices and health care systems have successfully achieved satisfactory blood glucose levels through aggressive programs that assist clinicians and patients, other constraints and the inability or reluctance of patients to adhere to treatment protocols remain problems in other settings.⁵³
2. The microvascular end points in most RCTs were primarily intermediate (eg, ETDRS scales, nerve conduction velocity, urinary albumin excretion) or surrogate (eg, laser phototherapy) outcomes rather than health outcomes. Few trials were designed to measure health outcomes, providing limited data on the extent to which the symptoms that patients experience (eg, visual impairment, paresthesias, complications of renal failure) are reduced by intensive treatment. Such complaints generally do not occur until the patient has end-stage disease and are often forestalled by early treatment (eg, laser phototherapy). It is reasonable to infer that long-term benefits result from glycemic control-the intermediate end points affected are known risk factors for clinical disease-but one cannot assume that the observed magnitude of risk reduction for intermediate outcomes applies also to symptomatic disease.
3. Relative risk reductions are greater than absolute risk reductions. The 25% relative reduction in microvascular complications reported by the UKPDS represents an absolute reduction of only 2%: 8%, rather than 10%, of patients had complications during 10 years of treatment.¹⁰ Also, relative risk reductions generally refer to intermediate outcomes. The 76% reduction in the risk of retinopathy reported by the DCCT refers to a 3-step change on the ETDRS scale, not to improved vision.⁹ The number needed to treat to affect outcomes perceptible to patients is necessarily higher than that for retinopathy, delayed nerve conduction, or elevated urinary albumin excretion, because only a subset of patients with these intermediate outcomes go on to develop symptomatic disease.¹⁵ According to the UKPDS, 37 patients would require intensive treatment for 10 years to prevent one patient from undergoing laser treatment; 208 would require treatment to prevent one case of blindness.¹⁰ The observed 16% difference in the incidence of blindness in the UKPDS was not statistically significant.On the other hand, when examined at the population level, even modest absolute risk reductions can translate into large numbers of persons in society for whom clinical benefit is achievable. Given the millions of people in the United States with type 2 diabetes, even a 2% absolute reduction in the risk of microvascular complications represents many thousands of people who would benefit from glycemic control.
4. Because of the average time required for glycemic control to affect outcomes, some patients with diabetes may not live long enough to benefit, because of the competing risks of death of macrovascular complications and other comorbid diseases. Although elevated blood glucose levels are a likely risk factor for cardiovascular disease, glycemic control has not been shown to enhance life expectancy or prevent heart disease. The 16% reduction in myocardial infarction reported by the UKPDS was of borderline statistical significance.¹⁰ Another RCT did find that improved glycemic control reduced the incidence of ischemic cardiac events, stroke, and cardiovascular deaths in patients with acute myocardial infarction.⁴⁸ Two other trials that failed to show a benefit may have lacked adequate duration and sample size.^16,40
5. For any given patient, the absolute magnitude of risk reduction is a continuous variable that is a function of the patient’s current glycated hemoglobin level, the duration and magnitude of previous hyperglycemia, and the extent of preexisting microvascular complications. The probability that the patient will live long enough to experience the benefits of reduced complications depends on cardiovascular risk factors other than blood glucose (eg, smoking, hypertension, lipid levels, physical inactivity, obesity, preexisting coronary artery disease) and other determinants of life expectancy (eg, age, coexisting diseases, health status). Of these, the most critical variable is the patient’s current glycated hemoglobin level. Because of their increased risk of complications, individuals with marked elevations generally benefit more (in absolute terms) from the same absolute reduction in glycated hemoglobin levels than do individuals with mild to moderate elevations.⁵³ Although it is obviously important for clinicians to keep patients from progressing from mild (eg, hemoglobin A1c levels of 6% to 8%) to marked hyperglycemia (eg, hemoglobin A1c levels >9.5%), in those patients who have already developed marked hyperglycemia, efforts directed at achieving even moderate control (eg, hemoglobin A1c levels of 8% to 9.5%) will yield greater health benefits than pursuing euglycemia in patients with moderate elevations.

Recommendations for clinical practice

For any patient with type 2 diabetes, the better the glycemic control, the lower the probability of chronic microvascular, neuropathic, and possibly cardiovascular complications. However, because of differences in patients’ life expectancies, comorbidities, and preferences, it is inappropriate to set a uniform target glycated hemoglobin level for all patients. Individuals with long life expectancies and few comorbidities may wish to pursue euglycemia, but less vigorous goals may be appropriate for others, such as patients with multiple comorbid conditions or with limited life expectancies.

Whether the magnitude of benefit of a given treatment goal justifies the potential inconvenience, harms, and costs involves value judgments that must be tailored to the individual patient. Patients’ personal risk profiles and capabilities and the relative importance they assign to the potential outcomes and supporting evidence are integral in determining how intensively to treat.

Cardiovascular disease is the most likely cause of death in patients with type 2 diabetes, and attention to glycemic control should not distract clinicians and patients from other interventions that may be more effective in preventing coronary artery disease and stroke. These include smoking cessation, serum lipid management, control of blood pressure, diet, physical activity, and weight management. Guidelines for the control of these risk factors appear elsewhere.^54-56 Clinicians should also pursue treatments other than glycemic control for preventing microvascular complications (eg, blood pressure control, angiotensin-converting enzyme inhibitors for diabetic nephropathy, laser treatment for diabetic retinopathy).

Whatever the desired goals and intensity of treatment, patients face considerable barriers in implementing recommendations. Modifying diet and other personal habits; complying with self-monitoring, medication, and home care; and returning for follow-up visits are difficult. Physicians should work with patients to overcome remediable barriers and should use recommended techniques for patient education and counseling to offer the necessary information and motivation for meaningful change.⁵⁷

Acknowledgments

The systematic review on which this guideline is based was supported in part by funding from the Health Care Financing Administration. We thank Richard D. Kahn, PhD, (American Diabetes Association), and Herbert F. Young, MD, and Bellinda Schoof (American Academy of Family Physicians) for their assistance, as well as the expert panel that externally reviewed the full report: Eugene Barrett, MD; John A. Colwell, MD; Richard C. Eastman, MD; Saul Genuth, MD; Ronald Klein, MD, MPH; Martin Mahoney, MD; James W. Mold, MD; David M. Nathan, MD; Jonathan E. Rodnick, MD; Jeffrey L. Susman, MD; Sandeep Vijan, MD, MS; and Bruce Zimmerman, MD. Their participation in the review process does not necessarily imply endorsement of the report or its recommendations.