Even though hypoglycemia is a major public health challenge, and even though people with diabetes spend an enormous amount of time trying – and often failing – to stave off low blood sugars, it’s surprising and troubling how little is known about diabetic hypos.
That’s one of my takeaways from interviews with participants in Hypo-RESOLVE, a promising new European-based initiative to unravel the mysteries of hypoglycemia in people with diabetes and “alleviate its burdens and consequences.”
Meeting in Copenhagen for the first time in mid-May, the Task Force for this initiative brings together a score of experts from academia, private industry and -- what's especially exciting -- the diabetes patient community.
They will analyze data from 100-150 clinical trials and do extended, collective brainstorming to figure out new ways to define, predict, treat and maybe even prevent hypoglycemia and its nasty cousin, hypoglycemia unawareness (the inability to detect when the blood sugar is plunging dangerously low).
The Hypo-RESOLVE Project
Hypo-RESOLVE is supported by a grant of $32 million from the Innovative Medicines Initiative (IMI), a European public-private partnership that works to speed up the development of, you guessed it, innovative medicines -- as well as by the JDRF and the Leona M. and Harry B. Helmsley Charitable Trust.
A small sampling of the questions to be addressed:
- What are the underlying causes of recurring hypos and hypo unawareness?
- How can hypos be measured and monitored in clinical trials?
- Why are some people with diabetes more prone to these problems than other PWDs?
- Is there a way to prevent hypoglycemia in the first place?
This is a four-year project so it’s too early to tell how much concrete impact it will have on the bane of my existence after being T1D for 55 years now: hypos and the fear of hypos.
But at this point it’s worthwhile to examine some of the difficult challenges Hypo-RESOLVE will confront and how participants hope to overcome them.
People with Diabetes Weigh In
One of the most praiseworthy things about Hypo-RESOLVE is that it is tapping into the expertise of people with diabetes to ensure that “patients’ insights, opinion and wishes are taken into account across all the multiple components of the project.” The organizers have heeded the rallying cry of D-advocates and people with other chronic diseases — “Nothing about us without us” — who are pressing for more inclusion of patient voices into the design and implementation of medical research.
Among other contributions, these PWDs will play the vitally important role of helping researchers “understand what hypos feel like, and not just rely on blood glucose numbers to dictate their interpretation of what people feel,” according to Sanjoy Dutta, Assistant VP of Research and International Partnerships at JDRF.
Scibilia did that in a presentation on the first day of the Copenhagen meeting, when she explained the difference between so-called “severe” hypos (when blood sugar is so low that PWDs require the assistance of other people) and “mild” ones.
“The researchers focus only on severe hypos,” she told me. “Nobody pays attention to the mild ones that still have an impact on our lives, the ones that can ruin our days. We need to bring that to the table.”
Dutta said he hoped that the lived experience shared by PWDs will help researchers solve some important, confounding problems. For example, scientists need more sophisticated ways to monitor and measure hypoglycemia in clinical studies.
Right now, hypos are only measured by blood glucose levels in most studies, but Dutta hopes the PWDs will help scientists figure out “What else should be captured in clinical trials? Should we be doing thermal readings? Measuring heart rates? Is there a correlation between what a patient feels like and what the CGM says?”
Another challenge is that it is hard to define hypoglycemia with the kind of precision researchers need. That’s because hypos are so variable: I tend to feel weak and cranky with a BG reading of 75 mg/dL, while other people with diabetes feel just fine. And the BG levels that mark the point at which symptoms of hypos develop – known as “glucose thresholds” – can differ within each person.
It’s a key reason why “no approved guidelines or methods for how hypoglycemia should be measured exist,” a European Commission report says.
That should matter to every PWD because it is a major barrier to getting innovative therapies for hypos approved by regulatory bodies and covered by “payers” (private and public insurers).
Right now, the FDA and regulators abroad rely almost entirely on the A1C levels of PWDs to gauge the effectiveness of diabetes treatments, including those that target hypoglycemia. That makes no sense, mostly because the A1C is an average and can represent just a mid-point between highs and lows. Therefore, the diabetes community has spearheaded a #BeyondA1C effort and defined new parameters to assess the health and well-being of PWDs.
In 2017, a number of advocacy groups including ADA and JDRF agreed on helpful numerical classifications of hypos:
- Below 54 mg/dL is considered "meaningful hypoglycemia" that urgently requires treatment and has serious side effects if not quickly addressed.
- Below 70 mg/dL but above 54 mg/dl is considered an "alert level for hypoglycemia" – warranting action and a reminder that glucose levels are approaching a more dangerous zone.
- 70-180 mg/dL is considered “in range,” serving as a target that could apply widely to many people with diabetes.
In the June 2018 edition of Diabetes Care, this #BeyondA1C writing group described some hypos as “an event characterized by altered mental/and or physical status requiring assistance.” Yep, that certainly applies to the times that I babbled Slavic-sounding gibberish on a New York City train, howled like a wolf in front of my wife-to-be and other embarrassing hypo-induced actions.
Nevertheless, while Dutta says, “we’ve made a lot of progress” in defining hypoglycemia, there is still no universally accepted classification of hypos.
The Hypo-RESOLVE folks hope that by using the power of Big Data from clinical trials and other sources, they will be able to develop what Dutta called “harmonized guidelines” and, most importantly, “get the regulators and payers on board” -- a specific goal also outlined by the Beyond A1C writing group.
Let’s hope that happens soon.
Understanding and Preventing Hypos
Last but not least, Hypo-RESOLVE will try to address yawning gaps in knowledge about what happens to the body during hypoglycemic episodes. The initial press release puts it in stark terms: ”much about hypoglycemia remains unknown.”
For example, in the normal pancreas “alpha cells” detect when the blood glucose is too low and then churn out glucagon, which prompts the body to make its own glucose. Alpha cells don’t function properly in PWDs, especially T1Ds. Yet scientists just don’t know a whole lot about alpha cell dysfunction.
Still, some promising work is going on out there to understand how alpha cells work. restore their ability to produce glucagon and reduce or even prevent hypos. The Helmsley Charitable Trust is funding a scientific workgroup to focus on that and in April, the accelerator-org announced new funding for Zucara Therapeutics Inc., which is working on a daily pill that could turn back on the body’s natural ability to make glucagon.
That could be a gamechanger.
And that’s the kind of breakthrough Hypo-RESOLVE could help to encourage by charting new directions in basic research on hypoglycemia and hypoglycemia unawareness. This effort should be applauded and encouraged by PWDs, especially because research focused on understanding and preventing hypos tends to be underfunded and underappreciated.
As far as I’m concerned, other than being completely free from diabetes and avoiding its scary complications, it’s hard to come up with a more important goal than liberation from the persistent threat of hypoglycemia. I hope the people engaged in Hypo-RESOLVE can move us closer to transforming that dream into reality.