ADA Boston. 75th ADA Meeting. Looking back to Science in Diabetes last 20 years

The discovery of insulin in 1921 and the availability of home blood glucose monitoring in 1981 perhaps represent the greatest advances thus far in the world of diabetes. But in the past 20 years, numerous incremental developments have also remarkably improved the prognosis and quality of life for patients with both type 1 and type 2 diabetes.

"Twenty years ago, every minute of every day there were patients in my lobby with below-the-knee amputations, seeing-eye dogs, or white canes. Today this is so rare, I am convinced that we are only beginning to understand what the natural history of diabetes will be in the 21st century," says John Buse, MD, PhD, professor of medicine, dean for clinical research, and chief of the Division of Endocrinology at the University of North Carolina School of Medicine, Chapel Hill. In contrast, he says,

"The prognosis for a normal lifespan free of disabling complications, I think, is excellent for people living with diabetes today."

Of course, progress is often cumulative, and the advances over the past 20 years were built on earlier progress, such as the

1. 1993 landmark Diabetes Control and Complications Trial and the Lower Extremity Amputation Prevention (LEAP) program. The former study found that maintaining blood glucose levels as close to normal as possible slowed the organ damage that often occurs in diabetes. The latter study established the use of the monofilament as an easy, in-office test for foot sensation, notes Charles Clark, MD, professor emeritus of medicine and now associate dean for continuing medical education at the Indiana University School of Medicine.

Looking back over the past 20 years, five particular advances stand out for their role in improving the lives of people with diabetes.

2. Metformin: The Game Changer

In the United States, 2015 marks the 20-year anniversary of the arrival of the first oral medication for type 2 diabetes that does not cause hypoglycemia. Metformin had been available outside the United States for over a decade, but its approval here was delayed while the US Food and Drug Administration (FDA) focused on removing a related but more toxic compound, phenformin, from the market.

Today, metformin still is used as first-line therapy for type 2 diabetes, owing to its relative efficacy, safety, and low price as a generic.

Add-on glucose-lowering medications offer the advantages of weight loss and improved blood pressure levels. In 2005, the FDA approved the first glucagon-like peptide 1 receptor agonist (exenatide), followed in 2006 by the first dipeptidyl peptidase 4 inhibitor (sitagliptin); the first sodium/glucose cotransporter 2 inhibitor (canagliflozin) arrived in 2013.

For type 2 diabetes, the biggest advance is "the sheer number of effective drugs that have been developed within the past 15 years," says Cyrus Desouza, MBBS, professor and chief of the Division of Diabetes, Endocrinology and Metabolism at the University of Nebraska Medical Center. "Physicians treating type 2 diabetes have never had so many choices and combinations as now," he continues. "From a patient's perspective, this has led to better diabetes control and hence decreased microvascular complications."

Still, lingering long-term safety questions, the high cost, and the moderate (at best) ability of these agents to lower blood glucose mean that there is plenty of room for further innovation in the years to come.

As Dr Clark sees it, "Once you had metformin, everything else was incremental. Metformin was the game changer."

3. Glucose Monitoring and Insulin Pumps - a Real Paradigm Shift in Diabetes

Continuous glucose monitoring (CGM) has revolutionized the care of type 1 diabetes, and it has also allowed for better troubleshooting in some patients with type 2 diabetes.

CGM can provide information on daily glucose fluctuations and how those numbers are affected by everyday activities and stress levels.

It also plays an integral part in emerging technology billed as an "artificial pancreas," partnering with continuous sensing technology to form a closed-loop glycemic control system that includes an insulin pump and controlling algorithms.

The first home-use CGM system, for physician downloading only, was approved in 1999. It allowed clinicians to establish baseline glucose profiles for patients, and it helped inform the initiation and monitoring of treatment.

In 2004, the approval of the first patient-use CGM, Medtronic's Guardian, allowed patients themselves to see their own glucose trends in real time and alert them when glucose levels approach dangerous lows or highs.

"For physicians, the CGMs and insulin pumps are invaluable tools to help manage type 1 patients, although CGM is valuable in type 2, too," Dr Desouza says.

"From a patient's perspective, especially for younger patients, these two developments have made it much easier for them to control their diabetes with much greater flexibility." (The first commercial insulin pump was introduced over 30 years ago.)

Indeed, says Anne Peters, MD, director of the University of Southern California clinical diabetes program in Los Angeles.

"The real biggest advance in the past 20 years is CGM. It has really changed my practice of diabetes."

4. Anti-VEGF Intravitreal Injections in the Eye

In patients with diabetic macular edema, laser photocoagulation prevents further vision loss but can't recover lost vision. In the mid-1990s, research began focusing on the use of anti-vascular endothelial growth factor (VEGF) therapy as a sight-restoring alternative.

In 2015, the FDA approved ranibizumab (Lucentis®) and aflibercept (Eylea®) for the treatment of diabetic retinopathy in patients with diabetic macular edema. A third anti-VEGF agent, bevacizumab (Avastin®), is not FDA-approved for that indication, but is often used off-label.

"Laser still has a role in diabetic retinopathy, but it has diminished greatly in the era of anti-VEGF injections," says T. Mark Johnson, MD, attending vitreoretinal surgeon, Retina Group of Washington, Chevy Chase, Maryland. In fact, laser treatment is less effective in patients with diffuse edema than in those with focal edema.

"Anti-VEGF injections have addressed both these issues with all forms of edema, showing benefit of treatment and patients recovering vision with therapy," Dr Johnson says. "Injections have become first-line therapy at this point in time."

5. Diabetes as Part of the Cardiometabolic Syndrome

If there's one thing that has become abundantly clear about type 2 diabetes over the past 20 years, it's that it is not simply a disease of high blood sugar.

Indeed, study after study in the past two decades has attested to the increased cardiovascular risk among people with type 2 diabetes, the importance of blood pressure and lipid control, and the lack of macrovascular benefit—and in some cases, even harm—associated with strategies focused solely on intensive glycemic control, particularly in patients with disease of long duration.

Although the evidence pointing to diabetes as part of an adverse cardiometabolic profile had been accumulating for decades, it wasn't until 2002 that an expert panel declared that patients with type 2 diabetes should be managed as having equivalent cardiovascular risks as patients with coronary heart disease (CHD).

As the guideline authors noted, "It should be pointed out that hyperglycemia by itself does not raise risk to the level of a CHD risk equivalent. Instead, type 2 diabetes generally is accompanied by a constellation of metabolic risk factors that combine with hyperglycemia to impart a high risk."[1]

As a result, Dr Clark says, the current mantra in treating type 2 diabetes is, "First treat the blood pressure, then lipids, then blood sugar."

Today, the routine use of antihypertensives and statins along with glucose-lowering medications—still important for prevention of microvascular complications—among people with type 2 diabetes can be viewed as an "advance," although targets still often aren't reached.

6. Models of Patient-Oriented Care in Diabetes

The notion that the complexity of diabetes management is best addressed with multispecialist team care predates 1995, but implementation of the organizational concept known today as the "chronic care model" is still evolving.

The idea that the patient should be the central player on the "team" may be obvious to those who understand the condition, but only became the focus of management guidelines in 2012, in a joint position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes.[2]

In the ADA's January 2015 Standards of Care, the following are listed as recommended strategies[3]:

1. A patient-centered communication style that incorporates patient preferences, assesses literacy and numeracy, and addresses cultural barriers to care should be used;

2. Treatment decisions should be timely and founded on evidence-based guidelines that are tailored to individual patient preferences, prognoses, and comorbidities;

3. Care should be aligned with components of the Chronic Care Model to ensure productive interactions between a prepared, proactive practice team and an informed, activated patient; and

When feasible, care systems should support team-based care, community involvement, patient registries, and decision support tools to meet patient needs.

"The chronic care model has become widely adopted for all kinds of chronic diseases, but in diabetes it fits perfectly with the research," says Dr Clark. "In fact, if you look at the Affordable Care Act, they've basically taken the Chronic Care Model as the model for the accountable care organizations."

Dr Clark adds, "The biggest change in diabetes the past 20 years has been the final acceptance that diabetes is a collaborative disease rather than a disease where you just tell people what to do.

The big difference is the way we're going about taking care of people with diabetes."



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