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:
- 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
- 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.
- 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.
- 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
- 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.