Decoding The ADA Scientific Sessions

by joseph shivers, jessica swienckowski, and adam brown

This Learning Curve will guide you through exciting findings from the largest diabetes meeting of the year, the American Diabetes Association’s annual Scientific Sessions.

The annual meeting of the American Diabetes Association is without question our most important conference of the year. Not only are the most critical new products and research presented at the meeting, but it also serves as a strong review of the important research from the past year and what we can look forward to on the road ahead. This Learning Curve is dedicated to what we found most exciting for patients at this year's meeting, including emerging information about potentially “the most powerful treatment for type 2 diabetes,” a trial demonstrating one of the strongest A1c declines ever with diabetes technology, and a review of a highly anticipated new class of type 2 diabetes drugs.

an intriguing combination: glp-1 and basal insulin therapy

In the world of diabetes care, the wide variety of treatments targeting different aspects of glucose regulation makes combination therapies quite attractive. Insulin and GLP-1s (Byetta and Victoza) have been around for a while, but only recently have the two therapies been examined in combination – drawing strong interest from the physicians in attendance at ADA.

As leading researcher Dr. John Buse noted (see our diaTribe Dialogue in this issue), the combination of a long-acting insulin (such as Lantus or Levemir) and GLP-1 along with metformin could be “the most powerful treatment for type 2 diabetes” we have. Why? To start, GLP-1s reduce appetite – most people taking Byetta or Victoza experience several pounds of weight loss in the first year. This is hugely important considering insulin is associated with weight gain, and it doesn’t take much weight loss (or gain) to have a substantial effect on glycemic control. It can also be more motivating to stick with a treatment if it produces positive effects on body weight.

Second, long-acting insulin and a GLP-1 address different facets of hyperglycemia, thus providing more comprehensive treatment when used in combination. Insulins like Lantus or Levemir target background, basal insulin levels needed by the body. However, when a quick rise in blood sugar occurs (such as after a meal), long-acting insulins are not optimal because they work at a constant rate. Fortunately, Byetta and Victoza stimulate the secretion of insulin only at times when glucose levels are high and thus are very effective at reducing the spike in blood sugar that occurs after meals. This is the same principle underlying multiple daily injection therapy (using both a long-acting and a rapid-acting insulin) – though as the GLP-1s are dependent on glucose levels, they are not associated with the frequent hypoglycemia that accompanies use of fast-acting insulins.

Data presented at the ADA meeting confirmed much of this thinking. In a study that examined the addition of Byetta to Lantus. patients treated with both therapies exhibited a strong A1c decline of 1.7% (from 8.4%), while those on basal insulin alone saw a smaller decrease of 1.0%.  Notably, those who received Byetta lost almost four pounds over 30 weeks of treatment, compared to a two pound increase in weight in the group treated with insulin only. We look forward to seeing more emphasis on this combination therapy in the coming years – Amylin plans to file an application with FDA for this indication by the end of 2010, and both Novo Nordisk and sanofi-aventis are investigating the combination with their respective therapies in clinical trials.

big benefits with integrated diabetes technology: the star-3 trial

Over the past few years we have seen an incredible amount of innovation in diabetes devices. Not only have there been solid improvements in insulin pumps, but we’ve also seen novel developments with the advent of continuous glucose monitoring (CGM). Both technologies are still evolving, but research has suggested that insulin pumps and CGM can both help improve glucose control and make management easier. While it seems natural to combine the two technologies, there hasn’t been any “gold standard” research to confirm doing so could actually make a meaningful impact on diabetes management. The STAR-3 trial, presented at ADA this year, addresses this very question.

The STAR-3 trial was designed to help us understand if a sensor-integrated pump (SAP; simply put, an insulin pump combined with a CGM sensor) could improve diabetes management compared to multiple daily injection (MDI) therapy with enhanced support (e.g., software to help people track self-monitoring blood glucose values). As a reminder, the only SAP available in the US right now is Medtronic’s Paradigm Revel system, but there are more on the way (see New Now Next from this issue), pending regulatory approval. In the study, people with type 1 diabetes were randomly selected to be in either the SAP group or MDI group for one year. Patients were trained how to use their type of therapy over the first five weeks of the study and then for the remaining year would only visit the clinic once every three months. 

The exciting news is that people (especially adults) in the SAP therapy group were able to reduce their A1c levels significantly more than the people on MDI. For people age 18 and older, those in the SAP group were able to reduce their A1c by 1.0% on average (from a baseline of about 8.3% to approximately 7.3%), compared to patients on MDI, who were able to reduce A1c by only about 0.4% (from 8.3% to 7.9%). Younger patients on SAP also significantly reduced their A1c levels, but less robustly (children age 7-18 were able to reduce A1c by 0.4%, compared to a 0.2% increase seen in children on MDI). Importantly, these achievements were accomplished without increasing hypoglycemia, diabetic ketoacidosis, or weight gain. We see this as very good news – the tools out there are getting significantly better, and we hope studies like this will help convince insurance companies that they should make them more readily available.

what factors influence accuracy?

A wealth of new data was presented at ADA on the SGLT-2 inhibitors, a new class of oral drugs in development that lowers blood sugar by causing users to urinate out excess glucose. We have previously reviewed the drugs’ mechanism (see Learning Curve from diaTribe #8), but the basic idea is this: SGLT-2 is the protein mainly responsible for ensuring that glucose returns to the bloodstream after being filtered out in the kidneys. Thus, blocking SGLT-2’s ability to return glucose to the blood causes 100 to 300 calories worth of sugar per day to be eliminated in the urine – a mechanism that sounds promising for both hyperglycemia and weight loss.

So far, late-stage results have been released for only one SGLT-2 inhibitor: dapagliflozin (this is the scientific name as the drug does not have a trade name yet), made by Bristol Myers Squibb and AstraZeneca. In an earlier presented 24-week trial of people with recently diagnosed type 2 diabetes, dapagliflozin produced drops in A1c of up to -0.89%. Excitingly, people also lost over four pounds when on the drug – though other trials have recorded weight loss of more than 6.5 pounds. These results were confirmed in the most recent trial presented at ADA – in the trial, 807 people with type 2 diabetes taking insulin demonstrated A1c declines of over 0.9% while taking dapagliflozin, evident at 24 weeks but sustained through 48 weeks of treatment.

Paralleling the growing excitement we heard from leading physicians at ADA, numerous other companies are pursuing SGLT-2 inhibitor candidates as well. Johnson & Johnson presented new data on its candidate, canagliflozin, at the meeting. In a 12-week trial, canagliflozin was added to metformin treatment and produced a 0.7% drop in A1c along with over 4.4 lbs of weight loss compared to metformin alone. Astellas’s candidate (which still sports the developmental name ASP1941) is also looking strong – over 12 weeks of treatment, ASP1941 was associated with -0.81% declines in A1c and weight loss as much as 4.4 pounds of weight loss.

How about side effects? The good news is that given only excess glucose is secreted, SGLT-2 inhibitors present with very low risk of hypoglycemia. The less good news is that they do seem to be associated with small increases in mild-to-moderate urinary tract and genital infections, liekly because indigenous bacteria grow more rapidly in the newly sweetened urine. These effects certainly warrant watching, especially for when data is released breaking down the incidence of infections by demographics (in general, women present with a higher risk of such infections). Until then, we hope that these seemingly controllable risks are outweighed by the SGLT-2’s versatile array of benefits. As these improvements are achieved regardless of how much beta cell function remains, these drugs will possibly be effective regardless of how long the user has had type 2 diabetes. Notably, this also means that the SGLT-2 inhibitors could potentially benefit people with type 1 diabetes as well – this of course is theoretical until it has been proven, but we have heard many doctors voicing strong interest in testing this.