Framing the Issue

  • Nearly 11 percent of respondents to a 2005–2006 survey of type 2 diabetics reported experiencing severe hypoglycemia — low blood sugar. Severe hypoglycemia was common across all levels of glycemic control.
  • Older adults with type 2 diabetes who experienced a hypoglycemic event were twice as likely to develop dementia than those who didn't have a hypoglycemic event, found a study in the July 2013 JAMA Internal Medicine.
  • Severe hypoglycemia is associated with twice the risk of cardiovascular disease, according to a meta-analysis published by The BMJ in July 2013.
  • Growing awareness of hypoglycemia and its risk is shifting treatment and research toward drugs that lower diabetic patients' blood sugar without causing low blood sugar.

For many years, much of the research and many advances in type 2 diabetes treatment focused on ways to keep patients' blood sugar levels from going too high to protect them from a host of serious complications. However, a growing understanding of the risks associated with low blood sugar has sparked the development of medications and technology to keep blood sugar levels in check without driving them too far down.

It's also prompting calls for a more individualized approach to diabetes care — a shift that could make quality measurement and pay-for-performance more complicated.

"The thought had been that hypoglycemia is probably inevitable in some patients," says Kasia Lipska, M.D., instructor in medicine, endocrinology, in the Yale University Department of Internal Medicine. "Now, we understand better that it's not simply this inconvenient side effect that we can deal with, but this is something that can be very serious and that we should pay more attention to it than we have previously."

Even mild or moderate hypoglycemia — low blood sugar — may significantly impact quality of life and ability to function, says Robert Ratner, M.D., American Diabetes Association chief scientific and medical officer. It can cause absenteeism from school or work and difficulty with fine motor coordination. Severe hypoglycemia can cause loss of consciousness, stroke or heart attack and, at its worst, coma and death. It also is associated with elevated risk of cardiovascular disease.

In some patients, diabetes damages the nerve cells that would make them aware of hypoglycemia and chest pain, making them at even higher risk for silent heart attacks, says Robert Vigersky, M.D., a past president of the Endocrine Society. "Hypoglycemia in and of itself puts you at risk for cardiovascular episodes in the long run, even if you are aware of it," he adds. "There are a lot of theories about this, but nobody really understands how that happens."

Hyper vs. hypo

Doctors have gotten better at controlling hyperglycemia — high blood sugar — in an effort to prevent its long-term complications, including heart disease, stroke, and eye, kidney and nerve disease.

The recommended target for most patients is an A1C of less than 6.5 or 7 percent, depending on which guidelines are used. But progress in preventing hyperglycemia seems to have come at the cost of boosting hypoglycemia.

"In the end, hypoglycemia is probably the most significant risk factor for any patient on a short-term basis," Vigersky says. "In our effort to improve glycemic control to prevent complications, we have a trade-off in that as we add medications and drive the A1C down, we increase the number of hypoglycemic events."

A study of Medicare beneficiaries showed that hyperglycemia-related hospitalizations fell 39.5 percent from 1999 to 2010. But hypoglycemia-related hospitalizations rose 38 percent — from 94 per 100,000 patient-years to 130 — from 1999 to 2007. By 2010, it had declined 11.5 percent, to 115 per 100,000 patient-years.

"It's possible that the greater use of medications that do not cause hypoglycemia might have contributed to that decrease over the last five years or so," says Lipska, who was lead author of the study.

The rise in hypoglycemic events has led to growing awareness that the recommended A1C targets are too low for some people, including the frail elderly, people with comorbid conditions and those with known cardiovascular risks. That understanding, in turn, has sparked a push to individualize A1C targets, Lipska says. The most recent guidelines on A1C targets reflect that goal.

But the change poses a complication for quality measurement and pay-for-performance programs that rely on outcomes measures. Typically, these programs take into account whether the patient's A1C, blood pressure and cholesterol levels are in the recommended range. Any program that strictly adheres to the general A1C guidelines could penalize physicians for adjusting the A1C goal upward for patients who have risks that predispose them to hypoglycemia.

This raises the question of how well quality measurement and pay-for-performance programs assess patient case mix, Vigersky says. "If you have an elderly geriatric population or have a lot of patients with type 1 diabetes who have hypoglycemic unawareness, you don't want those patients to have an A1C of less than 6.5 or 7 percent. It's more complex than the people who are writing the checks appreciate."

New drugs: Promise and perils

The increased focus on preventing hypoglycemia has impacted drug development and prescribing. "We're getting away from the older classes of agents, like the sulfonylureas, which cause hypoglycemia and weight gain, and we're moving preferentially toward those drugs that don't cause hypoglycemia and may be weight-neutral or achieve weight loss," Ratner says.

Medication options increased in 2005 and 2006 with Food and Drug Administration approval of the first GLP-1R agonists and DPP-4 inhibitors for type 2 diabetes. These two classes of drugs are known as incretin-based therapy because they help to lower blood sugar by affecting gut-derived hormones called incretins. Neither class of incretin drugs is associated with hypoglycemia or weight gain.

Incretin-based therapies were the center of controversy earlier this year because of concern in some corners that they might increase the risk of pancreatitis and perhaps pancreatic cancer. However, the FDA and the European Medicines Agency have studied existing data and recommended no changes to the medications' labels, which already include a warning.

The FDA requires post-market studies of new glucose-lowering drugs to check their cardiovascular safety. As a result, eight incretin-based therapies are subject to post-market trials, a byproduct of which will be a settling of the question of their effect on the pancreas. The first trial, of saxagliptin (Onglyza), showed no increased risk of pancreatitis. The results of the remaining trials will filter out through 2019.

In the meantime, U.S. and European diabetes organizations are following the FDA's and EMA's lead and are not recommending any change in incretin-based therapy.

"Providers should make patients aware of the potential side effects and tell them about the symptoms of pancreatitis," Vigersky says. "We don't want patients, if they're already on it, to stop it without having a discussion about relative risks and benefits of the various drugs."

This spring the FDA approved the first in a new class of type 2 diabetes medications that fits the bill of lowering blood sugar levels without increasing hypoglycemia risks or causing weight gain. Canagliflozin (Invokana) is an SGLT2 inhibitor that doesn't affect insulin. Instead, it works by blocking reabsorption of glucose by the kidneys, which increases glucose excretion into the urine.

Although trials showed the drug has the upsides of promoting weight loss and lowering blood pressure, it has the downside of increasing the risk of yeast and urinary tract infections because of the increase in sugar in the urine. "Whether or not [the infection risk] is going to be something to prevent significant numbers of people from using it, or there are other problems, remains to be seen," Vigersky says.

Invokana's maker, Janssen Pharmaceuticals Inc., must conduct FDA-required post-marketing studies that include testing the drug's cardiovascular and pancreatic safety.

The recent history of new diabetes drugs is littered with medications that were approved and afterward, major side effects emerged, notes David Nathan, M.D., director of Massachusetts General Hospital's Diabetes Center. "The issue with diabetes drugs is that they may be tested in thousands of people but as soon as they're introduced, they're being used by millions of people," he says. "Side effects surface that had not been seen previously because the drugs weren't tested in combination with X drug or Y drug or because it's relatively rare."

Nathan points to the thiazolidinedione class of type 2 diabetes medicines. These drugs reduce A1C levels by helping insulin to work better in the muscles and fat, as well as by reducing glucose production in the liver. The first drug in the class, troglitazone, was removed from the market because it caused serious liver problems in a small number of people.

Two other thiazolidinediones — rosiglitazone (Avandia) and pioglitazone (Actos) — are on the market, but their labels include warnings about heart failure risk. Avandia's label also cautions that the drug may be associated with angina or heart attacks. Concerns about rosiglitazone largely prompted the FDA's 2008 requirement for cardiovascular safety studies in new diabetes drugs.

Mix-and-match meds

To discover which diabetes medications work best and to better understand their side effects, the National Institutes of Health are funding the Glycemia Reduction Approaches in Diabetes study, of which Nathan is study chair. The project compares the effectiveness of drugs from four classes of diabetes medications used in combination with metformin. The classes are sulfonylureas, long-acting insulin, and the two types of incretin-based therapies.

"We have one of the most expensive, most common, long-lasting diseases there is and yet, we don't know what are the best combinations of drugs to use, and we don't know which groups of patients might respond," Nathan says. "We know people have different flavors of type 2 diabetes. The problem is that we treat them as if they're all vanilla or chocolate."

The study, which is in the recruitment phase, will assess the drug combinations' impact on blood sugar control, their side effects, their acceptability by patients, and differences in performance by gender, age and race, Nathan says.

Investigators selected the four classes because they have a track record and are considered safe. The SGLT2 class wasn't selected because it is too new. Only one drug per class was chosen to keep the study affordable and because the medications within each class have similar profiles, Nathan says.

Because new diabetes drugs and even drug classes emerge rapidly, some researchers worry the study will be obsolete before it's completed. Already, sulfonylureas are declining in favor because of their hypoglycemia risk.

Investigators took those concerns into account and picked the four classes they think are most likely to survive, Nathan says. "One of the reasons I'm confident that the study will be relevant is because I don't see anything on the horizon that's clearly spectacular."

The future of insulin

Advancements in diabetes treatment aren't limited to newer drugs. Progress is expected soon for the oldest diabetes medication — insulin, the drug that poses the greatest hypoglycemia risk.

In October 2013, MannKind Corp. resubmitted its application for FDA approval of Afrezza, its rapid-acting, inhaled mealtime insulin. The initial application was rejected because MannKind had revised its inhaler and the FDA wanted retesting with the new inhaler. The new application comes after two positive Phase III trials, one with type 1 diabetics and the other with type 2 diabetics.

The insulin inhaler is about the size of an asthma inhaler. The product could be attractive to patients because it does away with injections. Another advantage is its quick action.

"The big challenge in insulin therapy, even with newer analog insulins, is they don't have a peak effect for one or two hours," Vigersky says. "Most patients take their insulin right before they eat, but the food is being absorbed in 15 to 30 minutes, so the peak of the insulin is arriving late."

By comparison, Afrezza dissolves upon inhalation and peak insulin levels are reached within 12 to 15 minutes, according to MannKind. "Any insulin that has a faster onset of action and also a faster disappearance rate is going to be a major advance," Vigersky says.

If the FDA approves Afrezza, the agency might require post-market studies to test whether it has any long-term effects on the lungs, Ratner notes.

An advance in injected insulin also could be on the horizon. In October 2012, the European Medicines Agency approved Novo Nordisk's Tresiba. Its active ingredient is insulin degludec, an ultralong-acting basal insulin. Basal insulin is the background insulin that the pancreas normally supplies throughout the day.

Insulin degludec shows promise, says Ratner, who was involved in some of its clinical trials. "It gives you equivalent glucose control to other basal insulins, but with less hypoglycemia," he says. "It goes beyond 24 hours. The way it's formulated, you are better able to predict what the biologic response will be, so there is less variability in your blood sugars."

The FDA, however, declined to approve insulin degludec in February 2013 and, instead, asked for more data on its cardiovascular outcomes. Those studies will take several years, Ratner says.

Device developments

In the technology realm, the latest development is FDA approval in September 2013 of a first-generation continuous glucose monitoring insulin pump that automatically shuts off basal insulin delivery if the wearer's blood sugar level drops too low. Medtronic's Enlite sensor, which works with the company's MiniMed 530G pump, detects up to 93 percent of hypoglycemic episodes.

"Since hypoglycemia is such a big problem, the low-glucose, insulin-suspend feature is a major step ahead," Vigersky says. It will be particularly helpful at preventing hypoglycemia among insulin-dependent diabetics while they're sleeping.

The insulin-suspend function brings development of an artificial pancreas, also known as a closed-loop system, closer to reality. The remaining hurdle is software that automatically would deliver not just basal insulin, but insulin anytime it's needed. Currently, pump wearers, most often type 1 diabetics, must program mealtime insulin delivery. Medtronic and others are working on fully closed-loop systems.

"There has been tremendous progress," Vigersky says. "There are a lot of technical issues that the FDA investigators and the companies will have to work out, but there is a real impetus to get this right and get it to market."

— Geri Aston is a contributing writer for H&HN.

Executive Corner

New findings on diabetes come out almost daily, which makes keeping up with changes
a challenge. Here are some of the latest major trends.

Diet

Anyone looking for an ideal diet for all type 2 diabetics would come up empty-handed. Because no standard meal plan or eating pattern universally works for diabetics, nutrition therapy should be individualized based on such factors as the patient's health goals, personal and cultural preferences, and willingness to change, note American Diabetes Association guidelines, updated in October 2013.

Medications

No new game-changing type 2 diabetes drugs are on the horizon. However, new classes of medications that bring down high blood sugar levels without causing hypoglycemia have entered the market in recent years and others are in development. The first of a new class of type 2 diabetes medications — SGLT2 inhibitors — gained Food and Drug Administration approval in spring 2013 and others are in trial. However, because diabetes drugs are tested in thousands of patients but used by millions, side effects sometimes surface after approval. This has led to stiff FDA post-market testing requirements.

Health information technology

Electronic health records can help providers to better manage diabetes. That's the conclusion of two studies of nearly 170,000 Kaiser Permanente Northern California patients with diabetes. EHR use modestly reduced emergency department visits and hospitalizations among diabetics, although it didn't statistically reduce office visit rates, found one study, published by The Journal of the American Medical Association in September 2013. The EHR was associated with improved drug treatment intensification, monitoring, and A1C and cholesterol control among patients with diabetes, with greater improvements among patients with worse control, concluded an October 2012 study in the Annals of Internal Medicine.

Unraveling the mysteries of type 1 diabetes

As many as 3 million Americans have type 1 diabetes, an autoimmune disease that causes the pancreas to stop producing insulin. The condition strikes children and adults and has no cure. Many initiatives are under way to determine the causes of type 1 diabetes, identify people at risk, prevent the disease from manifesting itself, and develop a cure, says Richard Insel, M.D., Juvenile Diabetes Research Foundation chief scientific officer.

Causes

Finding out what triggers type 1 diabetes among children who have a genetic predisposition to it is the goal of six groups of researchers from the United States and Europe. The Environmental Determinants of Diabetes in the Young study is following more than 8,000 children, recruited as newborns, to determine the genetic and genetic-environmental interactions that could play a role in the disease's development. The theory is that viruses, nutrition or toxic agents may contribute to type 1 diabetes alone or in combination.

Identification

People with a relative with type 1 diabetes are able to get screened for the disease through Pathway to Prevention, run by TrialNet, a National Institutes of Health-funded network of researchers studying type 1 diabetes. The blood test screens for the presence of diabetes-related autoantibodies. The greater the number of autoantibodies, the more likely the person will develop symptomatic disease, Insel explains. People who test positive are offered monitoring and participation in applicable studies aimed at arresting development of symptomatic disease.

Drug trials

TrialNet is recruiting subjects for three studies of people at risk for type 1 diabetes. These projects are testing whether daily oral insulin can prevent or delay the disease, whether the experimental drug teplizumab helps to stop or slow the autoimmune reaction that destroys insulin-producing pancreatic beta cells, and whether the anti-rheumatoid arthritis drug abatacept (Orencia) can to help delay or prevent type 1 diabetes onset.

Vaccine

JDRF is funding research on more than a dozen possible vaccines to retrain the immune system to prevent or stop its attack on pancreatic beta cells, Insel says. Unlike regular vaccines that help the immune system to fight off invading bacteria, a type 1 diabetes vaccine would decommission the immune cells attacking the pancreas. Tolerion Inc.'s TOL-3021 vaccine made a splash in June 2013 when results of a Phase II study found it improved levels of a biomarker for insulin production. More study is needed.

Embryonic pancreas cells

For years, JDRF has helped to fund efforts to convert human embryonic stem cells into pancreatic beta cells that could be transferred into type 1 diabetics and start producing insulin, essentially curing the disease. Already one company, ViaCyte Inc., has successfully tested in preclinical mice studies its pancreatic progenitor cells and an encapsulation device to protect them from immune system attack. The company, supported in part by JDRF, hopes to begin human trials in 2014. — Geri Aston