ADA 2017: Type 2 highlights (part 2) – by Emily Burns
This is the final part of our ADA series, covering updates on Type 1 and Type 2 diabetes research from the American Diabetes Association’s 77th Scientific Sessions.
Well done if you’ve stuck with us, we hope you’ll enjoy this final part on looking after our hearts and minds.
Hearts and minds
In 2007, we didn’t know much about the effects of Type 2 diabetes drugs on cardiovascular health. That’s because trials focused on whether or not the drugs lowered blood glucose levels – their primary purpose. But merely lowering blood glucose levels isn’t a guarantee to improving overall health.
Regulatory bodies then put in place requirements for all Type 2 drugs to have information on their effect on cardiovascular health, resulting in an explosion of research in this area.
Here’s an example of why this was needed. Gliptins were thought to have a positive effect on cardiovascular health, based on an analysis of clinical trials to date, but the full cardiovascular trials showed that this wasn’t the case. For alogliptin and saxagliptin, there was no effect. In fact, treatment with saxagliptin resulted in a higher rate of hospitalisations for heart failure – something we wouldn’t have known had the trial not been carried out.
We hope to find glucose-lowering drugs which also have other health benefits, and we’re getting there. The EMPA-REG and LEADER trials both showed that empagliflozin and liraglutide (respectively) reduced the risk of death from cardiovascular complications, stroke and heart attacks.
Cardiologist Dr Steve Nissen described the move towards establishing the health benefits of Type 2 drugs in large clinical trials as a “huge triumph for evidence-based medicine.”
Update on LEADER results
The results of the LEADER clinical trial were announced at the ADA last year, and the researchers were back this year to discuss what they’ve learned since. One of the key aims was to understand how liraglutide reduced the risk of cardiovascular complications: was it due to better blood glucose control, or bigger weight loss?
This isn’t published yet, but their analysis suggests that the outcome of the trial wasn’t linked to blood pressure, body weight, blood glucose levels, lipid levels or hypos. The benefits of the drug were also seen in people using different background medications.
This means that so far, liraglutide’s invisible effects can’t be fully explained. We do know that GLP-1 agonists (the class of drug that liraglutide falls into) have effects on the pancreas, intestine, kidney, brain, fat tissue and immune system. So not too many avenues to look down then…
DEVOTE & CANVAS
The DEVOTE trial set out to compare the effects of two forms of insulin in people with Type 2 diabetes: insulin degludec and insulin glargine. According to results published during the ADA, both forms were shown to have no negative effects on the risk of cardiovascular disease. But insulin degludec appeared to protect against low blood glucose levels.
The two-year trial involved 7,637 people with Type 2 diabetes, and insulin degludec was found to reduce the rate of severe hypos by 40 percent and halve the rate of severe nocturnal hypos.
Following in the footsteps of LEADER and EMPA-REG, CANVAS was another huge clinical trial investigating the effects of a Type 2 diabetes drug (called canagliflozin) on the risk of cardiovascular complications. (The results were also published during the conference).
Canagliflozin is an SGLT2 inhibitor, meaning it increases the amount of glucose released in our urine, which in turn lowers levels of glucose in the blood. Research so far has suggested that SGLT2 inhibitors could have beneficial effects on the cardiovascular system, but as mentioned earlier, a large-scale clinical trial can help us understand this better.
For CANVAS, 4,330 people with Type 2 diabetes were recruited in 2009 and another 5,812 in 2014 (officially named CANVAS-R). For the first phase, each participant took a 100 mg dose, a 300 mg dose, or a placebo. For CANVAS-R, which ran alongside, participants took a placebo or a 100 mg dose (with the option to increase to 300mg if necessary).
For the analysis, scientists pooled the data from both doses and compared this to the placebo, meaning they had a huge amount of data from 10,142 people.
The results? They found that canagliflozin reduced blood glucose levels, blood pressure, and the risk of cardiovascular death, heart attack or stroke. It also reduced the risk of heart failure and showed potential protective effects on the kidneys. So good news. The bad news was that there was also an increased risk of amputations (mostly toe), particularly in those who had had previous amputations.
So with the results of LEADER, EMPA-REG and CANVAS now in, can we work out which Type 2 drugs are best? It’s actually incredibly difficult to compare the results of these trials. They had different number of participants living with different existing conditions, the drugs work in different ways, the trials were done at different times – the list goes on. To give an example, 65 percent of the participants in the CANVAS trial had a medical history of cardiovascular complications – a more accurate reflection of real life perhaps than the 99 percent of participants in the EMPA-REG trial.
It takes a million people
In a separate study called CVD-REAL, researchers looked at data from 1.3 million (!) people with Type 2 diabetes to identify any relationship between SGLT inhibitors (as a whole, rather than a specific drug) and cardiovascular health.
Of those 1.3 million, 164,000 were taking an SGLT2 inhibitor and 1.2 million were taking a different type of glucose-lowering drug. Researchers matched each person using an SGLT2 inhibitor to a similar person in the other group, which meant they could compare around 150,000 in each group.
They found the rates of death and heart failure were lower in those using SGLT2 inhibitors, for people who either had or didn’t have cardiovascular disease. We have to take this observational data with a pinch of salt (a link between SGLT2 inhibitors and better cardiovascular health doesn’t mean SGLT2 inhibitors are behind this lower risk). But overall, the results add a little more confidence to the EMPA-REG and CANVAS results.
Exercising the mind
Rates of depression are often higher in people with diabetes, and this can have consequences on blood glucose control and complications down the line. Cognitive behavioural therapy, or CBT, has been shown to be an effective treatment for people with Type 2 diabetes and depression. Alongside this, some early research has suggested that exercise may also help.
The ACTIVE trial set out the compare the effectiveness of CBT and community exercise, both together and separately, on depression and blood glucose control in people with Type 2. The trial involved 140 people who each took part in either CBT, exercise, both, or ‘usual care’ for 12 weeks.
All three groups receiving a therapy (whether it be CBT, exercise, or both) were five times more likely to be in full remission of their depression at the end of the study than those receiving usual care.