Invokana: Heart & Kidney Benefits, Same Safety Concerns on Amputation

By Lynn Kennedy, Payal Marathe, and Kelly Close

CANVAS study presented at ADA 2017 highlights heart and kidney protection for type 2 diabetes drug Invokana, and questions persist over an increased risk of amputations

CANVAS study results released at ADA 2017 highlighted welcome heart and kidney benefits of the once-daily type 2 diabetes pill Invokana (an SGLT-2 inhibitor) and also confirmed concerns about the increased risk of lower limb amputations that first arose last year, resulting in a “black box” warning from the FDA. On a very exciting note, the lessons from this trial have reinforced that as a type of drug (also called a “class”), SGLT-2 inhibitors (others include Jardiance and Farxiga) are positive for people at high risk of heart disease.

In total, the CANVAS study enrolled over 10,000 people (for context, this is a massive trial size) with type 2 diabetes at high risk of heart problems. Invokana use (as opposed to placebo – a “nothing” pill) was associated with:

• A 14% lower risk of negative heart outcomes (including heart-related death and non-fatal heart attack or stroke);

• A 33% lower risk of being hospitalized due to heart failure (this was terrific to see since people with diabetes have a 9 times higher risk of heart failure than others without diabetes);

• A 27% lower risk for developing “albuminuria” (when certain molecules that indicate kidney disease are present in urine);

• A 40% lower risk of developing kidney problems such as kidney death, needing dialysis, etc.;

• And nearly double the risk for needing a lower limb amputation, regardless of pre-existing risk factors for amputation or previous amputations, in trial participants – all of whom had a high risk of heart disease. Although risk doubled, note the “absolute” risk change was low at 2% to 4%.

Said another way: For every 1,000 people with diabetes who are treated with Invokana over five years, the study results indicate that on average, there will be:

• 23 fewer to experience a negative heart outcome;

• 17 fewer to experience hospitalization for heart failure;

• 16 fewer to experience one of the kidney problems measured;

• And 15 more to experience a lower-limb amputation (including 10 toe or forefoot amputations and five above-the-ankle amputations).

Overall, the CANVAS results have been met with a range of responses, and it is far from clear what the numbers mean – and far be it from diaTribe to attempt to interpret them in a vacuum! We urge people taking Invokana to ask their healthcare teams about their recommendations, given the data. For anyone interested in reading the full CANVAS data, or sharing them with a healthcare provider, see this New England Journal of Medicine article.

Ultimately, the field agrees that it is terrific to see very positive data that show Invokana is “cardioprotective” – meaning it protects heart health (similar to a related drug, Jardiance). And, it is worrisome to see the heart benefit accompanied by a doubled increase in the risk for lower limb amputation, particularly given that it is not easy to explain. Several months ago, based on a smaller subset of data, the FDA responded by adding a “boxed warning” to Invokana, and we believe the FDA would do more if it felt Invokana deserved more limitations.

Read on for a deeper dive into the CANVAS results (or click one of the questions below to jump directly to that section):

What is Invokana and what was the CANVAS trial investigating?
How serious are the safety concerns about lower limb amputations?
What does this mean for me if I am taking Invokana?
How does Invokana compare to other SGLT-2 inhibitors?
What do the CANVAS results mean for the future of Invokana?

FAQs

What is Invokana and what was the CANVAS trial investigating?

Invokana is a type 2 diabetes glucose-lowering medication from a category of medications called SGLT-2 inhibitors. It is taken once daily as an oral pill and works by helping the kidneys to rid the body of excess glucose through urine. (Some people with type 1 diabetes also use this medication, but only “off-label” and hopefully in close consultation with their healthcare provider.)

The CANVAS trial began in 2009 to determine whether Invokana was safe for the heart, how effective it was, and if it was associated with any other health risks. After initial results indicating it was safe for the heart, the FDA first approved Invokana for use in type 2 diabetes in 2013, with EMA approval (Europe) following less than a year later. The study was then continued, and the CANVAS-R trial was added as an expansion to further evaluate heart and kidney safety as part of an ongoing commitment to regulators like the FDA. All in all, the CANVAS trials studied over 10,000 people with type 2 diabetes and high risk of heart problems to arrive at the results recently presented at the ADA 2017 conference.

How serious are the safety concerns about lower limb amputations?

Many experts have shared with diaTribe that more data and more time will be needed before the full picture is understood – including the significance of the CANVAS results. As noted, the CANVAS trials found that amputation risk nearly doubled for trial participants taking Invokana – all of whom had advanced diabetes and were at high risk for many serious complications. However, although experts have noted that the risk increased from a “low base” (from 2% to 4%), and double the risk is still quite low, it is important that each person gets individualized advice on benefits and risks before more conclusive data (that should be very instructive) is available.

In addition, some experts like Dr. George King from Harvard University and the Joslin Diabetes Center have suggested that the amputation risk with Invokana could be managed, allowing people to still experience the medicine’s heart and kidney benefits. “There’s ample evidence to show that if you examine the feet at every doctor’s visit, you can decrease amputation rate by 50%,” Dr. King shared – great advice for everyone with diabetes! Echoing this sentiment, Dr. Robert Cuddihy (Janssen, VP of Global Medical Affairs for Cardiovascular & Metabolism) also stated that "people [in the trial] didn't just walk in feeling fine one day and end up with an amputation out of the blue – there was something that led to a procedure like an infection, ulceration, etc.," adding that regular foot screening and increased awareness about foot complications can lower the existing amputation risk. 

The FDA has already responded to safety concerns arising from the CANVAS trial – first by launching an investigation after interim study results began raising concerns in the spring of 2016, and more recently by issuing a boxed warning in May 2017 for all products in the Invokana family (Invokana, Invokamet, and Invokamet XR).

What does this mean for me if I am taking Invokana?

Although many point out it’s unclear how regulators will react to these mixed results, we do emphasize that they already added a “black box” warning to Inovkana’s label. Hopefully, healthcare teams will raise this with all people on Invokana to discuss benefit and risk trade-offs. From a regulatory perspective, we assume that the FDA is not surprised by this outcome, since this was foreseen in previous data. Based on discussions with multiple doctors and nurses, we note that it is very important that people do not stop taking medicine – if you are on Invokana, we recommend that you speak to your doctor and ask him or her what he or she thinks about the outcomes. It is a great rule to remember that if you ever have any concerns about your current diabetes treatments, always speak to your doctor, especially if you are considering changing or stopping any medications.

Very importantly, for all people with diabetes and healthcare providers, these results should serve as a strong reminder that proper foot care is a very important and very often overlooked part of managing diabetes. Read more about foot care in a Healthline article found here – with tips to avoid infections like moisturizing, cutting toenails after a shower, and more.

How does Invokana compare to other SGLT-2 inhibitors?

While Invokana was the first SGLT-2 inhibitor medication to be approved, it does have competitors (Jardiance and Farxiga) that have not demonstrated any increased risk of amputations to date – although, some experts have pointed out that it is difficult to “compare” these trials because not all of the data was collected in the same way. The EMPA-REG OUTCOME trial also showed that Jardiance has heart benefits very on par with those seen in the CANVAS trial for Invokana.

Notably, Europe’s regulatory agency, the EMA, has taken a more cautious stance on the whole category of SGLT-2 inhibitor medications now that the increased risk of amputations for Invokana is known. After a safety review conducted last year, the EMA recommended a warning be added to all medications in the SGLT-2 inhibitor category earlier this year in order to let people know of the possible increased amputation risk. It is easier for us to understand this following ADA, where we learned that the data on this risk was not all collected in the same way, so experts are still assessing the risk per drug.

What do the CANVAS results mean for the future of Invokana?

The simple answer is the field just does not yet know! If you have any concerns or questions about your diabetes therapies – whether or not you currently take Invokana - talk to a healthcare provider to get the best advice specific to you and your diabetes. We do recommend going in with an understanding that all this is new information for your healthcare providers as well, and they may still be developing their own views.

If you want to discuss the CANVAS results with your healthcare provider, you can find the New England Journal of Medicine article, with the full study results, here. 

[Photo Credit: Janssen]