ADA Scientific Sessions 2020 Report

Given that people with diabetes are 2-4X more likely than non-diabetics to develop cardiovascular disease (CAD), it is important to evaluate risk factors and perform regular screenings.  The “plaques” that cause coronary arteries to harden and occlude usually include a considerable amount of calcium.  So, measuring calcium is an effective way to assess risk for heart attacks and strokes.  The MESA study evaluated thousands of patients and found that calcium scores were a better predictor of risk than traditional criteria such as elevated cholesterol, obesity, and… diabetes.

In fact, people with elevated cholesterol but very low calcium scores had a very low risk of CAD.  In fact, they saw little to no benefit from use of lipid-lowering statins, whereas those with elevated calcium saw a significant benefit.

RF = cardiac risk factors | CAC = carotid artery calcium score

Low calcium scores in people previously thought to be “high risk” can be spared from chronic use of medications that have potential side-effects, such as aspirin.  Elevated calcium scores, by contrast, can motivate people to make lifestyle changes necessary to reduce their risks, and begin taking risk-lowering medications such as statins.

THE BOTTOM LINE:  Most adults with diabetes should discuss carotid artery calcium testing with their physician.

Many people recognize Tidepool for their excellent work in developing software that integrates data from a multitude of diabetes devices. A lesser-known project undertaken by Tidepool is to develop a version of the DIY “Loop” app that can be submitted and approved by the FDA for more widespread use.

Based on results of a 3-month study, Tidepool reports that users of the DIY Loop app experience significant improvement in a number of quality-of-life measures, including sleep quality, diabetes distress, and confidence to avoid hypoglycemia. Users of Loop also report that the system works extremely well during both day and night, and that they are highly likely to recommend Loop to others. Perhaps the only area where Loop did not receive outstanding marks is in the work required set it up. Use of Loop requires users to build, install and maintain the app individually.

This is what Tidepool hopes to overcome with their version of Loop, which will utilize the OmniPod pump and Dexcom CGM. The company hopes to complete preliminary testing of their product and submit their results to the FDA within the next 12 months. Tidepool plans to keep many of the elements of Loop that appeal to users – such as the unique active carbs vs active insulin predictive algorithm – but make it “turn-key” so that users will not have to build the app from scratch or troubleshoot independently.

Activity trackers take a variety of forms: cell phone apps, wrist watches and traditional clip-on devices. There is growing interest in building activity trackers into insulin pumps or CGMs so that hybrid closed loop systems can make appropriate adjustments to insulin delivery when physical activity increases and decreases.

That said, research on activity trackers has shown that pedometers and accelerometers generally produce the most accurate data when worn on the WAIST. Wrist-worn devices tend to overestimate actual movement, and devices worn in the pants pocket tend to under-estimate.

A review of multiple research studies on the use of activity trackers has shown that they tend to increase overall physical activity, but there is no discernable long-term improvement in measures such as A1c, blood pressure or lipid profile among users. Nevertheless, change is needed. Self-reported physical activity among adults in the US is abysmally low, with patterns that mirror the regional prevalence of type-2 diabetes. Interestingly, research reported by the Sansum Diabetes Research Institute shows that for many populations, activity levels are actually lower on weekends than on weekdays, and more common during the evening hours.

I, for one, long for incorporation of physical activity into hybrid closed-loop systems. Physical activity can amplify the effects of insulin and delay nutrient absorption; lack of activity has the opposite effect. Current HCL systems do a poor job of keeping glucose levels within a safe range during most forms of sport and exercise, relying on the user to make traditional adjustments.

Stanford University researchers reported on the most common barriers to exercise among people with type-1 diabetes. The results (shown to the right) indicate that the only thing that holds people back from exercise more than time/scheduling is fear of hypoglycemia.

The presenters stressed a structured approach to determining optimal adjustments for physical activity, including consideration for the type/duration/intensity of activity, basal and bolus insulin levels, ability to plan ahead (vs spontaneous activity), and the level of insulin sensitivity (based on prior activity or hypoglycemia). Adding to the challenge is the reliance on CGM for glucose data. A recent study showed an average lag time of about 12 minutes during aerobic exercise, and upwards of 30 minutes during high-intensity interval training. This, of course, represents a virtual “eternity” during exercise as glucose levels can change rapidly.

Another new variable to add to the mix is body composition. Greater fat mass seems to contribute to a glucose rise post-workout, whereas greater muscle mass leads to a glucose decline post-workout.

Xeris Pharmaceuticals announced positive results from a Phase 2 study of its developmental Gvoke RTU Micro™ for the prevention of hypoglycemia during and after moderate-to-high intensity aerobic exercise in adults with T1D who use insulin pumps. Study subjects who received the micro dose of glucagon in addition to making their usual pump adjustments for exercise were able to maintain near-normal glucose levels during prolonged moderate-to-intense aerobic exercise.

Given the complexities of managing glucose levels during exercise, there is greater reliance on automated insulin adjustments via a hybrid closed loop (HCL) system. Although HCLs are not yet able to produce perfect glucose levels during exercise, they do produce better control than most people can achieve on their own – particularly for preventing delayed-onset hypoglycemia. Below is a summary of recommendations for those using HCL (closed loop) systems vs non-HCL systems.

On a very positive note, a study involving Medtronic’s next-generation 780G (also called “Advanced Hybrid Closed Loop) during high-intensity interval exercise produced more than 80% of time in-range (70-180 mg/dl) during the workout and 24 hours later.

With all that’s going on in the world, you would think that the healthcare community would have better things to do than worry about the exact definition of hypoglycemia. However, the way we define hypoglycemia has important implications in terms of:

1. How we go about treating it
2. How we evaluate the effectiveness of new therapies
3. Allowing multiple studies (META-analyses) on hypoglycemia to be compared

Despite the development of better treatments over the past 30 years, the incidence of severe hypoglycemia in people with type-1 diabetes has hardly changed. The most recent studies show an average of just over one severe hypo event per person per year, with nearly 30% of insulin users experiencing at least one event annually.

Definitions of hypoglycemia vary by organization and country. Most include three categories: Mild (self-treatable with mainly physical symptoms), Moderate (self-treatable, but with some degree of cognitive dysfunction) and Severe (requiring outside assistance). However, there is little agreement about the exact glucose levels that correspond to these categories.

Novo Nordisk has sponsored a consortium called the International Hypoglycemia Study Group, whose responsibility is to evaluate existing data and make recommendations related to how we evaluate and manage hypoglycemia. This group is urging the diabetes community and researchers to consider glucose levels below 55 mg/dl (3 mmol/l) to be particularly dangerous, due to their association with altered mental states, cardiac arrythmias, hypoglycemia unawareness, and progression to severe hypoglycemia. A recent study confirms this theory, as reaction times and intellectual capabilities take a serious downturn with glucose below this level (see below). Note that the glucose is measured in mmol/l. To convert to mg/dl, multiply by 18.

Recent research on the brain’s role in detecting hypoglycemia has produced some interesting findings. Most sensing of glucose levels takes place in a part of the brain called the “hypothalamus” (the hypo part is just a coincidence). However, glucose-sensing neurons have been detected in dozens of areas of the brain, as well as some peripheral parts of the body. Once hypoglycemia occurs, these cells are responsible for triggering the counterregulatory hormone response and symptoms commonly associated with hypoglycemia. Recurrent hypoglycemia causes an adaptive response that lowers the glucose threshold for this response.

A number of theories have been professed for this adaptive response – including increased glucose uptake by the brain, enhanced brain glycogen storage, use of alternate fuels, and stress de-sensitization. Of these, the only one that appears to have validity is the alternate fuels theory. Lactate is an energy source that can be used by brain cells in times of crisis. Tests have shown that lactate uptake is increased by the brain in people with hypoglycemia unawareness. In other words, the cells of the brain that detect low blood sugar fail to detect the lows because they can make use of other energy sources.

Nearly 80% of people with type-1 diabetes fail to meet recommended A1c targets. That’s worth repeating. FOUR OUT OF FIVE PEOPLE WITH T1D HAVE A1Cs THAT ARE TOO HIGH. Forty to sixty percent are also classified as overweight or obese. And nearly one in twenty experience DKA on an annual basis. Although the potential for better diabetes management improves with expanded use of CGM and hybrid closed loop systems, the number remain pretty grim.

A number of pharmaceutical companies and research scientists reported on novel uses for medications that are traditionally reserved for the type-2 population in people with type-1. Metformin, an oral medication whose primary function is the slowdown of glucose production & secretion by the liver, is one of those medications. A 2017 meta-analysis of metformin use in T1D showed limited benefit: a .11% (non-significant) reduction in A1c, modest 3-4 lbs weight loss after one year, a 6-7 unit reduction in daily insulin requirements, and a slight increased risk of hypoglycemia. However, long-term use of metformin also showed a tendency towards better kidney function, a reduction in LDL cholesterol and less arterial thickening.

GLP-1 receptor agonists are injectable medications whose effects include decreased gastric emptying (slower digestion), satiety (blunting appetite) and blocking glucagon production by the pancreas. In those with type-2 diabetes, they also improve the pancreas’s beta cell function (no such effect is seen in type-1 diabetes). These medications come in mealtime, once-daily, and once-weekly formulations; the shorter-acting versions produce greater effects on gastric emptying than the weekly versions.

The first study of a GLP-1 receptor agonist (liraglutide) in T1s was published in 2016. It showed slight but not significant reductions in A1c and glucose variability along with an increase in nausea and non-severe hypoglycemia. However, significant weight loss was achieved, along with lower basal and bolus insulin requirements compared to those who took a placebo. The greatest benefits were seen for those taking the maximum dose of liraglutide (1.8 mg). A follow-up study of overweight, poorly-managed pump users showed clinically significant reductions in weight, A1c and insulin requirements with 3-6 months of liraglutide use.

A recent 26-week study of another GLP-1 receptor agonist, exenatide, showed very little improvement in A1c, but a significant decline in mealtime (bolus) insulin and body weight. Exenatide was taken before each meal and produced a modest improvements in post-meal glucose control.

A third class of medications studied in people with type-1 diabetes were sodium-glucose-transport enzyme inhibitors (SGLT-1 & -2). These oral medications cause the kidneys to excrete glucose, which results in lower blood sugar levels and some weight loss. Dapagliflozin, one of the SGLT-2 meds, was shown to reduce A1c and improve time in-range among adults with T1D. It also led to a 10-15% reduction in basal and bolus insulin doses with no increase in hypoglycemia when insulin doses were reduced proactively. More significantly, dose-dependent weight loss was seen, on the magnitude of approximately nine pounds in one year. On the downside, due to increases in urine glucose concentrations, an increase in urinary tract infections was seen, along with an increased incidence of diabetic ketoacidosis. The increase in DKA can be attributed so several factors, including:

• A tendency towards dehydration
• (Sometimes) Sharp reductions in insulin doses
• Slightly higher baseline ketone levels
• Late detection of insulin/insulin delivery problems (due to more modest & gradual glucose rises when SGLT-1 & -2 inhibitors are used)

It is worth noting that dapagliflozin was recently approved as a preventive therapy for heart disease. After factoring out the various other beneficial effects of dapagliflozin, the 10mg dose was found to reduce heart failure risk by approximately 26% in people with or without diabetes.

Sotagliflozin, an SGLT-1 & -2 inhibitor (which acts on both the kidneys and intestines), produced a nearly .5% reduction in A1c in adults with T1D. Use of this drug also contributed to significant weight loss and systolic blood pressure reduction. There was a dose-dependent impact on time within a target glucose range (TIR), with those taking 200mg increasing TIR by 1hr 17min/day, and those on 400mg increasing by 2hrs 49min/day – with no increase in hypoglycemia (see below).

Side effects of sotagliflozin were similar to those seen with dapagliflozin: an increase in urinary tract infections, along with an increased incidence of diabetic ketoacidosis.

The third SGLT medication studied was empagliflozin. With empagliflozin, similar improvements were seen in A1c, weight and daily insulin requirements at doses of 10 or 25 mg. At a very low dose (2.5 mg), there were more modest limprovements. DKA was increased at the 10 & 25mg doses. However, the risk of DKA was almost identical to placebo at the very low dose. Similar results were found when using a lower-than-usual dose of dapagliflozin in overweight individuals.

The presenters concluded that SGLT-1 & -2 inhibitors may be useful when prescribed to patients with type-1 diabetes under the correct circumstances. Optimal patients are those with A1c’s below 9% who are overweight and with whom the clinician has a long-standing and collaborative relationship. It will also require the patient to be educated on the importance of proper hydration, avoidance of low-carb diets, ample insulin dosing, aggressive ketone monitoring/troubleshooting, and instruction on situations that call for the discontinuation of the medication.

Say what you will about the complexity of Medtronic’s hybrid closed loop systems. When used properly, they can produce some pretty impressive results. At a large west-coast institution, patients were provided with an intensive level of training/guidance before, during and after starting on the Medtronic 670G system. Participants saw their average A1c drop from 8.4% at baseline to 6.7% after three months, and time in-range increased from 47% to 75%. A few interesting stats from this successful batch of users:

• The system was kept in “auto-mode” about 90% of the time
• Auto-mode exits decreased substantially after the first two weeks of use
• Users calibrated an average of 3.4 times per day
• Meal boluses (insulin-to-carb ratios) increased about 25% from baseline

Preliminary studies were reported from Otago University in New Zealand on Medtronic’s new 780G system with “Advanced Hybrid Closed Loop” technology. 780G uses the same hardware (pump & sensor) as 670G. But it features a basal algorithm with a lower target (100 mg/dl / 5.6 mmol/l), auto correction to a lower target (120 mg/dl / 6.7 mmol/l), and fewer auto-mode exits. Despite featuring patients with relatively fair-to-poor control prior to using the system and not adjusting carb ratios at all, 780G achieved some impressive outcomes:

• Average glucose of 152
• Over 70% of time in-range overall
• 75% of time in-range at night
• 2% of time below 70

While glucose control improvements were seen across most age groups, they were most prevalent in the teen/adolescent population.

Turning our attention to BetaBionics, the 3^rd generation iLet Bionic Pancreas features an insulin-adjustment algorithm that initializes by only entering one’s body weight. It adapts to individual needs and eliminates the need for meticulous carb counting. Insulin-only and bihormonal (insulin and glucagon) versions are in development.

The bihormonal version uses dasiglucagon, Zealand pharmaceutical’s version of glucagon that is stable in liquid form at room temperature. In a preliminary study comparing insulin-only vs dual-hormone versions of iLet, the dual-hormone approach yielded significantly tighter control in 8 out of 10 participants, along with less hypoglycemia in nearly all subjects. Nausea is a common side-effect of glucagon use, but no substantial increase in nausea was seen in those using the dual-hormone system. Pivotal studies are current taking place.

Eli Lilly has also thrown its hat into the ring in developing an automated insulin delivery algorithm. The algorithm was embedded in an experimental insulin pump and combined with the Dexcom CGM to automate basal insulin delivery only. They investigated the ability of the system to automatically “cover” different types of meals without the user having to act. Data was analyzed for four hours following a high-fat/slowly digesting meal (pizza), as well as a low-fat/rapidly digesting meal (pancakes). Overall, the system failed to achieve adequate post-meal glucose control without any bolus being delivered.

Scientists are getting closer to developing insulin that mimics the speed of insulin produced naturally by the body. Arecor, a pharmaceutical company in the United Kingdom, reported the results of a phase-1 study of AT247 – an ultra-rapid formulation of insulin aspart. Compared to Novolog/NovoRapid and Fiasp, AT247 demonstrated a faster onset of action, earlier glucose lowering effect, and shorter duration of action.

So… if Novolog is considered “rapid-acting” insulin, and Fiasp is considered “ultra-rapid-acting” insulin, AT247 must be “ultra-ultra-rapid-acting” insulin. We can only hope the developer comes up with a better name.

Speaking of Fiasp, a study comparing Fiasp to traditional Novolog in Medtronic’s next-generation 780G advanced hybrid closed-loop pump showed slight (but not significant) improvements in average glucose, post-breakfast (but not lunch or dinner – see graph below) glucose control and overall time in-range. Concerns persist over the long-term use of Fiasp in pumps, as many cases of site/absorption irregularities have been reported.

Research was also presented on a once-weekly basal insulin. Why pursue a once-weekly insulin? Other than the obvious convenience and improved chances for user adherence, such an insulin would produce less day-to-day variability in insulin levels (and hence less risk for hypo- and hyperglycemia). Novo Nordisk announced results from a 26-week phase 2 clinical trial of Icodec once-weekly basal insulin in adults with type 2 diabetes. Icodec achieved similar blood sugar control and a similar safety profile compared to once-daily glargine U100. Icodec is 7X as concentrated as glargine, so the dosing is similar for once-weekly Icodec as once-daily glargine. However, the overall dose of Icodec is slightly lower when used over time. Icodec owes its prolonged activity to reduced breakdown in the bloodstream and a circulating depot of temporarily inactive insulin in the body.

Lilly just received FDA approval on their version of an ultra-rapid insulin called Lyumjev (if you can pronounce it, you get a free lifetime supply). Lyumjev is essentially lispro (Humalog) with two ingredients to help it absorb a little bit faster: citrate (which increases blood vessel premability) and treprostinil (which acts as a vasodilator). Fiasp does the same, but with aspart (Novolog) as the insulin, and niacinamide as the vasodilator.

Compared to Humalog, Lyumjev appears in the bloodstream 5-10 minutes earlier, has much greater effect in the first 15-30 minutes, and clears a bit sooner.

A 52-week study of Lyumjev showed no change in A1c or hypoglycemia, but 10-15 mg/dl reductions in post-meal glucose levels (at 1-2 hours) compared to Humalog. A 4-week study of Lyumjev in pump therapy showed no differences in average glucose, post-meal control, time in-range or time above or below target range.

And finally, MannKind reported the results of a long-term study on the effects of Technosphere (Afrezza) on pulmonary function. Essentially, no significant issues were detected. After two years of use, 98% of Afrezza users had no persistent or significant decline in forced expiratory volume (FEV), compared to 99% of non-users.

It is well-understood that sleep deprivation causes insulin resistance, which makes diabetes harder to control. Sleep that is often interrupted can also be problematic, as this limits the amount of time spent in non-REM Stage 3 sleep – the stage when the body relaxes, restores and refreshes.

As the graph below indicates, the percent of sleep time spent in stage 3 sleep correlates with a tighter A1c.

Additional studies have shown that sleep inconsistency – varying bedtimes and wake times – correlates with a rise in A1c, average glucose, and time out of one’s target range.

Unfortunately, 50-70% of adolescents do not achieve recommended sleep patterns. Children with T1D are 3X more likely and adolescents with T1D are 6X more likely than kids without diabetes to experience too little sleep. In addition to insufficient sleep, young people with T1D also experience higher rates of sleep apnea – particularly when glucose is not well-managed.

Insufficient sleep causes a cascade of behaviors that can hinder diabetes management. Daytime sleepiness often leads to poorer food choices (particularly frequent & unhealthy snacks), less exercise, higher levels of stress, missed mealtime insulin doses, and fewer blood sugar checks. And sleep deficiency is known to increase cortisol levels in the evening and growth hormone levels overnight – both of which cause glucose levels to rise.

Strategies that have been shown to improve sleep duration and quality in young people (and likely in adults as well) include:

• Turning on the lights or opening window shades upon waking
• Changing out of sleep clothes upon waking
• Regular exercise in the morning or afternoon
• Getting outdoors during daylight hours each day
• Avoiding naps during the day. If you must nap, limit it to 45 minutes, and prior to 4pm.
• Avoiding heavy/spicy/caffeinated snacks at night
• Treating any nighttime lows with caffeine-free foods
• Minimizing unnecessary alarms from pumps & CGMs during the night

Microbiome refers to the delicate bacterial balance that exists in the digestive tract. Recent research on the microbiome has investigated the role gut bacteria play as a potential risk factor in developing type 1 diabetes (T1D). To date, there have been four studies exploring the association between gut microbiome diversity and the incidence of T1D in high risk populations. Three of the 4 studies showed an association between specific bacterial strains and microbiome diversity with the of risk developing of T1D. Specifically, there was a strong association between development of T1D and a large population of Bacteriodes dorei in the gut.   There is also some evidence linking the genetic makeup of the microbiome to protective bacterial strains and possible genetic markers for autoimmunity.

The recent TEDDY study did not find an association between microbiome diversity and the risk of developing T1D in a high-risk infant population. However, the TEDDY results showed that prior to an infant’s first birthday, it is possible to manipulate the microbiome diversity and perhaps affect long term health outcomes.

Researchers are also investigating the microbiome as a potential treatment for T1D. A soon-to-be-published study in Australia investigated the effect of a high fiber diet on a small cohort of people with T1D. The researchers used short chain fatty acids in the diet to increase SCFA acetate and butyrate microbes in the gut for 12 weeks. Results included an association between high acetate levels and lower HbA1C values. In addition, increased levels of butyrate were associated with an increase in insulin sensitivity and lower basal insulin requirements.

Fecal transplants have also been investigated as a potential T1DM treatment. Recently, a small study focused on newly diagnosed persons with T1DM and found a positive association between fecal transplants and an extended honeymoon period. This positive association was only seen with subjects who received self-donated fecal transplants and was not seen in subjects who received a donor fecal transplant.

Abbott has announced a partnership with Insulet to eventually pair the Libre sensor with the OmniPod Horizon hybrid closed loop system. Insulet already has a partnership with Dexcom. Insulet is hoping to launch their Omnipod 5/Horizon system in the second half of 2021.

Abbott also received approval of the Libre 2 in the US for ages 4 and up. Libre 2 is a 14-day sensor that transmits data to a receiver every minute and includes customizable high/low alerts without having to “scan” the sensor.

Zealand Pharma acquired Valeritas, signaling potential inclusion of Zealand’s dasiglucagon in the V-Go patch pump.

Lilly received FDA clearance for Lyumjev, their ultra-rapid insulin analog.

Pump maker Ypsomed and glucose management platform Livongo announced partnerships with Dexcom.

Companion Medical, makers of InPen, announced a collaborative agreement with Senseonics, makers of the implantable Eversense glucose sensor. Companion also received FDA clearance for use with Fiasp insulin, as well as an updated bolus calculator for meal dose estimation (designating meals as small/medium/large).

Roche launched a cloud-based platform for healthcare professionals allowing remote visualization of diabetes data.

Tandem’s Control IQ hybrid closed-loop system received clearance for ages 6 and up.

Medtronic received a CE mark and can begin marketing their 780G Advanced Hybrid Closed Loop System in Europe. Medtronic also presented data on their new 7-day infusion set which features better adhesive and a new tubing connector which improves insulin stabilization. The set worked for a full week without compromising glucose control for approximately 80% of test subjects.

Lifescan announced the launch of the OneTouch Verio Reflect meter, which analyzes fingerstick glucose data and provides real-time feedback to the user based on patterns detected