June 8-12, 2012; Philadelphia, PA Day #4 – ORIGIN – Full Commentary

Executive Highlights

Now that we’ve had some time to digest ORIGIN, we provide you with full coverage of the session at ADA, as well as our high-level takeaways from the trial. The ORIGIN Trial – Final Results session was held in a truly packed Hall A (with an overflow hall of over 1000 people), which was nevertheless anticipatorily quiet as Dr. Ambady Ramachandran (India Diabetes Research Foundation, Chennai, India) and Dr. Giles Dagenais (Laval University, Quebec, Canada) began their introduction. Following these investigators’ overview, Dr. Rafael Diaz (Instituto Cardiovascular de Rosario, Rorasio, Argentina) described the trial’s design, two presenters discussed its omega-3 fatty acid results, and four investigators presented its insulin glargine findings. From among these presentations, we found Dr. Hertzel Gerstein’s (McMaster University, Ontario, Canada) most riveting, as he repeatedly paused (kind of like in a game show), right before uncovering several of the trial’s most exciting insulin glargine results.

As a reminder, the ORIGIN trial was designed to investigate the effects of insulin glargine therapy versus standard care and omega-3 fatty acids versus placebo on cardiovascular (CV) outcomes in people at risk for CV disease with either impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or early type 2 diabetes. The study randomized 12,537 participants to a 2x2 factorial design at 573 sites in 40 countries. Patients were followed for a median of 6.2 years (IQR 5.8-6.6 years), with the final site visit in 2011. Overall, ORIGIN demonstrated no increased risk with insulin glargine for cardiovascular (CV) outcomes or cancer versus standard care. Insulin glargine treatment did, however, reduce the risk of progression to diabetes by 28% versus standard treatment at 25 days following discontinuation of treatment. Notably, both insulin glargine and standard care maintained median A1c at or below 6.5% throughout the study, although insulin glargine was associated with a small A1c advantage (0.3%) at study end. As expected, insulin glargine treatment modestly increased weight and the risk for hypoglycemia. Finally, with regards to omega-3 fatty acid supplementation, no effect on CV outcomes was observed, although a significant benefit on triglyceride levels was detected. From KOLs with whom we have spoken, the results of ORIGIN were mostly unsurprising, and many believe the trial will unlikely impact the ways diabetes and prediabetes are treated today. We discuss our high-level views and takeaways from ORIGIN below.

• The lack of significant benefit on microvascular outcomes observed with insulin glargine therapy in ORIGIN is unsurprising for several reasons. First, A1c levels were maintained at or below 6.5% in both the insulin glargine and standard care arm throughout the trial. As demonstrated by UKPDS and DCCT, the relative risk for developing microvascular complications at an A1c of 6.5% or less is low. Second, there was little difference in median A1c between the two arms throughout the trial, with a 0.3% lower A1c at study end in the insulin glargine arm. Third, the average follow up time (6.1 years) in the trial was relatively short compared to the ten-year follow up period in UKPDS. As a reminder, UKPDS demonstrated a 25% reduction in microvascular complications with intensive glucose therapy versus conventional therapy at ten years in newly diagnosed individuals with type 2 diabetes . However, the differencein A1c obtained between the two arms was 0.9% (7.0% versus 7.9%) at study end. It will be interesting to see whether any difference in risk for microvascular complications emerges in the ORIGIN follow up study ORIGINALE, which will follow-up with trial participants for at least two years – we hope to see a longer follow up.

• For similar reasons, the lack of significant benefit of insulin glargine on macrovascular outcomes is also unsurprising. Despite the higher baseline A1c and study end A1cs, greater divergence in A1c between the study arms, and longer follow up period in UKPDS, statistically significant reductions in MI, diabetes related mortality, and all-cause mortality did not emerge until the 1o-year follow up period. Additionally, it is worth noting that blood pressure and lipid control was worse in UKPDS and that UKPDS only enrolled individuals with recently diagnosed type 2 diabetes, not individuals with prediabetes. Again, we’ll be interested to see whether any difference in macrovascular outcomes risk is demonstrated in ORIGINALE, although we view it as unlikely given the short planned follow up period and the minimal glycemic control difference between the groups.

• Because A1c was maintained at 6.5% or below throughout the trial in both arms, and because the A1c difference between the arms was modest at study end (0.3% in favor of insulin glargine), the trial suggests that insulin is not required to control the worsening of glycemia during prediabetes and the early stages of type 2 diabetes. Rather, standard care with lifestyle modification and oral medications appears to be just as effective. In our view, this result highlights the importance of diagnosing and treating individuals with type 2 diabetes early in the course of the disease regardless of what therapy is used, as long as it is shown to be reasonably safe.

• Insulin glargine treatment did, however, lower the risk for progression to type 2 diabetes. Since this risk was assessed at a median of 25 and 100 days after cessation of glargine treatment, this effect does not seem to be the result of glargine-mediated masking of high glucose levels. Again, this result was somewhat expected given the results from diabetes prevention studies with other anti-diabetic agents, including the DPP (31% reduced incidence with metformin at three years; 18% reduced incidence at 10 years), DREAM (60% reduced relative risk with rosiglitazone at three years), ADOPT (72% reduced relative risk with pioglitazone at 2.4 years), and STOP-NIDDM (25% reduced relative risk with acarbose at 3.3 years). Altogether, the results from each of these trials appears to suggest that treatment with any glucose lowering agent will delay the progression from prediabetes to type 2 diabetes – although some agents may be more effective than others. We are cautious about drawing any conclusions from cross-trial comparisons, of course – these are challenging due to different study populations, study designs, etc.

• Given these findings, a number of important issues or questions emerge, including: 1) how much do patients, insurers, etc. wish to spend to delay diabetes development; 2) does the delay in diabetes development with drug therapy impact the rate of long-term complications; 3) should we expose individuals with prediabetes to drug therapy (possibly for life) given that not all prediabetic individuals progress to diabetes (an estimated ~25% progress over three to five years; Nathan et al., Diabetes Care 2007) and that most drugs have potential side effects; and 4) by starting drug therapy for life in people with prediabetes, are we in essence diagnosing diabetes at an earlier stage?

• We’ll be eager to assess through ORIGINALE the durability of insulin therapy’s effect on diabetes prevention once treatment is stopped; at least in the DPP, the effects of anti-diabetic agents on diabetes prevention appear to wane with time. We’ll also be interestedto see whether any long-term benefits emerge from the diabetes progression delay, although we believe the chances for such a finding are limited given the study population size, the short planned follow up period, and the modest difference in median A1c observed between those who progressed and did not progress to diabetes by study end.

• Despite early insulin glargine therapy’s apparent diabetes progression benefits, we do not believe there will be any movement toward giving patients insulin at such an early stage. Given that most real-world patients are treated by primary care physicians, we assume that early insulinization will not be realistic or viewed with much enthusiasm given its complexity and side effects (hypoglycemia, weight gain), although it’s an interesting question given that basal insulin will be generic soon. Additionally, even with the seemingly more robust impacts of pioglitazone on diabetes progression in ACT NOW (cross trial comparisons are challenging) and its easier administration than insulin, a noticeable shift toward earlier use of the drug to prevent diabetes has not been observed and a prediabetes indication has not been pursued – we assume both have been hampered by the drug’s side effects and potential safety concerns. We also highlight the applicability of ORIGIN’s progression to diabetes findings to clinical practice. Experts have emphasized for years that even if a drug is extremely effective in a trial setting, its full potential won’t be realized if patients are not adherent to it in everyday practice. While the rate of adherence to insulin therapy was remarkably high in ORIGIN, given insulin’s complexity, side effects, and risks, it is almost certain that adherence would not be equally high in a non-trial setting. With that in mind, we wonder what results would have been like with a once-weekly GLP-1 or DPP-4 inhibitor, and we believe there will be at least some movement toward testing these therapies in pre-diabetes or, at least, in determining a pre- diabetes regulatory pathway. We strongly believe that trial and real-world adherence would be closer for these therapies, and their use early in the course of diabetes might be viewed more favorably by PCPs, making them appealing for future study. Without question, a pre-diabetes pathway will be needed before diverse diabetes therapies (and especially more expensive ones) are reimbursed in pre-diabetes; as such, we hope that the results from ORIGIN in addition to DPP, ACT NOW, and DREAM help catalyze the FDA and other regulatory agencies to establish such a pathway. Encouragingly, from our understanding, some movement is currently underway toward establishing a pre-diabetes indication for metformin.

• Hypoglycemia and weight were both increased with insulin treatment – will these outcomes translate into worse outcomes in the long run? The jury is still out. Specifically, in ORIGIN, incidence of any (i.e., confirmed or unconfirmed) non-severe symptomatic hypoglycemia was 16.72 and 5.16 per 100 person-years with glargine and standard treatment, respectively (p<0.001), while incidence of severe hypoglycemia was 1 vs. 0.3 per 100 person-years with glargine versus standard treatment, respectively; (p <0.001)). Weight change was +1.6 kg [3.5 lbs] with glargine versus -0.5 kg [1.1 lbs] with standard treatment (p <0.001). While these increases in hypoglycemia and weight gain (which are risk factors for CV events) could be expected, ORIGIN showed that they did not lead to increased CV risk in the insulin glargine group, suggesting that over the short run, insulin glargine treatment is safe (in terms of outcomes at least) in the studied patient population. However, the benefits of such treatment and the impacts of these side effects over the long run remain unknown.

• Over six to seven years, there was no increased risk for cancer with insulin glargine treatment. While these data (in addition to those described below) are certainly encouraging, some have said that a definitive answer regarding insulin glargine’s cancer association would come over a longer period of time. That said, it would be a lot to ask for a randomized, controlled trial to go on up to a decade or longer – however, it may well be the case that follow-up data for10-plus years would be necessary to see a cancer-promoting effect. We will be interested to see data on cancer risk by level of exposure to insulin (these individuals weren't very insulin resistant, so they probably received lower doses of insulin) and results from the ORIGINALE extension trial. As a reminder, three database analyses presented at this year’s ADA also examined the risk for cancer associated with insulin glargine. While the average exposure to insulin glargine in the studies was relatively short (1.2 to 3.1 years), each found no increased risk for a wide range of cancers with insulin glargine treatment. The one exception was a suggestion of a possibly increased risk for breast cancer in the Kaiser Permanente study, which the lead investigator Dr. Laurel Habel (Kaiser Permanente Northern California, Oakland, CA) argued was likely a chance finding (see our ADA Days 4-5 coverage at http://www.closeconcerns.com/knowledgebase/r/e511b0e2 for more information).

• Work by Dr. Paresh Dandonna (SUNY University of Buffalo, Buffalo, NY) and others have demonstrated that insulin possesses anti-inflammatory and anti- oxidant effects, and that these effects may help reduce the risk for micro- and macro-vascular complications. Additionally, Dr. Dandonna’s research has found that the anti-inflammatory and anti-oxidant effects of insulin are diminished or negated during periods of hyperglycemia, highlighting the importance of euglycemia maintenance. These findings have prompted some KOLs with whom we have spoken to wonder whether the use of a therapeutic regimen in the trial that addressed both elevated fasting and post-prandial glucose would have demonstrated a greater impact on both macro- and microvascular complications, either during ORIGIN or in the subsequent follow-up extension. While implementation of a basal-bolus insulin regimen would not have been practical given safety and complexity concerns, at least in theory, it is interesting to consider what would have happened in the trial if a GLP-1 agonist would have been used, either as a monotherapy or in combination with insulin glargine.

• GLP-1 agonists help provide weight loss and have a low associated risk for hypoglycemia, and some preclinical and limited clinical evidence suggests that the class may provide cardiovascular benefits and help preserve beta cells. Further, trials examining combination GLP-1 agonist and basal insulin therapy have demonstrated robust effects on glycemic control over either therapy alone with low risk for hypoglycemia and no weight gain. Over the coming years, we’ll be eager to hear the results from the ongoing CV outcomes studies for lixisenatide (ELXIXA, 2014), liraglutide (LEADER, 2016), and exenatide once weekly (EXSCEL, 2017). We believe that if ORIGIN had been initiated four years later, the inclusion of a GLP-1 agonist would have at least been heavily considered by the planning committee. That saying, we assume that the use of a GLP-1 agonist in this patient population (especially in individuals with prediabetes) would be similarly viewed as impractical given cost considerations and the potential need for frequent injections (up to three per day for insulin glargine plus exenatide BID). The use of exenatide once weekly greatly reduces injection frequency, but longer- acting GLP-1 agonists typically have less pronounced effect on post-prandial hyperglycemia compared to shorter-acting agents in the class, perhaps resulting in less robust effects on glycemic control when used in combination with basal insulin. Whether exenatide once weekly used as monotherapy would provide similar or improved impacts on diabetes-associated complications or progression to diabetes as insulin glargine is unclear, but at minimum, we believe the former treatment would be favored given its reduced risk for hypoglycemia and effect on weight (although insulin glargine will be generic in a few years). We note that both Sanofi and Novo Nordisk are developing combination GLP-1/basal insulin products that could be administered with a single injection (see the Sanofi 1Q12 report at http://www.closeconcerns.com/knowledgebase/r/6c74a946). We’ll be interested to see whether any further movement emerges to examine GLP-1 agonist/basal insulin early in the course of type 2 diabetes or during prediabetes once these products become available.

Detailed Discussion and Commentary

Symposium: ORIGIN Trial – Final Results

INTRODUCTION

Giles Dagenais, MD (Laval University, Quebec, Canada); Ambady Ramachandran, MD, PhD (India Diabetes Research Foundation, Chennai, India)

Dr. Ramachandran measuredly started off the session by describing ORIGIN’s international nature, population (12,537 subjects with cardiovascular risk factors plus recently diagnosed diabetes, IFG, or IGT), and aims (to assess the effects titrated insulin glargine or 1 g/day of omega-3 fatty acids on cardiovascular and other outcomes).

Upon taking the stage, Dr. Dagenais provided a brief history of ORIGIN and then detailed the trial’s sponsorship, leadership, and organization. He recalled for the audience how the trial’s protocol was developed in 2000 and finalized in 2003. Its first participant was screened in Australia in 2003, while its first and last patients were randomized in September 2003 and December 2005, respectively. ORIGIN’s first and second extensions occurred in November 2004 and December 2008, respectively. More recently, the trial’s last visit and last OGTT occurred in December 2011. The trial was sponsored by Sanofi and headquartered at the Population Health Research Institute at McMaster University & Hamilton Health Sciences. Its leadership represented 40 countries. Sanofi and Pronova BioPharma respectively provided insulin glargine (Lantus) and omega-3 fatty acid (Omacor) for the trial. According to Dr. Dagenais, the trial’s event adjudication committee adjudicated nearly 12,000 first and recurrent CV events, cancer, and other outcomes. In addition to an independent monitoring committee, the trial also had a glycemia management committee and a publication management committee.

DESIGN OF ORIGIN

Rafael Diaz, MD (Instituto Cardiovascular de Rosario, Rorasio, Argentina)

The ORIGIN trial was designed to investigate whether insulin glargine therapy in people at risk for cardiovascular (CV) disease with either impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or early type 2 diabetes reduces CV outcomes more than standard approaches to dysglycemia. ORIGIN was also conducted to determine whether omega-3 fatty acids can reduce CV death in the same patient population. The study randomized 12,537 participants to a 2x2 factorial design to receive either insulin glargine (targeted to a fasting glucose level of 95 mg/dl) omega-3 fatty acids (Omacor) or standard care Omacor. ORIGIN was conducted at 573 sites in 40 countries (North America 11%; South America 31%; Europe/Africa 48%; Asia 9%; and Australia 2%) and patients were followed for a median of 6.2 years (IQR 5.8-6.6 years), with the final site visit in 2011. For insulin glargine, the first co- primary endpoint was non-fatal myocardial infarction, non-fatal stroke, or CV death, and the secondco-primary endpoint was a composite of the aforementioned events, a revascularization process, or hospitalization for congestive heart failure. Secondary endpoints included a composite of microvascular complications, a diagnosis of type 2 diabetes, or all-cause death. The primary endpoint for the omega-3 fatty acid investigation was CV death and secondary endpoints were CV death, myocardial infarction, stroke, all-cause death, or arrhythmic death. The trial also studied the effects of insulin glargine therapy and omega-3 fatty acids on cancers, angina, hospitalizations from CV-related or other causes, hypoglycemia, weight, cognition, and erectile dysfunction.

• The study’s three key inclusion criteria were: 1) age ≥50 years; 2) having either impaired fasting glucose, impaired glucose tolerance, new diabetes diagnosed before randomization, or previously diagnosed type 2 diabetes treated with stable doses of an oral antidiabetic medication (OAD) for at least 10 weeks (the cutoff A1c level depended on whether the participant was taking no OAD [A1c <9%], one OAD at less than half-maximum dose [A1c <8.5%], or one OAD at more than half-maximum dose [A1c <8.0%]); and 3) having high cardiovascular risk, defined as prior myocardial infarction, stroke, revascularization procedure, angina with documented ischemic changes, microalbuminuria, left ventricular hypertrophy, >50% artery stenosis, or an ankle/brachial index <0.9. Full inclusion criteria can be found at http://1.usa.gov/KxZXHw.

• At baseline, 82% of participants had prior diabetes, 6% had newly diagnosed diabetes, and 12% had prediabetes. Participants had a mean age of 63.5 years; 35% of participants were female. Additional information on baseline characteristics and drug use are summarized below:

OMEGA-3 FATTY ACID AND CARDIOVASCULAR OUTCOMES

Jacqueline Bosch, MSc (McMaster University, Ontario, Canada)

Supplementation of 1 gram of omega-3 fatty acids for over six years did not reduce CV outcomes in people with early type 2 diabetes, IGT, or IFG at high CV risk. No statistically significant improvements were observed in the primary outcome of CV death (HR=0.98; 95% CI 0.87-1.10; p=0.72) or the secondary outcomes of the composite of myocardial infarction, stroke, or CV death (HR=1.01; 95% CI 0.93-1.10; p=0.81), overall death (HR=0.98; 95% CI 0.89-1.07; p=0.63), and arrhythmic death (HR=1.10; 95% CI 0.93-1.30; p=0.26). There was no significant between-group difference in the primary outcome in the subgroups examined, including groups defined by baseline consumption of omega-3 fatty acids, baseline triglyceride levels, baseline glycemic status, statin use, heart rate under or over 69 beats/min, assignment to insulin glargine versus standard glycemic treatment, and age under or over 65 years. While significantly greater reductions in triglyceride levels were observed in the omega-3 fatty acid group (23.5 mg/dl from a baseline of 142 mg/dl) versus the placebo group (9 mg/dl from baseline of 140 mg/dl; p<0.001), no significant changes were observed on LDL or HDL levels in either arm. Dietary omega-3 fatty acid intake did not differ significantly between the omega-3 fatty acid and placebo groups at baseline (210 mg/day in each arm), two years (230 mg/day in each arm), and at study end (253 mg/day and 257 mg/day, respectively). Adherence to therapy was reported to be high and similar between the two groups, with an end-of-study adherence of 88% in both arms.

IMPLICATIONS FOR OMEGA-3 FATTY ACID THERAPY

Aldo Maggioni, MD (Italian Association of Hospital Cardiologists, Florence, Italy)

Dr. Maggioni highlighted results from several recent studies documenting the benefits of omega-3 fatty acids. In the GISSI Prevenzione trial, omega-3 fatty acid treatment (1 g/day) decreased the composite primary endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke by 15% after 3.5 years of treatment (GISSI Prevenzione Investigators, Lancet 1999). In a recent meta-analysis of 11 randomized, controlled trials, omega-3 fatty acid treatment was associated with a 9% risk reduction of cardiovascular death (HR=0.91; 95% CI: 0.84-0.99) (Kwak et al., 2012). Dr. Maggioni calculated that if the results from ORIGIN were included in the meta-analysis, omega-3 fatty acid treatment would come close to statistical significance in reducing the risk of cardiovascular death (HR=0.94; 95% CI: 0.87-1.00). Dr. Maggioni suggested that the fact that patients in ORIGIN were at lower risk for cardiovascular disease and were on optimized background therapy could potentially explain the neutral findings, versus the positive findings from previous studies in higher-risk populations (e.g., those with recent myocardial infarction or heart failure). Further trials, including the Rischio e Prevenzione and ASCEND trials, will also provide important information related to omega-3 fatty acids and cardiovascular disease.

BASAL INSULIN AND CARDIOVASCULAR/OTHER OUTCOMES

Hertzel Gerstein, MD (McMaster University, Ontario, Canada)

In his suspenseful presentation, Dr. Gerstein revealed the ORIGIN trial results regarding insulin glargine’s effects on cardiovascular (CV) outcomes and cancer. He opened by briefly reviewing the purpose and protocol of ORIGIN before noting that adherence in the insulin glargine group remained high (~80%) at the study end. At year seven of the follow-up period, there was little change in median A1c from baseline in both the insulin glargine group (6.4% at baseline to 6.2% at year seven) and the standard care group (6.4% to 6.5%). In the same period, median fasting plasma glucose decreased in those taking insulin glargine (from 125 mg/dl to 94 mg/dl) while remaining constant in the standard care arm (~124 mg/dl). Insulin glargine therapy decreased the need for other antidiabetic medications, but had no effect on CV risk factors or the use of CV-related medications compared to standard care treatments. Notably, over the six-to-seven-year trial duration, insulin glargine therapy conferred no impact on cardiovascular (CV) outcomes for both the first co-primary endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) (HR=1.02; 95% CI: 0.94-1.11; p=0.63) and the second co-primary endpoint (a composite of the aforementioned plus revascularization and hospitalization for heart failure) (HR=1.04; 95% CI: 0.97-1.11; p=0.27). This neutral effect was similar across subgroups. Similarly, no difference was observed in the incidence of cancer (HR=1.00; 95% CI: 0.88-1.13) or in death from cancer (HR=0.94; 95% CI: 0.77-1.15) with insulin glargine therapy versus standard care. The results indicate that within the first six to seven years of treatment, insulin glargine confers neither benefit nor harm on CV outcomes or cancer in people with high CV risk and either pre-diabetes or early type 2 diabetes. However, several questions still remain, including whether the use of metformin mitigated any harmful CV influences of insulin glargine and whether the study duration was long enough to capture a treatment effect.

• Dr. Gerstein cited several lines of evidence suggesting that basal insulin therapy may reduce cardiovascular (CV) outcomes: 1) it restores the insulin deficit in dysglycemia;2) it partially relieves the pancreas from producing insulin, allowing the pancreas to better buffer glucose changes; 3) it may reduce the toxic pro-oxidant effects of glucose; 4) experimental studies show that insulin has anti-inflammatory, vasodilatory, and antithrombotic properties; 5) insulin improves endothelial repair and dysfunction; and 6) in UKPDS and DCCT, participants receiving more frequent and higher doses of insulin appeared to have a decreased risk of CV outcomes.

• As a reminder, ORIGIN was conducted to determine whether insulin glargine therapy in people at risk for cardiovascular (CV) disease with either prediabetes or early type 2 diabetes reduces CV outcomes more than standard approaches to dysglycemia. The trial’s 12,537 participants were randomized according to a 2x2 factorial design to receive insulin glargine an omega-3 fatty acid (Omacor), or placebo Omacor. The first co- primary endpoint was non-fatal myocardial infarction, non-fatal stroke, or CV death while the second co-primary endpoint was a composite of the aforementioned events, a revascularization process, or hospitalization for congestive heart failure.

• In the insulin glargine group, 83.6% of participants were taking insulin by year seven of the follow-up and only 19% had permanently discontinued insulin by the study end. The most cited reason for stopping insulin glargine therapy was refusal to treatment (90.3%) followed by “other” (5.0%; specifics not given), hypoglycemia (4.1%), weight gain (0.3%), and hyperglycemia (0.3%). The median insulin dose rose from 0.31 U/kg during the first year toU/kg by year six (IQR: 0.27-0.56 U/kg). Insulin use was relatively low in the standard-caregroup, with only 11% of participants on insulin by the end of the study.

• Median A1c in the insulin glargine group remained relatively constant from 6.4% at baseline to 6.2% (IQR 5.8-6.8) at year seven, and median fasting plasma glucose (FPG) levels dropped from 125 mg/dl to 94 mg/dl (IQR: 81-113 mg/dl) during the same period. Dr. Gerstein noted that the IQR for FPG levels at year two of the follow up was 79- 104 mg/dl, meaning that 75% of participants on insulin glargine had FPG <104 mg/dl within two years of treatment. Participants in the standard care group experienced little change in medianA1c or median FPG from baseline (6.4%; 124 mg/dl) to year seven (6.5%; 94 mg/dL) or study end (123 mg/dl), respectively.

• By the end of the study, participants on insulin glargine used significantly fewer antidiabetic medications than those on standard care treatments. No between-group difference was seen in the use of other drugs.

Table 1. Drug use at study end, before participants in the insulin glargine group without diabetes stopped insulin therapy.

• Insulin glargine therapy had no meaningful effect on cardiovascular risk factors compared to standard care. Dr. Gerstein mentioned that the statistically significant differences in HDL and triglycerides between the two arms were likely due to the nature of the statistical protocol, and are not clinically relevant.

Table 2: Cardiovascular risk factors at study end.

• During the six-to-seven-year trial, insulin glargine therapy had a neutral effect on cardiovascular (CV) outcomes for both the first co-primary endpoint (HR=1.02; 95% CI: 0.94-1.11; p=0.63) and the second co-primary endpoint (HR=1.04; 95% CI: 0.97- 1.11; p=0.27). Similarly, insulin glargine had no impact on microvascular outcomes (see table below). Notably, metformin was ultimately used in 47% of the insulin glargine group and, givenits possible cardioprotective effects, may have mitigated any harmful impacts of insulin glargine. While the influence of metformin on CV outcomes during this trial is uncertain, any confounding effects were also applied to the 60% of the standard care group that used the drug (see Table 1 above).

Table 3: Effects of insulin glargine therapy on the co-primary and other outcomes.

• Data show that within the first six to seven years of treatment, insulin glargine had no impact on the incidence of cancer or on death from cancer.

Table 4: Effects of insulin glargine therapy on cancer.

• Subgroup analysis revealed that insulin glargine therapy had similar effects on both co-primary outcomes regardless of co-treatment with omega-3 fatty acids, gender, age, BMI, A1c level, history of cardiovascular events, or drug use. Only the relationship between insulin glargine’s potential cardiovascular (CV) effects and patients’ CV history approached statistical significance for the first co-primary endpoint (p=0.05), and this correlation disappeared in the second co-primary endpoint analysis (p=0.83).

Table 5: Subgroup analysis for cardiovascular outcomes.

BASAL INSULIN AND DIABETES PREVENTION

Jeffrey Probstfield, MD (University of Washington, Seattle, WA)

Dr. Probstfield announced ORIGIN results on insulin glargine and diabetes prevention. At the time of the first oral glucose tolerance test following the last visit (a median of 25 days following discontinuation of treatment), individuals with prediabetes on insulin glargine therapy (n=737) had a 28% lower risk (HR=0.72; 95% CI: 0.58-0.91, p= 0.006) of progressing to diabetes than those who were not on insulin treatment (n=718). For those still without diabetes after the first OGTT, insulin glargine treatment reduced the progression from prediabetes to diabetes versus comparator with borderline significance (HR=0.80; 95% CI: 0.64-1.00; p=0.05) at the time of the second OGTT (a median of 100 days following treatment discontinuation). In conclusion, Dr. Probstfield stated that although insulin glargine titrated to normal fasting plasma glucose reduces the incidence of diabetes compared to standard care, the durability of the effect beyond three months following the end of treatment remains unclear.

SAFETY OF INSULIN (HYPOGLYCEMIA, WEIGHT GAIN)

Lars Rydén, MD, PhD (Karolinska University, Stockholm, Sweden)

Dr. Rydén reviewed the safety results from the ORIGIN trial, focusing on hypoglycemia and weight gain. In the trial, any non-severe hypoglycemia was defined as exhibiting signs and/or symptoms of hypoglycemia; confirmed non-severe hypoglycemia was defined as signs and/or symptoms of hypoglycemia as well as capillary glucose < 54 mg/dl; and severe hypoglycemia was defined by signs and/or symptoms of hypoglycemia, required assistance, and any measured glucose <36 mg/dl or spontaneous recovery with carbohydrates or glucagon. The rates of any non-severe hypoglycemia (0.17 per patient-year versus 0.05 per patient-year; p <0.001), confirmed non-severe hypoglycemia (0.10 per patient-year versus 0.03 per patient-year; p <0.001), and severe hypoglycemia (0.01 per patient-year versus 0.003 per patient-year; p <0.001) were statistically significantly greater i/em>n the insulin glargine arm than the standard care arm. Dr. Rydén noted that the rate of severe hypoglycemia with insulin glargine versus standard therapy in the ORIGIN trial (0.7% per year) was comparable or lower to that observed between the intensive glycemic control and standard therapy arms in other major outcomes trials, including ACCORD (2%), ADVANCE (0.3%), UKPDS (1.0%), and VADT (2.0%). Weight change was also significantly greater in the insulin glargine arm (+1.6 kg [3.5 lbs] versus -0.5 kg [1.1 lbs]; p <0.001). Baseline weight was 85 kg (187.4 lbs) in the insulin glargine arm and 83 kg (183.0 lbs) in the standard therapy arm.

IMPLICATIONS FOR INSULIN THERAPY

Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)

Dr. Riddle summarized ORIGIN’s conclusions and laid out its implications for a captive audience. He emphasized that ORIGIN’s results demonstrate a clearly neutral effect of once-daily insulin glargine (used for a median of 6.2 years to target an FPG of on ≤95 mg/dl in people with early diabetes, IGT and/or IFG) on CV outcomes and cancer. Additionally, when used as in the trial, insulin glargine treatment slows the progression of dysglycemia versus standard care, even after treatment is ceased for a month or more. Dr. Riddle posited that this effect is more likely related to enhancement of beta cell function than to reduction of insulin resistance (the mechanism proposed for other therapies thought to be associated with a reduced risk of progression to dysglycemia). Once-daily insulin glargine treatment can additionally maintain near-normal glycemic control over a median of 6.2 years and has a small A1c advantage over standard treatment. Finally, it has a greater effect on FPG than standard treatment, but modestly increases hypoglycemia and weight. According to Dr. Riddle, these findings imply that: 1) supplementing endogenous insulin with basal insulin slows the progression of dysglycemia; 2) exogenous basal insulin flexibly lowers glucose levels over six to seven years (later harms or benefits cannot be ruled out); 3) despite this lowering of glucose levels, routine use of basal insulin glargine is not better than guideline-based care in limiting health outcomes in the population studied over the duration of treatment; 4) basal insulin glargine is the best-studied glucose-lowering drug currently available; and 5) no new safety concerns (aside from hypoglycemia and weight gain) need limit insulin glargine’s early use. We’ll be quite curious to see if ORIGIN’s results drive any significant change in use of early medication in the long term. We assume that due to both physician and patient hesitance around the use of insulin, daily insulin use wouldn’t be used in most cases in the short term. Still, we can see the call for more studies looking at the impact of other medicines early in disease therapy that aren’t associated with hypoglycemia or weight gain and may provide for improved adherence (i.e., DPP-4 inhibitors and GLP-1 agonists). However, even if these therapies demonstrate an ability to delay progression to diabetes (which we believe is likely), it seems clear that this effect will have to be linked to improvements in long-term complications to have an impact on clinical practice. To date, no study has shown a reduction in the risk for long-term complications with the earlier initiation of glucose lowering therapies. Critics of the gluco-centric approach to diabetes care (such as Dr. Steven Nissen) have argued that increasing emphasis should be placed on studying ways to prevent complications, not just only on ways to lower glucose levels.

• Dr. Riddle summarized ORIGIN’s findings for an eager audience. He noted that when used for a median of 6.2 years to target an FPG of ≤95 mg/dl in people with early diabetes, IGT and/or IFG, insulin glargine treatment:

1. Has a clearly neutral effect on CV outcomes and cancer compared to standard glycemic treatment. Per Dr. Riddle, this finding withdraws support from the hypothesis that use of systematically titrated basal insulin might reduce CV risk. Yet it also doesn’t aid the proposal (based on epidemiological findings) that insulin therapy increases CV risk via hyperinsulinemia or due to hypoglycemia. Similarly, this conclusion supports neither suggestions of an association between glargine treatment and increased cancer risk, nor proposals (again based on epidemiological findings) of a link between insulin glargine treatment and higher cancer risk. Dr. Riddle emphasized that this finding is based on a strong outcomes dataset, as outcomes ascertainment was high in the trial (medical outcomes were known for over 99% of ORIGIN’s participants by the trial’s end).
2. Slows the progression of dysglycemia compared to standard treatment. This effect notably persists even after insulin glargine treatment is ceased for a month or more. According to Dr. Riddle, this finding is not only statistically significant, but clinically important as well. Dr. Riddle emphasized that since this effect was seen in the context of a modest insulin-associated increase in weight, it is more likely related to enhancement of beta cell function than to reduction of insulin resistance (the mechanism proposed for other therapies thought to be associated with a reduced risk of progression to dysglycemia).
3. Maintains near-normal glycemic control and has a glucose-lowering advantage (both in terms of A1c and FPG) over standard treatment. It should nonetheless be noted, Dr. Riddle said, that glycemic control was strong in both of ORIGIN’s arms – at the end of the study, median A1c was either about the same as or lower than at baseline with both glargine and standard treatment. Notably, these results were achieved through high insulin adherence and appropriate insulin titration. 85% and 80% of subjects were still on insulin at five years and the study’s end, respectively, and at the end of five years, more than 75% of subjects had kept an FPG of <108 mg/dl.
4. Modestly increases hypoglycemia and weight versus standard treatment.

• To conclude, Dr. Riddle reminded the audience that despite ORIGIN’s findings, we are not finished learning about the values or difficulties of insulin therapy. He also excitingly told the audience that further analyses of the ORIGIN database are forthcoming “in due time.”

PANEL DISCUSSION

Giles Dagenais, MD (Laval University, Quebec, Canada); Ambady Ramachandran, MD, PhD (India Diabetes Research Foundation, Chennai, India); Rafael Diaz, MD (ICR Rosario, Rosario, Argentina); Jacqueline Bosch, MSc (McMaster University, Ontario, Canada); Aldo Maggioni, MD (Italian Association of Hospital Cardiologists, Florence, Italy); Hertzel Gerstein, MD (McMaster University, Ontario, Canada); Jeffrey Probstfield, MD (University of Washington, Seattle, WA); Lars Rydén, MD, PhD (Karolinska University, Stockholm, Sweden); Matthew Riddle, MD (Oregon Health and Science University, Portland, OR)

Q: Does this trial give us information about whether to position basal insulin in type 2 diabetes earlier rather than later? And what do you think the impact will be on guidelines around the world?

Dr. Gerstein: It is always difficult to know how any research findings will affect clinical practice guidelines. I personally think that it will have a big effect on how we manage people with diabetes. I am always asked by my patients, “Doctor, if you put me on insulin, isn’t it going to increase my risk of cancer and heart disease?” Until now, I would say, “I don’t believe so.” Now, I can say “No, at least over seven years time.” I think that’s an important piece of information I can tell my patients. I can also tell patients at this point in time that it doesn’t look like there are any new mysterious hidden side effects of basal insulin other than those we know – a little bit of hypoglycemia and weight gain.

Q: Do you think there will be better beta cell preservation with basal insulin? I noticed very few people in the trial were on prandial insulin.

Dr. Gerstein: It’s true that very few patients were on prandial insulin. They achieved better glycemic control on glargine. Whether glargine has long-term effects on beta cell function is not known. We are planning a passive follow-up study right now. It is already being implemented as we speak. It is called ORIGINALE and will look at legacy effects. We will see if anything comes from that.

Q: Three short points. Does the data you present validate use of an A1c of 6.5% for diagnosis? Because, many patients had an A1c lower than 6.5% at baseline and saw a benefit in the trial. Perhaps we are diagnosing too late? Second, do you think that a counterview in terms of beta cell preservation is that subcutaneous liver fat is dissipated over time? The final thing is that I think the data suggests that if we pick up diabetes care early, even in the standard care arm, we can have a significant effect on glycemic control.

Dr. Riddle: The central issue concerns the relative success of the standard treatment arm. Patients entered with an A1c of 6.5% and exited with an A1c of 6.4% or 6.5%. It is not easy to argue that either standard treatment or insulin treatment should not be used in this population. Many of the patients were on oral therapy already to achieve the baseline level. I think the data supports both forms of treatment. It is arguing that standard treatment can be very effective if systematically used and adjusted. It also suggests that there is no reason to withhold basal insulin for safety concerns.

Q: What about subcutaneous fat versus beta cell preservation?

Dr. Riddle: I don’t think that we can get a correct answer to that question from this study. There are many hypotheses that will drive future analyses.

Dr. Gerstein: No difference in the waist to hip ratio was seen.

Q: In the data you presented, the standard arm had a higher use of metformin than the glargine arm. In UKPDS, metformin was associated with a CV protective effect. Do you believe these results could have been impacted by the use of metformin being greater in the standard therapy arm?

Dr. Rydén: If metformin had a truly protective effect, that would have made it more difficult for us to show a benefit. That may be a reasonable assumption. But there is a low event rate in both groups, so it means that if you can control glucose by any safe and reasonable means, you’ll be similarly effective in reducing the risk for CV events. For me as a cardiologist, these results make me feel a bit more secure. It is a bit harder for us to use insulin therapy. The fact that easier to introduce oral therapies may not increase the risk for CV events is reassuring.

Dr. Gerstein: We did randomize patients in the trial, so you can look at the results and make some conclusions. There was less metformin in the glargine arm. It is hard to know what it means. A lot of the data around metformin is from epidemiological studies. These studies are not the same as randomized controlled trials. They can only be hypothesis generating.

Q: It is rather disappointing that most of the primary endpoints in the study were negative. And then we come to the secondary endpoint, which is the only one that was significant – the reduction of risk in diabetes. Now it’s not unexpected that during the study, the group randomized to glargine would have less manifestation of hyperglycemia than the control group, that’s for sure. My only question is whether you are going to repeat the OGTT one or two months from now to see if this is a treatment of hyperglycemia or whether there really is a reduction of diabetes.

Dr. Gerstein: We have no plans to repeat the OGTT. The last patient visit was in 2011, so that’s not going to happen now. We are following patients in a legacy follow-up study called ORIGINALE, in which we will use A1c to detect new diabetes. The first OGTT was done a median of 25 days after stopping insulin. The duration of glargine action is one day. The second OGTT was done 100 days after stopping therapy. It is unlikely that there is a residual effect of insulin in the blood. But we will have to wait longer to find out whether the effect on beta cell function lasts longer.

Q: To be provocative, do any of you want to comment on the proper role of observational studies? They often seem to be conducted without prior leading hypotheses, and the results are pushed into publication with great fanfare in the press. These results then have an effect on the worldwide practice of medicine.

Dr. Gerstein: I agree completely with what you said. When designing a randomized controlled trial, we write out our protocol and our analysis plan. We then stick with and follow this plan. Additionally, by randomizing, you are helping ensure that the two groups are exactly the same. That way, you know that you are only introducing one difference between the groups. You can then with more confidence make conclusions about the effect of that difference between the groups. With epidemiological studies, if you give some group Drug A and see an effect, you won’t be able to tell for sure whether the effect was due to Drug A or due to some other variable that existed before Drug A was given. This is a major limitation of all epidemiological studies – you can’t absolutely ascribe the reason for an effect to a medication regardless of how many things you control for in the study.

Q: When patients were on metformin, there was a trend towards favoring conventional treatment instead of Lantus. Also, when patients were on statins, there was a trend towards favoring conventional treatment compared to insulin treatment. What would be the impact for patients on both metformin and statin treatment, which is very often used for patients with newly diagnosed diabetes?

Dr. Gerstein: When one does a study of this size, trends are not really relevant to look at. If you have a neutral effect, there will be a subgroup where you see a more favorable trend, and another where you see a less favorable trend. These are all totally random and by chance alone. We should be cautious not to overinterpret the trends. All of the things that you suggest are perfectly appropriate to explore as hypothesis generating analyses.

Q: There was a 3% reduction in microvascular outcomes in the insulin glargine group. Looking at previous trials, like UKPDS, the degree of risk reduction was around 8-10%. Is there anything treatment mediated that is decreasing this risk?

Dr. Riddle: There are two comments here. First, while the standard treatment group had an average A1c that was 0.3% higher than the insulin glargine group at the end of the trial, the standard treatment group was still below 6.5% A1c throughout the trial. At this A1c level, the slope of the relationship between A1c and complications is very shallow. We would not expect to see very big differences in microvascular outcomes from what we what we know from other studies. Second, the data that we have analyzed and showed you today is on composite microvascular outcomes. These are mostly clinically relevant endpoints on the eye and the kidney, like vision loss, end-stage renal disease. We are going to have to dig deeper into more minor endpoints before we can answer the question on microvascular outcomes.

Q: Have you found any difference in cancer incidence according to age and insulin dose requirements?

Dr. Gerstein: We did not find any difference with respect to age. We haven’t yet completed a careful analysis with respect to cancer. There will be a separate publication on cancer that will look at this a lot more carefully.

Q: This question is half comment half question. Do you think this that this study pretty much shows that getting good control stops progression significantly? Does that mean that glucose control can delay the progression of diabetes? Also you presented the results for prediabetes separately. But the side-effect profile was for the whole cohort. Do you actually have the side effect profile for prediabetes?

Dr. Probtsfield: It was similar in this part of the cohort. There were slightly fewer side effects, but it was really quite similar.

Dr. Riddle: Regarding the comment with the question wrapped in it – the most solid finding we have about beta cell protection and the natural history of diabetes is in the subset of 1,400 people who did not have diabetes and very clearly showed that over the short term, there is a slow worsening of beta cell functioning at least. The bigger question is – what about people who already have diabetes? Are we doing anything favorable to slow its progression? There is a hint that we might be doing so. Because we were very successful throughout the study in maintaining some very good glucose control in the glargine arm, but on the other hand the standard arm was very successful as well. The only additional clue is that the glargine dose did not increase over time beyond year three. So it’s a plausible hypothesis, but I can’t answer that. I know what you’re thinking though.

Q: In the group that had impaired glucose tolerance, did you have any patients that had fasting glucose levels less than 95 or 90 mg/dl, but an impaired postprandial glucose response? In this group, how did you initiate glargine, and wouldn’t this cause hypoglycemia?

Dr. Gerstein: We started and maintained individuals at two units per day unless glucose levels started to rise, then we started to up-titrate from there.

Q: So these individuals didn’t experience any hypoglycemia?

Dr. Gerstein: Hypoglycemia was less in the group without diabetes receiving glargine than in the group with diabetes receiving insulin glargine. This was likely because the individuals without diabetes still had residual beta cell and alpha cell function that could help regulate blood glucose levels.

Dr. Rydén: There will be a separate paper on hypoglycemia that will explore both the rate of hypoglycemia and between group differences.

Q: Beta cell preservation is very important in diabetes. Having said that, obviously we have trouble convincing patients and primary care physicians to treat patients to a target A1c of 6.0-6.5%. Do you think ADA would take this information and change their guidelines back to 6.0%?

Dr. Gerstein: I wrote guidelines for 13 years, and I could never predict what guideline writers would do.

Q: The messages that you are sending are a little bit mixed. The good news is that you can use fasting plasma glucose to safely titrate insulin, and that there is no extra harm, including cancer. However, I’m a bit disappointed on the results of macrovascular complications.

Dr. Gerstein: I think there are a few points to make. First of all, we’re not out to show what the effects of more versus less intensive glucose-lowering therapy does. We studied people very early in the dysglycemia spectrum, so you would expect the actual incidence of macrovascular disease to be lower than those further along in the disease. This study tells us if you manage patients according to the standard of care, six to seven years later, you get the same macrovascular outcomes. Whether this translates into a difference 10, 15, or 20 years down the line is obviously something we don’t know at this point.

Q: When my patients are deciding whether to start insulin, they don’t ask me, “is this insulin going to harm me?” but rather “if I go through the hassle of taking the shot every day, will I live longer and will I have fewer complications?” Yesterday I was prepared to say “maybe.” Tomorrow I’m prepared to answer “no.”

Dr. Riddle: First, we were studying recently diagnosed patients in whom it’s very easy to control them with oral antidiabetic medications, and the success of the standard arm verifies that. The treatment system implemented in the standard arm demonstrates that you can maintain glucose control and protect against complications with that means. These results may be helpful, however, because even in patients with a modest duration of diabetes, an event could lead to a short or prolonged loss of glucose control. There may be a strong reluctance to start insulin therapy when oral antidiabetic medications aren’t capable of doing the job. A clinical challenge is to define the subgroups of patients early in type 2 diabetes for whom early intervention with insulin would be very helpful. Our study isn’t going to answer that question.

Q: Do you have any data on hypoglycemia and cardiovascular events?

Dr. Rydén: We have no indication that hypoglycemia, not even the severe events, caused cardiovascular events. I think this is a very informative and interesting part of the study, that it was possible to titrate to almost normal glucose and still keep the patients pretty safe.

Q: The results are extremely disappointing. We know that people early in the course of the disease that experience hypoglycemia have an increased event rate for stroke and mocardial infarction. The study shows that there is no sense for early insulin because it increased the risk for hypoglycemia without decreasing the risk for CV events. Wouldn’t you agree?

Dr. Gerstein: That is a perfectly appropriate way to look at the data. We need to identify other ways to reduce CV events early in the course of the disease. We’ll see what the impact is in 10-15 years. But until then, you are right. We have not found the secret yet to reducing CV events in the short term. There is a lot of background therapy aimed at achieving this goal with ACE inhibitors and ARBs, but the event rate was still 3%.

Dr. Rydén: I would also point out that we predicted an event rate higher than 3% when planning the trial. We had a lower event rate than we had predicted. The result then seems to suggest that if we can lower glucose to a certain level, then it doesn’t matter which drug you use. Again in the long run, it is hard to keep patients on a drug. Perhaps glucose is not the appropriate target. I’m not exactly sure what the other target could be, but it should be something that provides a more complete picture. We need to look into this more.

Q: In my view, this is a neutral study. Personally, I expected better cardiovascular prevention with insulin therapy. I’m wondering whether the old treatment with metformin and sulfonylurea is the ideal one as a comparator, since several trials (e.g. UKPDS) indicated that it could increase cardiovascular events but not mortality. The combination of GLP-1 agonist therapy and metformin could be better.

Dr. Gerstein: I think that’s an excellent hypothesis that needs to be tested in a prospective study. Metformin and sulfonylurea have been the standard of care. The UKPDS did not randomize patients to metformin plus sulfonylurea – it was a later, hypothesis-generating analysis as far as I recall. We did not in any way inhibit the use of other drugs in the control group; most were on metformin and sulfonylurea. All we can compare insulin glargine to is the standard of care. Maybe some of the new drugs being tested in randomized, controlled trials will show cardiovascular benefit – we’ll have to wait and see.

--Ben Kozak, Nina Ran, Lisa Rotenstein, Vincent Wu, and Kelly Close