Increased Time in Range and Fewer Missed Bolus Injections After Introduction of a Smart Connected Insulin Pen

In the paper

“The impact of missed insulin injections on HbA1c levels is well established,7–12 leading to an increasing risk of diabetes-related complications.13,14”

What the sources say

• Supported

  The source supports the part of the citing sentence concerning missed injections and HbA1c: its Results report that simulated missed injections increased HbA1c. The complications-risk clause has separate citations (13, 14), so it is not attributed to this source. (LLM, conf=0.92)

  cites [7] Randlov J, Poulsen JU: How much do forgotten insulin injections matter to hemoglobin a1c in people with diabetes? A simulation study. J Diabetes Sci Technol 2008; 2: 229– 235 19885347 PMC2771482 source
• ?Could not verify

  The Conclusions describe reluctance to adjust insulin doses and associated high glucose excursions; the Abstract Results report changes in A1C after a self-care intervention. Neither passage addresses missed insulin injections specifically or links them to increased diabetes-related complications (searched: missed injections, missed doses, A1C, complications). (LLM, conf=0.73)

  cites [8] Munshi MN, Segal AR, Suhl E, et al.: Assessment of barriers to improve diabetes management in older adults: a randomized controlled study. Diabetes Care 2013; 36: 543– 549 23193208 PMC3579376 sourceExperimental — accuracy not yet measured
• Not checked yetcites [9] Hood KK, Peterson CM, Rohan JM, et al.: Association between adherence and glycemic control in pediatric type 1 diabetes: a meta-analysis. Pediatrics 2009; 124: e1171– e1179 19884476 source
• Not checked yetcites [10] Spaans E, van Hateren KJJ, Groenier KH, et al.: Mealtime insulin bolus adherence and glycemic control in adolescents on insulin pump therapy. Eur J Pediatr 2018; 177: 1831– 1836 30238153 source
• Partly supported

  The Results and Discussion report that poorer self-perceived adherence to insulin therapy was associated with higher HbA1c in patients with type 1 diabetes. The paper does not specifically measure missed injections or establish that they cause the increase. In the citing sentence, separate citations are attached to the complications claim. (LLM, conf=0.85)

  cites [11] Andrade CS, Ribeiro GS, Santos C, et al.: Factors associated with high levels of glycated haemoglobin in patients with type 1 diabetes: a multicentre study in Brazil. BMJ Open 2017; 7: e018094 PMC5736030 29247092 sourceExperimental — accuracy not yet measured
• Supported

  The Results section reports that adolescents who missed more bolus doses had higher HbA1c, and the Discussion says less frequent bolus dosing could explain the difference. This source is cited among references 7–12 for the HbA1c point; the complications-risk point is attached to references 13–14, not this source. (LLM, conf=0.90)

  cites [12] Olinder AL, Kernell A, Smide B: Missed bolus doses: devastating for metabolic control in CSII-treated adolescents with type 1 diabetes. Pediatr Diabetes 2009; 10: 142– 148 19175898 source
• Not checked yetcites [13] Nathan DM, Genuth S, Lachin J, et al.: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977– 986 8366922 source
• Supported

  The citation is attached to the increased risk of diabetes-related complications, not to the preceding claim about missed injections. In the Results, a lower glycosylated hemoglobin value was associated with a lower risk of cardiovascular events; the paper also reports that hyperglycemia plays a causal role in microvascular complications of type 1 diabetes. (LLM, conf=0.92)

  cites [14] Nathan DM, Cleary PA, Backlund JY, et al.: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643– 2653 16371630 PMC2637991 source

In the paper

“The change in MBD injections by visit is included in Supplementary Figure S2, which shows that a significant effect was seen from visit 3, and that it was relatively consistent from this point onward.”

In the paper

“The change in TIR was relatively stable from visit 4 onward, as shown in Supplementary Figure S1.”

In the paper

“Based on these analyses, the 8.5% increase in TIR reported here would be expected to correspond to an improvement in HbA1c of ∼0.4–0.7% (4–7 mmol/mol).”

In the paper

“This amounts to five meals with a missed dose per week on average.”

In the paper

“The study data also confirmed that missing bolus injections can be common for people with T1D, where on average at least 25% of meals had a missed dose, assuming three meals per day.”

In the paper

“The number of participants with data at visits 1, 2, 3, and 4 was 57, 30, 21, and 15, respectively.”

In the paper

“A significance level of P < 0.05 was predefined for all statistical comparisons.”

In the paper

“Reductions in HbA1c have been reported with CGM use in people on multiple daily injection (MDI) therapy,19 and continuous subcutaneous insulin infusion therapy,20 with reduced time spent in hypoglycemia,20 and improved hypoglycemia awareness.21”

What the sources say

• Not checked yetcites [19] Lind M, Polonsky W, Hirsch IB, et al.: Continuous glucose monitoring vs conventional therapy for glycemic control in adults with type 1 diabetes treated with multiple daily insulin injections: the GOLD randomized clinical trial. JAMA 2017; 317: 379– 387 28118454 source
• Not checked yetcites [20] Battelino T, Conget I, Olsen B, et al.: The use and efficacy of continuous glucose monitoring in type 1 diabetes treated with insulin pump therapy: a randomised controlled trial. Diabetologia 2012; 55: 3155– 3162 22965294 PMC3483098 source
• Not checked yetcites [21] Heinemann L, Freckmann G, Ehrmann D, et al.: Real-time continuous glucose monitoring in adults with type 1 diabetes and impaired hypoglycaemia awareness or severe hypoglycaemia treated with multiple daily insulin injections (HypoDE): a multicentre, randomised controlled trial. Lancet 2018; 391: 1367– 1377 29459019 source

In the paper

“The recent Advanced Technologies & Treatments for Diabetes Congress consensus recommendations suggest that an approximate 5% increase in TIR is associated with clinically significant benefits.27”

What the sources say

• Not checked yetcites [27] Battelino T, Danne T, Bergenstal RM, et al.: Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care 2019; 42: 1593– 1603 31177185 PMC6973648 source

In the paper

“Participants were blinded to the injection data overview during the baseline period (baseline until visit 1; Fig. 1).”

In the paper

“There was no indication of a relationship between baseline parameters (age, glycemic control, or insulin dose) and study duration or visit frequency.”

In the paper

“All statistical models were verified based on residual plots (not shown).”

In the paper

“The key benefits of CGM include real-time data monitoring for people with T1D and access for them and their HCPs to complete glucose datasets17; both of which help people to achieve their target time spent within the acceptable range (time in range [TIR]: 3.9–10.0 mmol/L [70–180 mg/dL]) and avoid hyper- and hypoglycemia.18”

What the sources say

• Not checked yetcites [17] Slattery D, Choudhary P: Clinical use of continuous glucose monitoring in adults with type 1 diabetes. Diabetes Technol Ther 2017; 19(Suppl 2): S55– S61 28541131 PMC5444504 source
• Not checked yetcites [18] Bergenstal RM, Ahmann AJ, Bailey T, et al.: Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP). Diabetes Technol Ther 2013; 15: 198– 211 23448694 source

In the paper

“Robustness with respect to the choice of follow-up period was evaluated by estimating the change from baseline for each single visit.”

• Also stated in: § Statistical analyses · plain

  “Robustness with respect to the choice of follow-up period was evaluated by estimating the change from baseline for every visit.”

In the paper

“Of the final cohort of 94 participants, 14 made ≥5 visits to a HCP (Supplementary Fig. S1).”

In the paper

“A previous study has demonstrated that improvements in glycemic control and glycemic variability were associated with an increased frequency of blood glucose testing and administration of bolus insulin.30”

What the sources say

• Not checked yetcites [30] Pfutzner A, Weissmann J, Mougiakakou S, et al.: Glycemic variability is associated with frequency of blood glucose testing and bolus: post hoc analysis results from the ProAct study. Diabetes Technol Ther 2015; 17: 392– 397 25734860 PMC4432784 source

In the paper

“Therefore, even small improvements in TIR can yield corresponding improvements in HbA1c, and result in clinically significant benefits.”

In the paper

“The number of participants achieving ≥5 visits was 10.”

In the paper

“The finding of only a small, nonsignificant, increase in basal dose may be due to relatively few participants in the study using connected pens for their basal insulin.”

In the paper

“Nonetheless, our findings suggest that connected pens such as the NovoPen® 6 have the potential to improve glycemic control, decrease glucose variability and increase treatment concordance in people with T1D, addressing the large unmet need for optimal insulin treatment.”

In the paper

“Many people treated with insulin fail to reach their glycemic targets, which is known to increase the risk of microvascular and macrovascular complications, resulting in substantial morbidity and mortality.13,14,24”

What the sources say

• Not checked yetcites [13] Nathan DM, Genuth S, Lachin J, et al.: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329: 977– 986 8366922 source
• Not checked yetcites [14] Nathan DM, Cleary PA, Backlund JY, et al.: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353: 2643– 2653 16371630 PMC2637991 source
• Not checked yetcites [24] Bailey TS, Stone JY: A novel pen-based Bluetooth-enabled insulin delivery system with insulin dose tracking and advice. Expert Opin Drug Deliv 2017; 14: 697– 703 28359171 source

In the paper

“This suggests that evaluating past dosing data together with HCPs may have helped participants to remember and administer their meal-time doses, or to improve the timing of the dose relative to the meal.”

In the paper

“Supporting people to engage with and optimize their insulin regimens is a key challenge for HCPs, with educational interventions having limited effects.38”

What the sources say

• Not checked yetcites [38] Doggrell SA, Chan V: Adherence to insulin treatment in diabetes: can it be improved? J Diabetes 2015; 7: 315– 321 25195971 source

In the paper

“Our findings indicate that a connected pen may help people to reduce the number of missed bolus injections and to properly adjust doses, thus leading to better glycemic control.”

In the paper

“Since visits were conducted according to local clinical practice, the time in study, number of HCP visits, and time between visits varied considerably between participants.”

In the paper

“As this was a short single-arm study, we cannot conclude with certainty that the use of a connected pen directly improved glycemic control, and other factors may have played a role.”

In the paper

“As measurements of HbA1c do not reflect glycemic variability and target HbA1c values may be achieved while still experiencing marked daily glycemic fluctuations, people with T1D may regard reducing glucose variability and improving TIR to be as important as achieving their target HbA1c value.36,37”

What the sources say

• Not checked yetcites [36] Dandona P: Minimizing glycemic fluctuations in patients with type 2 diabetes: approaches and importance. Diabetes Technol Ther 2017; 19: 498– 506 28771387 PMC5647495 source
• Not checked yetcites [37] Runge AS, Kennedy L, Brown AS, et al.: Does time-in-range matter? Perspectives from people with diabetes on the success of current therapies and the drivers of improved outcomes. Clin Diabetes 2018; 36: 112– 119 29686449 PMC5898169 source

In the paper

“A recent study observed that the rate of late or missed bolus injections was 27% in people using MDI therapy, and that missed bolus injections correlated with higher HbA1c levels.40”

What the sources say

• Not checked yetcites [40] Norlander LM, Anderson SA, Levy CJ, et al.: Late and missed meal boluses with multiple daily insulin injections. Diabetes 2018; 68(Suppl 1): A259

In the paper

“Other studies have demonstrated that fluctuations in blood glucose levels may contribute more to outcomes than constant high blood glucose concentrations.31–35”

What the sources say

• Not checked yetcites [31] Ceriello A, Esposito K, Piconi L, et al.: Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 2008; 57: 1349– 1354 18299315 source
• Not checked yetcites [32] Esposito K, Nappo F, Marfella R, et al.: Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002; 106: 2067– 2072 12379575 source
• Not checked yetcites [33] Hirakawa Y, Arima H, Zoungas S, et al.: Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care 2014; 37: 2359– 2365 24812434 source
• Not checked yetcites [34] Ceriello A, Kilpatrick ES: Glycemic variability: both sides of the story. Diabetes Care 2013; 36(Suppl 2): S272– S275 23882058 PMC3920802 source
• Not checked yetcites [35] Sartore G, Chilelli NC, Burlina S, et al.: The importance of HbA1c and glucose variability in patients with type 1 and type 2 diabetes: outcome of continuous glucose monitoring (CGM). Acta Diabetol 2012; 49(Suppl 1): S153– S160 22466072 source

In the paper

“Previous studies have identified that an engaging and open dialogue between HCPs and people with T1D is highly important for optimal disease management, as it promotes collaboration, communication, and people's participation in their own treatment decisions.25,26”

What the sources say

• Not checked yetcites [25] Heisler M, Bouknight RR, Hayward RA, et al.: The relative importance of physician communication, participatory decision making, and patient understanding in diabetes self-management. J Gen Intern Med 2002; 17: 243– 252 11972720 PMC1495033 source
• Not checked yetcites [26] Ritholz MD, Beverly EA, Brooks KM, et al.: Barriers and facilitators to self-care communication during medical appointments in the United States for adults with type 2 diabetes. Chronic Illn 2014; 10: 303– 313 24567195 PMC4157962 source

In the paper

“For the TIR analysis, only 14 participants had data from visit 5 onward (Supplementary Fig. S1), meaning that the estimated change is based on the data from these, while the remaining data are used to estimate the random variation between participants, visits, and days and thus contribute to degrees of freedom in the variance estimates.”

In the paper

“Furthermore, as data were unbalanced, the use of a linear mixed model with different levels of correlations was necessary.42 This allowed all data to be used, and by including participant as a random effect, it ensured that each participant had their own baseline level, and the estimated change from baseline to visit 5 can be interpreted as the mean change from this level.”

What the sources say

• Not checked yetcites [42] Harrison XA, Donaldson L, Correa-Cano ME, et al.: A brief introduction to mixed effects modelling and multi-model inference in ecology. PeerJ 2018; 6: e4794 29844961 PMC5970551 source

In the paper

“Studies have found significant correlations between HbA1c levels and the number of missing bolus injections.7,39”

What the sources say

• Not checked yetcites [7] Randlov J, Poulsen JU: How much do forgotten insulin injections matter to hemoglobin a1c in people with diabetes? A simulation study. J Diabetes Sci Technol 2008; 2: 229– 235 19885347 PMC2771482 source
• Not checked yetcites [39] Burdick J, Chase HP, Slover RH, et al.: Missed insulin meal boluses and elevated hemoglobin A1c levels in children receiving insulin pump therapy. Pediatrics 2004; 113(Pt 1): e221– e224 14993580 source

In the paper

“In addition, the visit frequency for most participants seemed to be higher than what would be expected in normal clinical practice.41”

What the sources say

• Not checked yetcites [41] Kavanos P, Van den Aardweg S, Schurer W: Diabetes expenditure, burden of disease and management in 5 EU countries. www.lse.ac.uk/business-and-consultancy/consulting/assets/documents/diabetes-expenditure-burden-of-disease-and-management-in-5-eu-countries.pdf (accessed 12 2020)

In the paper

“There was limited access to background participant information within the dataset, such as diabetes status and comorbidities.”

In the paper

“Many participant IDs (65%) were excluded from the analyses during data cleaning.”