This year’s Diabetes UK Professional Conference brought renowned thought leaders from around the world to Manchester, UK. We were keen to hear commentary on new drug classes like SGLT-2 inhibitors and GLP-1 agonists, on new insulins and how they’re changing best practice diabetes management, on closed loop and the bihormonal bionic pancreas, and much more – the researchers didn’t disappoint. This full report covers some of the meeting’s most notable sessions, posters, and exhibits, in our opinion. Before you get to our detailed discussion and commentary, here’s a quick take on what we thought were five of the most interesting points from the conference (with lots of competition!).
Top Five Highlights
1. Dr. John Petrie presented highly-anticipated full renal results from the LEADER trial of Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). In a separate session, Dr. Christoph Wanner (a very well-respected voice on microvascular complications of diabetes) emphasized the importance of liraglutide’s renal benefit – the agent now joins empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) as a type 2 diabetes therapy capable of renal protection, which is tremendously exciting from both a patient and systems perspective.
2. In the exhibit hall, we spoke to reps at Novo Nordisk about plans to launch Fiasp (faster-acting insulin aspart) swiftly in the UK at a price on par with NovoRapid (pricing will be key for any new diabetes therapy released today, and especially for insulin products). We also learned some logic behind the company’s strategy to continue prioritizing Tresiba (basal insulin degludec) and Victoza (GLP-1 agonist liraglutide) for now, rather than allocating major resources to their combination, Xultophy (insulin degludec/liraglutide).
3. A poster highlighted promising clinical evidence for GI Dynamics’ EndoBarrier device. Dr. Bob Ryder shared his perspective on why this is an important therapeutic option for type 2 diabetes and obesity, making a point that continues to stick with us – there’s a population of patients for whom nothing seems to work (not insulin, not GLP-1 agonists, not dedicated lifestyle modification), and here the risk of not acting outweighs any adverse events associated with EndoBarrier. We’re very impressed that renowned obesity thought leader Dr. David Cummings has recently joined their board.
4. Dr. Monika Reddy presented additional data from the I HART CGM study comparing Dexcom’s G5 (CGM) vs. Abbott’s FreeStyle Libre (flash glucose monitoring). She showed how the G5 is associated with less time spent in hypoglycemia vs. the FreeStyle Libre, while the two products perform similarly on time-in-range and time spent in hyperglycemia.
5. Friday’s packed hot topics sessions featured engaging talks on some controversies in diabetes care, including the practicality of type 2 diabetes reversal by medical methods (by Dr. Roy Taylor) and the use of SGLT-2 inhibitors in type 1 diabetes (by Dr. Parth Narendran).
Dive into all this coverage and more, below! We’re missing Manchester already, but at least we can look forward to next year’s Diabetes UK Professional Conference in London!
Detailed Discussion and Commentary
Cardiovascular Risk and Outcomes
liraglutide and Renal Outcomes in Type 2 Diabetes: Results of the LEADER trial
John Petrie, MD (University of Glasgow, Scotland)
Glasgow’s Dr. John Petrie presented highly-anticipated full renal data from the LEADER trial of Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). Topline renal results were included in the ADA 2016 LEADER presentation: liraglutide therapy was associated with a 22% risk reduction (p=0.003 vs. placebo) for the composite renal outcome, comprised of (i) new-onset persistent macroalbuminuria, (ii) persistent doubling of serum creatinine, (iii) end-stage renal disease (ESRD), and (iv) death due to renal causes. Dr. Petrie acknowledged that this benefit was largely driven by new-onset macroalbuminuria – risk for this first component of the composite outcome was 26% lower with liraglutide vs. placebo (p=0.004). For the first time, Dr. Petrie shared data for the other components of the composite renal outcome. Risk reduction for doubling of serum creatinine and for renal replacement therapy (indicating ESRD) trended in a positive direction in favor of liraglutide, but did not reach statistical significance: 2x serum creatinine risk declined by 11% (HR=0.89, 95% CI=0.67-1.19), while risk for renal replacement therapy declined by 13% (HR=0.87, 95% CI=0.61-1.24). The hazard ratio point estimate for death due to renal disease was 1.59, favoring placebo. However, the finding was not statistically significant (95% CI=0.52-4.87) and the event rate across both groups was very low (eight deaths accounting for 0.2% of liraglutide-treated participants vs. five deaths accounting for 0.1% of placebo-treated participants). Dr. Petrie also pointed out that if investigators had seen a reverse imbalance in renal deaths (favoring liraglutide), no one would have claimed a benefit on this endpoint. The wide confidence interval and low event rate are highly-reassuring, though we would nonetheless love to see more details on the specific characteristics of the participants who died during the trial – is risk for renal death something that can be predicted and managed through careful selection of the appropriate patient population for liraglutide therapy? These numbers overall seem very low so we are not sure of course of the significance, if any, at this stage. Participants in the placebo arm of LEADER were receiving standard of care for both CV risk factors and renal risk factors.
- Liraglutide demonstrated a sparing effect on natural, gradual decline in renal function. On average, eGFR dropped for patients in both the treatment and placebo arms of the LEADER trial, but declined slightly less (~2% less) for people on liraglutide at 48 months (p=0.013).
- Individuals with lower baseline kidney function benefited the most from liraglutide on renal endpoints. Dr. Petrie showed four graphs depicting decline in eGFR over time for four sub-groups divided by baseline eGFR: >90, 60-90, 30-59, or <30 ml/min/1.73m2. The latter sub-group, with most impaired glomerular filtration at study start, experienced the greatest magnitude of renal benefit, or the greatest slowing of renal decline over the course of the study. This particular sub-analysis was not pre-specified, so Dr. Petrie underscored that it is only hypothesis-generating.
- This analysis also probed for safety signals surrounding kidney failure, and found 234 total events in the liraglutide group vs. 262 events in the placebo group (5% event rate vs. 5.6% event rate, respectively). Acute kidney injury was more frequent in the liraglutide arm (111 events or 2.4% event rate) vs. the placebo arm (99 events or 2% event rate), but this did not reach statistical significance. Similarly, there were 20 cases of renal impairment among liraglutide-treated patients (0.4% event rate) and only 15 cases among placebo-treated patients (0.3% event rate), but this correlation did not reach statistical significance. Increase in blood creatinine occurred in 16 liraglutide patients and 13 placebo patients (both 0.3% event rates). Proteinuria and renal failure were each more common in the placebo group.
- Dr. Petrie attributed liraglutide’s overall microvascular benefit entirely to its lowering of nephropathy risk. As presented at ADA 2016, time to first microvascular endpoint, either nephropathy or retinopathy, was delayed by 16% for patients on liraglutide (p<0.05). Dr. Petrie reviewed that retinopathy risk trended against the active agent in the LEADER trial (HR=1.15) but did not reach statistical significance.
- Dr. Petrie emphasized that mechanism of renal protection is still up for speculation and debate. He shared that some mechanistic studies suggest that renal benefit is largely independent of A1c-lowering and weight loss, but rather has something to do with receptors on the kidney itself. We’re impressed by the renal data thus far, and we look forward to further commentary from endocrinologists and nephrologists on potential mechanisms. We’re also particularly interested in learning how much overlap the potential mechanism of renal protection for liraglutide might have with the mechanism of renal protection for SGLT-2 inhibitor empagliflozin. Our sense is, given the two divergent effects of atherosclerotic disease and heart failure, the mechanisms may very well be entirely separate. In that case, we’d be especially interested to learn if there may be additive renal benefits to co-administration of liraglutide and empagliflozin – or possibly even synergistic.
- Dr. Christoph Wanner (University of Würzburg, Germany) also discussed this data during an earlier session at Diabetes UK, placing it into context with renal findings from the EMPA-REG OUTCOME study (of Lilly/BI’s SGLT-2 inhibitor Jardiance [empagliflozin]). He concluded that renal protection with liraglutide is not as “impressive” or clinically-meaningful as renal protection with empagliflozin, but that it is still statistically significant. And, he noted that it’s exciting to see some positive effects on the kidneys with liraglutide therapy as well.
Novel Approaches to Treatment
Impact on Hypoglycemia Awareness of Real Time Continue Glucose Monitoring and Intermittent Continous Glucose Data (I HART CGM)
Monika Reddy, MD (Imperial College London, UK)
Dr. Monika Reddy presented data from the I HART CGM study (n=40) comparing Dexcom’s G5 (n=20) vs. Abbott’s FreeStyle Libre (n=20) in adult, CGM-naïve type 1 diabetes patients with impaired hypoglycemia awareness (Gold score ≥4). The findings largely matched what we first heard at EASD 2016, when Dr. Nick Oliver (Imperial College London, UK) discussed interim results (n=32) – Dexcom’s G5 did markedly better in this small study on the primary hypoglycemia endpoint of time spent with blood glucose <60 mg/dl. Participants using CGM spent a mean 7.7% of time <60 mg/dl at baseline, which dropped to 3.5% in the last four weeks of the eight-week trial (p=0.004). Participants using FreeStyle Libre spent 7% of time <60 mg/dl at baseline, which actually increased to 7.8%, though this did not reach statistical significance (p=0.433). This amounts to a 4.8% difference in favor of the G5 (p=0.004). Similarly, overnight, time spent <60 mg/dl fell from 9.6% to 4% for the G5 group (p=0.002) and increased from 8.6% to 11% for the FreeStyle Libre group (p=0.339), which amounts to an 8% difference in favor of the G5 (p=0.001). Time-in-range (70-180 mg/dl) increased for all participants, with no statistically significant difference between the two arms: from 53.6% to 63.4% in the Dexcom G5 arm (p=0.007) and from 54.8% to 60.9% in the Abbott FreeStyle Libre arm (p=0.001). Time spent in hyperglycemia also improved across the board, with no statistically significant interactions between G5 vs. FreeStyle Libre. Dr. Reddy’s last piece of data was regarding the Hypoglycemia Fear Survey, which investigators administered at baseline and again at week eight – the mean absolute difference in change of score (reflecting a lessening of fear) was 9.8 points in favor of Dexcom’s G5 (p=0.04). Dr. Reddy concluded that real-time CGM (vs. intermittent flash glucose monitoring) has a beneficial impact on hypoglycemia outcomes and in reducing hypoglycemia-related fear. She explained this benefit using the same vocabulary as Dr. Oliver at EASD – Dexcom’s G5 is “reactive” (especially considering the alarms feature) while Abbott’s FreeStyle Libre is more “reflective.” In our view, the major implication of this data is not that one product is decidedly better than the other, but rather that we need to appreciate the unique aspects of diabetes devices and match them to the unique needs of the individual patient (important knowledge for patients, providers, and payers, alike).
- The trend for the primary endpoint held true for various thresholds of hypoglycemia, both overall and overnight, with Dexcom’s G5 showing superiority.
- Time <70 mg/dl dropped from 11.5% to 7.2% in the G5 arm (p=0.006) and increased from 11.2% to 12.5% in the FreeStyle Libre arm (p=0.372). The mean absolute difference in change in time was 5.6% in favor of the G5 (p=0.008 for the interaction).
- Time <50 mg/dl dropped from 5% to 1.6% in the G5 arm (p=0.004) and increased from 4.3% to 4.9% in the FreeStyle Libre arm (p=0.401). Mean absolute difference was 4% in favor of the G5 (p=0.003 for the interaction).
- Overnight, time <70 mg/dl dropped from 13.5% to 7.5% in the G5 arm (p=0.003) and increased from 13% to 16.1% in the FreeStyle Libre arm (p=0.179), leading to a mean absolute difference of 9.1% in favor of the G5 (p=0.003 for the interaction).
- Overnight, time <50 mg/dl dropped from 6.8% to 2.1% in the G5 arm (p=0.003) and increased from 5.4% to 7.6% in the FreeStyle Libre arm (p=0.059), leading to a mean absolute difference of 6.7% in favor of the G5 (p<0.001 for the interaction).
- Time-in-range results were similar for patients using Dexcom’s G5 and those using Abbott’s FreeStyle Libre (no statistically significant interactions).
- Time between 70-140 mg/dl rose from 36.5% to 42.9% among G5-users and from 37.5% to 41.3% among FreeStyle Libre-users, though neither of these improvements reached statistical significance.
- Time between 70-180 mg/dl rose from 53.6% to 63.4% among G5-users (p=0.007) and from 54.8% to 60.9% among FreeStyle Libre-users (p=0.001)
- Overnight, time between 70-140 mg/dl rose from 32.8% to 41.2% among G5-users (p=0.012) and from 37.2% to 40.4% among FreeStyle Libre-users (p=0.238, not meeting the threshold for statistical significance).
- Overnight, time between 70-180 mg/dl rose from 51.6% to 62.3% among G5-users (p=0.009) and from 52.8% to 59.6% among FreeStyle Libre-users (p=0.038).
- Time spent in hyperglycemia was also similarly affected by both glucose monitoring devices (no statistically significant interactions).
- Time >140 mg/dl fell from 52% to 49.9% in the G5 group and from 51.4% to 46.2% in the FreeStyle Libre group, though neither of these improvements reached statistical significance.
- Time >180 mg/dl fell from 34.8% to 29.4% in the G5 group (p=0.104, not meeting the threshold for statistical significance) and from 34% to 26.6% in the FreeStyle Libre group (p=0.007).
- Time >270 mg/dl fell from 11.9% to 7.3% in the G5 group (p=0.005) and from 9.3% to 5.1% in the FreeStyle Libre group (p=0.009).
- Overnight, time >140 mg/dl fell from 53.6% to 51.3% in the G5 group and from 49.8% to 43.5% in FreeStyle Libre group, though neither of these improvements reached statistical significance.
- Overnight, time >180 mg/dl fell from 34.9% to 30.2% in the G5 group (p=0.228, not meeting the threshold for statistical significance) and from 34.2% to 24.3% in the FreeStyle Libre group (p=0.01).
- Overnight, time >270 mg/dl fell from 11.8% to 7.7% in the G5 group (p=0.07, not meeting the threshold for statistical significance) and from 9.7% to 3.8% in the FreeStyle Libre group (p=0.009).
GLP-1 and SGLT-2: Changing Paradigms in Prevention of Complications of Diabetes?
Review of Relevant Studies and Summary of Microvascular Outcomes
Christoph Wanner, MD (University of Würzburg, Germany)
Dr. Christoph Wanner summarized major renal findings from EMPA-REG OUTCOME and presented some yet-unpublished renal data from LEADER, highlighting the positive renal benefits of empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) and liraglutide (Novo Nordisk’s GLP-1 agonist Victoza), respectively. A manuscript on renal outcomes in LEADER is still in process, but Dr. Wanner shared early results: Over four years, as reported at ADA 2016, liraglutide treatment reduced risk for the composite endpoint of new-onset macroalbuminuria, doubling of serum creatinine, end-stage renal disease, or renal death by 22% (p=0.003). The composite outcome was driven primarily by a reduction in risk of new-onset macroalbuminuria alone, which declined by 26% (p=0.004). On the other hand, neither of the risk reductions of the other two components of the composite endpoint reached statistical significance: risk of 2x serum creatinine declined by 11% (HR=0.89, 95% CI=0.67-1.19) and need for renal replacement therapy declined by 13% (HR=0.87, 95% CI=0.61-1.24). The hazard ratio point estimate for death due to renal disease was 1.59, favoring placebo. Reassuringly, this finding was not statistically significant (95% CI=0.52-4.87) and the event rate across both groups was very low (eight deaths accounting for 0.2% of liraglutide-treated participants vs. five deaths accounting for 0.1% of placebo-treated participants). This data was also the subject of an oral presentation by Dr. John Petrie (University of Glasgow, Scotland) on Thursday afternoon. We’re very eager for these renal LEADER results to be unpacked further, and to hear hypotheses for potential mechanism. Dr. Wanner’s overarching takeaway from this preliminary data is that renal protection with liraglutide is not as “impressive” or clinically-meaningful as renal protection with empagliflozin, but that it is still statistically significant. He noted that it’s exciting to see some positive effects on the kidneys with liraglutide therapy as well. Dr. Wanner also reviewed the renal data from EMPA-REG OUTCOME that he first presented at ADA 2016 and EASD 2016 – given the encouraging results across subgroups (baseline kidney function, age, sex, race, BMI, diabetes duration, blood pressure, etc.) we’d love for Lilly/BI to initiate a dedicated renal outcomes trial for Jardiance and potentially pursue a diabetic nephropathy indication given the high unmet need in this area.
- Regarding EMPA-REG OUTCOME, Dr. Wanner acknowledged that A1c reduction is not as robust in patients with eGFR <60 ml/min/1.73m2, but emphasized that outcomes are still highly favorable in this sub-population. Among patients with eGFR >60 ml/min/1.73m2, A1c drops from a mean baseline of 8.1% to a mean 7.3%. This change is smaller in magnitude among patients with eGFR <60 ml/min/1.73m2, falling from 8.0% to 7.6% on average. However, this latter subgroup of patients with baseline kidney dysfunction still experiences a 30% risk reduction for CV death with empagliflozin vs. placebo (p=0.0265). Dr. Wanner thus argued that Jardiance “appears to work below the eGFR listed on the label” (the FDA-approved label contraindicates the drug for anyone with eGFR <45 ml/min/1.73m2). Again, we’d love for a dedicated renal outcomes study to clarify this, thereby allowing a maximum number of patients to benefit from empagliflozin therapy.
Questions and Answers
Q: Clearly the data is stunning in terms of stabilizing eGFR. Presumably, we’re wrong to judge empagliflozin as a successful drug for A1c-lowering within the 30-60 ml/min/1.73m2 eGFR range. Is that a reasonable conclusion?
A: Yes, that’s what it looks like in the data.
Q: How many patients in EMPA-REG OUTCOME had a urinary tract infection (UTI)? Did the investigators select for participants with normal or high BMI? I’m interested because empagliflozin produces weight loss as well.
A: The only exclusion criteria for EMPA-REG OUTCOME was that individuals with BMI >45 kg/m2 were not allowed to enter the trial. Nearly one-third of people in the empagliflozin cohort had a UTI, so that’s quite substantial, but note that the UTI rate was similar in the placebo group. Genital infections are the other concern when it comes to SGLT-2 inhibitors, and these were much higher in the empagliflozin group: 1/10 women and 1/20 men. The issue here is hygiene, hygiene, hygiene and also water, water, water. If you have repeated episodes of genital infection, you may stop using the drug.
Q: If these renal effects are not glucose-driven, presumably we’d see the same benefits in type 1 diabetes as well?
A: Yes, in type 1 diabetes, I think empagliflozin works well. However, randomized clinical trials with type 1 diabetes are still ongoing, so no consensus yet exists. We were a bit hesitant when we first saw the DKA side-effects in type 1 patients, and later on we also saw a few DKA episodes in type 2. We need more experience before we can include type 1 diabetes in this discussion, but it is my thinking that the SGLT-2 inhibitor will work in a similar way.
Q: Is there any plan to look at inflammatory markers, particularly fibrosis markers, with empagliflozin treatment?
A: Unfortunately, there was no bio bank behind this study. Many smaller, investigator-driven trials are ongoing to look at these markers, but thus far we have no clear signal. We believe the effect is mediated by salt effects in the kidney – hyperfiltration and intraglomerular pressure come down, which leads to the renal protection.
Q: Can you speak to any data on empagliflozin in patients older than 70? What evidence do we have on the drug’s impact on patients when they’re fasting? We’re coming up to the month of Ramadan.
A: There were >500 patients older than 75 in EMPA-REG OUTCOME – they achieved the same outcomes, based on the data collected. You should be cautious when fasting, especially because when you reduce your insulin dose and continue taking an SGLT-2, ketone bodies could come up. We have a consensus saying that if you go into elective operation, or if you’re experiencing high fever or dehydration, you should stop SGLT-2 inhibitors for a couple of days. This could apply as well to people observing Ramadan and on insulin.
Q: What can you say about empagliflozin on top of treatment with ACE inhibitors and/or ARBs (angiotensin receptor blockers)?
A: In EMPA-REG OUTCOME, 80% of participants were on ACE inhibitors or ARBs. The forest plot shows that if you combine empagliflozin with an ACE or an ARB, you see an even better risk reduction than you see with any agent alone. But, this is not highly significant and can only be considered hypothesis-generating.
Summary of Macrovascular Outcomes and Review of Underlying Mechanisms
Naveed Sattar, MD (University of Glasgow, Scotland)
Dr. Naveed Sattar dove deep into the possible mechanism of cardioprotection associated with SGLT-2 inhibitors (namely, Lilly/BI’s empagliflozin) and GLP-1 agonists (namely, Novo Nordisk’s liraglutide and semaglutide). Based on the early divergence of the Kaplan-Meier curves in EMPA-REG OUTCOME, and given the “unusual pattern” of CV effects – significantly reduced risk for three-point MACE and CV death, nonsignificant reduction in MI, and nonsignificant increase in stroke – Dr. Sattar ruled out an atherosclerotic effect and instead proposed a hemodynamic one. He explained this possible mechanism (outlined in his 2016 Diabetologia paper) in terms of the cardio-renal axis: (i) SGLT-2 inhibition lowers glucose/sodium reabsorption in the kidneys and reduces hyperfiltration in the nephrons, which has a direct influence on slowing renal dysfunction; (ii) SGLT-2 inhibition also increases glucose/sodium concentration in the urine, leading to intravascular decongestion which contributes to lower cardiac pre- and after-load, systolic and diastolic dysfunction, heart failure hospitalization risk, and in turn, potentially, fewer fatal arrhythmias; (iii) Dr. Sattar suggested that this bucket of cardiac effects may also circle back to slow renal dysfunction. In contrast to the results from EMPA-REG OUTCOME, Dr. Sattar suggested that, based on what we’ve learned from statin trials, drugs with an atherosclerotic effect would demonstrate a divergence in Kaplan-Meier curves around several months, and there would be a more consistent impact on risk reduction across non-fatal MI, non-fatal stroke, possibly CV death, and three-point MACE – these features more closely fit the data from LEADER (divergence of the Kaplan Meier curves at 12-18 months) and SUSTAIN 6. Dr. Sattar attributed the cardioprotection found in these CVOTs to an atherothrombotic effect, or accumulating benefits from blood pressure decline, glucose lowering, weight loss, and perhaps direct actions of the GLP-1 hormone (although he pointed out that less hypoglycemia in LEADER may also be relevant). He concluded that reducing blood glucose in general is advantageous for CV disease, but the way in which specific drugs lower glucose and their ancillary effects are also important, and could help providers identify which cardioprotective agent is best for the individual patient.
- Will other SGLT-2 inhibitors show the same “unusual pattern” as empagliflozin? We won’t have to wait much longer for an answer, Dr. Sattar reminded us – CANVAS for J&J’s Invokana (canagliflozin) is scheduled to report full results at ADA 2017. He expressed confidence that we’ll see highly-similar results in CANVAS and EMPA-REG OUTCOME, which echoes some slight optimism some have interpreted from J&J management.
- Results from the EXSCEL trial for AZ’s Bydureon (exenatide once-weekly) will similarly enrich our understanding of how GLP-1 agonists reduce CV risk, and according to Dr. Sattar, some data could be presented at EASD 2017 (this year in Lisbon, Portugal). According to ClinicalTrials.gov, the study is expected to complete in April 2018. We continue to look very forward to this data.
Questions and Answers
Q: How does this drug reduce cardiac after-load?
A: I’m not a cardiologist, but I’ve had long discussions about this. I think you’re right – that the predominant effect is probably pre-load – but there’s likely some influence by after-load as well. Recent papers point to this.
Clinical Relevance and Application to the Diabetic Patient
David Matthews, MD (Oxford University, UK)
Following two very positive discussions of GLP-1 agonists, SGLT-2 inhibitors, and their impact on micro- and macrovascular outcomes, Oxford’s Dr. David Matthews (one of our favorite thought leaders ever) offered some qualifying commentary. He argued that we should be “pragmatic but not cynical” in applying findings from EMPA-REG OUTCOME, LEADER, and SUSTAIN 6 to real-world patients. He focused on the fact that patients enrolled in these CVOTs were at exceptionally high risk for CV events, unlike the average person with diabetes walking into a clinic. In LEADER, 82% of participants had established CV disease, 33% already had an MI, 15% had prior stroke or TIA (transient ischemic attack), and 40% has prior revascularization. In SUSTAIN 6, average baseline body weight was quite high (~202 lbs +/- 45 lbs), 60% of participants had existing ischemic heart disease, and 32.5% already had a heart attack. A similar group of high-risk patients was enrolled in EMPA-REG OUTCOME – Dr. Matthews pointed out that you’d have to read section C of the supplementary appendix in the NEJM publication for a comprehensive list of baseline characteristics. Given that CV risk reduction might not be as pronounced for a real-world patient as it appears in these clinical trials, Dr. Matthews highlighted other important considerations for real-world treatment decisions: For one, these therapies are expensive – “you’ve really got to look at resources, because these drugs are not cheap.” The injection burden associated with GLP-1 agonists, along with the GI side-effects, might deter some patients, he said – we agree, particularly if their doctors are not well-trained (what a bummer for patients). Moreover, SUSTAIN 6 found a 76% increased risk for retinopathy with semaglutide vs. placebo (p=0.02) – we think the numbers are pretty small at this point to draw conclusions (look at DCCT early results!) though we agree this is hardly reassuring. As we heard from Novo Nordisk management during the company’s 3Q16 earnings call, Dr. Matthews explained that retinopathy was likely due to very rapid reductions in blood glucose, but used this to further his point that providers should be careful in initiating patients on a GLP-1 agonist (starting with a low dose, and not starting too early before the patient is well-informed of this microvascular risk – we agree though we doubt most patients are going to figure out on their own what to do!). SGLT-2 inhibitors come with their own side-effects, including genital mycotic infections, heightened risk of bone fracture, and elevated DKA risk in type 1 diabetes (which could result in poor outcomes if not managed – but the management is pretty easy). Dr. Matthews urged providers to “be realistic about who your patients are” and to manage expectations. We aren’t really sure based on any of these thoughts that anyone should not get an SGLT-2 if they would benefit in the short-term – the long-term benefit is still very striking to us given how enormously much is spent on CV disease and kidney disease – even in the UK! He ended on an optimistic note, suggesting that as we build a database of real-world findings – in both high- and low-risk populations – we’ll be able to form stronger conclusions on the efficacy of GLP-1 agonists and SGLT-2 inhibitors across the spectrum of patients with diabetes. Agreed – and to develop this database, real patients will need to be on these drugs for significant periods of time.
- Dr. Matthews also suggested that upcoming CVOT results might better inform cardioprotective class effects and could make a more compelling case for use of these advanced agents in all type 2 diabetes patients. CANVAS and CANVAS-R for J&J’s Invokana (canagliflozin) are slated to report at ADA 2017, and will shed more light on CV and renal benefits of SGLT-2 inhibitors. The EXSCEL trial (scheduled to complete in April 2018) for AZ’s Bydureon (exenatide once-weekly) will add to our understanding of CV outcomes associated with GLP-1 agonist therapy, although Dr. Matthews pointed to skepticism within the field on a cardioprotective class effect for GLP-1 agonists due to resoundingly neutral results from ELIXA for Sanofi’s Lyxumia (lixisenatide). We don’t think much can be said about a class effect so far since different manufacturers used different populations and were at different degrees of being “in a hurry”. We’d love to see another CVOT study diabetes and pre-diabetes and heart disease and look at GLP-1 and SGLT inhibitors.
- While we appreciated Dr. Matthew’s remarks on the need to manage expectations and be practical in prescribing these relatively new therapies, we worry that if anything, too few providers are recognizing the potential long-term value of GLP-1 agonists and SGLT-2 inhibititors. Pooled sales for the SGLT-2 class didn’t grow as rapidly as we would’ve expected following EMPA-REG OUTCOME. We hope that sales and volume growth pick up again, now that the FDA has approved a CV indication for Jardiance. But ultimately, we see tremendous need for education on the CV effects of diabetes drugs so that more people can reap the benefits of CV and kidney risk reduction when it’s been clearly demonstrated.
- Given the massive investment of time and resources that go into a CVOT, it’s no wonder that investigators thus far have enrolled high-risk participants. Yes, this means CV benefit will be demonstrated on an expedited timeline. And yes, there are caveats to what we can extrapolate from a clinical study of high-risk individuals to the real-world diabetes population. That said, we think it would truly be a shame to hinder patients from any potentially life-changing therapy that could lower their risk for CV events and CV death. Access concerns are critical, and very real – we hope to see better reimbursement in the near-future, so that patients can afford these medicines and so that payers and the healthcare system overall see cost-savings associated with better CV outcomes. To this end, we’re quite excited about what Dr. Matthews referred to as a database of real-world findings, which could add to the body of evidence showing the health and health economic advantages of a cardioprotective diabetes drug. We’re very interested in innovative, cost-effective methods of gathering evidence for clinical decision-making and hope that manufacturers and healthcare systems will take these ideas seriously into consideration.
Questions and Answers
Q: Even after taking into account your point that we have to select the right group of patients for these therapies, the data still implies a broad benefit, doesn’t it?
A: Indeed. That’s why I say “don’t be cynical.” It’s brilliant that we’ve got new agents that lower glucose without side-effects, and I hope cost will eventually come down. But we must be pragmatic about the patients we prescribe these drugs to in the moment. We’ll gradually garner more experience giving these agents to low-risk patients, collecting data that reflects the general population.
Q: Is it time to start all high-risk patients on an SGLT-2 inhibitor now? Or should we wait for more data?
A: No, I think it’s perfectly reasonable to start people at high-risk for CV events and especially CV death on empagliflozin. The EMPA-REG OUTCOME data is telling you that for people with really incipient cardiac failure and high risk factors, you’re going to see a really good outcome. You’re going to reduce their CV risk. I’m not trying to say that these trials are wrong – not at all. You’re saying what I’m saying – if you’ve got patients with extremely high risk for CV events, those are the individuals to start on SGLT-2s.
Hot Topics 1
Diabetes: Prevention and Reversal by Medical Methods
Roy Taylor, MD (Newcastle University, England)
The truly exciting work of Dr. Roy Taylor continues with the DiRECT trial – a two-year trial (now fully enrolled) to assess whether primary care can deliver remission of diabetes using a very low calorie diet. There is a reasonable amount of skepticism, particularly for the long term, but Dr. Taylor has previously done some careful work to demonstrate the mechanism of action and the feasibility of the intervention. His patients can lose 15 kg and discontinue all diabetes therapies. Dr. Taylor announced that we can expect full results from the first complete year by the end of 2017.
- The twin cycle hypothesis, presented 10 years ago, outlines a pathophysiology for type 2 diabetes, mediated by excess liver fat, which is in turn taken up by the pancreas, causing metabolic dysfunction over time. The two cycles are (1) positive calorie balance causes liver fat to increase, causing insulin resistance and increased insulin output. This creates a vicious cycle of fatty liver disease. (2) The spillover fat (as triglycerides) is taken up by pancreatic islets causing insulin resistance and another vicious cycle, which culminates in an acute insulin crisis and the diagnosis of type 2 diabetes. In a lecture last year, Dr. Taylor suggested that there is a ‘personal fat threshold’ below which these cycles normalize and therefore diabetes can be reversed, although it’s easier with less than ten year’s duration of diabetes.
- The inverse of this hypothesis suggests a path to resolving diabetes by rapid weight loss and normalization of liver and pancreatic fat. Dr. Taylor stated that patients achieve a 15kg weight loss after two months on an 800 kcal/day low calorie liquid diet, they immediately stop all hypoglycemic and anti-hypertensive agents on day 1 and rapidly normalize fasting plasma glucose. After transitioning to six months of normal eating, glucose and insulin remains normal. Superb in vivo imaging shows that intra-pancreatic fat levels fall and it is now known that this allows beta cell re-differentiation.
- Dr. Taylor commented that “believing this [works] … is perhaps an act of faith!” and so the DiRECT (Diabetes REmission Clinical) trial was commissioned to assess whether the results can be achieved in practice. It’s a remarkable result, and it’s clear that there was some skepticism from the audience that it could be translated into clinical practice.
- The DiRECT trial seeks to understand if primary care can achieve sustained substantial weight loss leading to long term diabetes remission, and to assess the popularity of the program. The primary outcome is the number of people achieving a 15kg weight loss at 12 months and the resolution of diabetes (A1c < 6.5%). The study randomized over 300 people with baseline A1c 7.8%, age 54 years, BMI 35 kg/m2, and average duration of diabetes of three years. Patients were not taking insulin. It was a popular trial - 27% of those invited wished to take part. The two-year intervention consists of visits every two weeks with a trained practice nurse or dietitian. The liquid low calorie diet is supplied by Cambridge Weight Plan. All oral hypoglycemic agents and anti-hypertensives are discontinued immediately. After weight loss, coaching is given on transitioning to a weight maintenance phase. The program is called Counterweight Plus. The trial completed recruiting in August 2016, so complete one year data is intended to be presented in December 2017.
- Somewhat surprisingly, the randomized patients already suffer from fatty liver disease. This is consistent with Dr. Taylor’s model. Liver fat was 15% (upper limit of normal is around 5%). Triglycerides were also elevated – in keeping with the model.
Questions and Answers
Q: What proportion are expected to respond (i.e. could resolve their diabetes)?
A: For the first four years post diagnosis, we expect 90% of people to respond. Of course, we have to have the diagnosis right, we have to exclude MODY, slow onset type 1 and pancreatic diseases. We expect everyone in the first three years will respond. By 10 years, this is down to about 60% who respond. I have even heard of one person responding at 24 years.
Q: Why did you exclude those on insulin?
A: We had to go through ethics committee who felt this was more difficult. We know that people do come off insulin fine. But for the purposes of this study, we need a homogeneous group. Also, people on insulin tend to have longer duration of diabetes.
Q; What is the role of physical activity?
A: We don’t allow exercise during the low-calorie phase because otherwise they will have compensatory over-eating. So, no exercise if you want to lose weight. But exercise is critical for keeping weight steady.
Q: In Torbay, we had a similar experiment, but after five years, there was total weight regain and even bouncing above baseline weight.
A: Yes, I am familiar with the observation that people rebound. Continuing support is necessary. We are applying for funding to allow follow-up out to five years.
Q: What is the role of literacy and numeracy?
A: We have observed that results in poorest areas of Newcastle are at least as good as the posh parts. I believe that it is about motivation.
Microbiome and Diabetes: Fact or Fiction?
Hilde Herrema, PhD (Academic Medical Center, Amsterdam, the Netherlands)
Dr. Hilde Herrema gave an up-to-date review of the microbiome. Her key points were that the diversity and composition of the microbiome is likely linked to obesity and diabetes, but the quality of the evidence and clarity around causality is a work in progress. In Amsterdam, her team is using fecal microbiota transfer (FMT) to study causality in humans. She has found that FMT influences insulin sensitivity, but there is a strong donor-recipient interaction. Some patients don’t respond because they don’t retain the profile of the donor bacteria. However, it’s believed that an analysis of existing recipient profile can be used to predict outcomes and provide personalized therapy.
- The microbiome is currently a hot topic. It’s been noted that the number of microbial cells in the body is equal to human cells. But the majority of genes are in the microbiome and are yet to be identified. The majority of the microbiome is in the GI tract.
- There are large differences in microbial composition over various life stages, because of diet, host genetics, the environment (housemates, pets) and medication (antibiotics, acid inhibitors). In infants there is a clear difference in composition between those breast fed and formula fed, but this then becomes similar once they start solid food. Old people have a fairly distinct composition too.
- The use of antibiotics is linked in many studies to obesity and diabetes. US antibiotic use by state correlates to obesity by state. There are studies showing that antibiotic use is retrospectively associated with weight gain in children. Adult data suggests that a greater number of courses of antibiotics affects the risk of diabetes. Antibiotics massively affect the composition of gut microbiota, but these changes don’t immediately reflect changes in the host metabolism. So, the issue has yet to be resolved.
- In obesity, there is a reduced bacterial diversity. Diversity is termed ‘gene count’. Subjects with ‘low gene count’ tend to be obese. In a 7 year follow up study, subjects with a low gene count were likely to gain more weight. Cohort studies are ongoing to link microbiota composition over time to outcomes.
- Fecal microbiota transfer (FMT) is being used to study causality in humans. Lean, highly screened donors provide a stool sample that is diluted with saline. Using a nasogastric tube, it is deposited in the proximal part of the ileum. It’s thought that this is the area of the GI tract which most determines metabolic effects. (The team doesn’t believe that prebiotics or transplants to the fecal compartment are particularly effective).
- Subjects receiving transplants from lean donors had improved insulin sensitivity vs control (who received their own FMT), but some subjects were found to be good responders and non-responders. It was found that there were large differences in how the profile of donor bacteria is retained. This is called engraftment. High engraftment correlates with the metabolic effects.
- Microbiota profile can be used by an algorithm to predict individual response to a glucose challenge. So it’s believed that existing diversity might predict the responsiveness to FMT interventions and help control for the donor-recipient interactions.
Chronic Kidney Disease in Diabetes: New Insights of Clinical Relevance
Luigi Gnudi, MD (King’s College, London, UK)
London’s Dr. Luigi Gnudi discussed kidney disease in people with diabetes and noted that some SGLT-2 inhibitors and GLP-1 agonists have protective renal effects. Indeed, we heard much about the renal benefits of SGLT-2 inhibitor empagliflozin and GLP-1 agonist liraglutide at this meeting. We’ve been surprised not to hear more about this topic in the US.
- Over a third (!) of people with with type 2 diabetes have impaired kidney function and it’s correlated with other complications. To avoid micro and macrovascular disease it’s important to start early (metabolic memory) and maintain good glycemic control.
- Many drugs are prohibited as kidney function declines, making metabolic control harder. But intensifying therapy in chronic kidney disease (CKD) has to be personalized based on risk of hypoglycemia. When the kidney doesn’t work well, patients with diabetes are at a higher risk of hypoglycemia. A1c sometimes even improves in ESRD. For patients on hemodialysis, the appropriate A1c target is around 7%.
- Blood pressure has to be managed in CKD without exception. A lower systolic blood pressure results in slower progression of kidney disease. New drugs such as endothelins and new mineralocorticoid receptor antagonists (MRA) are in the pipeline.
- Some SGLT-2 inhibitors and GLP-1 agonists provide renal protection (as well as an improvement in cardiovascular outcomes). In the EMPA-REG OUTCOME trial, empagliflozin cut renal hazard ratios in half. This is an exciting area for future work. We might see some class effects when all the data is in, Dr. Gnudi suggested.
Hot Topics 2
Adjunct Therapies in Type 1 Diabetes: An Update
Parth Narendran, MD (University of Birmingham, UK)
Dr. Parth Narendran spoke to the potential and challenges of the use of type 2 diabetes drugs for type 1 diabetes. We’re always eager to hear thoughts on this topic, though much uncertainty remains on the path forward given modest results from trials like ADJUNCT ONE and TWO for GLP-1 agonist Victoza (liraglutide) in type 1 diabetes. Back in the day, CGM wasn’t used (or it wasn’t the best tools available now) – we believe if these trials were done again, possibly with different dosing, benefit would be shown. Back then, the appropriate insulin dosing changes were not well understood, from our view. Overall, Dr. Narendran looked ahead with some optimism to two important trials: (i) DEPICT 2, AZ’s investigation of dapagliflozin in type 1, scheduled to complete in August 2017, which he called “the big study we need” to make a determination on the value and risk-benefit profile of SGLT-2 inhibitors for type 1 diabetes; and (ii) REMOVAL, an investigation of metformin in type 1, slated to report at ADA 2017. Whilst a phase 2 trial of empagliflozin in type 1 diabetes has already been conducted (Pieber 2015), Dr. Narendran suggested that DEPICT 2 will potentially have a stronger influence on the field since the trial is larger (enrolling >700 adults with type 1) and longer (52 weeks). We just hope the part of reducing insulin was carefully figured. He underscored that despite structured education, pump therapy, and new advanced insulins, we’re falling short of glycemic targets in type 1 diabetes care – so, we must give due consideration to adjunct therapies. We certainly echo that adjunct therapies for type 1 diabetes is an area of unmet need and therapies that can lower glycemic variability in a safe and tolerable manner would be enormously welcome.
- Patients care about glucose variability, and SGLT-2 inhibitors make for tighter CGM profiles. Dr. Narendran presented this as a key selling point for SGLT-2 inhibitors in type 1 diabetes. Indeed, J&J’s small study (n=351; 18 weeks) of Invokana (canagliflozin) in type 1 presented at ADA 2016 found striking reductions in glycemic variability and remarkably high patient satisfaction scores. Safety concerns, and especially elevated DKA risk in this patient population, are not to be overlooked, but several thought leaders including Dr. Anne Peters suggest that this risk can be managed with patient education on ketone monitoring and with lower doses. Fortunately, the J&J trial showed significant benefits at the lower dose of canagliflozin and we expect that the lower doses of SGLT-2 inhibitors – or even half-doses, as suggested by Dr. Peters – may become the norm for use in type 1 diabetes should the class gain popularity for this indication. DEPICT 2 is also investigating two doses of dapagliflozin (AZ’s Farxiga) – 5 mg and 10 mg daily – and we’ll be curious to see how the data compares to canagliflozin results.
- Dr. Narendran also highlighted results from the inTandem2 trial of Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. Once again, he reminded the audience that DKA risk is real, but can be managed by diligent ketone monitoring and avoidance of excess alcohol/dehydration. We’re quite excited about the inTandem clinical program, especially since Lexicon management has suggested that sotagliflozin could be filed for a type 1 indication ahead of type 2. As a result, sotagliflozin could potentially become the first oral adjunct therapy to insulin indicated for type 1 diabetes – a huge win for Lexicon, Sanofi, and the diabetes field as a whole.
- Dr. Narendran briefly reviewed results from ADJUNCT ONE, which investigated Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) in type 1 diabetes. The company later decided not to pursue a type 1 indication for Victoza, at least at present – we expect due to part to the drug’s safety profile in type 1 diabetes, including the increased risk for ketosis and DKA found in the trial – leaving some with a sense of bleak prospects for GLP-1 agonists as adjunct type 1 therapies. Dr. Narendran discussed an important post-hoc analysis of ADJUNCT ONE, which found that the benefits were greater – and the risks of ketosis and hypoglycaemia much lower – in type 1 patients with some evidence of residual beta cell function. He described a need for further stratification of patients with type 1 diabetes on residual beta cell function so that these adjunctive therapies can be further investigated. From our view, we think GLP-1 agonists will be used eventually – but the right study has to be done, using the right tools.
Heart Failure in Diabetes: How Much Are We Missing?
Mark Kearney, MD (University of Leeds, UK)
Dr. Mark Kearney gave an authoritative perspective on heart failure in patients with type 2 diabetes. Almost half of patients in Dr. Kearney’s heart failure clinic also have type 2 diabetes and, unfortunately, the outlook is often very poor for patients facing these co-morbidities. Dr. Kearney recommended that people with type 2 diabetes and heart failure be treated with diuretics, beta blockers/ACE inhibitors, and potentially device therapy. He also emphasized that metabolic management should be optimized. Notably, Dr. Kearney suggested that SGLT-2 inhibitors may become accepted as dual therapy drugs for managing both glucose and heart failure. He highlighted the EMPA-REG OUTCOME trial, which demonstrated an impressive and unexpected 35% reduction in the secondary endpoint of hospitalization for heart failure with empagliflozin therapy. The secondary endpoint finding did not support a label update for hospitalization for heart failure specifically, but the empagliflozin label was updated with an indication for cardiovascular death, a finding that many believe was driven by the heart failure results. Indeed, the ESC guidelines for heart failure were updated to include a recommendation for empagliflozin therapy in patients with both heart failure and type 2 diabetes. On the other hand, most diabetes guidelines updates thus far have pointed to a preferential role for empagliflozin in patients with type 2 diabetes and pre-existing cardiovascular disease, but have not gone so far as to emphasize a heart failure benefit specifically. Lilly/BI have two large-scale studies of empagliflozin in patients with heart failure with and without diabetes planned – if positive, these trials could greatly accelerate empagliflozin’s journey toward blockbuster status with potential indications for both type 2 diabetes and heart failure separately.
- People with type 2 diabetes and heart failure have only a three-year survival rate. Forty percent of patients at Dr. Kearney’s heart failure clinic have diabetes and he noted that heart failure patients with type 2 diabetes have more ischemia, lower hemoglobin, and worse renal function. As sudden cardiac death rates diminish due to the use of beta blockers and implantable defibrillators, patients increasingly die of progressive heart failure instead. Heart failure is progressive because of maladaptions of the body’s own protective systems – enlarging the heart, raising blood pressure, and giving rise to abnormalities of the sympathetic nervous system. Given the challenges of heart failure treatment, it’s no wonder that we’ve observed immense interest in heart failure therapies such as Novartis’ Entresto at cardiology conferences and that empagliflozin has drawn such excitement from cardiologists for its heart failure treatment potential in this extra vulnerable population.
Blood Pressure Targets in Diabetes Post-SPRINT: The Same or Different?
Martin Rutter, MD (University of Manchester, UK)
Manchester’s Dr. Martin Rutter advocated for a new paradigm in blood pressure-lowering among patients with diabetes – a target blood pressure range (rather than a target level) of 120-130 mmHg for clinic readings and 110-120 mmHg for home readings/mean of three clinical values. He drew insights from the SPRINT and ACCORD trials, emphasizing that ACCORD has been incorrectly labeled as a “negative” trial and that people have tended to focus too much on the harms rather than the benefits of normalizing blood pressure. Indeed, in the wake of ACCORD, guidelines committees raised the blood pressure target for a diabetes patient population to 140 mmHg – Dr. Rutter deemed this to be an overreaction. He shared data from an exploratory secondary analysis of ACCORD, which found that intensive blood pressure-lowering alone reduced risk by 26% without causing significant uptick in adverse events. The significant safety concerns were only apparent in the subgroup treated with simultaneous aggressive A1c-lowering and aggressive blood pressure-lowering. Dr. Rutter thus argued that it may be the interaction of these two intensive treatments that poses risk for harm. While he acknowledged that overtreatment can of course be dangerous, he explained how the field’s reaction to ACCORD has perhaps been excessively fearful, since bringing a patient’s blood pressure down is still a key component of optimal diabetes care. Blood pressure ranges (instead of targets) could provide a solution to this fear, giving providers a clear, step-down protocol to follow in treating blood pressure in the context of diabetes. Dr. Rutter pointed out that no such step-down protocol existed in the methodology for SPRINT or ACCORD (blood pressure-lowering could thus be made safer in clinical practice than it was in these trials). He also suggested that target ranges could allow for more personalization of treatment vs. specific target values, arguing that we should have personalized blood pressure goals alongside personalized glycemia goals. We’re keen for this idea, and would love to see it implemented more broadly in managing diabetes.
The Efficacy, Cost, and Benefits of the Newer Injectables in Diabetes Management
Where Does the Evidence Place the New Insulins in Clinical Practice?
Philip Newland-Jones, MPHARM (University Hospital Southampton, UK)
Mr. Philip Newland-Jones expertly navigated through the world of new insulins, discussing their differing concentrations from a pharmacist’s perspective. With the advent of biosimilars (Lilly/BI’s Basaglar just hit US pharmacies in December 2016), we imagine the science of prescribing insulin is growing more complicated from the provider’s perspective. Clear guidelines and education on new products is thus critical.
- Dr. Newland-Jones said comparisons of Basaglar (biosimilar insulin glargine) and Sanofi’s Lantus (insulin glargine) show that they perform identically within a 90% CI on PK/PD, A1c, fasting plasma glucose, dose, and weight. We have not seen this data. He said the two are considered to have comparable clinical and safety profiles (we have not seen this), though Basaglar is meant to be priced at a 15% discount (but is not yet available in a vial, he said). The responsibility to switch is left to the clinician and a dose reassessment is recommended on switching. We look forward to hearing patient feedback on this.
- Comparing insulin glargine U100 and U300 (Sanofi’s Lantus and next-gen Toujeo, respectively) we see a later peak and less weight gain with the more concentrated insulin. UK guidance is that the two insulins are equivalent in A1c and hypoglycemia, but that Toujeo requires a 18% higher dose. In Scotland, Toujeo is restricted to those with nocturnal hypoglycemia or those with caregivers administering insulin.
- Compared to Toujeo, Novo Nordisk’s Tresiba (insulin degludec) showed a longer half-life, a longer steady state, longer duration of action (42 hours vs. 24 hours), and greater dosing flexibility. However, Tresiba costs £3.10/unit vs. £2.45/unit for Toujeo – which could be £115 difference per patient year if doses are the same. We imagine that much of the difference between these products emerges from price, reimbursement, and marketing rather than the clinical trial data. Moreover, we’d love to see a head-to-head study comparing these two next-generation basals. Data from a small, Sanofi-sponsored head-to-head trial was presented recently at ATTD 2017; better evidence could come from a larger clinical trial.
- Mr. Newland-Jones underscored that basal insulin/GLP-1 agonist combinations are good products (in England, that’s often code for “very good”), showing hope for the future once they are priced attractively. This new class of therapies includes Novo Nordisk’s Xultophy (insulin degludec/liraglutide) and Sanofi’s Suliqua (insulin glargine/lixisenatide), both of which have demonstrated strong A1c improvement, weight loss, and less hypoglycemia vs. either monotherapy in clinical trials.
CSII: Current and Future
Automated Control of glycemia with a Bihormonal Bionic Pancreas
Steven Russell, MD (Massachusetts General Hospital, Boston, MA)
Dr. Steven Russell provided a comprehensive update on the bihormonal bionic pancreas, reviewing findings from the 11-day home use study recently-published in the Lancet, confirming the latest timing for a pivotal trial powered for superiority on the co-primary endpoint (0.5% drop in A1c from baseline and 60% reduction in time <60 mg/dl) to begin mid-2018, and discussing the hurdles that still lie ahead. He noted that the greatest challenge from a reimbursement perspective may be competition from an insulin-only version of the bionic pancreas. Preliminary results have been positive for the insulin-only system (with a pivotal trial slated to start by end of this year or early next), and glucagon is an added expense for payers. That said, Dr. Russell pointed out that patients on the bihormonal system spend less time <60 mg/dl, require fewer hypoglycemia treatments, and show higher treatment satisfaction – all key outcomes, in our view, and Dr. Russell argued that glucagon is thus essential for fully automated management of glycemia that minimizes risk of lows.
- The instability of glucagon is another potential challenge, though Dr. Russell remarked that it shouldn’t be a substantial barrier. The bionic pancreas team is currently working on a study that compares Lilly’s and Zealand’s glucagon in the system, and has also involved Xeris’ glucagon in clinical studies. Moreover, he suggested that glucagon analogues in development will be much more stable and will eventually power the bihormonal bionic pancreas.
Questions and Answers
Q: What happens to endogenous glucagon in a setting of giving exogenous glucagon? Are you able to measure it in any way?
A: Unfortunately, we can’t yet measure that, because we’re using human glucagon as opposed to an analogue. As we move to glucagon analogues, we’ll be able to answer that question, because an analogue won’t be picked up by a regular glucagon assay. It’s a very interesting question, and it can now be addressed in upcoming clinical trials.
Q: Have you considered this system for other populations, such as people who have undergone a pancreatectomy?
A: We haven’t done that yet, but I don’t see why it won’t be applicable to people with a history of pancreatitis or complete pancreatectomy. We have started some studies in type 2 diabetes, and it seems to work well. We’ve also tested the system post-bariatric surgery, but don’t have that data quite yet. But yes, we’re certainly looking at expanding into other populations. First, we have to do our due diligence in making sure glucagon is safe.
Insulin Closed Loop
Roman Hovorka, PhD (University of Cambridge, UK)
Dr. Roman Hovorka gave an authoritative overview of the recent history of the closed loop, presenting highlights of his own, impressive work and selections from other groups. He demonstrated that closed loop improves time in the target range, can also improve time below target (particularly for those with lower A1cs) and the majority of the benefit comes from overnight. He also noted that the nature of the algorithm and the population studied does matter. Now that the first generation commercial closed loop systems are appearing, the next step is reimbursement!
- For many years, we’ve been waiting for the first commercial closed loop system – now it’s here! The Medtronic 670G hybrid closed-loop pump was approved by the FDA, and will be commercialized in spring 2017. Dr. Hovorka believes that the outside-US launch will occur in spring 2018.
- Dr. Hovorka took us on a historical tour of closed loop development and trials. In 2007, he used an inpatient bedside laptop system, moving to today’s ‘free-living’ outpatient system which runs an algorithm on an Android phone. By 2013, the state of the art was one night on closed loop at diabetes camp. In 2014, the field moved to outpatient overnight studies.
- Dr. Hovorka presented the results of five free living home use studies that his team had performed since 2015. These trials were (i) n=33 adults three month 24/7 home study, (ii) n=25 children 6-18 years three month overnight closed loop versus sensor augmented pump (SAP), (iii) n=12 teenagers three week 24/7 home study, (iv) n=29 well controlled (baseline 6.9% A1c) adults three week 24/7 home study, and (v) n=16 pregnant women four week overnight closed loop study.
- In these groundbreaking studies, time in target was improved by 11-19 percentage points, and time below target was reduced by up to half, depending on the trial. Time in hypoglycemia was reduced the most in well-controlled adults, showing a clear benefit of the technology even for those who are considered to be doing well. The technology showed the greatest benefit overnight, and the systems were well tolerated.
- Following this tour de force, results from other groups were presented, including a meta-analysis of approximately 17 trials, demonstrating an increase in time in target of roughly 9 percentage points and a mean reduction in hypoglycemia of 1.2 percentage points. The work chosen included Dr. Phillip’s team in Tel Aviv, the Medtronic 670G pivotal study published by Dr. Bergenstal et al in JAMA, and work from Dr. Kovatchev’s team at UVA. In the meta-analysis, improvement in time in range was largely driven by overnight performance.
- This body of evidence shows that the algorithm and/or the baseline characteristics do matter. But because there is such an enormous amount of day-to-day variability in overnight insulin requirements for an individual, everyone can benefit from closed loop.
- As we look to the future, we see developments in dual hormone devices and large outcome studies. Dual hormone (insulin and glucagon) closed loop devices can achieve similar mean glucose improvements, but a further reduction in hypoglycemia. Future studies involving 80-200 participants over three months to two years are being sponsored by parties such as NIDDK, JDRF, National Health Service, Helmsley Charitable Trust.
- Despite the progress, the world is not quite ready for the closed loop – adoption and performance challenges still remain. We are still waiting for more systems to be approved, for target populations to be identified and for reimbursement. We also have barriers in the speed of insulin absorption and reliability of delivery. Sensors have improved a lot, and are not really the barrier they used to be.
Questions and Answers
Q: Which target populations are best for closed loop?
A: We think the best improvement is for patients with A1c > 7.5%. But some of the most enthusiastic are those who are already well-controlled. They will probably represent the early self-pay segment.
Q: Will dual hormone become the standard?
A: I think that cost will be an issue. We will need to have hard data on the benefits. One day on glucagon currently costs $30-$60. I expect that there will be space for both technologies with different populations. (Editor’s note – we doubt this would be close to the cost “in real life” – the daily cost today is a very different use.)
Glucose Variability: A New Way of Thinking in the Children’s Diabetes World, Too
What Is Glucose Variability and Why It Matters?
Nick Oliver, MD (Imperial College, London, UK)
Most people would tend to accept that glycemic variability is important in diabetes, but the question has not yet been satisfactorily resolved. Dr. Nick Oliver presented balanced evidence that was suggestive of an effect, but the jury is still out. In vitro and rodent studies show some support for negative effects, but the human data is not yet compelling – we would emphasize that the best way to measure this is with CGM and there hasn’t yet been time for a long-term study (or resources). There is little longitudinal data, and most measures are strongly associated with A1c. One of our fondest hopes is to see more use of CGM in clinical trials to provide much more clarity on glucose variability. Also not-to-be overlooked is the strong correlation between reduced glucose variability and higher patient satisfaction with their diabetes care. As was clear at the FDA’s workshop on outcomes beyond A1c last August, A1c does not begin to capture it all when it comes to diabetes treatment, and it’s important that all players seriously look at time-in-range, patient-reported outcomes, and patient quality of life metrics.
- A famous interpretation of the DCCT (since retracted) suggested that the risk of complications was not only driven by A1c, but by other factors – postulated to be glycemic variability. Members of the control group still had higher risk than those of equal A1c in the intervention group. The authors subsequently claimed that 96% of the effect was A1c, but the “genie was out of the bottle.”
- From a mechanistic and basic science perspective, there is plenty of plausibility that variable glucose causes detrimental effects at the cellular level. Significant mechanisms exist to cause problems at the cellular level. In the lab, oscillating glucose levels have a more detrimental effect on cells than a stable glucose level, even a very high one. Glucose variability has been shown to create inhibition of mitochondrial activity, worsen markers for atherosclerosis in rats, and inhibit angiogenesis in mice. These effects are also demonstrable for oscillations into hypoglycemia as well as hyperglycemia.
- Turning to humans, in his famous paper, Dr. Monnier showed a relationship between glycemic variability and oxidative stress in type 2 diabetes, but it wasn’t replicable for type 1 diabetes. Dr. Oliver provided some evidence that bigger glucose excursions after eating thicken the carotid artery (a measurement associated with cardiovascular disease). He noted that in low birth weight newborns high glycemic variability is associated with mortality in the intensive care unit. It’s also shown that slow changes in A1c over time are associated with microvascular complications – but the association with CV disease is less tight. However, there is very little longitudinal data, most measures are strongly associated with A1c, and there is no gold standard measurement. Hopefully, more frequent use of the latest versions of the most accurate CGM, and access to the data, will help address these questions.
How to Measure and Ascertain Causes of Glucose Variability
Pratik Choudhary, MD (King’s College London, UK)
Dr. Pratik Choudhary presented a practical approach to glycemic variability in the clinic. He finds it quite useful in coaching patients – a high variability can be used to focus on mismatched insulin and glucose, and a low variability to reassure patients that they are doing well. Most patients find simple measures more intuitive – time in target seems to be the best.
- A high degree of glucose variability makes adjustment of therapy much more challenging. Day-to-day variability makes it tricky to adjust basal insulin dose, and in this way, variability is inextricably linked with mean glucose.
- Time-in-range is increasingly becoming a standard measure of variability. The target range is typically 70-180 mg/dl, he said – this will be discussed in greater depth at the 2917 ADA. As expected, people with higher A1cs have lower time-in-range. Typically, those with low A1cs (<7.5%) have ~60% time in range, but those with A1c >9% have only 40%. Time-in-range is a metric that resonates with patients, who intuitively understand that a low A1c with a lot of hypoglycemia is not desirable.
- There are numerous measures of glycemic variability – SD, CV, MAGE, CONGA, MODD, GRADE, LBGI, etc. – and still no consensus on which is most appropriate. Some are intra-day variances, some are day-to-day, some even indicate health risk (LBGI). In patient studies, all these metrics appear to correlate with each other across groups, so Dr. Choudhary recommends using a simple metric (like standard deviation) with patients.
- The ambulatory glucose profile (AGP) is becoming more popular – this is partly due to the growth of Abbott’s Freestyle Libre, according to Dr. Choudhary. The product gives an indication of both mean glucose and variability across the time of day. It’s important that clinicians know how to interpret this, and that they’re able to explain it to patients, he emphasized.
- The root cause of variability is the mismatch between glucose and insulin, which is caused by a myriad of factors, some known, some unknown and therefore uncontrollable. Factors affecting variability include food, exercise, insulin absorption, insulin sensitivity, illness/stress, day vs. night, co-morbidities, c-peptide, and insulin antibodies, plus a whole host of unknowns. Typically, people with diabetes can have overnight insulin requirements that vary from 50% to 200% of their expected basal rates. Since variability is to be expected, patients can’t be blamed for not getting it right every time.
- For patients with high variability (standard deviation >5), the root cause is often that food and insulin are not correlated. Patients can be coached to avoid the most frequent patterns – such as under- or over-bolusing, rage boluses, overtreatment of hypoglycemia, and managing activity better. We’d love to see more focus on this with patients.
Questions and Answers
Q: Isn’t there a potential for being overwhelmed?
A: I think that A1c trumps variability. Until we have evidence that variability has a huge impact, we know that A1c does. The kind of patients who worry about variability are the perfectionists. We do find variability useful in clinical practice. We use high variability to diagnose too many hypos or hypers, and we use low variability to reassure patients they are doing well. What really matters is maximizing time-in-range.
What New Technologies Should We Be Offering Now in Secondary Care?
Gerry Rayman, MD (Ipswich Hospital, England)
Dr. Gerry Rayman led a somewhat informal, anecdotal discussion on the use of technology in the hospital and the clinic. He’s considered an expert in diabetes care in inpatient settings, and expressed his personal views based on his clinical experience, while also asking for input from the audience. Major takeaways included:
- Blood glucose data management systems, electronic medical records and inpatient dashboards are useful in improving inpatient patient care. For example, using a data management system, Dr. Rayman found that 70% of hospital hypoglycemia occurred between 9pm and 9am and was able to reduce hypoglycemia by 85% over three years.
- Closed loop systems improve time in zone in an inpatient setting. But Dr. Rayman believes they ‘can’t really be rolled out’ to the hospital – at least in their current form. We’d love to see more investment in this arena given the systems upside alone.
- Ketone testing should be more prevalent, but strips are expensive. The Keya Smart meter tests ketones on the same strip as glucose. Dr. Rayman commented that it “looks like a really good system and I suspect we will switch over to this, although there is no bolus calculator.” We discovered recently that the Abbott Libre also has a ketone strip port.
- For outpatients, doctors are overwhelmed by the ‘explosion’ in the number of meters and pumps and different CGM systems. There is a big training gap and possibly the need for specialized diabetes technicians. We believe everyone using AGP would help a great deal.
- Dr. Rayman commented that the Diasend data management system is “really valuable” and “a real revolution.” A show of hands indicated that most trusts had access to it.
- The Abbott Libre flash glucose monitoring system and the ambulatory glucose profile have been useful in changing patient behavior, according to Dr. Rayman.
The New Toys That Will Be Coming to Your Toy Box Soon
Nick Oliver, MD (Imperial College, London, UK)
In a breathtakingly rapid-fire talk, Dr. Nick Oliver somehow managed to cover all the burgeoning technology areas in diabetes, hardly pausing for breath – thereby illustrating just how much activity is taking place. He covered flash glucose monitoring, CGM, closed loop, ultra-rapid acting insulin, connected health, decision support, and home-engineered solutions.
- NICE guidance (NG17) now supports the use of CGM in adults with type 1 diabetes. This applies specifically for those with persistent or unexpected hypoglycemia and hyperglycemia. Reimbursement is coming more slowly, although Dr. Oliver has been instrumental in securing CGM reimbursement in north west London.
- Studies on flash glucose monitoring (the Abbott Libre) indicate that the technology can reduce time spent in the hypoglycemia range. Dr. Oliver suggested that more data is required, particularly to determine in which specific populations the benefit lies. We also need to develop a framework for NHS reimbursement.
- There is a changing landscape in CGM technology. Examples include the recently approved Medtronic Guardian Connect, the new Roche CGM, and Senseonic’s Eversense implantable CGM device. Next generation sensors will be smaller, have improved accuracy, less frequent (or zero) calibration, longer wear and reduced interference (from acetaminophen). It’s hoped that the DVLA (UK driving license issuing authority) will allow the use of CGM in driving. For example, Dexcom is licensed for non-adjunctive use which is not currently acceptable to the DVLA.
- The Medtronic 670G closed loop pump was approved by the FDA for use in the US last year. It has a true automatic delivery mode, although boluses for food must be given manually. The system delivers a 0.5% reduction in A1c although Dr. Oliver commented that he is “not sure we will see European approval in the near future”, which was a surprise for us to hear. Nonetheless, home based closed loop systems increase time in target, reduce hypoglycemia and A1c. There are some implementation challenges, but the area is very exciting. We are starting to see longer closed loop studies in the home, in specific populations such as young people and in type 2 diabetes.
- Novo Nordisk’s Fiasp (rapid-acting insulin aspart) will be available shortly in the UK. Fiasp is detectable in the blood in four minutes rather than 15 minutes with traditional insulin aspart. The area under the curve in the first hour is twice that of regular insulin aspart. Pump users notice that the post-prandial rise is attenuated with Fiasp. Simulations show a material benefit in closed loop systems.
- Connected health is booming – phones make it easy to record glucose, insulin, macronutrients, activity, and health events. Most devices are becoming connected, including pens. Glooko and Diasend are merging.
- Some ‘big hitters’ are entering decision support, which has huge potential. These include Verily (formerly known as Google Life Sciences) partnering with Dexcom and IBM Watson Analytics partnering with Medtronic. The area covers dosing, education, lifestyle coaching, and behavior change. Voluntis’ Insulia app has already been FDA- and EMA-approved. Additionally, the Glytec Glucommander has shown dramatic glucose improvements in early data. The product uses a cloud based algorithm to calculate dose recommendations.
- There is a lot of movement in home-engineered solutions. xDrip takes data from G4 and sends it to a phone. NightScout is an open access cloud based data repository. There is an open source AP system (Loop) with combines a Dexcom receiver and a Medtronic pump, which would normally never be available. This movement is unified under the hashtag #wearenotwaiting. The movements attempts to find solutions to challenges of using technology, open access to device data, data sharing, device integration, and closed loop control. On the other hand, it’s unregulated, and Dr. Oliver said it presents a potential cybersecurity liability for manufacturers which might ironically slow developments down. But the movement has already influenced the speed and direction of commercial development.
Questions and Answers
Q: Closed loop systems – will the best algorithms get to the patients, or will commercial decisions dictate what we can have?
A: Every developer believes that their algorithm is best. Maybe different patients will need different algorithms, but we won’t really know until we get head to head data.
Q: The long-term gain in these devices is in quality of life, which is driven by consumer acceptance, not things like A1c.
A: We are obsessed with glucose outcomes, and the regulatory process heavily relies on glucose. But we do need to change that. We are beginning to understand that patient reported outcomes and usability are critically important. So we need patient input.
Q: Can you tell us more about implantable CGM for pediatrics?
A: Dr. Choudhary at King’s College Hospital did the Eversense (Senseonics) work. It goes in the back of the arm with a needle type inducer, similar to an implanted contraceptive, and it is explanted after 90 days. The first studies look promising. But it’s probably not suitable for pediatrics right now.
RD Lawrence Lecture
Incretins: The Intelligent Hormones in Diabetes
Victor Gault, PhD (Ulster University, Coleraine, UK)
Every year, the RD Lawrence Lecture recognizes a young scientist or clinician who has already made outstanding contributions to diabetes research. This year, Dr. Victor Gault discussed his work on the GIP hormone, and spoke to challenges and opportunities for GIP-based diabetes therapies. GIP is an attractive therapeutic option, according to Dr. Gault, due to its diverse physiological effects – enhancing beta cell mass, increasing insulin secretion, and increasing proinsulin biosynthesis. GIP analogues that can evade degradation by the DPP-4 enzyme could thus be very effective in preserving beta cells and treating hyperglycemia, and indeed, companies like Lilly and Sanofi are working on GLP-1/GIP dual agonists (both in phase 1). For these products, Dr. Gault identified the critical hurdle as getting the combo preparations into solution and into patient-friendly pens. Dr. Richard DiMarchi, in particular, is a major proponent of polyagonists involving GIP agonism – he and close colleague Dr. Matthias Tschöp highlighted several such efforts at the 2016 Keystone Symposia on New Therapeutics for Diabetes and Obesity. We certainly view GIP agonism as a promising therapeutic target, despite its status as the “forgotten incretin.” Moreover, Dr. Gault put forth a positive outlook on “incretin +” therapy, or an incretin hormone in combination with another agent, such as an SGLT-2 inhibitor. “This will be a very important therapeutic area for diabetes in the future,” Dr. Gault asserted. We saw the first study in this category at EASD 2016 – DURATION-8 found more effective A1c-lowering with AZ’s GLP-1 agonist Bydureon (exenatide once-weekly) co-administered with SGLT-2 inhibitor Farxiga (dapagliflozin) vs. either monotherapy. We’ll certainly be watching closely for developments in this area.
- Models of Alzheimer’s disease show the protective effects of incretin hormones on cognitive function. Liraglutide-treated Alzheimer’s mice show memory preservation (measured by superior performance in an object recognition test), improvements in long-term potentiation (LTP) in the hippocampus, and a higher number of synaptic connections compared to placebo. Dr. Gault also presented results from pilot studies in humans – PET scans reveal a decline in brain glucose metabolism (reflects disease progression) when individuals with Alzheimer’s take liraglutide, and exendin-4 (a GLP-1 agonist, synthetic version is exenatide) improves motor skills and cognitive performance in people with Parkinson’s disease. This impact of incretins on the brain is important for two key reasons: First, Alzheimer’s has been described as a possible “type 3 diabetes,” given its roots in insulin resistance in the brain. In addition, Dr. Gault summarized recent research linking diabetes and obesity to cognitive decline, suggesting that incretin-based therapies could go beyond glycemic control to also sustain brain function. Dr. Gault expressed clear enthusiasm on this front: “These are very positive, encouraging results for the GIP and GLP-1 molecules.” We echo his excitement for this emerging area of therapeutic investigation.
Dorothy Hodgkin Lecture
Bringing the Human Pancreas into Focus: New Paradigms for the Understanding of Type 1 Diabetes
Noel Morgan, PhD (University of Exeter, UK)
In this year’s Dorothy Hodgkin Lecture – a staple of Diabetes UK and an annual favorite at this conference – Dr. Noel Morgan proposed two distinct phenotypes of type 1 diabetes which may require two distinct therapeutic approaches. Patients diagnosed with type 1 diabetes at seven years-old or younger predominantly display a “CD20Hi” profile, where CD8+ t-cells predominate and the ratio of CD20 antigen/CD4 antigen is >one. Patients diagnosed at an older age predominantly display a “CD20Lo” profile, where, again, CD8+ t-cells are in the majority, but the ratio of CD20 antigen/CD4 antigen is <one. Dr. Morgan went on to explain that the older, CD20Lo patients typically have a higher number of residual beta cells, or beta cells that escape destruction during the progression of type 1 diabetes. The jury’s still out on a definitive explanation for these lingering beta cells, but Dr. Morgan’s group at the University of Exeter has a two-pronged hypothesis: (i) islets that survive lose their hyper-expression of the MHC-1 protein complex over time, making them less visible to the immune system and thus less vulnerable to autoimmune attack; and (ii) beta cell proliferation in a type 1 diabetes patient occurs at a higher rate vs. an individual without diabetes. It also seems that, over time, beta cells show lower expression of MHC-1, protecting them from autoimmunity. If this hypothesis is corroborated by further research, Dr. Morgan highlighted one major implication for approaches to treatment – rather than transplanting new beta cells, perhaps we should be devising ways to reinvigorate residual ones. As we further our understanding of type 1 diabetes pathophysiology, we hope that more of these early research findings can be translated into viable therapies for patients. While on one hand organizations like City of Hope are making bold promises of a cure for type 1 diabetes within five or six years (which is naïve from our view), we recognize that “cures” will likely involve much more time to steadily build on findings like these from Dr. Morgan and his colleagues.
- Dr. Morgan described enterovirus infection as a possible “precipitating event” that kick-starts progression of type 1 diabetes in our conventional view of the disease. There is a clinically-significant association between enterovirus and type 1 diabetes, and his team went on to model enterovirus in type 1 patients. They found that the virus is located exclusively in beta cells within pancreatic islets, and that beta cells can develop a persistent, low-level of infection, which propagates the virus. Dr. Morgan emphasized that much more research is needed before drawing any conclusions about the precipitating event in type 1 diabetes, but added that if enterovirus does in fact play a role, it could also inform better treatments.
- “Bringing the pancreas into ever-sharper focus is key to understanding type 1 diabetes.” Dr. Morgan pointed out that <200 individual human pancreases with new-onset type 1 diabetes were studied in the entire century between 1900 and 2000. This is ironic, considering that the pancreas lies at the center of this disease, and we agree with Dr. Morgan’s advocacy for more pancreas-focused research in recently diagnosed patients. He mentioned a few bright spots, including the JDRF-sponsored nPOD (Network for Pancreatic Organ Donors with Diabetes) in the US. We’ve been very impressed by the work of nPOD – see our coverage of the organization’s 2016 annual meeting for a closer look at their incredible efforts.
Rank Nutrition Lecture in Honour of Harry Keen
Dietary Solutions for Diabetes Prevention: Challenges, Opportunities, and New Horizons
Nita Forouhi, MD (MRC Epidemiology Unit, University of Cambridge, UK)
Calories matter, but diet quality is critical – that’s the take home message from Dr. Nita Forouhi who has collected nutritional evidence with painstaking care and critical thinking. She concludes that certain foods are beneficial for diabetes prevention (fruits, nuts, fish, veggies, vegetable oils, whole grains, beans, and yogurt). Meanwhile, cheese, eggs, milk, poultry, butter, and red meat are neutral on the diabetes prevention front, and sugar, starches, refined grains, and processed meat are all harmful.
- There is a lot of public fervor over various diet options, but appropriate diet recommendations are not clear, and actual diets are difficult to measure, making trials and diet modification difficult. There are vested interests – the food industry, advertisers, celebrity endorsements, books etc. Nutrition is effectively a branch of the entertainment industry and the plausibility of results is under question.
- We know that calorie restriction works in the short term, but the key is adherence. So the diet that works for you is the best diet. A meta-analysis of various diets showed that low fat and high fat diets gave similar weight loss results. The same was true for low and high carb diets. A meta-analysis of ‘named’ diets (i.e. Atkins, Ornish, Jenny Craig, etc.) showed that all diets worked in the short term, weight loss was similar, but adherence was poor across the board. Although individual trials showed differences, it’s important to look at the totality of the evidence.
- There is a lot of interest in low carb diets, but the body of evidence is that although there are lipid and weight improvements in the short term, they even out by a year. There also wasn’t an overall difference in insulin and glycemic markers. However, these diets had a broad range of the types of carbs eaten. A prospective study of bran and whole grains showed a decreased risk of type 2 diabetes. It seems important to choose high quality carbs and avoid foods with high total carb to fiber ratios.
- A major meta-analysis shows that consumption of sugar sweetened beverages (SSBs) is associated with an increased risk of type 2 diabetes, and that fruit juice and artificially sweetened beverages (ASBs) were not suitable alternatives for prevention of type 2 diabetes. After adjusting for BMI (and other factors), sugar sweetened soft drinks still presented a clear risk. The increased risk is such that 2m diagnoses could be avoided over 10 years in the USA by avoiding SSBs. There was an even larger risk associated with consumption of ASBs, but this went to zero after adjustment for BMI – presumably because those most at risk already consumed diet drinks.
- The emphasis on total saturated fat is misplaced. Different foods that contain saturated fat have different influences. Saturated fat (SFA) is not homogenous – even chain SFA increases risk while odd chain SFA decreases it. Even chain SFA is derived in the liver from carbs, alcohol, while odd chain SFA comes from such dietary fat such as dairy. Red meat has a neutral effect, while fermented milk products show a 12% reduction in risk. Also, what replaces saturated fats in foods has an implication – such as a zero fat yoghurt with 20g of added sugar.
- All calories are not equal for long term health. The verdict seems to be that fruits, nut, fish, veggies, vegetable oils, whole grains, beans and yoghurt are beneficial in reducing the risk of diabetes; cheese, eggs, milk, poultry, butter, and red meat are neutral; and sugar, starches, refined grains, processed meat are harmful.
- We already have public health advice in the absence of randomized controlled trials. This seems appropriate because the prospective trials agree with the small number of randomized controlled trials we do have.
Promoting Physical Activity in Diabetes: Why, How, and Wow
The Physiology of Exercise in Relation to Diabetes
Robert Andrews, MD (University of Exeter, UK)
It’s great to see doctors increasingly putting physical exercise on a par with drug therapies in real-world clinical practice, and Dr. Robert Andrews spoke to the importance physical activity during this valuable session. Physical activity has enormous benefits for prevention of diabetes for those at risk. Clinical models exist for encouraging exercise, finding motivation, and overcoming barriers.
- Doctors recommend 150 minutes of moderately intense aerobic exercise per week to prevent diabetes. This yields a 26% reduction in the risk of getting diabetes, but there is no ceiling to this benefit. For example, 780 minutes/week yields a 53% risk reduction. But the majority of people aren’t reaching this basic goal. In addition, it’s recommended to accomplish at least two weekly sessions of anaerobic exercise, such as weight training.
- Most people, however, don’t reach these levels of activity. It turns out that there is little difference in activity between races, or those with normal or impaired glucose tolerance.
- The key motivators for activity are improvement in health, goal setting and self-tracking, exercising with others – friends or groups, and role models. Doctors can provide information on local resources, such as religious and community centers and provide advice on safety.
- Doctors can encourage activity by use of the 5 A’s model. The 5 A’s are: (i) Assess activity level; (ii) Advise on type of activity; (iii) Agree regular activity and document goals; (iv) Assist patient to reach their goals by planning and providing resources; and (v) Arrange follow-up to revisit plans. It’s best to assemble resources, such as prompt sheets for tackling barriers (lack of time, lack of energy, lack of motivation, lack of resources, weather conditions), or a website with local resources for group activities.
Promoting Physical Activity in Type 1 Diabetes
Ian Gallen, MD (Royal Berkshire Hospital, Reading, England)
In type 1 diabetes, exercise is highly beneficial, but can cause problems in glucose management. Many people with type 1 diabetes have lower level of physical activity, particularly older people and women. Unfortunately, it’s hard to predict the effects of exercise on glucose levels in type 1. These were the major takeaways from Dr. Ian Gallen’s presentation on exercise in type 1 diabetes.
- Many people with type 1 diabetes have lower level of physical activity, particularly older people and women. It’s likely the same as the general population – about two thirds don’t reach the recommended targets. But even a small amount of activity – e.g. walking 1.5 km each day – can have significant benefits (~30% cardiovascular risk reduction in one study).
- The German Diabetes Registry shows that almost every physical or metabolic parameter is improved in those exercising more frequently, including hypoglycemia A1c, BMI, blood pressure. The registry also shows that the more exercise, the better the improvement.
- Physical exercise neither reduces or increases microvascular complications in type 1 diabetes. This is a source of concern for some patients, so the data should be reassuring.
- In type 1 diabetes, physical activity causes problems in glucose management. Examples include falling glucose and risk of hypo in continuous aerobic exercise, blood glucose rising in anaerobic exercise, control after exercise is hard, hypoglycemia at night after exercise, excessive fatigue compared to pre-diagnosis.
- Exercise should be part of the routine patient review by primary care doctors. Doctors should explain benefits on a par with other therapies, review levels and reassure on safety.
Institution of the UK’s First NHS EndoBarrier Service for Type 2 Diabetes and Obesity
Gupta S, Ryder R, et al.
A team at Birmingham City Hospital in the UK has initiated a program that has implanted 48 patients with GI Dynamics’ EndoBarrier device since October 2014. This service was reimbursed under the NHS at a cost of £790 for the implantation and £3,300 for the device. A registry has been established to follow patient outcomes. The outcomes have been very positive – average weight loss at one year is 16 kg, mean A1c is reduced from 9.6% to 7.4%, hepatic fat is essentially eliminated, and average daily dose of insulin is reduced from 104 units to only 12 units. Approximately 40% of patients taking insulin have discontinued it altogether. The device is explanted after 12 months, but early data shows that 75% of patients maintain their weight in six months follow-up. Dr. Ryder showed us some impressive before and after photos of participants, including a woman who took 260 units of insulin daily, lost 38kg and was able to discontinue insulin entirely within 12 months. He noted that he prefers to select patients who are obese with poor diabetes control despite all the standard diabetes treatments. It turns out that typically these are middle aged patients with high BMI (>40 kg/m2), and longer duration of diabetes, who are not well controlled on insulin and GLP-1 agonists. This is a population for whom nothing is working. He did note that there had been two early discontinuations and one case of hepatic abscess in the service (note that this isn’t a trial). Some of these events could have been avoidable with improved patient adherence, and he has modified clinical protocols. Nevertheless, he feels certain that in this population the risk of not acting, particularly from CV disease, is particularly high and justifies the intervention.
Abbott put up a characteristic booth in this year’s Diabetes UK exhibit hall. The company has been enjoying strong growth of the FreeStyle Libre in the self-pay market, although reps wouldn’t share the number of users in the UK. The company has submitted trial data to the NHS Business Services Authority and is following the process in search of UK reimbursement. Reps suggested that the healthcare economics behind the FreeStyle Libre make it an ideal, most-appropriate product for patients on MDI currently.
AgaMatrix was riding high with its WaveSense Jazz Wireless Bluetooth connected meter, which is the second most-used, low acquisition cost test strip in the UK (there are two tiers of strip pricing). The meter sports cloud connectivity, a nice iPhone/Android app, and push notifications.
Amgen occupied a small booth in the exhibit hall, highlighting PCSK9 inhibitor Repatha (evolocumab). A poster and video monitor boasted that Repatha was the first of its class approved in the EU, and emphasized that the agent produces consistent, superior LDL lowering vs. standard lipid-lowering therapy. There was no fanfare surrounding positive topline FOURIER results, announced in early February – Repatha met its primary CV endpoint, significantly reducing risk for the composite outcome consisting of CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, and coronary revascularization, and also met a key secondary endpoint by significantly reducing risk for three-point MACE (CV death, non-fatal MI, and non-fatal stroke). Full results from FOURIER will be reported at ACC 2017 – this is going to be huge!
Ascensia’s booth was focused on its Contour Next One Bluetooth-enabled BGM, which received CE Mark for approval last May and received FDA clearance in November. Reps emphasized accuracy of the Contour line of products alongside an intuitive, unaccusatory (! cool) smartLIGHT feature (green for in-range, red for low, yellow for high). The exhibit’s bold banner picked up on the light theme: “seeing how everyday activities affect their blood glucose – that’s illuminating.” We like this campaign very much and we’re happy to see Ascensia continue to innovate as a player in the BGM market. Most recently, the company announced plans to integrate into Glooko’s data management system, and we look very forward to this launch to come later in 2017.
AstraZeneca’s large booth featured all major therapies within its diabetes portfolio (DPP-4 inhibitor Onglyza, GLP-1 agonists Bydureon and Byetta, SGLT-2 inhibitor Forxiga/Farxiga, and fixed-dose combination Qtern), but really spotlighted the last two. One message dominated the exhibit – that prescribing Forxiga ahead of a DPP-4 inhibitor could offer patients additional benefit. This falls very much in line with the company’s strategy to focus on its SGLT-2 inhibitor business. Management has expressed tremendous confidence in the Forxiga franchise on recent earnings calls, and has even shown some willingness to allow SGLT-2 inhibitor sales to cannibalize its DPP-4 inhibitor (Onglyza) sales – this was the sense we gathered from AZ’s exhibit hall presence as well. We were excited to note the emphasis on Qtern, which was the first drug in this relatively new combo class (fixed-dose SGLT-2 inhibitor/DPP-4 inhibitor) to be approved in Europe, and which was just recently approved by the FDA. In our view, AZ is well-positioned to make Qtern a global commercial success, given impressive sales growth and blockbuster potential for Forxiga, and given the company’s commitment to the entire Forxiga family of products. This would be fantastic for patients, as Qtern has demonstrated superior glycemic control and weight loss vs. either monotherapy.
Dexcom reps were very positive about the outlook in the UK despite the ongoing tough reimbursement climate. Using a smartphone instead of a receiver in the G5 has made the product somewhat more affordable for self-pay. In North West London, eight Clinical Commissioning Groups (CCGs) have been reimbursing CGM (with alarms) for adults with type 1 diabetes and problematic hypoglycemia. Their policy doesn’t apply to all people with type 1 diabetes, but it is a promising start.
The company was proud of positive clinical results reported by Dr. Bob Ryder of Birmingham. See our poster coverage of EndoBarrier for the highlights.
We heard very positive things about Glooko/Diasend at this meeting! The two groups were mixing and matching their corporate attire on the exhibition booth. Notably, Diasend was getting a lot of support from speakers and attendees in the lectures and many other device manufacturers were advertising their Diasend compatibility. We are hopeful that more joint product announcements are in the works.
GlucoRx is considered to be the leader in the low-cost segment. Like their competitors, they advertise compliance with the new ISO standard ISO 15197:2015 (which specifies that 95% of readings should be within +/- 15% above 100mg/dl and +/- 15mg/dl below 100mg/dl). Their list price is £9.95/50 strips.
J&J’s booth was all about SGLT-2 Invokana. A large sign boasted that >one million patients have been treated with the SGLT-2 inhibitor globally (!), and reps presented the compelling clinical data showing its A1c-lowering efficacy, weight loss, and other health benefits. The company has an exciting milestone coming up in CANVAS results (to be presented at ADA 2017), and also has interesting clinical development projects in the works for Invokana, including a study of the agent as a weight loss therapy and a potential CVOT in prediabetes.
Lilly/BI’s shared booth created a 360-degree experience, with circular banners overhead listing their major diabetes products (including SGLT-2 inhibitor Jardiance, DPP-4 inhibitor Tradjenta, biosimilar insulin Abasaglar, and rapid-acting insulin Humalog). One side of the exhibit was dedicated to GLP-1 agonist Trulicity, with an emphasis on the patient-friendly pen design. A poster highlighted three core tenets of this design – (i) fewer injections vs. a once-daily GLP-1 agonist, (ii) an easy-to-use device; and (iii) low potential for immunogenicity – which could also be seen up-close on demo pens, interactive monitors, and a holographic pen demo.
MSD continued to celebrate the 10-year anniversary of DPP-4 inhibitor Januvia (this was also the theme of the company’s exhibit at EASD 2016), but in even more spectacular fashion. The booth was decorated with pink and blue balloons, as well as a large inflatable “1” and “0” announcing the product’s 10th birthday. The company hired two artists to create a chalkboard mural over the course of the three-day meeting – attendees were asked “what are we trying to achieve in treating type 2 diabetes, and why?” and their answers were added to the mural wall. Responses ranged from “abolish stigma” to “don’t let blood sugar control my patients’ lives.” The art project fit quite well with the overarching theme of the booth, which we loved – getting visitors to think bigger about how we can make life better for people with type 2 diabetes – and it certainly attracted a lot of traffic.
Nipro’s booth demonstrated the TRUEyou basic meter, promoting that it’s easy for practices to switch to lower-cost strips.
We spoke to Novo Nordisk reps about next-gen rapid-acting insulin Fiasp (EMA-approved on January 10), basal insulin/GLP-1 combo Xultophy, and obesity drug Saxenda. The company is moving to launch Fiasp swiftly in EU countries – while the official launch date for the UK isn’t until April 10, reps told us that the product was already on wholesalers’ shelves as of February 27. They also shared that Fiasp will be priced on par with the NovoRapid FlexPen (the most commonly used presentation). This is terrific news, as it will allow more patients to access a better prandial insulin with faster onset and offset. Down the line, we’re hoping to see a similar pricing strategy in other markets including the US (where notably, the drug is not yet approved and we await Novo Nordisk’s resubmission to the FDA), as parity pricing could incentivize many more payers to reimburse the more advanced agent.
On Xultophy, reps suggested that the limiting factor for uptake is unfamiliarity with this class of basal insulin/GLP-1 combination therapy. Xultophy was first-to-market within this class, so we understand the hurdle in patient/provider education, though we imagine that with Sanofi’s Soliqua now available and with the ADA’s endorsement for these combinations in its 2017 Standards of Care that awareness should spread more quickly. Reps added that insulin degludec itself is new and not so well-known – normally, you’d want a lot more familiarity with all components before launching a combination product. In line with this, we’ve heard from management that the company will prioritize Tresiba (insulin degludec) and Victoza (liraglutide) individually for now, holding off on full-scale promotion efforts for Xultophy. This was somewhat surprising to us, given the tremendous glycemic benefits and more mild side-effect profile associated with Xultophy though we also imagine if CV or kidney benefits could eventually be shown with Xultophy, that may also be a better time to launch in earnest (this is pure speculation). There is logic in Novo Nordisk’s strategy to first and foremost establish familiarity of both monotherapies, and we also hope that patient access to Xultophy is prioritized – it’s disappointing for such a highly-anticipated and effective diabetes therapy to finally make it to market but remain out of reach.
On Saxenda, reps shared that Novo Nordisk is targeting the private health insurance market initially, with a longer-term ambition to make the obesity therapy very widely available and accessible. Obesity occupies a substantial portion of the company’s R&D budget, and reps told us that this includes education efforts, so that more providers and payers understand obesity as a biological, treatable, not-to-be stigmatized disease. This was reassuring – Saxenda is currently driving 100% of growth for the obesity drug arena, and we’re glad to note Novo Nordisk’s commitment to obesity as a therapeutic area. We think J&J and others may follow.
Sanofi’s booth highlighted flagship diabetes product Lantus (“choose the 1 you know”), next-gen basal insulin Toujeo, and PCSK9 inhibitor Praluent (conveniently available in two starting doses, 75 mg or 150 mg). A lunchtime presentation called attention to treatment inertia in diabetes, which was a prominent theme of Sanofi’s overall exhibit hall presence. In fact, the company’s medical information booth offered an analogy for this issue: It’s like a wave, where progression of diabetes always seems to be ahead of our efforts to manage it, and instead of playing constant catch-up we should be riding the crest of the wave. Interestingly, there was no mention of new combination therapy Suliqua (which was a highlight of Sanofi’s booth at ATTD 2017 last month). Reps shared that the product has been licensed and will be available in the UK starting in June. We’re very excited about this emerging class of basal insulin/GLP-1 fixed-ratio combinations, and were happy to hear of Sanofi’s plans to price Soliqua on par with other GLP-1 agonists in the US. We’ll be eager to see how pricing, promotion, and sales play out internationally as well.
Takeda’s small white booth promoted DPP-4 inhibitor Vipidia (branded Nesina in the US). Conference attendees could view posters on Vipidia’s beneficial effects in reducing A1c for type 2 diabetes patients, and could take away informational materials as well. Takeda has been such a powerhouse in the diabetes arena and we’d love to see them stay.
-- by John Close, Payal Marathe, Helen Gao, and Kelly Close