Medtronic’s OpT2mise Trial published in The Lancet: pumps superior to MDI in poorly controlled type 2 diabetes; should be very helpful for reimbursement – July 9, 2014

Last week, The Lancet published full results from the Medtronic-sponsored OpT2mise trial, a randomized, six-month study comparing insulin pump therapy (n=168) to MDI (n=163) in type 2 patients in poor control (mean A1c: 9.0%) – these published results were more comprehensive than those shown in a late-breaking poster a few weeks ago at ADA 2014. After 27 weeks, A1c declined by 1.1% in those on an insulin pump compared to 0.4% in the MDI group (p<0.001); notably, 55% of the pump group achieved an A1c <8% vs. 28% of the MDI group. Masked CGM data (iPro2; baseline vs. six months) revealed no significant increase in hypoglycemia and significantly greater reductions in time spent >180 mg/dl in the pump group (-226 minutes per day vs. -57 minutes per day; p<0.001). In addition, the group on pumps used 20% less insulin vs. those on MDI at the end of six months (122 vs. 97 units; p<0.001), a major positive given less insulin should be associated with less weight gain, a big positive for type 2 patients in particular. One episode of severe hypoglycemia occurred in the MDI group, while none occurred in the pump group - also a positive (though probably not generalizable). Surprisingly, there was no significant difference in weight gain between the two groups; however, we believe in the "real world" there may be. Medtronic has summarized the main data in an instructive illustrative infographic posted here – “Insulin Pumps Beat Injections in Type 2 Diabetes Management.”

Overall, it was valuable to see these results from a randomized, controlled, multi-center study of pumps in type 2 diabetes – this is the largest comparative study ever done examining pumps vs. MDI in type 2 diabetes, and it overcame some of the limitations of previous data (e.g., non-randomized, non-poorly controlled patients, small n’s). One could argue that a 1.1% reduction in A1c is fairly small given the high baseline, but we emphasize that this is a highly challenging patient group – late stage type 2s failing MDI. It was quite significant that nearly double the number of patients got to an A1c <8% using a pump, while simultaneously using 20% less insulin and not experiencing any additional hypoglycemia or weight gain. We expect the real-world results in a poorly controlled population would be even better, since control group patients of course received a lot of attention, dose titration, and education.

An accompanying comment from Dr. Pratik Choudhary is quite enthusiastic: “OpT2mise provides a compelling case for the clinical effectiveness of insulin pump treatment in type 2 diabetes, suggesting that it can help improve glycemic control in this difficult to treat group of patients who are unable to achieve glucose control despite increasing doses of insulin.” The short opinion piece compares pumps quite favorably to the proposed alternatives for this patient group – GLP-1 agonists and bariatric surgery.  

The study’s completion is another sign of Medtronic’s recent commitment to type 2 diabetes, first expressed in its 2014 Analyst Day one month ago, as well as with the ADA 2014 announcement of a partnership with Sanofi. We believe there are many directions Medtronic could dive into type 2 diabetes – simpler insulin delivery devices, pre-filled devices, wearable patch-like devices, pump delivery of concentrated insulin and non-insulin hormones like GLP-1 agonists, intermittent CGM to aid HCPs in optimizing care, and more. While many orals and GLP-1 agonists are delaying the move to mealtime insulin for type 2 patients, as these patients live longer, we assume more patients will ultimately lose beta cell function and will need mealtime (which is really “mealtime/snack”) insulin. We expect to see a big focus on cost-effectiveness and new business models as well, given management’s comments from the Analyst Day and new Medtronic Diabetes President Hooman Hakami’s previous experience at GE; this published piece should be very helpful on the reimbursement front in particular. 

• Following a two-month run-in phase to optimize MDI therapy, 331 patients were randomized to six months of either pump therapy (n=168) or MDI (n=163). The objective of the run-in phase was to optimize MDI therapy. All oral medications were replaced by metformin, and insulin therapy was intensified to >0.7 units/kg/day. On completing the run-in phase, patients whose A1c was between 8% and 12% who had done at least 2.5 SMBG tests per day, and had daily insulin requirements of 0.7-1.8 units per kg (max: 220 units per day), were randomly assigned (1:1) to continue injection treatment or to receive pump treatment (Medtronic’s MiniMed Paradigm Veo system). After six months, the MDI arm crossed over and switched to the pump. Both groups then spent months six through 12 on the pump during the study’s continuation phase. Only data from the first six months was reported in The Lancet paper.
  
  • Both treatment groups received identical continuing scheduled support from health-care providers (i.e., seven visits for both groups), with continued encouragement to self-monitor, maintain a healthy lifestyle, and titrate to target. Carbohydrate counting was not required. Pumps were initially set to deliver half of patients’ total daily dose of insulin as a continuous basal flow. Bolus dosing was left to investigators’ discretion in both treatment groups. Bolus dosing ranged from set bolus doses at meals to dosing based on insulin:carbohydrate ratios or variable scales.
• Patients had a mean age of 56 years, a mean 15 year duration of diabetes, a mean A1c of 9.0%, a mean BMI of 33 kg/m², a mean total daily dose of ~109 units per day. The study had a high completion rate – 90% in the pump group vs. 96% in the MDI group.
• From a baseline of 9.0%, A1c declined by 1.1% in those on an insulin pump compared to 0.4% in the MDI group (p<0.001) after 27 weeks; 55% of the pump group achieved an A1c <8% vs. 28% of the MDI group. As would be expected, patients in the highest tertile of baseline A1c realized the largest improvement in A1c after six months of pump use.

• Despite the improved A1c, the group on pumps used 20% less insulin vs. those on MDI (p<0.001) at the end of six months. The MDI group saw total daily insulin dose steadily increase from 106 units per day to 122 units per day. Meanwhile, the pump group saw total daily insulin dose decline from 112 units to 97 units per day.
• Blinded CGM data (Medtronic iPro2; baseline vs. six months) revealed a significant improvement in 24-hour mean glucose, a significant reduction in hyperglycemia, and no significant increase in hypoglycemia. Glucose data was recorded over six days before randomization and on completion of six months’ of randomized treatment

*p<0.01; **p<0.001

• Data for the number of insulin boluses with pump treatment vs. multiple daily injections were not available. Patients in the pump treatment group had access to the pump bolus calculator, though it was “used inconsistently” – 59% of 158 patients used it less than 25% of the time. However, use of the bolus calculator was not associated with a reduction in A1c. With this in mind, the authors concluded, “Among pump users, the infrequent use of the bolus calculator and its lack of association with outcome also suggests that pump treatment can be effectively implemented in patients with type 2 diabetes.” We thought this was an encouraging finding that substantiates the clinical value of very simple type insulin delivery devices that do not have bolus calculators.
• One episode of severe hypoglycemia occurred in the MDI group, while none occurred in the pump group. There were no episodes of DKA in either group. Four device-related serious adverse events occurred in the MDI group: two hyperglycemic hospitalizations (not DKA), one episode of cellulitis, and one abscess.
• The paper concludes, “In view of these findings, the results from OpT2mise suggest that selection of patients who could most benefit from pump treatment is of paramount importance....The two-month run-in period before randomization, the dose adjustment schedule, and the guide for applying such adjustments, enabled us to identify patients who were good potential candidates for pump treatment because their glycated hemoglobin had not improved despite optimization of multiple daily injection treatment.” Optimal patient selection is especially critical given the growing number of treatment options for type 2 diabetes, along with the need to show cost-effectiveness.
  
  • “Previous studies of the efficacy of pump treatment for patients with type 2 diabetes enrolled few participants and yielded inconclusive results.” Indeed, only four previous randomized controlled studies have compared pump treatment to MDI in type 2s: Raskin et al., Diabetes Care 2003; Herman et al., Diabetes Care 2005; Berthe et al., Horm Metab Res 2007; and Wainstein et al., Diabet Med 2005. The two parallel-group studies (Raskin et al., and Herman et al.), which included patients with moderate hyperglycemia (A1c’s 8.0-8.4%), demonstrated that the benefits from pump treatment and multiple daily injection treatment were similar for glycemic control. By contrast, results from two small crossover studies (Berthe et al. and Wainstein et al.) of patients with poorly controlled type 2 diabetes (A1c ≥9%) showed that pump treatment was more efficacious than MDI.
• The study was designed and sponsored by Medtronic, and amended with input from a data and safety monitoring committee. Medtronic had no role in data collection. Medtronic statisticians analyzed the data according to a pre-specified analysis plan. Medtronic paid for the development and publishing of the manuscript, including writing assistance.
• Of the estimated 344 million adult type 2s around the world (IDF Atlas, 2013), Medtronic estimates that ~20 million require insulin (6%). The company also cites data from Peyrot et al., Diabetes Care 2010 that approximately 57% of patients on MDI therapy admit to omitting insulin injections, yet another reason why the convenience of pump therapy is also critical for type 2s.

-- by Adam Brown, Varun Iyengar, and Kelly Close