EASD had plenty of discussion on basal insulins, a reminder of all the innovation happening in this area. Novo Nordisk’s exhibit hall booth was dedicated entirely to Tresiba (insulin degludec) on the day of the hall’s opening – it was swarming with visitors eager to learn more about the ultra-long-acting basal insulin, which was recently launched (as of Novo Nordisk 2Q13, Tresiba had launched in the UK, Denmark, Switzerland, Mexico, and Japan). Dr. Matthew Riddle (Oregon Health and Science University, Portland, OR) reminded us of the Sanofi’s new insulin glargine formulation’s hypoglycemia benefits relative to Lantus (insulin glargine). On a broader level, we enjoyed a lively debate on the pros and cons of longer-acting basal insulins. Drs. Luigi Meneghini (University of Miami, Miami, FL) and Philip Home (Newcastle University, Newcastle upon Tyne, UK) both agreed that variability, consistency, and bioavailability are of great importance, and that the current “gold standard” for basal insulin needs is pump therapy. However, they diverged on many other topics, including the safety of once-weekly insulin. This is not a clear-cut debate that we expect to be resolved anytime soon – aside from safety, once-weekly drugs also have other important considerations like convenience (Is it hard to remember once-weekly?), ease of delivery device, titration, and side effects.
Combination therapies for type 2 diabetes received a substantial amount of attention this year. The star of the show, so to speak, was basal insulin/GLP-1 agonist co-therapy, a combination that Dr. John Buse (University of North Carolina, Chapel Hill, NC) characterized as potentially “unparalleled” in terms of efficacy — he specifically mentioned Novo Nordisk’s IDegLira, a fixed-ratio combination of Victoza (liraglutide) and Tresiba (insulin degludec).
There was unfortunately no notable new data on the ultra-rapid-acting insulin front; however, the HypoAna trial was a great reminder of why analog insulin truly makes a difference for patients. The two-year crossover trial randomized 159 type 1 patients with recurrent severe hypoglycemia (≥2 episodes in the past year) to either analog insulin (detemir and aspart) or to human insulin/NPH. Significantly, treatment with analog insulin resulted in an absolute rate reduction of 0.5 severe hypoglycemia episodes per patient-year, meaning the number needed to treat with insulin analogs to avoid one episode of severe hypoglycemia is just two patients per year! What a victory for patients – our hope is that payers and governments see this data and realize the true value of reimbursing analog insulin.
A retrospective database study presented by Dr. Craig Currie (Cardiff University, Cardiff, UK) on the effect of insulin on all-cause mortality found a significant, dose-dependent increase in risk for all-cause mortality with insulin therapy, which we found slightly more surprising. However, indication bias could have played a significant role in the insulin study, as a provider’s decision to place a patient on insulin likely reflected more poorly controlled diabetes. We believe that retrospective studies can generally only be seen as hypothesis-generating, especially when data from prospective studies (such as ORIGIN) are available.
In our report below, talks highlighted in yellow are on our list of our ten favorite talks of the entire conference, while those highlighted in blue are new additions to the report that were not included in our daily updates from Barcelona.
- Executive Highlights
- Insulin Therapy
- Michael Berger Debate: New Basal Insulins – The Longer the Better?
- Oral Presentations: Hypoglycemia – Balancing Glucose Control
- THE EFFECT ON INSULIN ANALOGS ON THE RISK OF SEVERE HYPOGLYCAEMIA IN PATIENTS WITH TYPE 1 DIABETES AND RECURRENT SEVERE HYPOGLYCAEMIA: THE HYPOANA TRIAL
- LOWER RATES OF OVERALL, NOCTURNAL AND SEVERE HYPOGLYCAEMIA DURING MAINTENANCE TREATMENT WITH IDEGASP VS BIPHASIC INSULIN ASPART 30 IN PATIENTS WITH TYPE 2 DIABETES MELLITUS: A META-ANALYSIS
- Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?
- EXOGENOUS INSULIN AND RISK OF ALL-CAUSE MORTALITY IN TYPE 2 DIABETES: A DOSE-RESPONSE ASSOCIATION
- NEW INSULIN GLARGINE FORMULATION: GLUCOSE CONTROL AND HYPOGLYCAEMIA IN PEOPLE WITH TYPE 2 DIABETES USING BASAL AND MEALTIME INSULIN (EDITION I)
- THE EFFECT OF EARLY INTENSIVE DIABETES TREATMENT ON LONG-TERM GLYCEMIC CONTROL IN NEWLY DIAGNOSED TYPE 2 DIABETES: MULTICENTRE RANDOMISED PARALLEL TRIAL
- Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
- Corporate Symposium: Basal Insulin Therapy — Combining to Target (Sponsored by Novo Nordisk)
- Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)
Michael Berger Debate: New Basal Insulins – The Longer the Better?
Luigi Meneghini, MD, MBA (University of Miami, Miami, FL)
After highlighting some of the current limitations of insulin therapy and describing the evolution of basal insulin analogs, Dr. Luigi Meneghini made the case for longer-acting basal insulins. Reviewing clinical data for insulin degludec, U-300 insulin glargine, and PEGylated insulin lispro, Dr. Meneghini noted that these longer-acting agents provide: 1) more consistent biologic activity over a 24-hour period (e.g., insulin degludec has a half life of 24.5 hours, versus 12.5 hours with insulin glargine [Heise et al., Diabetes 2011; Heise et al., Diabetologia 2011]); 2) comparable efficacy with current long-acting agents; 3) no increased risk of overall hypoglycemia, and reduced risk of nocturnal hypoglycemia (e.g., significantly lower rates with insulin degludec versus insulin glargine); and 4) no specific issues regarding exercise or recovery from hypoglycemia.
Philip Home, MD, PhD (Newcastle University, Newcastle upon Tyne, United Kingdom)
Dr. Philip Home deemed Dr. Meneghini’s predominant focus on duration of action to be “unsophisticated thinking,” arguing that other properties and circumstances matter, and matter a lot. Specifically: 1) variability of subcutaneous absorption matters; 2) bioavailability can become a problem; 3) longer duration of action could preclude fast dose adjustments required in some circumstances; 4) weekly insulin dosing could be dangerous; and 5) rapid-acting insulins in pumps will be better than short-acting insulins even for basal insulin delivery, particularly for closed-loop control. Dr. Home drew upon numerous examples, some from insulin’s earlier days. For example, even though insulin detemir has a shorter duration of action than insulin glargine, it has been documented to have lower variability. In addition, he pointed out that bovine ultralente insulin never caught on even though it had a duration of action of ~36 hours, explaining how the formulation had low bioavailability and was thus difficult to titrate to get good control. On a final note, Dr. Home emphasized that the metabolic properties of insulin matter – in a 12-week study comparing the liver-selective PEGylated insulin lispro with insulin glargine in patients with type 2 diabetes, those who received PEGylated lispro had elevated triglycerides and ALT levels, suggesting the insulin could contribute to the development of fatty liver (Bergenstal et al., Diabetes Care 2012).
Luigi Meneghini, MD, MBA (University of Miami, Miami, FL) and Philip Home, MD, PhD (Newcastle University, Newcastle upon Tyne, United Kingdom)
[In a poll of the audience, more people voted for Dr. Meneghini than Dr. Home.]
Q: Is there anything you could say to one another to challenge one another directly?
Dr. Meneghini: [Jokingly] First of all, I thought it was a clinical debate, and not a political English type of exercise. I appreciate the weak arguments that you proposed, which although very enthusiastic, they are delusional. I think one thing we agree on is that “longer-acting” may not be the right word for new basal insulins. I think you and I referred to it in terms of consistent action. A lot of evidence shows that these newer insulins have a more consistent biological effect. You mentioned that using rapid-acting insulin in a pump is the ideal way; on that point, we do agree. I think maybe we should have named the debate something else, like longer acting is almost always better.
Dr. Home: Thank you for agreeing with me that variability and consistency are important. Ultimately, Luigi explained very nicely why longer-acting insulins at least up to 24 hours are advantageous, but as I said, other properties do matter. What I’d like to do is just ask my penultimate point, and say, what about weekly insulins? A yearly insulin? Would you be happy?
Dr. Meneghini: Yes. Let me qualify that. We’re talking about basal insulin. I don’t think the beta cell ever goes on vacation, except obviously if blood sugar goes low. But that is unpredictable with exogenous insulin. I think there is a place for weekly insulin for patients. If we’re able to optimize basal insulin replacement [in terms of daily amount], then I think it will be a safe option [in terms of daily distribution]. What I’m going to agree with you now is that a lot of individuals put on basal insulin are over-basalized. They get too much basal for their needs, and when they do exercise or skip a meal, excessive basal insulin drives hypoglycemia.
Dr. Home: I would like to suggest there is more of a problem with weekly insulin. I can’t always predict how active I am going to be later in the week. Whether I’m enjoying myself in my garden when I get home depends on the weather in Newcastle. I have no idea what it will be.
Dr. Meneghini: Are you telling me you don’t know how to use basal insulin?
Dr. Home: Fortunately, I don’t have to take it. The beta cell is a lovely example of basal insulin – it has a duration of action of five minutes. That tells us something else, doesn’t it? Unless you have a smart insulin in the system, it is certainly better to inject more frequently.
Q: I do not believe you have to say that for all patients with type 1 or type 2 diabetes, longer-acting agents are better. For clinicians whose patients regularly say they have nocturnal hypoglycemia, I think this is an option. I think that at a certain time for certain patients, going on long-acting insulin is probably good, but putting them all on these treatments is probably not right.
Dr. Meneghini: I think you bring up an absolutely correct point. We’re looking at options – the more options we have in the armamentarium, the better. For example, for patients with strong dawn phenomenon, a longer-acting insulin might be less effective than NPH.
Dr. Home: Other things come into play if you want to give insulin in the morning, and some patients don’t want to do that. You really do need a 24-hour insulin to cope with the end of the night.
Q: Is there a difference between using long-acting insulin for type 1 versus type 2 diabetes?
Dr. Meneghini: The evidence [available] shows less risk of hypoglycemia, and that relates to more consistent biologic activity. Obviously you have to individualize treatment. Would I use them [longer-acting basal analogs] for type 1 and type 2? Absolutely. The best test tube is type 1 diabetes – it is the most insulin-deficient environment. Historically, whatever worked for type 1 [diabetes] worked for type 2, whether it was multiple daily injections or some other therapy.
Dr. Home: But it is the case that people with type 1 diabetes are more sensitive to differences in pharmacokinetics and pharmacodynamics. People with type 2 diabetes produce a lot of insulin on their own, which buffers some of the issues. It makes my argument about variability less important.
Q: I was a little puzzled, Philip, by your comments on liver-preferential insulin. All my life I learned that subcutaneous insulin was wrong, and insulin going first to the liver would be expected to be beneficial. Of course no one wants too much and fatty liver. But, do we know if we don’t want one at all, or want some degree [of liver selectivity]?
Dr. Home: I don’t know, but for truly insulin-deficient, thin individuals with type 1 diabetes, or people with pancreatic diabetes, I suspect having hepato-preferential insulin will be a good thing. But in type 2 diabetes, the problem is different. I suggested to the EASD we ought to have a debate on liver-preferential insulin, whether it’s good or bad. My suspicion is that by driving more insulin at the liver, it would worsen the problem of calorie toxicity at the liver in type 2 diabetes. This, I would expect, needs a lot more study. My point here is that the metabolic properties of insulin matter, and not necessarily that that particular insulin has a problem.
Q: I think the most exciting thing is the lack of variability. I’m worried that our colleagues in industry will just develop long-acting insulins with this very useful quality. In type 1 diabetes, we have some quite good evidence against long-acting basals. In a structured education program, only twice-daily basal produced better control with the currently available basals. The advantage of pumps is that you can vary basal replacement over 24 hours. The focus is shifting away from shorter-acting, twice-daily basal insulin to long-acting basals, but what do you tell your patients when they want to go skiing?
Dr. Home: Thanks for the support. You present an even more sophisticated argument. But yes, we vary basal insulin during the night in pumps, don’t we? Don’t we need to find some way to do this with injected insulin?
Dr. Meneghini: I think it’s a good point; I think the gold standard in terms of basal insulin delivery is still fast-acting insulin in a pump because of the flexibility it affords. In terms of going skiing, plenty of exercise literature says you can reduce basal insulin doses, which might have some impact in reducing hypoglycemia; however, supplementing physical activity with carbohydrate [intake] would be a better option.
Q: Après skiing and drinking, what do you do with your basal insulin?
Dr. Meneghini: Didn’t anyone tell you not to drink after you ski?
Dr. Home: They don’t ski a lot in Miami.
Q: Could you comment about intra- versus inter-individual variability? I wonder if its low intra-individual variability that is important for patients, and low inter-individual variability that is important for prescribing physicians?
Dr. Home: Yes is the answer to that, in a way. When we talk about variability, some manufacturers have tried intentionally to confuse us about the different kinds of variability. As a prescribing physician, what you want to know is what does approximately the same thing in everyone, and to understand what you’re going to get – predictability, you might call it. Whereas, a person on insulin with titrated dosage wants the same effect every day. You’re probably right that for individuals, it’s intra-individual variability that matters, and that for physicians, it’s certainly helpful to have some predictability. But of course, if your patients have a lot of erratic insulin absorption from day to day, they would come back to you and report hypoglycemia, and you don’t want that either.
Q: Philip’s main argument is that it’s not a matter of duration, but a matter of variability. Luigi’s argument is that the newer insulins produced less hypoglycemia and more flexibility, with the same rate of hypoglycemia during exercise. Philip, what are your counterpoints to these?
Dr. Home: Don’t get me wrong, I think that insulins which give better duration of action are important. All I’m saying is that there’s more than one property that is important. I’ve worked with manufacturers to develop insulins for 33 years now. I know that if you don’t go to a sophisticated company like Novo Nordisk or Lilly, who have been in insulin for a long time, the first idea is that we must extend action. You must point out that other properties are just as important. Variability and bioavailability are the most important.
Q: From a practical perspective, how do you titrate longer-acting and very long-acting insulin?
Dr. Meneghini: There are quite a few titration algorithms, ranging anywhere from adjustments on a daily basis, to three days a week, to weekly. Given the nature of the longer-acting basals that we’ve talked about (it takes about three to four days to reach steady state), I would not advise any changes more than once every three to four days to stay on the safe side, looking at the studies done where weekly titration is made.
[Dr. Meneghini and Dr. Home gave each other a friendly embrace at the end of the session.]
Oral Presentations: Hypoglycemia – Balancing Glucose Control
Ulrik Pedersen-Bjergaard, MD (Hillerød Hospital, Hilleroed, Denmark)
Dr. Pedersen-Bjergaard presented notable results from the HypoAna study – the two-year crossover trial included 159 type 1 patients with recurrent severe hypoglycemia (>2 episodes in the past year). Patients were randomized to a basal-bolus regimen using analog insulins (detemir and aspart) or human insulin/NPH. Each patient underwent a three-month run-in period, nine months of treatment in one of the arms, a three-month washout period, and then nine months in the other arm. Significantly, treatment with analog insulin resulted in a 29% rate reduction (p<0.05) in severe hypoglycemia (intention-to-treat analysis), which rose to 34% when adjusted for A1c. This corresponds to an absolute rate reduction of 0.5 severe hypoglycemia episodes per patient-year, meaning the number needed to treat with insulin analogs to avoid one episode of severe hypoglycemia is just two patients per year. Striking and victorious results to say the least, and notably, the reduction in hypoglycemia in the analog arm still translated to a 0.13% A1c advantage over human insulin (p<0.05; baseline A1c: 8%). Dr. Pedersen-Bjergaard showed an interesting graph of severe hypoglycemia by time of day – the advantage of analogs only showed up in the nocturnal period. Overall, we were extremely glad to see the real-world ambition of this study and the inclusion of patients with recurrent severe hypoglycemia, those who arguably need analogs the most. We hope this data can be taken to governments and payers who do not cover analog insulin for type 1 diabetes – we think the study clearly supports cost savings with analog insulin.
- The HypoAna trial was a two-year, crossover, seven-center study. The protocol randomized 159 patients to treatment with basal-bolus therapy with insulin aspart/detemir or regular human insulin/NPH. Patients had a three-month run-in period with the insulins, followed by nine months of maintenance. There was then a three-month washout period, followed by crossover to the other therapy for nine months. The glycemic target was the maintenance of baseline A1c (8%), as these patients had a high frequency of severe hypoglycemia. The number of daily doses and adjustment of insulin was at the discretion of the local investigator.
- Dr. Pedersen-Bjergaard emphasized the key inclusion criterion: patients had to have had two or more episodes of severe hypoglycemia in the previous year. The study’s primary endpoint compared severe hypoglycemia between analogs and human insulin in the nine-month maintenance periods. Severe hypoglycemia was defined strictly as requiring third party assistance. Secondary endpoints included hypoglycemia as measured via CGM. The CGM data was not shown in this presentation. A blinded adjudication of endpoints according to Whipple’s triad and severity was applied.
- Fifty-three percent (53%) of the 159 patients were classified as hypoglycemia unaware and 41% had impaired hypoglycemia awareness (based on a Danish questionnaire). Patients had a mean duration of diabetes of 30 years and a baseline A1c of 8%.
- While 159 patients were randomized, there were 49 dropouts (36 while on human insulin and 13 while on an insulin analog). While that reflects a fairly high 31% dropout rate, it disproportionately occurred in the human insulin arm. We wonder if the dropout reflects patients seeing worse clinical outcomes with human insulin. We suspect if the dropout rate had been lower, the data would have been even more compelling.
- Overall, 64% of participants had an episode of severe hypoglycemia during the study. The mean rate during the maintenance periods was 1.3 episodes per patient per year. A striking 34% of these episodes resulted in a coma.
- The prevalence of severe hypoglycemia was 55% with human insulin vs. 39% with analog insulin – this translates to a 29% rate reduction, which rises to 34% when adjusted for A1c.
- The baseline A1c of 8% was maintained throughout the study in both groups – the slide showed no noticeable improvement or decrement in either group over the two-year trial. A1c was a very slight 0.13% better during analog treatment (p<0.05), though this was not a point of emphasis.
- To us, this study provides clear proof for why A1c does not tell the full story – anyone looking at this study would say patients were miles better off with analog insulin (and far less costly), though that improvement was not at all reflected in A1c. We hope that payers are governments will be very receptive to this type of severe hypoglycemia data, since it is so directly tied with economic data.
- Dr. Pedersen-Bjergaard highlighted a Swedish survey that found patients experience more than one episode of severe hypoglycemia per patient-year (Kristensen et al., Diabetes Res Clinc Pract 2012). Further, the survey discovered a disproportionate distribution of events: only 20% of patients had recurrent severe hypoglycemia, though they accounted for up to 90% of all events.
- To date, insulin analogs have shown a less clear impact on severe hypoglycemia for three main reasons: 1) high risk patients are excluded from studies; 2) studies are thereby deflated from statistical power; and 3) hypoglycemia events are mainly safety endpoints. These limitations were the rationale for conducting this study in patients with recurrent severe hypoglycemia.
Questions and Answers
Q: Did you think about the ethics of the study? Many of us would use analogs in people who have these problems already.
A: Of course, we all have used analog insulins in high-risk subjects. We have personal experiences indicating that it may be beneficial. Still, we felt that this study was needed, because there are no scientific data to support these experiences.
Q: Very nice paper. You had 50% of your population with hypoglycemia unawareness. How was that diagnosed – a questionnaire? And what did you do during the run-in period and the crossover period – did patients go back to their previous regimen?
A: Hypoglycemia unawareness was classified according to a Danish developed questionnaire, and it was classified in three groups: normal, impaired, and unawareness. This was not an inclusion criteria; it was only a description of the subject. 95% of patients had some degree of impaired awareness. During run-in and crossover, there was no insulin algorithm supplied. It was all at the discretion of the local investigator. Subjects came into the study with a certain insulin treatment, and the investigator shifted to the trial treatment based on their own experience.
Q: Congratulations on this study. Did you recommend a different carb distribution in the different treatment arms?
A: We did no other interventions other than the treatment.
Q: This was a real-world study, so you left it to the people and investigators. Did you collect data on how people used the insulin – twice-daily NPH and so on?
A: I did not show the distribution of insulin regimens for sake of time. We saw the same difference between the treatment arms regardless of how many basal injections they got in the study.
Q: There is a difference in PK and PD in the human insulin regimen. Did you give different instructions on one insulin regimen vs. another?
A: There were no standardized instructions given to the patients. They just followed usual care.
Allan Vaag, MD (Rigshospitalet, Copenhagen, Denmark)
Dr. Allan Vaag presented a post-hoc meta-analysis of two 26-week phase 3 trials comparing Novo Nordisk’s IDegAsp (a premix of 70% insulin degludec/30% insulin aspart) to biphasic insulin aspart (NovoMix: 70% insulin aspart protamine/30% insulin aspart). IDegAsp had a significant advantage over NovoMix in all measures of hypoglycemia: a 19% lower rate of overall confirmed hypoglycemia (p=0.03); a 57% lower rate of nocturnal confirmed hypoglycemia (p=0.0001); and a 39% lower rate of severe hypoglycemia (not statistically significant, as there were only 29 episodes). Dr. Vaag mentioned that in the FDA’s review of insulin degludec, the agency also requested hypoglycemia outcomes during the maintenance period (“when patients had been used to using these novel insulins”). When narrowing the IDegAsp vs. NovoMix data to the maintenance period, the hypoglycemia data looked even stronger – IDegAsp had a 31% lower rate of overall confirmed hypoglycemia (p<0.05), a striking 84% lower rate of severe hypoglycemia (P<0.05), and 62% lower rate of nocturnal confirmed hypoglycemia (p<0.0001). He emphasized that the these definitions of hypoglycemia were “discussed and challenged by the FDA,” but they were prespecified for insulin degludec, and thus, used in this meta-analysis.
Oral Presentations: Insulin in Type 2 Diabetes – Earlier? Dangerous? Stronger?
EXOGENOUS INSULIN AND RISK OF ALL-CAUSE MORTALITY IN TYPE 2 DIABETES: A DOSE-RESPONSE ASSOCIATION
Craig Currie, PhD (Cardiff University, Cardiff, UK)
Following his presentation on Day #5 of EASD on increased all-cause mortality seen with sulfonylureas compared to DPP-4 inhibitors (which you can read at http://www.closeconcerns.com/knowledgebase/r/a436c2c2), Dr. Craig Currie presented results of another study from his series of retrospective database studies drawn from the UK Clinical Practice Research Datalink (CPRD) showing an increased risk of all-cause mortality and other endpoints with high-dose insulin use. Dr. Currie began by noting that there has been longstanding uncertainty over the safety profile of insulins, citing an editorial published in Lancet this past June (Nolan et al., Lancet 2013). He discussed potential pathological mechanisms that could explain insulin’s hypothetical risk, including weight gain, hypoglycemia, dysrhythmia, and increases in insulin resistance. His group hypothesized that, if there was in fact an increased risk of death or adverse events with insulin, they would see a dose-dependent increase in such outcomes. They mined the CPRD (which covers over 10 million UK patients) for type 2 diabetes patients who had initiated insulin treatment between 2000 and 2012 (n=8,414), and used a Cox model to examine the effect of dosage on all-cause mortality, MACE, cancer, and a composite endpoint of all three factors. They found a dose-dependent increase in risk of all-cause mortality and the composite endpoint with insulin treatment; patients on a high daily dose (>1.5 U/kg/day) had an adjusted hazard ratio of 2.15 for all-cause mortality compared with the low daily dose group (<0.5 U/kg/day). A subgroup analysis showed that the risk was highest in patients with low baseline A1c and advanced age. MACE and cancer also showed borderline-significant increases at higher insulin doses. Interestingly, patients on combination therapy with insulin and metformin had only half the risk of all-cause mortality as those patients on insulin alone. Overall, we find it hard to put much stock in these results. Dr. Currie himself noted that indication bias could have affected the results — the decision to put a patient on a higher insulin dose likely reflected more poorly controlled diabetes, which in turn could indicate a higher risk of complications. Furthermore, the study lumped all forms of insulin together, which we feel may be an over-generalization of a heterogeneous class of drugs. Lastly, the limitations of retrospective database studies are well-known — they cannot be seen as more than hypothesis-generating, especially when we have data on the safety profile of insulin from large, prospective randomized control trials such as ORIGIN.
Questions and Answers
Q: Is it better to use less insulin or more metformin?
A: Both. I’m not a physician, I’m an epidemiologist. There’s clearly quite a complex issue here. Insulin isn’t necessarily safe in type 2 diabetes, and now the randomized trial guys have got to sort this out once and for all.
Q: I saw you had a few sub-analyses but I never saw renal function. We usually don’t put patients with renal failure on metformin, so that could be a major confounder, and that could be why ORIGIN didn’t see an increased risk.
A: We did look at that, but there was no change in risk for patients with renal problems.
Q: Which insulin was used in the study, human or analog?
A: This was a population data, so it’s a mixed bag of everything that was used in the past ten years.
Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)
Dr. Matthew Riddle presented the results of EDITION I, a six-month phase 3a study comparing the efficacy and safety of a new long-acting U-300 (300 U/ml) insulin glargine formulation to U-100 insulin glargine (100 U/ml) in very obese patients with type 2 diabetes (BMI: 37 kg/m2, baseline A1c: 8.2%). The data was first presented at ADA 2013 as a late-breaking poster (43-LB). Following six months of treatment, U-300 was non-inferior to U-100 in A1c-lowering efficacy (both groups dropped A1c by an average of 0.8% from baseline). However, patients receiving U-300 showed a significant 21% reduction in severe/nocturnal confirmed hypoglycemia from month three to month six (36% with U-300 vs. 46% with U-100; p=0.004). Furthermore, the occurrence of any hypoglycemic event was numerically lower, but not statistically significant, in patients receiving U-300 vs. U-100. The U-300 arm required a 10% higher insulin dose by the end of the trial (0.97 U/kg vs. 0.88 U/kg). Weight change were similar in both study arms: a gain of 0.9 kg. There were no differences in safety or adverse events between U-300 and U-100. We look forward to seeing results from other EDITION studies, which will test the new glargine in a variety other populations – topline results from EDITION III (n=800 type 2s on orals) and EDITION IV (n=500 type 1s) are expected in 2H13, and FDA submission is expected in 1H14.
Questions and Answers
Q: To what extent did this study deal with the massive obesity epidemic that one finds in the United States? What about much lower body weight patients? And from the economic perspective, can the company reduce the price of insulin?
A: On the economic one, I have no helpful information. We all hope insulins can be provided at reasonable cost. Regarding the first question, these were large patients with high doses, and we see them particularly in the US, but all over the world. We chose this study population in part because we know this is a growing problem, and we wanted to determine if the new insulin might have some clinical benefits. It does seem to, particularly for hypoglycemia. We will look at other populations in the EDITION program.
Q: Was there a cutoff for eGFR in the inclusion criteria?
A: There was. I cannot quote it, but they could not have renal failure. They had to have renal function at least adequate enough to permit metformin use.
Q: Patients were nearly morbidly obese people. Is there comparable data in lower BMI patients? What about those patients with a BMI of 30 kg/m2 or lower?
A: The other EDITION studies will look at different populations.
JT Woo, MD, PhD (Kyung Hee University Hospital, Seoul, South Korea)
This interesting study randomized patients to 12 weeks of early intensive insulin treatment (glargine and glulisine) or initial oral combination therapy (metformin and glimepiride). The 97 patients were newly diagnosed with type 2 diabetes, had a very high baseline A1c of 10%, and were followed over a two-year period (after the short-term 12-week intensive period, treatment switched to either diet/exercise [A1c <8%] or oral drug therapy [A1c>8%]). After early intensive treatment, A1c decreased significantly in both groups but was not statistically different: -3.3% (insulin) vs. -3.5% (orals). Throughout the 104 weeks of the follow-up period, both groups maintained an A1c around 7%, though those who had undergone intensive insulin treatment were more likely to be at an A1c <7%: 68%-89% vs. 41-65% with orals. The most notable data of the presentation was the comparison of diabetes remission rates (A1c <7% without medication) at 104 weeks – 46% of the intensive insulin therapy group had diabetes remission vs. just 18% of those in the orals group (p=0.02). This data seemed to confirm a number of previous studies out of Asia showing a benefit of short-term intensive insulin treatment. However, we thought some of the Q&A criticism was spot on regarding the study’s protocol – metformin plus sulfonylurea was likely under-treatment, as the baseline A1c was 10%. That said, we continue to be intrigued by the use of early insulin and hope to see a wider array of studies in the future.
- This trial took place at eight university hospitals in Korea in 97 patients newly diagnosed with type 2 diabetes (<1 year duration; baseline A1c: 10%). After screening, patients were randomized to 12 weeks of intensive insulin therapy (insulin glargine and glulisine) or combination oral drugs (glimepiride and metformin). Intensive treatment was stopped after 12 weeks if A1c <7% or total inulin requirement <10 units/day. Following the intensive period, patients underwent a short four-week period of lifestyle intervention. If A1c <8%, they continued on with lifestyle intervention. If A1c >8%, they went on “rescue drug therapy” (unspecified). Patients were followed up every one to three months for two years.
Questions and Answers
Q: I assume the remission rate at 12 weeks as very good predictor of long-term remission?
Q: I think it was problematic to use glimepiride and metformin for patients with an A1c around 10%. The ADA/EASD suggest insulin in this situation. It was absolutely clear why you had a high failing rate in that group – they had a very high A1c. Starting from these very high levels, you should use three drugs as Dr. DeFronzo did.
A: I don’t think they were initially at a very high A1c level – it was about 10% at the time of diagnosis. As I mentioned before, they had no symptoms of hypoglycemia.
Q: Why did you do an oral glucose tolerance test during the study? Did you measure C-peptide levels or insulin levels?
A: Yes, we checked insulin sensitivity and secretion parameters. Insulin secretion dramatically increased from baseline, but there was no difference between the two groups. The one difference was in disposition index, which was much higher in the IIT group compared to the orals group. We’re analyzing this very finely to confirm this result.
Oral Presentations: Defining Strategies for The Treatment of Type 2 Diabetes
THE EFFICACY OF METFORMIN-BASED OAD IS NOT INFERIOR TO INSULIN GLARGINE IN NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS PATIENTS WITH SEVERE HYPERGLYCEMIA AFTER SHORT-TERM INTENSIVE INSULIN THERAPY
Shumin Yang, MD (Chongqing Medical University, Chongqing, China)
Dr. Shumin Yang presented the results of a study investigating the efficacy of metformin-based oral antidiabetic (OAD) therapy versus insulin glargine in newly diagnosed patients with type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy (IIT). After a 10-14 day run-in phase of IIT, participants in the trial were randomized to receive metformin-based OAD therapy (n=24 completers at 48 weeks) or insulin glargine (n=20) for 24 weeks, followed by a 24-week extension on metformin-based OAD therapy. To be included in the study, patients must have been newly diagnosed with type 2 diabetes, drug naïve, and had fasting plasma glucose above 11.1 mmol/l (200 mg/dl), or postprandial glucose above 16.7 mmol/l (300 mg/dl). Metformin was initiated at 425 mg BID, and titrated to a maximum of 2,500 mg/day. If patients failed to achieve a target fasting plasma glucose of 4.4-8.0 mmol/l (79-144 mg/dl), gliclazide or glimepiride was added. Insulin glargine was initiated at 6-8 U per night, and titrated every three days to achieve target. At baseline, there were no significant differences between treatment arms – participants had an average age of 56-58 years, BMI of 24 kg/m2, A1c of 11.7-11.8%, and fasting plasma glucose of 16-18 mmol/l (288-324 mg/dl) before IIT. Following IIT, OAD therapy showed similar efficacy in sustaining both fasting and postprandial glucose control as insulin glargine, as well as reductions in A1c over 24 weeks. From baseline, the insulinogenic index increased significantly in both groups, and HOMA-B also increased, suggesting that beta cell function improved in both groups. No differences in hypoglycemia were observed between arms, and there were no cases of severe hypoglycemia during the trial. OAD therapy lowered weight an average of ~1.2 kg (2.6 lbs), compared to a ~0.4 kg (0.9 lb) gain with insulin glargine treatment.
Questions and Answers
Comment: Somehow I feel that you received a mixed message from your very important trial, because you allowed patients in the oral treatment group to add sulfonylurea, which really is the cause of the increase in hypoglycemia and also potentially the reason weight changes were not significantly different.
Corporate Symposium: Basal Insulin Therapy — Combining to Target (Sponsored by Novo Nordisk)
SYNERGIES OF COMPLEMENTARY DRUGS
John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC)
Dr. John Buse’s presentation, which focused on the combined use of basal insulins and GLP-1 agonists, was somewhat more narrow in scope than the ambitious talk title might have suggested but definitely worth attending. He began by providing broad background on the pathology of type 2 diabetes, beginning with Dr. Ralph DeFronzo’s study on the natural history of beta cell dysfunction, and subsequently covering the pleiotropic effects of basal insulin and GLP-1 agonists in type 2 diabetes patients. He characterized long-acting basal insulin as the most effective treatment option currently available for reducing fasting plasma glucose, and compared the magnitude of the advance from Sanofi’s Lantus (insulin glargine) to Tresiba (insulin degludec) to the previous leap from NPH to Lantus. Turning to the GLP-1 agonists, Dr. Buse remarked that the class is the most effective currently available tool for the reduction of postprandial glucose levels. He noted that Novo Nordisk’s Victoza (liraglutide) has generally proven to be more effective than the other GLP-1 agonists it has been compared to in clinical trials. Bringing the two halves of his presentation together, he expressed great enthusiasm about basal insulin/GLP-1 agonist co-therapies, stating that the combination could provide “unparalleled” efficacy in terms of both postprandial and fasting plasma glucose levels. He also noted that the combination would help mitigate the side effects seen with Tresiba monotherapy (hypoglycemia, weight gain) and Victoza monotherapy (nausea). For more background on Tresiba and its fixed-dose combinations
INSULIN-INCRETIN COMBINATION THERAPY
Stephen Gough, MD (University of Oxford, Oxford, UK)
Dr. Stephen Gough spoke on the subject of insulin/incretin co-therapies, focusing on Novo Nordisk’s IDegLira (a fixed-dose combination of the GLP-1 agonist Victoza [liraglutide] and the basal insulin Tresiba [insulin degludec]) – he suggested this product could have powerful antihyperglycemic effects and better safety profiles than other currently available therapies. He highlighted IDegLira’s simplicity — it is a once-daily injection that comes pre-mixed at a fixed dose. The majority of the presentation was given to an overview of the DUAL 1 study, which compared IDegLira to use of its individual constituent parts, Tresiba (insulin degludec) and Victoza (liraglutide) — for our coverage of the initial DUAL 1 presentation at this year’s ADA, see page four of our ADA 2013 Incretins Report at http://www.closeconcerns.com/knowledgebase/r/6001b62d. In the trial, over 80% of patients on IDegLira achieved an A1c target of <7.0% — Dr. Gough called the A1c levels in this treatment arm “some of the lowest we’ve seen.” Furthermore, IDegLira mitigated the side effects seen with Victoza monotherapy (nausea) and Tresiba monotherapy (hypoglycemia and weight gain). Despite his apparent strong belief in the potential of IDegLira, during Q&A Dr. Gough cautioned against the “knee-jerk response” of switching all type 2 diabetes patients to insulin/incretin therapy; rather, he recommended that providers view products like IDegLira within the scope of currently available treatment algorithms and continue to consider all options within the framework of individualized diabetes therapy.
Peter Kurtzhals, PhD (Novo Nordisk, Bagsvaerd, Denmark); Thomas Pieber, MD (University Hospital of Graz, Graz, Austria); Athena Philis-Tsimikas, MD (Scripps Health, La Jolla, CA); Luigi Meneghini, MD, MBA (University of Miami, Miami, FL); John Buse, MD, PhD (University of North Carolina, Chapel Hill, NC); Stephen Bain, MD (Abertawe Bro Morgannwg University NHS Trust, Swansea, UK); Stephen Gough, MD (University of Oxford, Oxford, UK)
Q: What is the effect of warming the injection site or of exercise if you inject degludec into a limb.
Dr. Kurtzhals: That was not studied directly, but the absorption would be subject to factors like blood flow to the same extent as other injections. Changes in blood flow would likely affect absorptions, but no more than it would for other insulins.
Q: Does degludec’s flexible dosing translate to a better quality of life?
Dr. Meneghini: In theory it should, but remember that these are forced flexible dosing studies, in which we took patients and forced them to take the insulin at different times. Perhaps a good opportunity would be to give patients a free-flex option when they could take the dose whenever they wanted.
Dr. Pieber: Some patients want to sleep in and don’t want to have to wake up at six in the morning, and some patients may want to go out at night and not have to take their insulin then. So I think there will definitely be an improvement in quality of life.
Dr. Gough: I don’t think the trial setting is the best way to pick up quality of life issues. We will learn about those things in the real world setting.
Q: Would you consider administering GLP-1 agonists earlier, even in prediabetes?
Dr. Buse: The health economics of using metformin right now are hard to deny, but with more time and greater assurance on safety, I think these GLP-1 therapies will progressively be used earlier and earlier. I do hope that the obesity program, which includes patients with prediabetes in those trials, will give us some indication of the benefits in the prediabetic period.
Q: The issue around pancreatitis — what is the current status of that debate regarding DPP-4 inhibitors and GLP-1 agonists? I’m afraid people are still talking about the Butler paper.
Dr. Buse: The way I would characterize it – there are now more opinion pieces on the issue than actual data studies – but if you look carefully at the data studies that do exist, the stronger the study design, the lesser the risk demonstrated for pancreatitis. But right now we cannot exclude the possibility of a slight increased risk of pancreatitis with these agents. Regarding pancreatic cancer, we can look at the current data from autopsy studies and animal models as hypothesis-generating, but there is not a shred of clinical evidence. Getting a definitive answer will take time. For now, if there is a risk (and there may be no risk), it is quite small and over intermediate periods of time.
Q: Are you encouraged by the results from SAVOR and EXAMINE, which showed no signal of pancreatitis, albeit up to only two years?
Dr. Buse: That’s the problem – we don’t have any five-year studies yet. For now, the safety looks good over at least two years.
Dr. Bain: For drugs in the incretin class, it is safe to say that we will have more safety data than we have ever had on most other classes.
Dr. Meneghini: I have been using these agents since 2005, and I have yet to see a case of pancreatitis or pancreatic cancer. I wouldn’t use them in patients that have pancreatic disease, but overall I’m pretty confident in their safety.
Dr. Philis-Tsimikas: I have one concern, that when topics like this reach the media like this one has, that even if you acquire data afterwards confirming the drugs’ safety, it is hard to overcome the huge media surge. I wish we could moderate some of the media pieces, although I know that cannot be done.
Dr. Buse: Recognize that we are going to have a lot of data in a couple years. LEADER will tell us about many thousands of patients over five years. We’ll have long term studies conducted on GLP-1 agonists and DPP-4 inhibitors. We’ll begin to understand the 5 year timeline in the coming few years, and the 10 year timeline in the next decade.
Q: What is the clinical paradigm for how we could use insulin/incretin therapy?
Dr. Gough: I think that it is important to follow existing guidelines, such as the ones released by ADA and EASD. I think there is a knee-jerk response to say that everyone should go onto insulin/incretin therapy, but I think we should still prescribe on an individual basis.
Corporate Symposium: Pathophysiology and Glycemic Control in T2D: Focusing on the Underlying Defect to Improve Treatment Outcomes (Sponsored by Sanofi)
BASAL INSULIN THERAPY: TIMELY INITIATION AND EFFECTIVE MANAGEMENT
Matthew Riddle, MD (Oregon Health Sciences University, Portland, OR)
Dr. Matthew Riddle discussed the rationale for timely initiation of basal insulin, noting that: 1) the treat-to-target concept can safely be used in clinical practice; 2) basal hyperglycemia is the main problem when oral anti-diabetics fail (Riddle et al., Diabetes Care 2011); 3) timely initiation of basal insulin is especially effective; 4) the risk of hypoglycemia can be further reduced; and 5) further intensification is possible for many patients. With regards to titration, Dr. Riddle commented that there is no single scheme that works better than any other; he emphasized that what is most important is to involve the patient early on in treatment decisions so they can better self manage their diabetes going forward. As for timely initiation, Dr. Riddle noted that individuals with lower A1c have a higher likelihood of achieving an A1c ≤7%. In a pooled analysis (n=2,193), ~56% of individuals with a baseline A1c of 8% and ~75% of those with a baseline A1c of 7.5-7.6% achieved an A1c of ≤7% over six months (Riddle et al., DOM 2013). Dr. Riddle highlighted that the risk of hypoglycemia with insulin glargine is already relatively low (~2%), but this risk can be further reduced with better patient education and new insulins. Specifically, he pointed out that both insulin degludec and Gla-300 (a new, higher concentration of insulin glargine) had reductions in hypoglycemia versus insulin glargine (Zinman et al., Diabetes Care 2012; Riddle et al., ADA 2013). He emphasized basal insulin as a platform from which further intensification is possible – with basal/bolus therapy, prandial insulin with the main meal, or the addition of a short-to-intermediate-acting GLP-1 agonist. In closing, Dr. Riddle stated that basal insulin can be part of a lifetime strategy of timely intensification of therapy, and that we should consider a “treat-to-defend-the-ceiling approach” in which an A1c of 7% is the upper limit.
-- by Adam Brown, Poonam Daryani, Hannah Deming, Jessica Dong, Hannah Martin, Manu Venkat, Vincent Wu, and Kelly Close