While patients with type 2 were not studied in the DCCT, the eye, kidney, and nerve abnormalities are quite similar in both types of diabetes, and it is likely that similar underlying mechanisms apply. Several important differences, however, must be considered. Since patients with type 2 diabetes are generally older with a high incidence of macrovascular disease, an episode of severe hypoglycemia entails much greater risk than it would in a younger patient with type 1 diabetes. Moreover, weight gain may be much greater in obese persons with type 2 diabetes in whom intensive insulin therapy is attempted. These risks take on a greater relevance in older patients with type 2 diabetes because the prevalence of microangiopathy is relatively lower than in those patients with type 1 diabetes; preventing microvascular disease in patients with type 2 diabetes is much less likely to influence morbidity and mortality because of the greater consequences of their macrovascular disease.
To address the issues raised by the DCCT findings as well as a previous concern that sulfonylureas may increase cardiovascular deaths, as reported in 1970 by the University Group Diabetes Program, randomized clinical trials of intensive therapy have been conducted in patients with type 2 diabetes.
1. The Diabetes Prevention Program - This study was aimed at discovering whether treatment with either diet and exercise or metformin could prevent the onset of type 2 diabetes in people with impaired glucose tolerance; 3234 overweight men and women aged 25-85 years with impaired glucose tolerance participated in the study. Intervention with a low-fat diet and 150 minutes of moderate exercise (equivalent to a brisk walk) per week reduced the risk of progression to type 2 diabetes by 71% compared with a matched control group. Participants taking 80 mg of metformin twice a day reduced their risk of developing type 2 diabetes by 31%, but this intervention was relatively ineffective in those who were either less obese or in the older age group.
With the demonstration that intervention can be successful in preventing progression to diabetes in these subjects, a recommendation has been made to change the terminology from the less comprehensible “impaired glucose tolerance” to “prediabetes.” The latter is a term that the public can better understand and thus respond to by implementing healthier diet and exercise habits.
2. Kumamoto Study - The Kumamoto study involved a relatively small number of patients with type 2 diabetes (n = 110) who were nonobese and only slightly insulin-resistant, requiring less than 30 units of insulin per day for intensive therapy. Over a 6-year period, it was shown that intensive insulin therapy, achieving a mean HbA1c of 7.1%, significantly reduced microvascular end points compared with conventional insulin therapy achieving a mean HbA1c of 9.4%. Cardiovascular events were neither worsened nor improved by intensive therapy, and weight changes were likewise not influenced by either form of treatment.
3. The Veterans Administration Cooperative Study - This investigation involved 153 obese men who were moderately insulin-resistant and who were monitored for only 27 months. Intensive insulin treatment resulted in mean HbA1c differences from conventional insulin treatment (7.2% versus 9.5%) that were comparable to those reported from the Kumamoto Study. However, a difference in cardiovascular outcome in this study has prompted some concern. While conventional insulin therapy resulted in 26 total cardiovascular events, there were 35 total cardiovascular events in the intensively treated group. This difference in the relatively small population was not statistically significant, but when the total events were broken down to major events (myocardial infarction, stroke, cardiovascular death, congestive heart failure, or amputation), the 18 major events in the group treated intensively with insulin were reported to be statistically greater (P =. 04) than the ten major events occurring with conventional treatment. While this difference may be a chance consequence of studying too few patients for too short a time, it raises the possibility that insulin-resistant patients with visceral obesity and long-standing type 2 diabetes may develop a greater risk of serious cardiovascular mishap when intensively treated with high doses of insulin. At the end of the study, 64% of the intensively treated group were either receiving (1) an average of 113 units of insulin per day when only two injections per day were used or (2) a mean dosage of 133 units per day when multiple injections were used. Unfortunately, the UKPDS, which did not discern any effect of intensive therapy on cardiovascular outcomes, does not resolve the concern generated by the Veterans Administration Study since their patient population consisted of newly diagnosed diabetic patients in whom the obese subgroup seemed to be less insulin-resistant, requiring a median insulin dose for intensive therapy of only 60 units per day by the twelfth year of the study.
4. The United Kingdom Prospective Diabetes Study - This multicenter study was designed to establish, in type 2 diabetic patients, whether the risk of macrovascular or microvascular complications could be reduced by intensive blood glucose control with oral hypoglycemic agents or insulin and whether any particular therapy was of advantage. A total of 3867 patients aged 25-65 years with newly diagnosed diabetes were recruited between 1977 and 1991, and studied over 10 years. The median age at baseline was 54 years; 44% were overweight (> 120% over ideal weight); and baseline HbA1c was 9.1%. Therapies were randomized to include a control group on diet alone and separate groups intensively treated with either insulin or sulfonylurea (chlorpropamide, glyburide, or glipizide). Metformin was included as a randomization option in a subgroup of 342 overweight patients, and much later in the study an additional subgroup of both normal-weight and overweight patients who were responding unsatisfactorily to sulfonylurea therapy were randomized to either continue on their sulfonylurea therapy alone or to have metformin combined with it.
In 1987, an additional modification was made to evaluate whether tight control of blood pressure with stepwise antihypertensive therapy would prevent macrovascular and microvascular complications in 758 hypertensive patients among this UKPDS population compared with 390 of them whose blood pressure was treated less intensively. The tight control group was randomly assigned to treatment with either an angiotensin-converting enzyme (ACE) inhibitor (captopril) or a β-blocker (atenolol). Both drugs were stepped up to maximum dosages of 100 mg/d and then, if blood pressure remained higher than the target level of < 150/85 mm Hg, more drugs were added in the following stepwise sequence: a diuretic, slow-release nifedipine, methyldopa, and prazosin - until the target level of tight control was achieved. In the control group, hypertension was conventionally treated to achieve target levels < 180/105 mm Hg, but these patients were not prescribed either ACE inhibitors or β-blockers.
a. Results of the UKPDS - Intensive treatment with either sulfonylureas, metformin, combinations of those two, or insulin achieved mean HbA1c levels of 7%. This level of glycemic control decreases the risk of microvascular complications (retinopathy and nephropathy) in comparison with conventional therapy (mostly diet alone), which achieved mean levels of HbA1c of 7.9%. Weight gain occurred in intensively treated patients except when metformin was used as monotherapy. No cardiovascular benefit and no adverse cardiovascular outcomes were noted regardless of the therapeutic agent. Hypoglycemic reactions occurred in the intensive treatment groups, but only one death from hypoglycemia was documented during 27,000 patient-years of intensive therapy.
When therapeutic subgroups were analyzed, some unexpected and paradoxical results were noted. Among the obese patients, intensive treatment with insulin or sulfonylureas did not reduce microvascular complications compared with diet therapy alone. This was in contrast to the significant benefit of intensive therapy with these drugs in the total group. Furthermore, intensive therapy with metformin was more beneficial in obese persons than diet alone with regard to fewer myocardial infarctions, strokes, and diabetes-related deaths, but there was no significant reduction by metformin of diabetic microvascular complications as compared with the diet group. Moreover, in the subgroup of obese and nonobese patients in whom metformin was added to sulfonylurea failures, rather than showing a benefit, there was a 96% increase in diabetes-related deaths compared with the matched cohort of patients with unsatisfactory glycemic control on sulfonylureas who remained on their sulfonylurea therapy. Chlorpropamide also came out poorly on subgroup analysis in that those receiving it as intensive therapy did less well regarding progression to retinopathy than those conventionally treated with diet.
Intensive antihypertensive therapy to a mean of 144/82 mm Hg had beneficial effects on microvascular disease as well as on all diabetes-related end points, including virtually all cardiovascular outcomes, in comparison with looser control at a mean of 154/87 mm Hg. In fact, the advantage of reducing hypertension by this amount was substantially more impressive than the benefit achieved by improving the degree of glycemic control from a mean HbA1c of 7.9% to 7%. More than half of the patients needed two or more drugs for adequate therapy of their hypertension, and there was no demonstrable advantage of ACE inhibitor therapy over therapy with β-blockers with regard to diabetes end points. Use of a calcium channel blocker added to both treatment groups appeared to be safe over the long term in this diabetic population despite some controversy in the recent literature about its safety in diabetics.
b. Implications of the UKPDS - It appears that glycemic control to levels of HbA1c to 7% shows benefit in reducing total diabetes end points, including a 25% reduction in microvascular disease as compared with HbA1c levels of 7.9%. This reassures those who have questioned whether the value of intensive therapy, so convincingly shown by the DCCT in type 1 diabetes, can safely be extrapolated to older patients with type 2 diabetes. It also argues against the concept of a “threshold” of glycemic control since in this group there was a benefit from this modest reduction of HbA1c below 7.9% whereas in the DCCT a threshold was suggested in that further benefit was less apparent at HbA1c levels below 8%.
Because of the complexity of the overall design in which many of the original therapy groups received additional medications to achieve glycemic goals but remained assigned to their group, statistical analysis may have been compromised by these multiple crossovers. For instance, in the diet group that was used as a control for all the drug treatment groups, only 58% of their total “patient-years” were actually drug-free while the remainder consisted of nonintensive therapy with various hypoglycemic drug regimens to avoid unacceptable hyperglycemia. This probably partly explains why the mean HbA1c for this group was only 7.9% on “diet alone” therapy for over 10 years. In view of these crossovers within treatment groups, caution is suggested regarding several subgroup analyses that are controversial. These include the implication that metformin was superior to insulin or sulfonylureas in reducing diabetes-related end points in obese patients compared with diet therapy even though all three treatment groups achieved the same degree of glycemic control. Conversely, the finding of excess mortality in the subgroup of patients receiving combination therapy with metformin and sulfonylureas need not necessarily preclude this combination in patients doing poorly on sulfonylureas alone, although it certainly indicates a need for clarification of this important question.
Probably the most striking implication of the UKPDS is the benefit to the hypertensive type 2 diabetic patient of intensive control of blood pressure. There was no demonstrable advantage of ACE inhibitor therapy on outcome despite a number of short-term reports in smaller populations, implying that these drugs have special efficacy in reducing glomerular pressure beyond their general antihypertensive effects. Moreover, slow-release nifedipine showed no evidence of cardiac toxicity in this study despite some previous reports claiming that calcium channel blockers may be hazardous in patients with diabetes. Finally, the greater benefit in diabetes end points from antihypertensive than from antihyperglycemic treatments may be that the difference between the mean blood pressures achieved (144/82 mm Hg versus 154/87 mm Hg) is therapeutically more influential than the slight difference in HbA1c (7% versus 7.9%). Greater hyperglycemia in the control group would most likely have rectified this discrepancy in outcomes.
5. The STENO-2 Study - The Steno-2 study was designed in 1990 to validate the efficacy of targeting multiple concomitant risk factors for both microvascular and macrovascular disorders in type 2 diabetes. A prospective, randomized, open, blinded end point design was used where 160 patients with type 2 diabetes and microalbuminuria were assigned to conventional therapy with their general practitioner or to intensive care at the Steno Diabetes Center. The intensively treated group had step-wise introduction of lifestyle and pharmacologic interventions aimed at keeping glycated hemoglobin less than 6.5%, blood pressure less than 130/80 mm Hg; total cholesterol < 175 mg/dL, and triglycerides < 150 mg/dL. All the intensively treated group received ACE inhibitors and if intolerant, an angiotensin II-receptor blocker. The lifestyle component of intensive intervention included reduction in dietary fat intake to less than 30% of total calories; smoking cessation program; light to moderate exercise; daily vitamin-mineral supplement of vitamin C, E, and chromium picolinate. Initially aspirin was only given as secondary prevention to patients with a history of ischemic cardiovascular disease; later all patients received aspirin. After a mean follow-up of 7.8 years, cardiovascular events (eg, myocardial infarction, angioplasties, coronary bypass grafts, strokes, amputations, vascular surgical interventions) developed in 44% of patients in the conventional arm and only in 24% in the intensive multifactorial arm - about a 50% reduction. Rates of nephropathy, retinopathy, and autonomic neuropathy were also lower in the multifactorial intervention arm by 62% and 63%, respectively.
The data from the UKPDS and this study provide support for guidelines recommending vigorous treatment of concomitant microvascular and cardiovascular risk factors in patients with type 2 diabetes.