Intensive Glucose Lowering Therapy -- Weighing the Evidence

A study by Lingvay et al. has compared two intensive therapies to lower blood glucose levels in patients with newly diagnosed Type 2 diabetes. The findings reveal the efficacy and safety of both insulin and triple oral therapy.

To achieve optimal glycemic control is of prime importance in the prevention of long-term cardiovascular complications of Type 2 diabetes, but the level of control required and the methods used to achieve this control are controversial. Insulin therapy is mostly advised for patients with inadequate glycemic control after treatment with oral antidiabetic agents. Adverse effects, such as weight gain and hypoglycemic episodes, however, are a great concern, which frequently delays the start of this treatment. Insulin therapy is at present not advocated for patients with newly diagnosed Type 2 diabetes, and treatment algorithms currently recommend diet and exercise in combination with or without administration of metformin. A new study by Lingvay et al. examines two regimens of intensive therapy -- insulin and triple oral therapy -- in patients with newly diagnosed Type 2 diabetes. Insulin therapy was as safe and as effective as oral therapy in the achievement of glycemic control, treatment compliance, treatment satisfaction and quality of life improvement. The investigators suggest, therefore, that insulin should be considered as a first-line treatment for Type 2 diabetes.

The study was a randomized, open-label trial designed to compare treatment of 58 drug-naive patients with newly diagnosed Type 2 diabetes with either insulin plus metformin or with triple oral therapy. The improvement in glycemic control seen in this trial was marked: HbA_1c levels dropped from 10.8% to 5.9% in the 3-month lead-in period, during which time all participants received insulin plus metformin. After the lead-in period, patients either continued treatment with insulin plus metformin or were switched to triple oral therapy, which consisted of glibenclamide, metformin and pioglitazone. Glycemic control was maintained at around 6% in both treatment groups throughout the 3 years of the trial. Treatment with triple oral therapy did not alter HbA_1c levels compared with insulin plus metformin treatment and no progressive deterioration of glycemic control could be detected in either group. The investigators attribute this finding to a reduction in glucose toxicity as a result of the initial insulin treatment. Furthermore, rates of hypoglycemia were low in both groups and comparable.

The study to some extent is comparable to the 3-year data from the United Kingdom Prospective Diabetes Study (UKPDS). The UKPDS also showed that good glycemic control can be achieved and maintained with insulin or oral agents in the first years after treatment is initiated. Notably, glycemic control eventually deteriorated in both treatment groups. This result was attributed to progressive β-cell failure, which is recognized as part of the natural progression of Type 2 diabetes. The maintenance or improvement of β-cell function is desirable in the treatment of Type 2 diabetes, and to date no treatment regime has been associated with long-term β-cell preservation. Further follow-up of the study will hopefully assess β-cell function in both treatment groups, and preservation of β-cell function in response to either treatment will be of great interest.

The benefits of tight glycemic control are increasingly controversial, and although long-term cardiovascular benefits have been demonstrated in the UKPDS, none have been found in the short term. The UKPDS follow-up has shown cardiovascular morbidity and mortality benefits 10 years after completion of the study, whereas three studies of shorter duration, ACCORD^,, ADVANCE, and VADT, did not show any benefit of tight glycemic control on cardiovascular outcomes. Notably, the ACCORD trial was stopped prematurely because of increased mortality in the intensive treatment group of the study. This finding has led to some anxiety about intensive therapies for Type 2 diabetes and the possible effects of hypoglycemia, weight gain and medication on mortality. Analysis of the VADT has shown that the greatest benefit on cardiovascular outcomes was seen in patients with diabetes of shorter duration, which suggests that intensive treatment early on in the disease might be desirable.

A limitation of the study that needs to be taken into consideration is the fact that the population of patients analyzed by Lingvay et al. was not typical of the majority of newly diagnosed patients seen in clinical practice. The trial enrolled obese (mean BMI 36 kg/m²), young patients (mean age 45 years) with very poor diabetic control at diagnosis (mean HbA_1c levels 10.8%). These patients could represent a highly motivated group of participants who showed symptoms of Type 2 diabetes at an early stage. These characteristics do not, however, apply to the majority of newly diagnosed patients, who are largely asymptomatic in the early years of their illness. Some doubts, therefore, remain as to whether the results of Lingvay et al. could be extrapolated to all patients with Type 2 diabetes.

In clinical practice, to convince patients with Type 2 diabetes to start daily insulin injections remains one of the greatest challenges. Compliance and treatment satisfaction rates were high in both treatment groups in this study and these levels were maintained over 3 years. Previous studies have shown that initiation of insulin therapy is often delayed because of patient apprehension. In conclusion, thisstudy is a small trial of relatively short duration that shows insulin therapy to be a safe and effective treatment for newly diagnosed Type 2 diabetes and comparable to triple oral therapy. Currently, neither of these treatment regimens is recommended for initial treatment of Type 2 diabetes, and although the findings revealed good compliance and satisfaction with insulin therapy, caution should be used in the recommendation of aggressive glucose-lowering strategies. Follow-up of current outcome studies should answer some of the important questions on intensive therapies and glycemic control that remain. How early should we treat? Which agents should we use? Which patients should be targeted? Is β-cell function preserved by early intensive treatment? Until these issues have been elucidated, insulin should remain an alternative option rather than the preferred first-line treatment in the management of newly diagnosed Type 2 diabetes mellitus.

• Insulin treatment could be as safe and as effective as triple oral therapy in patients with newly diagnosed Type 2 diabetes mellitus.
• Insulin therapy should be considered as an option rather than the preferred first-line treatment for newly diagnosed Type 2 diabetes mellitus.
• The benefits of tight glycemic control in Type 2 diabetes mellitus remain controversial, however, and intensive strategies might be associated with increased morbidity and mortality.

Nat Rev Endocrinol. 2010;6(1):9-10

The study concludes that intensive therapy with insulin is effective for newly diagnosed Type 2's and so is intensive therapy with three oral agents. 

Notably, glycemic control eventually deteriorated in both treatment groups. This result was attributed to progressive β-cell failure, which is recognized as part of the natural progression of Type 2 diabetes. The maintenance or improvement of β-cell function is desirable in the treatment of Type 2 diabetes mellitus, and to date no treatment regimen has been associated with long-term β-cell preservation.

Glucose toxicity occurs when blood sugars are above normal. So the question that comes into play is, "What is normal?" According to many studies, a normal A1c is below what we determine as the definition of pre-diabetes which is from 5.6 to 6.4%. So would an A1c of 5.3% be considered normal without glucotoxicity? If we look at young people without diabetes, who are not overweight, the norm is below 5%, probably about 4.3 to 4.5%.   If betacell failure occurs when blood sugars are above normal, which would be most likely below 5%, then could we prevent betacell failure if we were able to lower blood sugars below 5%? No studies have been done to aggressively lower A1c's into the normal range of below 5%. Is it possible that if we remove the glucotoxicity by having normal blood sugars that betacells could possibly regain their effectiveness and requirements for insulin would improve?

Why haven't we seen any studies where the goal is to get to normal blood sugars? Is it due to the fact that the only way that is possible today is with the use of insulin (or major weight loss) and that we have a fear that if we try to lower the A1c below 6% that hypoglycemia and weight gain might occur?

Could it be that when using industrial doses of insulin the results can be very unpredictable? Counting carbohydrates is not an accurate science: even the manufacturers can be off by 20%. What if just a couple of units of insulin could be used to control blood sugar levels? The risk for hypoglycemia would be considerably lower. How can a patient use just a few units of insulin? If they reduced their intake of carbohydrates their requirements for insulin would be reduced. This would allow for more predictability in insulin dosing and for reduction of A1c levels closer to normal without the risk of hypoglycemia.

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