Conference Pearls

The American Association of Clinical Endocrinologists (AACE) 16th Annual Meeting & Clinical Congress

The AACE (American Association of Clinical Endocrinologists) took place in early April in Seattle. The main themes, we found, were the lowering of glycemic targets (like A1c) and the growing recognition of the harmful effects of glycemic variability (when blood glucose fluctuates).

Better, tighter glycemic control is always a theme at this meeting. This year, the focus was on postprandial glucose management and the greater use of combination therapy to push A1c values below 6.5 percent. The American College of Endocrinology (ACE) and AACE will soon publish a joint “roadmap” for the prevention and care of diabetes. We were able to get a preview: Compared to the ADA’s guidelines, it will emphasize a lower A1c target as well as the need for patients to receive different treatments depending on their A1c level.

Fasting and postprandial glucose make different contributions to overall hyperglycemia. We note that this is based on the work of Dr. Louis Monnier, who published an important paper in 2003 that showed that post-meal glucose spikes are a bigger contributor to overall hyperglycemia for patients at lower A1c, while high fasting glucose is a bigger contributor for patients at higher A1c. For example, for patients with A1c <7.3 percent, postprandial glucose accounts for 70 percent of overall hyperglycemia while fasting glucose accounts for only 30 percent . The contributions are reversed for patients with A1c >10.3 percent. For patients with A1c between 7.4 percent and 10.3 percent, postprandial and fasting glucose make equal contributions to overall hyperglycemia.

Combination therapy is needed to treat both fasting and postprandial glucose. The logic, then, is that in order for patients to achieve lower A1c targets, they need a combination of treatments that target both fasting and postprandial plasma glucose levels. Examples of drugs that focus on fasting plasma glucose are: basal insulin (Lantus and Levemir), metformin (generic), and sulfonylureas (generic). Examples of drugs that focus on postprandial plasma glucose are: rapid-acting insulin analogs (Novalog, Humalog, and Apidra), pramlintide (Symlin), exenatide (Byetta), DPP-4 inhibitors (Januvia), and thiazolidinediones (Actos and Avandia). ACE/AACE recommends that diabetic patients achieve fasting plasma glucose <110 mg/dL (pre-meal) and postprandial plasma glucose <140 mg/dL (post-meal).

The ACE/AACE roadmap will include newer drugs. The ADA currently recommends metformin and lifestyle intervention (diet and exercise) as first-line therapy for patients diagnosed with type 2 diabetes, in order to achieve a target A1c <7 percent. For patients who still remain uncontrolled on metformin alone, it recommends adding a sulfonylurea, thiazolidinedione (TZD), or basal insulin. The ADA’s algorithm does not endorse newer drugs like Januvia or Byetta. However, in sessions at AACE this year we learned that the ACE/AACE roadmap will likely include more options for first-line therapy, including Januvia, and that it will also include other postprandial-specific drugs like Byetta and Symlin as additional therapeutic options for patients who are not at A1c goal on one drug alone.

There was a lot of focus on earlier insulin use as well as moving toward more use of meal-time insulin. Some research suggests that early use of insulin – at diagnosis of type 2 diabetes, even – can have long-term effects on reducing complications. Sanofi-Aventis is currently conducting a 12,500-patient 5-year trial called ORIGIN to determine whether early use of its basal insulin, Lantus, can delay the development of type 2 diabetes in people with prediabetes, or whether basal insulin can delay the development of complications in people with early type 2 diabetes. The trial results will likely be unveiled in 2010. Speakers at AACE also advocated earlier use of meal-time as well as basal insulin – this hearkens again to Dr. Monnier’s work, which showed that controlling mealtime glucose excursions is crucial for people at lower A1c’s.

Lots of focus on driving down A1c targets – some well-known endocrinologists recommended A1c <6 percent. This underscores the importance of achieving near-normal glucose targets – we thought it was great to hear a respected endocrinologist like Dr. William Cefalu actually say this. His whole point was that traditional drugs increase insulin action (metformin, TZDs, sulfonylureas, and insulin itself), but the new ones reduce glucose production (Byetta, Symlin, and Januvia), which should really help people achieve near-normal blood sugars. He gave a dramatic talk about how incretins are exciting because they may alter the natural history of diabetes by improving beta cell function and perhaps slowing what we used to think was the “inevitable” progression of disease in type 2 diabetes. Only time (and longer clinical trials) will tell whether these drugs can actually do this.

The 2nd International Congress on Prediabetes and the Metabolic Syndrome

This meeting took place in late April in Barcelona, with one of the strongest faculties we’ve ever seen for a diabetes meeting. Each room was filled with 600 people – to the limit! More than 3,000 doctors, researchers, and scientists attended this meeting in all. Here are some important takeaways, both for those with diabetes as well as any friends or family members you may have who are at risk for diabetes.

First, a few definitions: What’s the difference between prediabetes and the metabolic syndrome anyway? Prediabetes is a state of higher-than-normal blood glucose, but not high enough to count as diabetes. Prediabetes is often (though not always) a precursor to diabetes, so people with prediabetes are at high risk of developing diabetes. There are two tests for diagnosing prediabetes: first, a fasting plasma glucose test is used to diagnose impaired fasting glucose (IFG—when your blood sugar is always a little too high). Second, an oral glucose tolerance test is used to diagnose impaired glucose tolerance (IGT—when your blood sugar is too high after you eat). While IFG and IGT often come together, many people have only one or the other. In any case, either condition counts as prediabetes. At this conference, we heard the phrase ‘double prediabetes’ used to describe someone with both. Metabolic syndrome describes several risk factors (like high triglycerides, low HDL-cholesterol, high blood pressure, and high fasting plasma glucose) that often occur together and together signal a high risk for cardiovascular disease. According to the International Diabetes Federation, 20-25% of adults worldwide have the metabolic syndrome. People with metabolic syndrome can have diabetes, and vice versa – both are risk factors for cardiovascular disease. There are several different definitions of metabolic syndrome. Something called the NCEP-ATP III definition is used most often in the U.S., while the IDF definition is used more widely abroad.

Obesity is the 'root of all evils' - it is driving the prediabetes and metabolic syndrome epidemic (not to mention diabetes!). Visceral obesity was widely discussed as a major concern. Visceral fat is fat that’s inside the body – next to the liver, intestines, stomach, and other internal organs – where it can do harm. In contrast, subcutaneous fat is fat that’s under the skin and is a healthy way of storing extra energy. We heard doctors emphasize again and again the importance of measuring waist circumference, which they all agreed was the best way to measure visceral fat and to identify people at high risk of diabetes and cardiovascular disease. The IDF criteria for diagnosing metabolic syndrome use high waist circumference as a primary risk factor. The cut-offs for waist circumference vary by ethnicity:

• ≥94 cm (37 inches) for men and ≥80 cm (~32 inches) for women of ‘Europid’, Sub-Saharan African, and Eastern Mediterranean and Middle Eastern (Arab) ethnicity
• ≥90 cm (~35 inches) for men and ≥80 cm (~32 inches) for women of South Asian, Chinese, Japanese, and South and Central American ethnicity
• In the U.S., the NCEP-ATP III cut-offs are more commonly used: ≥102 cm (~40 inches) for men and ≥88 cm (~34 inches) for women. However, these are likely too high, particularly for individuals of Asian descent. Sir George Alberti, the president of the IDF< noted dryly that even though the U.S. is so heterogeneous, we only use one definition of the metabolic syndrome for everyone.

If your waist circumference is over the cutoff for your ethnicity, you may have metabolic syndrome, which can increase your chances of cardiovascular disease two-fold even if you already have diabetes! Ethnicity is a big deal. As the IDF criteria acknowledge, Asians and South Asians are prone to develop diabetes and cardiovascular disease at much lower body mass indices (BMI – see http://www.nhlbisupport.com/bmi/) and waist circumferences than Caucasians and Africans, respectively. Dr. Jean-Claude Mbanya, president-elect of the IDF, also pointed out that Africans are at highest risk for high blood pressure, followed by Asians and then Caucasians.

Prediabetes is multi-faceted: impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) represent different disease entities. The proportion of people who have IFG and IGT differ in different ethnic populations and the overlap between the two conditions is only partial. People with IFG tend to have liver insulin resistance, which means their livers continue to produce glucose even when there is enough glucose in their blood. People with IGT tend to have muscle insulin resistance, or an inability for their muscle cells to take up glucose, often made worse by sedentary living. This is why people with IGT probably benefit more from exercise while people with IFG would benefit from treatments that reduce liver glucose production, such as metformin or incretins (Januvia or Byetta).

Obesity is a growing problem in children and adolescents. We learned that your body mass index (BMI) when you are 17 years old can predict the onset of diabetes and cardiovascular disease when you are in your mid-30s. Adolescents with BMI over 21.5 or BMI over 23.2 had 3- and 4-fold increases in risk (and only BMI over 25 count as overweight). Broadly speaking, there has been a huge rise in metabolic syndrome in the young over the last few decades, caused by abdominal obesity. For example, in the last 10 years in the U.K., the fattest echelon of boys (the 90th percentile of waist circumference) has become three times as fat and of girls, four times. This is an unbelievable rate of change and, for us, the most disturbing set of statistics at the whole conference.

So what can we do to prevent prediabetes from becoming diabetes? Lifestyle interventions are the best way to prevent diabetes, and while they should be first-line therapy for diabetes prevention, drugs like metformin and acarbose also have a role for people who can’t or won’t make lifestyle changes, or for those at especially high risk. For people with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)…

• Lifestyle interventions include improving one’s diet and increasing physical activity. Several major diabetes prevention trials have shown that these changes reduce the risk of diabetes by almost 60 percent. We heard many speakers call out for doctors and governments to take lifestyle interventions more seriously. The optimism about this approach was completely different from what we hear at US meetings on diabetes, where diet and exercise are usually dismissed out of hand as too difficult to implement. Certainly, it can be hard for people to make major changes in their lives, but even minor changes help.
• Metformin (generic), which the American Diabetes Association currently recommends for people with ‘double prediabetes’ (both IFG and IGT), has been shown to reduce the risk of diabetes by about 30 percent, and is an extremely safe drug to take – it has been used to treat diabetes for decades. However, it causes gastrointestinal side effects in many patients. It may be possible to avoid some of these by changing dosing or the generic “brand” of metformin taken.
• Acarbose (Bayer’s Glucophage) reduces diabetes by about 25 percent, but it also causes gastrointestinal side effects – bloating, diarrhea, etc. – and is not very popular in the U.S. However, it is very safe, and there is now a large 7,000-patient diabetes prevention trial called ACE going on in China to look more closely at the ability of acarbose to prevent diabetes. We will be very interested to read the results.
• Thiazolidinediones (commonly known as TZDs or glitazones, Actos and Avandia) do a very good job of preventing diabetes – at 60 percent risk reduction, they are on par with lifestyle intervention – but no one recommended them for diabetes prevention because of their side effects: weight gain, fluid retention, and a higher risk of heart failure. They have been widely prescribed as diabetes drugs, however.
• Orlistat (Xenical, now available in a lower dose without a prescription as Alli) also reduces diabetes – by 37 percent in one major trial – but it can cause very unpleasant gastrointestinal side effects such as diarrhea, flatulence, and oily stools. Orlistat was not particularly recommended for diabetes prevention.

Societal solutions are needed: “As a society we’re faced with the choice of activity or inactivity – i.e. health or healthcare. The city and the home should be our exercise machine.” These words, from Professor of Architecture Avi Friedman, emphasized the need for large-scale change. We very much agree that we should encourage urban living, which forces people to walk and be more active. Suburban neighborhoods right now are designed for driving. To change that, we need stores within communities, small play areas close together, sidewalks, and bicycle lanes (Belgium has easily accessible bikes for rent throughout the communities and Denmark has free bikes for use throughout). We should introduce organized neighborhood physical activities, communal urban planting gardens instead of decorative gardens, and think about communities where people walk around and meet each other. Public transit should be easier to use and more engaging. We must admit we liked these solutions a lot but see them as extremely difficult to encourage and implement, but isn’t it worth it, with $92 billion a year spent on diabetes?

¹ According to these criteria, a person has the metabolic syndrome if he has three of the following: Abdominal obesity (waist circumference >40 inches in men or >34 inches in women); High triglycerides (triglyceride levels >150 mg/dL); Low HDL (“good”) cholesterol (<40 mg/dL in men or <50 mg/dL in women); High blood pressure (>130/85 mm or documented use of antihypertensive therapy); and High fasting glucose (>110 mg/dL).