Landmark trials in type 2 diabetes

As with my previous blog on landmark type 1 diabetes studies, recommendations for the management of type 2 diabetes are also based on evidence from large randomized clinical trials.

These trials answer two basic questions:

1. Does good glucose control decrease the risk of developing diabetes complications?
2. Are newer medications as safe – or safer – than older agents (i.e. standard of care) in reducing the cardiovascular complications associated with diabetes?

Diabetes complications are generally grouped into two categories: 1) small blood vessel, or microvascular, disease (eye, kidney and nerve damage); and 2) large blood vessel, or macrovascular, disease (stroke, heart attacks and amputations).  

Study in people with newly diagnosed diabetes and glucose control

The United Kingdom Prospective Diabetes Study (UKPDS)

The two questions this trial was meant to answer:

1. Does intensive use of pharmacological therapy to lower blood glucose levels have clinical benefits (i.e. a decrease in microvascular and macrovascular complications) versus lifestyle control with a higher glucose level?
2. Does the use of a sulfonylurea drug, metformin or insulin have specific advantages or disadvantages?

How the study was set up: 5,000 people with newly diagnosed type 2 diabetes, who were studied for an average of 10 years, were divided into 2 groups:

• Lifestyle control with fasting glucose <15mmol/L
• Medication controlled with fasting glucose <6 mmol/L

Results: The most important outcome of this trial, along with what was originally sought above, was learning about the natural history of type 2 diabetes: it is a progressive disease, and the ability of the pancreas to make insulin is already diminished by 50% at the time of diagnosis, and then continues to diminish over time despite treatment with medications.

What became clear from the study was that more than 80% of people who were managing their diabetes with diet alone needed the addition of medication as their fasting glucoses went over 15 mmol/L. Also, many people who were taking only a sulfonylurea drug, metformin or insulin needed to add on another medication for their glucose to reach <6 mmol/L.

Results from UKPDS established that using intensive therapy to lower blood glucose levels in type 2 diabetes results in a reduction in retinopathy, nephropathy, and possibly neuropathy, even with a fairly minimal difference in A1C. The average A1C was 7.0% in the medication-treated group, and 7.9% in the lifestyle therapy group. The rate of microvascular complications was decreased by 25%.

Analysis of the UKPDS data showed a continuous relationship between the risk of microvascular complications and blood sugar levels: for every 1% decrease in A1C (for example, from 9% to 8%), there was a 35% reduction in the risk of complications. A 16% reduction (which was not quite statistically significant) in the risk of combined fatal or nonfatal myocardial infarction (heart attack) and sudden death was observed.

Further analysis showed a continuous association between the risk of cardiovascular complications and blood sugar levels, such that for every 1% decrease in A1C (e.g., 9 to 8%), there was a 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal heart attacks. 

The UKPDS 10-year follow up study

After people finished this study, the A1Cs in the two groups became similar. The study participants were followed for 10 years to see if the reduction in microvascular complications persisted in the group that had been intensively treated with medication. The results showed a continued benefit to the group who had had a lower A1C during the study, despite a similar A1C for 10 years after. This became known as the “legacy” effect. This means that achieving good glucose control early in the course of type 2 diabetes will have continued benefits later on. Moreover, the 10-year follow-up showed a statistically significant reduction in heart attacks in the well-controlled group.

Effect on care: There is now proof that good glucose control (i.e. A1C <7%) in people who are newly diagnosed type 2 diabetes leads to fewer microvascular complications and, over time, fewer heart attacks. We learned that diabetes is a progressive disease and that to maintain good glucose control (in addition to lifestyle), medication needs to be added and intensified to maintain an A1C <7%.

Studies in people with established diabetes and glucose control

How these studies were set up: The studies below consisted of people with longstanding diabetes, many of whom already had cardiovascular disease. Different therapies were used to target near normal A1Cs (6% or 6.5%).

The Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes study (ADVANCE)

Results: Lowering A1C to 6.5% resulted in a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. There was an increase in hypoglycemia, but no increase in overall death.

The Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes (VADT) and VADT Follow-up studies

Results: The VADT study showed that intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events, death, or microvascular complications, with the exception of progression of albuminuria.

The VADT Follow-up study showed that, after nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy. Nonetheless, no improvement was seen in the rate of overall survival.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study

Results: Compared with standard therapy, the use of intensive therapy to target a normal A1C level led to a reduction in all microvascular complications and heart attacks, but did not significantly reduce major cardiovascular events. The intensive group also had an increase in hypoglycemia, and an increase in mortality. These findings identified a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes.

Effect on care: People with diabetes who are not at risk of hypoglycemia, and can achieve an A1C of 6.5%, may have a lower risk of developing microvascular complications, especially kidney disease. However, in people at high risk of both cardiovascular disease and hypoglycemia, and who have difficulty achieving an A1C of <7%, should have a less stringent A1C target.

Safety studies in people with type 2 diabetes and cardiovascular disease, and specific medications

In 2008, the U.S. Federal Drug Administration mandated that all new medications used to treat type 2 diabetes be tested to ensure that they do not cause more cardiovascular harm than the standard treatment. Initially, studies were able to show that many new medications caused no increased cardiovascular harm. Recently however, some studies have actually shown a cardiovascular benefit, and this has really changed practice. 

How these studies were set up: The safety studies were large randomised trials with two groups of participants – one group received usual care; the second group received usual care, plus a new medication.

Participants in both groups had a previous vascular event (for example, heart attack or stroke), or had a very high risk for having an event. Both groups had the same A1C target. After a period of time (about three to four years), the number of major adverse cardiac events (MACE) were compared.

Table 1: Results of studies in people with type 2 diabetes and cardiovascular disease, and specific medications

*SGLT-2 medication ** GLP-1 medication

Effect on care: It is now recommended that if a person with type 2 diabetes and cardiovascular disease is not at their A1C target, their next medication should be one of the ones listed in Table 1. Moreover, because of the harmful effects of hypoglycemia and weight gain, it is recommended that if hypoglycemia and weight gain are of concern, an SGLT2 or GLP-1 medication should be added to metformin in the management of type 2 diabetes.

Trial in which all the cardiovascular risk factors are addressed: the STENO study

Results: This trial demonstrated that, in people with type 2 diabetes and cardiovascular markers (for example, protein in their urine), intensive treatment for all their risk factors – A1C, cholesterol, blood pressure, smoking and lifestyle – resulted in an amazing decrease of 50% in MACE. This effect lasted many years after the trial ended.

Effect on care: The results of the STENO study underscore the importance of treating all risk factors for heart attack and stroke, not just blood glucose control.