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GLP-1 Agonists: From 2 Daily Injections to 1 Per Week and Beyond

By Abigail Dove and Payal Marathe

A review of how far GLP-1 agonists have come – drugs for type 2 diabetes that help with not only blood sugar management, but with weight loss and heart health too

GLP-1 agonists entered the type 2 diabetes drug landscape in 2005 with the launch of Byetta (exenatide), a twice-daily injection. Even though scientists and industry leaders have praised how valuable this class of drugs can be, GLP-1 agonists still make up only 7% of all diabetes drug prescriptions in the US, due to low awareness, preference for drugs that don’t require an injection, and access challenges like insurance coverage and cost. Read on for what GLP-1 agonists are, why many diabetes leaders advocate for more people with type 2 diabetes to use them, what to expect in the next few years, and how you can help teach your healthcare provider about them if they aren’t aware of all the new changes.

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What are GLP-1 agonists?

GLP-1 agonists are quickly becoming a mainstay of type 2 diabetes management.  Their substantial A1c-lowering ability – about 1% on average – with the additional benefits of weight loss and low risk of hypoglycemia (low blood sugar) is a game-changing combination, since the A1c-lowering effect of many traditional diabetes therapies like sulfonylureas (SUs) and insulin comes at the expense of weight gain and increased hypoglycemia. In fact, people with type 2 diabetes already taking insulin can add GLP-1 agonists, (or take combination drugs of GLP-1 agonists and insulin) in order to reduce their overall insulin dose.

In addition to helping with blood sugars and weight, GLP-1 agonists may also benefit heart health. Victoza is FDA-approved to reduce the risk of heart attack, stroke, and heart-related death – a big deal given the strong link between diabetes and heart disease.

The main downside of GLP-1 agonist treatment is that nausea is a common side effect, especially when people first begin taking them. Some people find the fact that these drugs are injected to be a downside as well: the most popular GLP-1, Victoza, is taken once-daily, while Trulicity,  Bydureon, and newly-approved Ozempic are taken once-weekly. Other GLP-1’s, Lyxumia and Byetta, are taken once daily and twice-daily, respectively.

Probably the biggest barrier to accessing GLP-1 agonists is cost; without insurance coverage, these drugs are often too expensive. Most GLP-1 agonists do have co-pay card savings programs, but there are eligibility requirements. Here are three options for popular GLP-1s:

Notably, GLP-1 agonists are only approved for people with type 2 diabetes. Research on the use of this drug in type 1 diabetes has been mixed. Novo Nordisk ended its type 1 diabetes program for Victoza in 2015 because the A1c lowering effects were too small (decrease of ~0.2%-0.3%); there were also high rates of hypoglycemia, hyperglycemia with DKA, and nausea. That said, even without major A1c-lowering, GLP-1s may help people with type 1 diabetes improve time-in-range. In a recent study, people with type 1 diabetes on Victoza spent an average of 14 hours in-range, versus 11 hours without. However, it’s unclear whether this will encourage diabetes companies to keep studying the potential benefits of GLP-1 agonists in type 1.

How do GLP-1 agonists work?

GLP-1 agonists mimic the effect of GLP-1, a naturally-occurring hormone in the body that is produced in the gut when eating.  GLP-1 has five key effects in the body to both lower blood sugar and reduce appetite:

Lower Blood Sugar

Reduce Appetite

  • Signals the pancreas to produce more insulin

  • Signals the pancreas to produce less glucagon

  • Decreases glucose production in the liver

  • Slows digestion in the stomach

  • Quiets the brain’s hunger centers

Who should consider GLP-1 agonists?

GLP-1 agonists are an ideal diabetes therapy for people with type 2 diabetes whose A1c is not at goal on metformin or other oral therapies. Furthermore, because of GLP-1 agonists’ added benefits of weight loss and low hypoglycemia risk, these drugs are an especially good option for people who would like to lose weight or have concerns about hypoglycemia.  

GLP-1 agonist combination drugs

For people with type 2 diabetes who need insulin, there is the option of taking a drug that is a mixture of a basal insulin and a GLP-1 agonist. Though these combination drugs do not have a distinct class name, they do have characteristics that differentiate them from the single-therapy drugs. Benefits of combining the two drugs include:

  • Fewer side effects than with the GLP-1 agonist or basal insulin alone

  • Greater A1c reductions than with the GLP-1 agonist or basal insulin alone

  • No weight gain, which occurs when taking basal insulin alone, and potential weight loss

  • Lower risk of hypoglycemia compared to taking basal insulin alone

  • Convenience of fewer injections

These combination products have generated a lot of excitement, and one diabetes drug expert, Dr. John Buse, has described Xultophy in particular as “the most effective glucose-lowering agent on the planet.”

Currently-available combination drugs include Soliqua (Lantus + Lyxumia) and Xultophy (Tresiba + Victoza). These medicines have never been directly compared to each other, but phase 3 studies demonstrate impressive ability for both drugs to maximize the benefits of GLP-1 agonists and insulin while minimizing their side effects.

In phase 3 trials, Xultophy lowered A1c by an average of 1.8% after one year, vs. 1.4% with Tresiba alone and 1.2% with Victoza alone. As for side effects, Xultophy was associated with less nausea and digestive side effects than Victoza alone and showed 37% less hypoglycemia than Tresiba alone. Furthermore, people taking Xultophy experienced an average weight loss of about one pound, vs. an average weight gain of five pounds with Tresiba alone. 

Similarly, in separate phase 3 trials, Soliqua led to an average A1c drop of 1.6%, vs. 1.3% with Lantus alone and 0.9% with Lyxumia alone. Nearly half of the people taking Soliqua achieved an A1c <7% with no weight gain, vs. only 1 in 4 with Lantus or Lyxumia alone.

GLP-1 agonists and diabetes complications

GLP-1 agonists are among the best-studied diabetes medicines, and over time have been shown in large trials to reduce the risk of diabetes complications: namely heart disease, kidney disease, and severe hypoglycemia (dangerously low blood sugar).

Victoza boasts perhaps the strongest evidence to this end. Results from the LEADER trial demonstrated that Victoza is associated with:

  • A 22% risk reduction of death from heart disease

  • A 22% risk reduction of kidney disease

  • A 31% risk reduction of severe hypoglycemia

And this was in addition to lowering A1c and causing weight loss. These are among the most positive results for a diabetes drug in recent memory. Victoza is now FDA-approved to reduce the risk of heart attack, stroke, and heart-related death. 

Similarly, newly-approved Ozempic showed a 26% risk reduction for death from heart disease, heart attack, and stroke in the SUSTAIN 6 trial, as well as a 36% lower risk of kidney disease and no increased risk of hypoglycemia. The trial, however, did raise some concerns about increased risk of retinopathy (eye damage), seen in 3% of trial participants taking Ozempic vs. only 1.8% of those taking placebo. New analyses suggest that the study population had already been at higher risk for eye damage, perhaps caused by a very rapid A1c reduction.

Results from the EXSCEL trial – which better mimicked real-world conditions – showed that Bydureon significantly reduces the overall risk of death and is not any riskier for the heart than placebo. Additionally, severe hypoglycemia occurred fewer times with Bydureon than with placebo, though this was by a small enough margin the results could have occurred by chance. Because EXSCEL was a “real-world” study, many opinion leaders believe that Bydureon could have shown protection against heart disease under stricter experimental conditions.

A trial for Trulicity’s influence on long-term complications is ongoing, with initial results expected in late 2018, and larger studies are being planned for Ozempic.

Ozempic: A Particularly Powerful GLP-1

Novo Nordisk’s GLP-1 agonist Ozempic (semaglutide) just received FDA approval. This once-weekly injection (an improvement from once-daily dosing of Victoza) promotes even greater level of blood sugar lowering and weight loss than seen with other available GLP-1 agonists.

Specifically, participants using Ozempic in the SUSTAIN 5 trial saw an average A1c reduction of 1.4% to 1.8% along with an average weight loss of 8 to 14 pounds.

The SUSTAIN 6 trial demonstrated that an impressive 1 in 5 people on higher-dose Ozempic lost 10% or more of their body weight (vs. 1 in 15 on placebo), and this weight loss was sustained over a two-year period. This trial also suggested that Ozempic could have a beneficial effect on the heart: compared to people on placebo, Ozempic users experienced a 26% lower risk for heart attacks, strokes, and heart-related death.

Furthermore, initial results from the SUSTAIN 7 trial implied that Ozempic may be better than the already-available once-weekly GLP-1 agonist Trulicity (dulaglutide) when it comes to weight loss and A1c reduction.

Ozempic will launch in the US in the first three months of 2018. It is also in development as a dedicated treatment for obesity.

Can GLP-1 agonists help with weight management?

Weight loss seen in people taking GLP-1 agonists is substantial enough that some of these treatments have become weight management drugs on their own. For instance, Novo Nordisk’s once-daily GLP-1 agonist Saxenda is approved as a weight loss drug in people with a body mass index (BMI) greater than 30 kg/m2 (considered obesity), or greater than 27 kg/m2 (considered overweight) with at least one additional weight-related condition (such as type 2 diabetes, high cholesterol, high blood pressure, etc.). Note that although Saxenda was actually developed for people with obesity – it is exactly the same drug as Victoza but approximately double the dose!

  • On average, people taking Saxenda in clinical trials lost about 5-7% of their body weight (10 to 14 pounds for someone who weighs 200 pounds)

  • More than one in four clinical trial participants lost over 10% of their body weight and about one in seven lost over 15% of their body weight. 

GLP-1 agonists as diabetes prevention?

Very early research suggests that GLP-1 agonists may also slow the progression of prediabetes to diabetes by preserving the body’s insulin production. This might be explained by the potential protective effect GLP-1 agonist drugs have on beta cells, the insulin-producing cells of the pancreas that gradually “burn out” as type 2 diabetes progresses (this is the reason people often must start taking insulin in later stages of type 2 diabetes).

Saxenda is an example of a GLP-1 agonist that may have the additional benefit of delaying or preventing type 2 diabetes. The latest results from the SCALE Obesity and Prediabetes trial showed that people who took Saxenda once a day for three years, in addition to making healthy changes to diet and exercise, were 79% less likely to be diagnosed with type 2 diabetes in that three-year timeframe compared to people who changed their diet and exercise alone (the placebo group).

Though the research is not conclusive by any means, GLP-1 agonists as a tool for diabetes prevention is a hot topic in the research community. The generic diabetes drug, metformin, also has some data on diabetes prevention, but so far, no drug has been specifically FDA-approved for the treatment of prediabetes.  

Around the Corner: GLP-1 Agonists without the Injection

Some people don’t like GLP-1 agonists because they require injections, and some doctors think their patients won’t take injections (often this is incorrect). Regardless, more convenient needle-free options are on the horizon:

Intarcia is developing an implantable GLP-1 agonist therapy called ITCA 650, which aims to remove the hassle of dosing completely. This novel option continuously releases the drug exenatide over the course of three to six months from a matchstick-sized mini-pump. The mini-pump is inserted just under the skin (in the abdomen) by a healthcare provider in a quick, minutes-long procedure. Once the mini-pump is inserted, there is no additional effort required by the user for the full three to six months. Intarcia submitted ITCA 650 to the FDA in November 2016, but it was not approved. The FDA wants more information before approving this first-of-its-kind innovation, and Intarcia plans to resubmit the therapy to the FDA – we hope this will be soon as no additional trials will be required. The same GLP-1 agonist in ITCA 650 is found in twice-daily Byetta and once-weekly Bydureon.  

Novo Nordisk is also developing a once-daily version of semaglutide in pill form. A series of phase 3 clinical trials, including a heart health outcomes trial, are ongoing to test the safety and efficacy of the GLP-1 agonist in pill form. These results are expected throughout 2018. If the data are strong, this could be submitted for FDA approval in 2019 or 2020. 

0
Type 2
Deeper Dive
1
Type 2

The First Trial to Test GLP-1 Agonists in Adolescents

By Ben Pallant

A new trial will test if the once-weekly injectable, Bydureon, is also safe and effective in adolescents.

Clinical Trials IdentifierNCT01554618

Trial Name: Safety and Efficacy Study of Exenatide Once Weekly in Adolescents With Type 2 Diabetes

Diabetes Type: Type 2 diabetes

What it’s testing: This trial is testing how effective Bydureon (exenatide), AstraZeneca’s once-weekly injectable, is for adolescents with type 2 diabetes between 10 and 18 years old. Exenatide is a GLP-1 agonist, approved for adults with type 2 diabetes in a once-weekly injectable form (Bydureon) and as a twice-daily injectable (Byetta).

What it’s measuring: The study’s will measure A1c and any side effects from the medication. Secondary outcomes will include weight, blood pressure, fasting plasma glucose (FPG), blood pressure, and lipids (cholesterol, triglycerides).

Why is this new/important: GLP-1 agonists, which offer the dual benefits of A1c reduction and weight loss, are an increasingly popular class of type 2 diabetes drugs. Approved GLP-1s include Bydureon, Byetta, Lyxumia/Adlyxin, Ozempic, Tanzeum, Trulicity, and Victoza. There are also two approved combination basal insulin/GLP-1 agonists: Soliqua and Xultophy. None of these drugs, however, has been specifically studied and approved for people under the age of 18. This is the first trial to see whether exenatide is effective and safe for adolescents.

The number of children and teenagers with type 2 diabetes has increased. Some research suggests that people diagnosed with type 2 as adolescents have high rates of complications, perhaps partly because the medical system is not as well prepared for managing type 2 diabetes in this age group. The only drugs approved for adolescents are insulins and metformin; increasing the number of drugs that are available and safe for teens may help them more easily and successfully manage their type 2 diabetes.

Trial Length: 1 year

Trial Locations: The trial is currently recruiting at 45 locations, including in sixteen US states and locations in Bulgaria, Hungary, Israel, Kuwait, Mexico, and Ukraine.

Do you qualify?

  • At least 10 years old and not yet 18 years old at the start of the trial

  • Diagnosed type 2 diabetes

  • A1c of 6.5% to 11.0% for those not taking insulin or sulfonylureas, or of 6.5% to 12.0% for those who are taking insulin and/or sulfonylureas

  • Treated with diet and exercise alone or in combination with an oral (pill) diabetes drug and/or insulin for their type 2 diabetes for at least 2 months 

  • Fasting plasma glucose concentration less than 280 mg/dl at the start of the trial

Exclusion criteria include:

  • Clinically significant medical condition that could potentially affect study participation and/or personal well-being

  • Pregnancy

  • Previous use of exenatide or another GLP-1 agonist.

For a full list of the trial’s inclusion criteria, please visit its webpage here.

Where to get more information: For more information about the trial, you can contact the AstraZeneca Clinical Study Information Center (1-877-240-9479, information.center@astrazeneca.com).

0
GLP-1 Agonist
AstraZeneca
Type 2
trial watch
1
Type 2

FDA Approves Bydureon BCise – New Autoinjector to Launch Early 2018

By Jeemin Kwon and Payal Marathe

Easy-to-use Bydureon pen cuts down on the hassle of once-weekly injections by offering convenient mixing, a hidden needle, and more​

Bydureon BCise – an improved pre-filled, single-use pen – has been approved by the FDA for adults with type 2 diabetes taking the once-weekly injectable GLP-1 agonist. The design of the new device incorporates user and healthcare provider feedback on the previous Bydureon dual-chambered pen. The new autoinjector features a simpler mixing process, a hidden needle, and a viewing window for users to confirm that they’ve received the medication. Bydureon BCise is expected to launch in early 2018.

The name “BCise” rhymes with “precise.” Why is the delivery device easier to use?

  • Easier mixing: To prep the BCise pen for injection, the user simply has to shake it for 15 seconds. By comparison, the older dual-chambered pen instructed users to tap it “80 times or more.”

  • Pre-attached needle: With the dual-chambered pen, users had to screw on the needle cap. Bydureon BCise comes with a hidden needle.

  • Easier injection: To administer Bydureon BCise, users are directed to push the pen against the skin and hold for 15 seconds, removing the hassle of needle insertion and holding down the plunger.

To get the new autoinjector, healthcare professionals must write a prescription specifically for Bydureon BCise. As a part of the launch, AstraZeneca will be releasing user-support resources, such as online videos to make learning how to use the device convenient. AstraZeneca has not specified what the price of Bydureon BCise beyond suggesting that it will be comparable to the dual-chambered pen pricing. In the US, GLP-1 agonists tend to cost $20-$25 per day if you are paying entirely out-of-pocket.

Bydureon BCise has also been submitted for European approval; a decision is expected in the second half of 2018. Other injectable GLP-1 agonists available include Victoza (once-daily) and Trulicity (once-weekly). Novo Nordisk’s once-weekly semaglutide is also under FDA review, with a decision expected by the end of 2017.

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GLP-1 Agonist
AstraZeneca
Type 2
new now next
1
Jeemin Kwon
Type 2

The Latest in Diabetes Drugs: Less Hypoglycemia, More Weight Loss

By Emma Ryan and Payal Marathe

Research presented at EASD 2017 showcased drugs, both new and old, that improve blood sugar management, weight loss, heart health, and even blood pressure

New research presented at the recent European Association for the Study of Diabetes (EASD) conference showed promising results, including lower A1c, better heart health, weight loss, and less hypoglycemia (low blood sugar). Click to read more about the most notable updates on new therapies:

  • Semaglutide – a once-weekly GLP-1 injection for type 2 diabetes (under FDA review after a very positive Advisory Committee meeting in which four diaTribe Foundation volunteers participated)

  • Bydureon – a once-weekly GLP-1 injection for type 2 diabetes (available now, with a newly-approved, easier way to take it)

  • Add-on pills for type 1 – SGLT “class” Farxiga (available now) and sotagliflozin (in development)

  • Tresiba – a once-daily basal insulin for type 1 and type 2 (available now)

  • Sulfonylureas versus pioglitazone – type 2 diabetes pills (available now)

  • Glimepiride versus ertugliflozin – type 2 diabetes pills (available now and in development, respectively)

The EASD meeting also included discussions of much more than diabetes drug therapies. You can read diaTribe’s coverage of a study showing improved outcomes from CGM use during pregnancy and The diaTribe Foundation’s event on “Solvable Problems in Diabetes.”  

Semaglutide– a once-weekly injection for type 2 diabetes (under FDA review)

Researchers presented new weight loss data on semaglutide, a once-weekly GLP-1 agonist that is currently under FDA review. The SUSTAIN 6 trial showed that people with type 2 diabetes on the lower dose of semaglutide lost more weight – an average of 8 pounds (4% of their body weight) – compared to about 1 pound lost on placebo. People taking the higher dose of semaglutide lost an average of 11 pounds (5% of their body weight) compared to 1.5 pounds on placebo. Additionally, an impressive one in five people on higher-dose semaglutide lost 10% or more of their body weight, compared to about one in 15 people on placebo. Notably, this weight loss was sustained over a two-year period.

Based on previous results showing that semaglutide lowers A1c, Novo Nordisk has submitted the drug to the FDA and EMA for approval. A decision is expected at the end of this year.

Bydureon – a once-weekly GLP-1 injection for type 2 diabetes (available now, with a newly-approved, easier way to take it)

Results from the EXSCEL trial showed that Bydureon, a once-weekly injectable GLP-1 agonist for people with type 2 diabetes, is not any riskier for the heart than placebo (a “nothing” pill). In fact, Bydureon narrowly missed the threshold for showing heart benefits. These positive results follow research announced earlier this year showing that 20% more people taking Bydureon achieved an A1c target of less than 7% than those on placebo.

Both sets of results contribute to evidence showing that the entire group or “class” of GLP-1 agonists reduce A1c and body weight and have neutral (Bydureon) to positive (Victoza) effects on the heart. On a related note, an easy-to-use autoinjector called Bydureon BCise (rhymes with “precise”), featuring easier mixing and injection and a pre-attached needle, has been approved by the FDA – stay tuned for full coverage.

Add-on pills for type 1 – SGLT “class” Farxiga (available now) and  sotagliflozin (in development)

Trial results for two non-insulin drugs that come in pill form offer exciting new options for people with type 1 diabetes to manage blood sugars. inTandem3 looked at sotagliflozin, a once-daily SGLT-1/2 dual inhibitor that has not yet been approved by the FDA. DEPICT 1 studied Farxiga, a once-daily SGLT-2 inhibitor that is approved for treating type 2 diabetes but not type 1. Both studies reported A1c reductions and weight loss – great for the push to approve add-on therapies for type 1. See our previous coverage for more details on this promising new group of add-on therapies for people with type 1.

Tresiba – a once-daily basal insulin for type 1 and type 2 (available now)

New analysis from the DEVOTE trial drove home the significance of severe hypoglycemia, expanding upon previous results showing that basal insulin Tresiba reduced the risk of severe hypoglycemia by 40% relative to basal insulin Lantus.

The analysis of DEVOTE 2 and DEVOTE 3 results showed significant links between daily blood sugar variability and death, suggesting that Tresiba benefits patients by reducing these swings (glycemic variability). This evidence reinforces that drugs that lower the risk of hypoglycemia – and therefore the possibility of hospitalizations and death – are critical in the diabetes treatment toolbox.

Sulfonylureas compared to pioglitazone – type 2 diabetes pills (available now)

The TOSCA.IT study examined the heart safety of pioglitazone, a once-daily pill (TZD), versus sulfonylureas in patients with type 2 diabetes on metformin. Both drugs are generic, low-cost options for additional therapy when metformin isn’t enough, but sulfonylureas have been attracting growing concern about safety. This large heart health outcomes trial compared pioglitazone with three sulfonylureas (glimepiride, glibenclamide, and gliclazide).

  • There was no difference in heart safety between pioglitazone and sulfonylureas, but pioglitazone did result in longer-lasting A1c-lowering and reduced hypoglycemia (low blood sugar).

  • Pioglitazone users had a 90% reduction in severe hypoglycemia – 2% of people on sulfonylureas had an incident of severe hypoglycemia (blood sugar less than 60 mg/dl AND requiring assistance), while less than 0.2% of pioglitazone patients experienced severe hypoglycemia.

  • There was also less than half as much moderate hypoglycemia (blood sugar less than 60 mg/dl, but not requiring assistance) in the pioglitazone group (10%) compared to the sulfonylurea group (32%).

Two other classes of A1c-lowering drugs, SGLT-2 inhibitors and GLP-1 agonists (Jardiance, Invokana, Victoza), have demonstrated heart benefits for people with diabetes. Based on this trial, neither TZD’s nor sulfonylureas showed similar benefits, but sulfonylurea was the clear loser on hypoglycemia. On the other hand, Jardiance, Invokana, and Victoza are not yet generic, meaning they tend to be more expensive. 

Glimepiride compared to ertugliflozin – type 2 diabetes pills (ertugliflozin in development)

The Vertis SU study compared glimepiride (a sulfonylurea) with a more advanced A1c-lowering drug, ertugliflozin (an SGLT-2 inhibitor in development). The trial looked at the A1c-lowering, weight loss, and blood pressure effects of the two drugs in people already taking metformin. After one year of treatment, the researchers found the following results:

  • There was no significant difference in A1c lowering between people taking glimepiride and people taking the higher dose of ertugliflozin (A1c was lowered 0.6% and 0.7%, respectively).

  • People on ertugliflozin lost an average of 7 to 8 pounds, while people on glimepiride gained an average of 2 pounds.

  • There was a significantly higher occurrence of hypoglycemia in the glimepiride group (19%) than on ertugliflozin (3% to 5%).

  • Blood pressure decreased by an average of 2 to 4 mmHg on ertugliflozin, and increased by an average of 1 mmHg in the group taking glimepiride.

Assuming it becomes accessible, this SGLT-2 – instead of a sulfonylurea, which has safety concerns – can offer many benefits for people with type 2 diabetes: a similar effect on A1c (with high dose ertugliflozin), weight loss, blood pressure, and hypoglycemia benefits.

0
Type 1 & Type 2
new now next
1

Bydureon Dual-Chambered Pen Receives FDA Approval After a Year-Long Wait

Bydureon Pen Instructions

On March 3, AstraZeneca announced FDA approval for the Bydureon dual-chambered pen (once-weekly exenatide) to improve glycemic control in people with type 2. The device is a pre-filled, single-use pen injector, which eliminates the need for patients to manually mix the drug before injection (“reconstitution”) and reduces some of the “hassle factor” of taking Bydureon. Before, users of Bydureon had to go through a more involved process to prepare and inject the drug. AstraZeneca plans to make the pen available in the US later this year, and it is still under regulatory review in Europe with a decision expected by the end of this year.

The new Bydureon pen preparation process does have a few hassles in this first generation and we look for more improvement over time. The pen will have to be refrigerated for storage and then must rest at room temperature for at least 15 minutes before use. The patient will attach the needle, then twist the base of the pen to mix the drug, and tap the pen firmly against the palm of their hand – the guide states that people may need to tap the pen “80 times or more” while rotating the pen until the solution is completely mixed. While this new process is a significant improvement from manual mixing, AstraZeneca is also working on a Bydureon suspension formula and auto-injector that will certainly increase convenience further.

Bydureon is a once-weekly GLP-1 agonist, which stimulates insulin production when blood sugar becomes too high. Please read our previous new now next articles about the approval of Bydureon, the action of GLP-1s, and our previous update about the Bydureon Pen for more information on GLP-1. We believe GLP-1 will continue to grow in use by patients due to its key advantages that differentiate it from insulin (weight loss or no weight gain, no association with hypoglycemia, and others). –NL/KC

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4
GLP-1
AstraZeneca
Type 2
62
new now next
1
Kelly Close
Type 2

Top Five Takeaways for Patients at the J.P. Morgan Healthcare Conference

By Nancy Liu and Adam Brown

Twitter summary: One of the best #JPM14 yet for #diabetes – exciting new data, pipeline updates, & more!

What a fantastic start to 2014! On January 13 to 16, investors and representatives of innovated healthcare technology companies flocked to our hometown of San Francisco to attend the 32nd J.P. Morgan Healthcare Conference. It was one of the best years at J.P. Morgan yet, with lots of data on new diabetes drugs and devices as well as pipeline updates. Below, we summarize our top five takeaways for patients at the conference.

  1. Intarcia impressed with preliminary phase 3 data on ITCA-650, a unique implantable GLP-1 device. ITCA-650 is an implantable mini-pump that delivers the GLP-1 agonist exenatide (currently sold as Byetta or Bydureon). The device is about the size of a matchstick (see a photo here) and lasts for up to a year of use – making the lives of patients and their providers that much easier. Intarcia CEO Kurt Graves presented the results for a small 60-person trial at J.P. Morgan. In the trial, the 25 patients who reached week 26 by the time of analysis saw A1c decline by an astounding 3.2% from a high 10.9% baseline. Amazingly, 22% of patients achieved an A1c reduction of at least 4.0%. diaTribe will be closely following the results of this promising new device as the full data is released.

  2. Medtronic announced that the Minimed 640G predictive low glucose suspend management pump is expected to launch in Europe by October 31, 2014. This is Medtronic’s third delay of the launch, although their current timeline for the launch is still pretty soon. The Minimed 640G is the next step in the path to automated insulin delivery and builds on the threshold suspend feature of the MiniMed 530G (read our test drive in this issue) – instead of suspending insulin delivery when hypoglycemia is reached, the MiniMed 640G will suspend delivery when hypoglycemia is predicted. Please read our new now next for more information on the Minimed 640G and our thinking like a pancreas article on the pathway to a closed loop system.

  3. Halozyme announced the upcoming release of data from a new 400-patient trial of Hylenex, an injectable drug that speeds up the action of insulin. The trial is testing preadministration of Hylenex, meaning patients would take an injection of Hylenex prior to inserting an insulin pump infusion set. Also on the ultra-rapid-acting insulin front, MannKind expects an FDA Advisory Committee on Afrezza in April 1 – at which time the panel will vote on whether they recommend approving the promising ultra-fast-acting inhalable insulin (read our latest update on Afrezza here).

  4. The Bydureon (exenatide once weekly) dual-chambered pen is now under regulatory review, and a US decision is expected by the middle of 2014. In Europe, a decision is expected by the end of the year. The dual-chambered pen will eliminate the need for manually mixing (“reconstituting”) the drug and make taking it much, much easier for patients.

  5. In 2014, Dexcom expects to launch the Animas Vibe integrated with the G4 Platinum CGM, as well as the Dexcom Share remote monitoring program. A Tandem t:slim integrated G4 integrated pump is expected in 2014/2015, with smartphone integration expected in 2015. During the Dexcom presentation, CEO Mr. Terry Gregg emphasized the impressive growth that Dexcom has seen in patient use of CGMs, which may be reaching tipping point for acceptance and use. This is certainly an exciting time for the company as the G4 Platinum was presented with the Everyday Health Award for Emerging Technology and received pediatric approval just this month. 

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4
Type 1 & Type 2
61
conference pearls
0
Adam Brown

Most at NIDDK and NCI Workshop on Incretin Therapies and Pancreatitis Do Not Find Significant Cause for Concern

The consensus from most speakers at the workshop was that, while this possible link does require further investigation, the available evidence does not suggest any need for current or prospective users to stop taking GLP-1 agonists or DPP-4 medications.

On June 13, the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI) concluded a two-day workshop on diabetes, pancreatitis, and pancreatic cancer. The workshop was prompted by studies suggesting a possible link between the use of incretin therapies, which includes GLP-1 agonists or DPP-4 inhibitors, and an increased risk of pancreatitis and pancreatic cancer. GLP-1 agonists include Amylin’s Byetta and Bydureon and Novo Nordisk’s Victoza, while available DPP-4 inhibitors include Bristol-Myers Squibb and AstraZeneca's Onglyza, Merck’s Januvia, Takeda's Nesina, and Boehringer Ingelheim and Eli Lilly’s Tradjenta. The consensus from most speakers at the workshop was that, while this possible link does require further investigation, the available evidence does not suggest any need for current or prospective users to stop taking GLP-1 agonist or DPP-4 inhibitor medications. Indeed, an increased risk of pancreatitis or pancreatic cancer has been a known possible side effect since the early development of these drug classes, and the FDA label already cautions people at risk for these diseases against using these drugs. This workshop does not represent a major change in experts’ thinking about either GLP-1 agonists or DPP-4 inhibitors, some sensationalist reactions in the popular press notwithstanding.

Recent studies appear to call the safety of these drugs into question, although it is important to understand where this new data is coming from. The Institute for Safe Medication Practices (ISMP) used the FDA’s adverse events (i.e. harmful side effects) database to track reports of pancreatitis and pancreatic cancer and found that they were significantly higher among uses of GLP-1 agonist medications. However, the adverse events database is generally considered useful only to suggest the possibility of risk, not to confirm it. (One reason is that the database relies on voluntary submissions from healthcare providers whose individual standards for reporting may vary.)

At the workshop, Dr. Solomon Iyasu, the FDA’s Director of Pharmacovigilance and Epidemiology, said that the agency has reviewed individual cases of people with pancreatic cancer, and they have not shown “any unique cancer signal or potential risk factor that stands out.” As for pancreatitis, the FDA required drug companies to analyze the potential for risk using insurance claims databases. Dr. Iyasu explained that this sort of observational study is imperfect by nature, but most of the published studies so far have not indicated an increased risk of pancreatitis.  

This meeting is unlikely lead to regulatory changes in the near term, in part because several large studies are already looking at incretin safety. These various safety trials and epidemiological studies will likely begin reporting data in a few years, although it will take much time for the data to be fully analyzed and understood.

In the meantime, the NIH workshop offers a good guide to the current thinking: GLP-1 agonists and DPP-4 inhibitors are certainly effective glucose-lowering drugs, and patients and their healthcare providers must weigh the benefits and risks of these drugs against those of other therapies in order to select the right treatments.–AW

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The American Association of Clinical Endocrinologists and the American Diabetes Association Respond to a Study Finding that GLP-1-Based Therapies Increase the Risk of Pancreatitis

A study in the Journal of the American Medical Association (JAMA) found that patients with type 2 diabetes who had been taking the GLP-1 agonists Bydureon (exenatide once-weekly) or Byetta (exenatide twice-daily) or the DPP-4 inhibitor Januvia (sitagliptin) within the last two years had higher odds of hospitalization for pancreatitis than those who never used these drugs. In response to the study, the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) released a joint statement, which argued that the study “does not provide the basis for changing treatment in people with diabetes,” and that we need to wait for results from “prospective randomized controlled clinical trials (RCT), the gold standard for evaluating treatments.” Prospective RCTs are designed to investigate cause and effect – they are designed up front to measure the impact of an “intervention” (in this case GLP-1 agonists or DPP-4 inhibitors) on an “outcome” (like pancreatitis); in contrast, observational studies like the JAMA study look at databases to analyze patient data that were collected in “real life” and outside of a controlled trial setting. The latter method makes it more difficult to determine the effects of GLP-1 agonists on pancreatitis because the relationship is more likely to be confused by other risk factors, called confounding factors. The AACE and ADA rarely comment on clinical studies, and their joint statement suggests they are concerned the results could be misconstrued and lead patients to stop their medications.

In the JAMA study, researchers analyzed data from administrative insurance claims from seven Blue Cross Blue Shield Association Plans. They compared 1,260 people with type 2 diabetes who had pancreatitis and took the drugs with 1,260 others who did not (the control group). People from each group were matched based on age, sex, and diabetes severity. Their statistical model compared these groups and took into account possible confounding factors, which include previously taking metformin, high triglycerides, alcohol use, tobacco abuse, obesity, and pancreatic cancer among others.

Since the study is based on administrative claims data, it has limitations. For example, the researchers could not know when patient information was not coded correctly: information about patients’ tobacco or alcohol abuse or if they have obesity is not always reported. Dr. Philip Home (DM, PhD, Newcastle University, Newcastle upon Tyne, UK) noted an issue with the data: "Unfortunately the authors document that there are marked differences in the characteristics and findings between the treated and control groups. This represents a fundamental flaw in the study and means that any comparison is invalid and should not have been made." This study is aimed at identifying safety risks, and along with knowing the study’s results, it’s important to understand its limitations as well.

Past studies of GLP-1 agonists (Bydureon, Byetta, and Victoza) and DPP-4 inhibitors (Januvia, Onglyza, Tradjenta, Nesina) – and their association with pancreatitis – give conflicting results about their safety, and this JAMA study adds to that list. However, most clinical studies do not suggest a link between the drugs and pancreatitis. When we spoke with Dr. Daniel Drucker (Samuel Lunefield Research­ Institute, Ontario, Canada), he said there is not currently a biological mechanism for how these drugs could cause pancreatitis. He is waiting for RCTs before making his own decision, and characterized administrative-database focused research as “weak and misleading”. Currently, AACE and the ADA are waiting on the results of ongoing RCTs with over 65,000 participants to get more information on whether the drugs increase the risk of pancreatitis. The FDA is also investigating this question and has opened its own safety review. In the meantime, the AACE, ADA, and FDA recommend that people who are concerned about these drugs discuss the topic with their healthcare providers and not change their medications on their own. For background on GLP-1 agonists and DPP-4 inhibitors, see the learning curve from diaTribe #8).–MN/NR 

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Combination of Novo Nordisk’s Insulin degludec and Victoza Provides Synergistic Benefits in Late-Stage Trial

By Hannah Deming

Lately, the use of basal insulins (such as Lantus and Levemir) in combination with GLP-1 agonists (such as Byetta, Victoza, and Bydureon) has been garnering increased attention. The combination therapy makes sense for several reasons: 1) the two therapies act in complementary ways to lower blood glucose, meaning that the combination could be more effective than either therapy alone; 2) the weight loss provided by GLP-1 agonists can help reduce (or overcome) the weight gain associated with long-acting insulin therapy; and 3) GLP-1 can be easier to take than short-acting insulin due to its glycemic-dependent nature (meaning it causes less hypoglycemia) and can delay the need for short-acting insulin. In 2011, Byetta and Victoza were approved for use in combination with basal insulin in the US and in Europe; several other GLP-1/basal insulin combinations are also being explored (see our new now next in diaTribe #42).

One such product in development, Novo Nordisk’s IDegLira, combines the company’s ultra-long-acting insulin degludec that has been submitted for approval to regulatory agencies worldwide and Victoza (liraglutide) in a fixed ratio (meaning, if users want to reduce the amount of insulin they wish to inject, the amount of Victoza they receive will also be reduced). On August 14, Novo Nordisk announced results of the phase 3 DUAL I study, which found IDegLira improved participants’ glycemic control significantly more than either degludec or Victoza alone. Over 26 weeks, participants who took IDegLira achieved an average A1c reduction of 1.9%, compared to 1.4% for degludec and 1.3% for Victoza. IDegLira also led to an average weight loss of a little over a pound, an improvement over the average three-pound gain with degludec alone, though those who used Victoza alone lost over six pounds. The next step for IDegLira is the follow-up phase 3 DUAL II study, which is slated to complete toward the end of this year. This schedule keeps IDegLira on track for FDA approval as early as the end of 2013.

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Bristol-Myers Squibb and AstraZeneca Purchase Amylin

In June, pharmaceutical giant Bristol-Myers Squibb (BMS) and its partner AstraZeneca (AZ) acquired the important biotech company Amylin for a cool $7 billion, which we believe will be good news for people with diabetes. Amylin manufactures two of the three currently available GLP-1 agonists – the twice-daily Byetta (exenatide) and the once-weekly Bydureon (exenatide once weekly) – as well as the type 1 and type 2 diabetes therapy Symlin (pramlintide). Besides these products, Amylin is developing a pen device for Bydureon that is expected to be easier to administer than the current version (approval expected in 2013), a once-monthly GLP-1 agonist (exenatide once-monthly) expected to enter phase 3 studies next year, and a new “dual-peptide” therapy for type 2 diabetes that remains in initial trials. The once-monthly is the part of Amylin that struck us as truly exceptional, although GLP-1, the main focus of the company, has also clearly begun to transform diabetes treatment for type 2 (and perhaps type 1, as we noted in our test drive in diaTribe #26).

Through their acquisition of Amylin, BMS and AZ will substantially strengthen their product offerings for type 2 patients. The companies already have one DPP-4 inhibitor on the market Onglyza (saxagliptin) and are trying to secure FDA approval for their SGLT-2 inhibitor, dapagliflozin. Now with Byetta and Bydureon, BMS and AZ become the only companies with approved products in two (and eventually perhaps all three) of the new major drug classes (GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors), providing more options to patients with varying treatment needs. The opportunity to provide a variety of treatments (either alone or in combination) will be especially important as doctors continue to focus more on personalized treatment regimens for each patient based on his or her medical profile, history of diabetes, and lifestyle – a strategy that was recently supported in a position statement from the American Diabetes Association and European Association for the Study of Diabetes.

With substantially more financial resources than Amylin, we hope to see BMS and AZ work to continually expand access to GLP-1 agonists to more patients and providers as well as speed improvements in this exciting drug class in the coming years. We expect that BMS/AZ/Amylin’s combined sales forces will be capable of educating even more healthcare providers about the benefits of GLP-1 agonists (strong improvements in blood glucose, weight loss, low risk for hypoglycemia, possible protective effects on the cardiovascular system) – AZ, especially, has significant experience with primary care providers. In the coming weeks, we hope to hear more about BMS and AZ’s plans for Amylin’s products as the companies provide updates about their overall business strategies. We’ll keep you posted! –NR/EC/BK

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