Optimal Glycemic Control in Type 2 Diabetic Patients

Volume 23 Supplement 2
Data, Results, and Consequences of Major Trials With Focus on Type 2 Diabetes
Proceedings from a Symposium

ORIGINAL ARTICLE

Optimal Glycemic Control in Type 2 Diabetic Patients

Does including insulin treatment mean a better outcome?

Stein Vaaler, MD, PHD

Type 2 diabetes is a progressive disease with a significant risk for developing late complications. This article presents evidence related to the effect of glycemic control on the outcome of daily symptoms, microvascular complications, and macrovascular complications. Literature limited to Medline and the Cochrane Library was searched primarily for randomized clinical trials. In terms of education, present intervention studies indicate a positive effect on surrogate end points such as glycemic control, knowledge, practical skills, and psychological performance. Studies show improved glycemic control and plasma lipid profiles after moderate weight reduction. However, this positive effect is limited in time because weight is regained. With regard to oral blood glucose–lowering drugs, clinical trials show a significant blood glucose–lowering effect of different available drugs. Both sulfonylurea and metformin have been shown to significantly reduce the risk of microvascular complications. In the U.K. Prospective Diabetes Study, intensive treatment with metformin in obese subjects reduced the risk for any diabetes-related event and stroke. A major problem is that many patients gradually experience increasing hyperglycemia, creating the need for combined treatment with several drugs including insulin. Insulin treatment has been shown to be effective in achieving satisfactory glycemic control over several years. There is also a positive effect on hard end points such as microvascular disease in the eye, kidney, and nerves. In conclusion, present evidence shows that optimal glycemic control can be attained in people with type 2 diabetes, resulting in fewer disease-related symptoms and a reduced risk of late complications.

Diabetes Care 23 (Suppl. 2):B30–B34, 2000

Type 2 diabetes, usually diagnosed after the age of 50 years, is a progressive disease challenging both the affected individual and the medical community. It is often part of a metabolic syndrome associated with an increased risk of cardiovascular disease. The treatment is multidimensional, with focus on blood glucose, blood pressure, and plasma lipid control. This article is limited to the effects on glycemic intervention.

OBJECTIVE — Outcomes related to the treatment of type 2 diabetes could be defined as follows: 1) absence of symptoms due to diabetes, 2) absence of microvascular complications, and 3) absence of macrovascular disease. This article presents evidence related to these key elements. Other important issues not dealt with are psychology and economy. Another important task is to differentiate between surrogate end points (e.g., blood sugar and HbA_1c) and hard end points (e.g., micro- and macrovascular disease).

METHODS — The literature was searched primarily for randomized clinical trials, but other forms of evidence were also assessed. Searching was limited to Medline (covering the last 10 years) and the Cochrane Library (the most complete register of all randomized clinical trials). Major terms were type 2 diabetes, glycemic control, outcome, education, diet, oral drugs, and insulin.

EFFECTS OF DIFFERENT TREATMENT MODALITIES ON SOME OUTCOME VARIABLES

Education
The search identified almost 200 intervention studies, the majority carried out with a control group or a pretest/posttest design. In a meta-analysis by Brown (1), 82 studies involving 118 experimental groups, not separated by type 1 and type 2 diabetic adults, conclude that educational intervention by nurses and specially trained health care providers is effective in producing positive outcomes in terms of moderate weight loss, decrease in HbA_1c, improved dietary knowledge, weight changes, insulin injection skill, and psychological performance. Positive outcome was only related to surrogate end points, and long-term results are lacking.

Weight loss
There were 89 studies of different designs reviewed by Brown et al. (2) involving 1,800 patients. These studies used behavioral, dietary, exercise, anorectic drug, surgical, and combined approaches to reduce body weight. Diet alone had the largest statistical impact on weight loss and metabolic control, whereas other approaches where less efficient. Even moderate weight loss has usually been followed by improved metabolic control (3) (decrease in blood glucose and HbA_1c) and improved plasma lipid profiles (4). During the last 2 years, a more efficient hypocaloric drug has been shown to improve weight loss during dietary therapy for a longer time period (5). Almost 400 individuals clinically stable on oral sulfonylureas received a hypocaloric diet plus orlistat or placebo. Both regimens introduced a moderate weight reduction during 1 year of treatment—the orlistat supplementation being more effective than placebo.

The major problem, however, with most of these studies is their relatively short duration and the poor long-term outcome, as illustrated in Fig. 1 (6). Figure 1 presents the results of different weight reduction strategies. Basic behavioral therapy included various self-control strategies, including self-monitoring, stimulus control, self-reinforcement, cognitive restructuring, and procedures to reduce the pace of eating. In addition to this therapy, other patient groups were given relapse training and others were offered posttreatment therapist contacts by mail or telephone to discuss eating, exercise, and weight. In spite of these efforts, most patients were unable to maintain their weight loss over time. The best results were attained when all three therapeutic strategies were implemented. No significant changes in hard end points have been shown.

Figure 1—Mean weight loss (kg) for different therapeutic strategies designed to enhance the long-term maintenance of weight loss. BT, behavioral therapy; RT, relapse-prevention training; THC, posttreatment patient–therapist contact.

, BT;

, BT + RT;

, BT + THC;

, BT + RT + THC.

Oral hypoglycemic drugs
There were 98 studies using oral hypoglycemic drugs (the majority randomized and controlled) assessed in the period of 1977–1998. Practically all studies were of a relatively short duration without the possibility to show any effect on hard end points. An important exception is the U.K. Prospective Diabetes Study (UKPDS) (7,8). This study recruited 5,102 newly diagnosed type 2 diabetic subjects. After a dietary run-in period, 3,867 patients were randomized to intensive treatment with a sulfonylurea, insulin, or conventional treatment (primarily treated with diet alone). A subset of an additional 342 obese patients were randomized to metformin and compared with obese patients in the main study allocated to intensive treatment or conventional treatment. Median HbA_1c over 10 years was 7.0% in the intensively treated group, compared with 7.9% in the conventionally treated group. In the obese subset, median HbA_1c was 7.4% in the metformin group, compared with 8.0% in the conventionally treated group. Intensive treatment with sulfonylurea or insulin was equally effective in controlling blood glucose levels and significantly reduced the risk of microvascular complications, whereas macrovascular disease was not affected the same way. In the obese subset, intensive treatment with metformin was as effective as sulfonylurea or insulin in controlling blood glucose but was associated with less weight gain and lower peripheral plasma insulin levels. Among these patients, metformin showed a greater effect than sulfonylurea or insulin on any diabetes-related end point, all-cause mortality, and stroke.

Troglitazone (9) and other thiazolidinediones have also been shown to reduce blood glucose significantly. A similar but weaker action has been documented for the disaccharidase inhibitors (10). Recently, a new nonsulfonylurea short-acting prandial glucose regulator, repaglinide, has been introduced. In short-term studies, this new insulin secretagogue given preprandially with main meals reduces postprandial blood glucose levels and HbA_1c significantly compared with placebo (11). A major problem with oral drugs is that a significant number of patients gradually experience increasing hyperglycemia not controlled by the initial drug alone (7,8,12). A combined treatment with several drugs, including insulin, is often needed (13). We found that despite a continuous increase in HbA_1c after the initial response following introduction of sulfonylurea therapy, the drugs were still active. When stopping sulfonylureas, hyperglycemia worsened dramatically (Fig. 2) (13).

Figure 2—Mean (SEM) HbA_1c during 2 years of therapy with glipizide (

), glibenclamide (

), and placebo (

) and 3 months after stopping the drugs.

Insulin
Various insulin regimens seem capable of improving surrogate end points such as HbA_1c. In the Veterans Affairs Cooperative Study on glycemic control and complications in type 2 diabetes (14), patients were divided into a standard insulin treatment group and an intensive insulin therapy group. In the standard group, patients received one or, if necessary, no more than two injections of insulin daily, resulting in a mean HbA_1c level of between 9 and 10% for the group during the 30 months of follow-up. The intensively treated group were given a stepped regimen beginning with intermediate- or long-acting insulin at bedtime. If the treatment goal was not achieved, the therapy was gradually intensified from evening insulin plus daytime glipizide to two daily insulin injections, and finally to a multi-injection regimen with rapid-acting insulin before meals and intermediate- or long-acting insulin at bedtime. The results of the intensive therapy group were significantly better than those in the standard group. HbA_1c remained 2% lower than that in the standard group for the follow-up time of 27 months. Another interesting point from the same study is shown in Fig. 3. At the end of 1 year, 85% of the intensively treated patients were in phase 1 or 2 (which meant they were taking intermediate- or long-acting insulin at bedtime or evening insulin plus daytime glipizide). Aiming to further lower HbA_1c, 64% of patients were advanced to phase 3 or 4 by the end of the study (which meant they were taking two daily insulin injections or multiple daily insulin injections). Figure 3 shows the overall effect of the different treatment phases, indicating increasing effect of more intensified treatment, although most of the decrease in HbA_1c was obtained by one daily insulin injection alone. As already mentioned, intensified treatment with insulin in normal weight and obese subjects in the UKPDS (7) did not improve metabolic control or long-term outcome compared with treatment with sulfonylureas or metformin. Compared with conventional treatment, intensified insulin treatment reduced the median HbA_1c level over 10 years by 0.9% and significantly improved the risk of developing microvascular disease. No effect on macrovascular end points was observed.

Figure 3—VA CSDM: maximal effect of each treatment phase in the intensively treated group. After 1 year, 85% of patients were on insulin X 1 (evening) and insulin + glipizide, whereas 15% were on two or multiple daily injections of insulin. Ins, insulin; MDI, multiple daily injections; SU, sulfonylurea.

Level of care
Current randomized clinical trials suggest that well-structured control systems (including general education, dietary guidance, and follow-up of self-monitoring and screening for micro- and macrovascular complications) in general practice can achieve the same kind of results as hospital care (at least in the short term) (15). Evidence favors that a model of shared care is optimal.

SPECIFIC EFFECTS ON THE CHOSEN OUTCOME — Optimal glycemic control, defined as HbA_1c levels <7.5% (assay with an upper normal limit of ~6%), can obviously be achieved with different treatment modalities depending on the development phase of type 2 diabetes.

Absence of symptoms due to diabetes
There are several pieces of evidence that show patient daily well-being is improved, and therefore the ability to continue with normal daily activity is usually restored parallel with an improvement in metabolic control. Cross-sectional results from newly diagnosed patients are shown in the UKPDS (16), where newly diagnosed patients after 2 months of dietary intervention reported symptoms related to concurrent fasting blood glucose. Cross-sectional data from established type 2 diabetic patients are seen in the Hoorn Study (17), which supports the view that better glycemic control enhances well-being. Finally, data from a prospective randomized treatment study from Finland (18) show that different insulin regimens are equally effective in improving glycemic control compared with the control group (oral drugs alone) and insulin-treated group, who report a significantly higher subjective sense of well-being.

Absence of microvascular complications
So far, only few randomized clinical trials give evidence that optimal glycemic control improves the prognosis related to microvascular disease. In a prospective randomized Japanese study (19), two groups of type 2 diabetic patients were given conventional or intensive insulin therapy for 6 years. In the intensively treated group, near-normoglycemia (HbA_1c 7.1 � 1.1%) was achieved within 3 months from the start of the study and maintained over the 6 years of the study, whereas the glycemic control in the conventionally treated group did not change significantly from the starting value (HbA_1c �1.5%). Intensified insulin treatment significantly delayed the onset and progression of microvascular disease in the retina, kidney, and peripheral nerves. In our own Octopus study (13,20), 55 patients with type 2 diabetes were originally randomized to insulin and sulfonylureas. Because of therapy failure, all but five patients in the sulfonylurea group were given insulin between 1.5 and 5.5 years, resulting in similar glycemic control in the two groups after 5.5 years. When dividing the patients by median HbA_1c through 5.5 years, 0 of 23 patients with values <8% showed any progression of albuminuria (measured every 6 months), whereas in the group with HbA_1c>8%, progression was seen in 6 of 32 patients. Progression of albuminuria was defined as an increase in the overnight albumin excretion rate from normoalbuminuria (<20 �g/min) to microalbuminuria (20–200 �g/min) or from microalbuminuria to proteinuria (>200 �g/min). Several studies with type 1 diabetes clearly show that the development and progression of microvascular complications are related to metabolic control.

Absence of macrovascular disease
Evidence from a large number of randomized clinical trials shows that other surrogate end points, such as plasma lipids, factors affecting fibrinolysis and thrombosis, microalbuminuria, and in some instances hypertension, also change in a favorable way when optimal glycemic control is achieved. These changes should in theory improve the prognosis related to the increased morbidity and mortality due to cardiovascular disease. So far, the UKPDS is the only properly designed study available to give some answers (7,8) (see below), although many cross-sectional and observational studies favor the coherence of metabolic control and the risk for different aspects of cardiovascular disease.

Klein (21) was one of the first scientists to show that in a group of older-onset diabetic subjects, 10 years of mortality was related to HbA_1c at baseline of the study. In a more recent study from Sweden, Andersson and Sv�rdsudd (22) followed more than 400 newly diagnosed diabetic subjects for 8 years and showed that mortality was associated with mean fasting blood glucose.

A recent, more controversial study by Malmberg et al. (23) (the DIGAMI [Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction] Study) showed a relative risk reduction for dying in the year after a myocardial infarction of 29% in the intensively treated group (insulin infusion) compared with a control group after 1 year of follow-up. All other aspects of acute and follow-up cardiac treatment were the same in the two groups. A major methodological problem with this study is that it originally was designed to last for 3 months. It was later extended, and the differences between treatment groups did not reach significant levels within the original study period.

The UKPDS (7,8) randomized more than 4,000 newly diagnosed type 2 diabetic subjects to intensive blood glucose control, with the aim of keeping the fasting plasma glucose level <6 mmol/l, and conventional treatment, with the aim of keeping the fasting plasma glucose level <15 mmol/l. End points related to macrovascular disease were fatal or nonfatal myocardial infarction, angina, heart failure, fatal or nonfatal stroke, and fatal or nonfatal peripheral vascular disease (including amputations). In the major study with nonobese patients, intensive treatment with sulfonylureas or insulin significantly reduced the risk for any diabetes-related end point by 12%, and most of this reduction was due to a 25% risk reduction in microvascular end points. In the obese subset, intensive treatment with metformin significantly reduced the risk for any diabetes-related end point by 32%, diabetes-related death by 42%, and all-cause mortality by 36%.

CONCLUSIONS — Type 2 diabetes has been viewed as a major disease with a high risk of negative outcome in terms of daily life and late complications and has been treated with major lifestyle changes and hypoglycemic drugs for at least 2 decades. Surprisingly, little evidence is found in the literature testing the hypothesis that optimal glucose control will lead to better outcome.

Available evidence supports the following:

Optimal glycemic control can be achieved with different treatment modalities.
Patient well-being is improved, and the ability to continue normal daily activity is restored.
Based on present evidence, the assumption that hyperglycemia is a major determinant of microvascular complications in type 2 diabetes is justified.
A large number of random clinical trials show that surrogate end points reflecting the risk for cardiovascular disease improve. This should, in theory, improve the patient's prognosis. Evidence from the UKPDS, where metformin was used to achieve better blood glucose control in place of conventional treatment, supports this view. The risk for any diabetes-related end points, diabetes-related death, and stroke are significantly reduced.
Results of more properly designed prospective studies focusing on macrovascular disease are still highly needed.

References

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From the Centre for Clinical Epidemiology, The National University Hospital, Oslo, Norway.

Address correspondence and reprint requests to Stein Vaaler, MD, PhD, Centre for Clinical Epidemiology, The National University Hospital, 0027 Oslo, Norway. E-mail: svaaler@online.no.

Received for publication 9 July 1999 and accepted 15 October 1999.

Abbreviations: UKPDS, U.K. Prospective Diabetes Study.

A table elsewhere in this issue shows conventional and Syst�me International (SI) units and conversion factors for many substances.

This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Aventis Pharma.

Copyright � 2000 American Diabetes Association
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