How Long Before Early Adoption of Insulin Becomes Rule Instead of Exception for Difficult to Control Type 2 Diabetes?

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Improved glycemic control in patients with type 2 diabetes is grounded in lifestyle modifications and pharmacologic therapy. Whether to introduce insulin early as a pharmacotherapy for patients with type 2 diabetes is a question that doesn’t have an easy, pat answer.

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Clinical studies have generated “a limited amount of evidence—but decent evidence—that treating with insulin early on improves outcomes and improves longer-term outcomes,” said Kevin Niswender, M.D., Ph.D., a staff physician at the Tennessee Valley Healthcare System in Nashville. In addition, an even more limited level of evidence suggests that extremely early initiation of insulin therapy could protect beta-cell function, slowing down the progression of the disease from mild diabetes to more severe diabetes that requires more intensive therapeutic approaches.

So in general, many clinicians are comfortable “with the idea that being on insulin and having better glycemic control early portends much, much longer-term protection from some of the comorbidities of diabetes like heart disease and premature death,” he explained.

However, insulin isn’t the first pharmacotherapy option for most type 2 diabetes patients, according to current clinical guidelines. Since the 1995-1996 introduction of metformin (the biguanide class) to the U.S. market, the number of pharmacotherapy options for treating type 2 diabetes has mushroomed. Previously, the only available type 2 diabetes drugs were insulin or one oral medication class, sulfonylureas (e.g., glipizide and glyburide). However, 11 classes of diabetes medications are now on the market, including a number of oral agents, according to researchers who conducted a comparative effectiveness review for the Agency for Healthcare Research and Quality (AHRQ) that was released in March 2011.

Metformin’s arrival on the scene heralded the launch of “a plethora of oral options for the treatment of type 2 diabetes,” said Col. Robert A. Vigersky, M.D., director of the Diabetes Institute at the Walter Reed Army Medical Center in the Walter Reed Health Care System in Washington. Today, metformin is “the first choice for pharmacotherapy,” he noted.

Vigersky’s comments are in line with the VA/Department of Defense (DoD) Clinical Practice Guideline for the Management of Diabetes Mellitus, which was updated in August 2010. That guideline states: “Metformin (preferred) or sulfonylureas should be given as first-line agents unless there are contraindications,” adding that “insulin should be considered in any patient with extreme hyperglycemia or significant symptoms.” The AHRQ review also substantiates this position. “Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent,” said the researchers in Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update.

Many patients with type 2 diabetes have been treated with oral hypoglycemic agents only, said Vigersky. While some patients are on a single oral agent, others often are treated with combinations of two, three, four and, rarely, five oral drugs that represent different classes. One recent study found that, from 2005-2006, 35.3 percent of all diabetes patients took two classes of anti-diabetes medications, and 14.2 percent took three or more classes, according to the AHRQ review.

However, clinicians have begun to recognize that “adding more and more oral drugs doesn’t always get patients to goal,” said Vigersky. “What you end up having is patients taking a lot of pills, [and] there are compliance issues with people taking multiple medications.”

So clinicians have introduced insulin “earlier and earlier in the course of management of type 2 diabetes,” said Vigersky. The relatively recent introduction of basal insulins has fostered the early adoption of insulin use in patients with type 2 diabetes because they allow patients to more safely and more easily initiate insulin, he explained.

“As a result of that trend, about one-third of people with type 2 diabetes are now on insulin,” said Vigersky. “That may be insulin in combination with oral agents or insulin alone, and that wasn’t true 10 or 15 years ago.”

A Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes in the Dec. 21, 2009, issue of Clinical Diabetes recommends the “early addition of insulin therapy in patients who do not meet target goals.” The VA/DoD guideline, as well as the guidelines of several other organizations, advises clinicians to consider the addition of insulin in combination with one or two oral agents when combination therapy is required to achieve adequate glycemic control.

The first question that clinicians need to address is what constitutes the target level of glycemic control for each patient, said Vigersky. Historically, the American Diabetes Association has advocated a blanket hemoglobin A1C target of under 7 percent. Other organizations have even supported an A1C goal of 6.5 percent, he noted.

However, recent data suggests that clinicians should be “a little more careful” about instituting intensive glycemic control to achieve an A1C in the below-7 range, said Peter Reaven, MD, director of the diabetes program at the Phoenix VA Health Care System in Arizona. “We have to move away from that all-encompassing algorithm.”

The revised VA/DoD guideline states: “In some circumstances, aggressive management of glycemic control may cause frank harm. This is particularly true for patients with type 2 [diabetes] treated with insulin.”

Recognizing that the standard goal of less than 7 percent “may not be appropriate for all people,” the VA/DoD guideline suggests using certain parameters to develop individualized A1c goals, explained Vigersky. The updated guideline includes a table that recommends A1C goals based on several factors, including life expectancy and the patient’s degree of concurrent complications. For example, a patient who is younger, has no complications, and has a life expectancy of more than 10 years should have an A1C goal of less than 7 percent. However, if a patient has terminal cancer and a life expectancy of less than five years, the A1C goal should be between 8 and 9 percent.

The VA/DoD guideline “is the first guideline that gives more specific guidance other than just saying, ‘Individualize therapy,’” said Vigersky. “There is actually guidance about what goals there should be in terms of numbers. This is a very different approach to management that has been evolving over the last few years compared to the ’90s and early 2000s.”

Once an appropriate A1C target is set for a patient, using insulin can be a means to obtain glycemic control quickly, said Niswender. However, insulin therapy may not be warranted in some patients, added Reaven. Like the A1C target ranges, the use of insulin should be individualized—balancing potential benefits and risks for each patient—and using the process of shared decision-making between the patient and clinical care team, according to the VA/DoD guideline.

The risks vs. benefits of adding insulin “is often a very difficult calculus,” said Vigersky. “On one hand, insulin has been around a long time, and we know its benefits and risks. But the alternatives have to be considered.”

Some of the potential risks with insulin are weight gain and hypoglycemic events. So, for example, a clinician who is thinking about starting a patient on insulin needs to assess whether that patient has hypoglycemia awareness, suggested Reaven. “Are they capable of handling intellectually the simple calculations that you tend to like to have them do with insulin?”

Another barrier with insulin is that “patients offer a lot of pushback,” said Vigersky. Psychological and subtextual issues can result in physicians and other prescribers shying away from insulin therapy. In addition to the need for injections, the use of insulin has some negative connotations because, in the past, it was often introduced late as opposed to early. For example, patients might have memories of a relative dying or undergoing an amputation soon after being started on insulin, he noted.

“So we have to overcome the barriers of that misconception. We have to overcome the barriers of the injection that people have to take,” explained Vigersky. “And often, the initiation of insulin is thought of as a punishment in a sense.” Patients feel they are being punished for noncompliance (e.g., not sticking to their diet, not exercising, not taking pills as directed), and they become resentful. “The doctor, in turn, doesn’t like being put in the position of being the disciplinarian,” he noted.

The veteran population has additional issues, such as homelessness and mental health disorders, that could affect patient compliance with insulin therapy, said Niswender. “When you are homeless or have mental health disorders, how do you keep your insulin cool? How do you keep your insulin syringes in a safe place? How do you do chronic disease management of any sort?”

Patients with profound depression or schizophrenia, for example, need to be plugged into significantly more counseling and support than other types of patients to be compliant with insulin therapy, said Niswender.

“The flip side is that the standard of care for full-blown, severe diabetes is physiological insulin replacement or basal-bolus insulin, which involves multiple injections and blood sugar checks per day and is a very intensive regimen,” said Niswender. By introducing insulin earlier in the disease process and potentially making the disease less severe over the long run, “it is conceivable that you can use simpler regimens, single daily injection types of regimens,” he suggested. An easier regimen could, in turn, reduce compliance issues for a relatively disadvantaged population.

The takeaway message is that physicians need to customize plans for individual patients, said Niswender. “All of our patients are different, and especially when you get into the veteran population, the diversity of different social, medical and psychological factors really requires that you begin to individualize treatment plans and support plans for patients.”

Diabetes mellitus is a significant medical issue, affecting 8.3 percent of the U.S. population or 25.8 million people (18.8 million diagnosed and 7 million undiagnosed) in 2010, according to the 2011 National Diabetes Fact Sheet from the Centers for Disease Control and Prevention (CDC). The numbers are even higher for the elderly: More than one-quarter (10.9 million) of U.S. residents age 65 and older had diabetes last year.

The numbers play out quite similarly for the TRICARE and VHA patient populations. The Military Health System (MHS) diagnosed about 737,000 individuals with diabetes in fiscal year (FY) 2009 out of a total of 10.18 million eligible beneficiaries, demonstrating a prevalence rate of 7.24 percent, according to TRICARE. FY 2010 estimates from the VHA put the number of veteran users of VHA clinical care with diabetes at 1.45 million – or 23 percent of the patient population.

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