Predictors of the Effectiveness of Insulin Pumps in Patients with Type 1 Diabetes Mellitus

Abstract

Purpose

Insulin pump therapy has become the preferential treatment for type 1 diabetes (T1D) as it mimics the physiological secretion of insulin better than multiple daily injections. However, not all patients improve with insulin pump therapy. This study aims to determine the predictors of the effectiveness of insulin pumps in T1D.

Methods

We conducted a retrospective observational study of patients who started insulin pumps. Data from four timepoints (before, at 6, 12 and 36 months) were evaluated for outcomes of glycemic control and safety. The association of baseline predictors with outcomes was analyzed using linear and logistic regression models.

Results

We evaluated 136 patients (57.4% females, age 36 ± 12 years, duration of T1D 14 ± 9 years). During the follow-up, there was a mean decrease of HbA1c of 0.9 ± 1.2%. The improvement in HbA1c was independent of sex, age and duration of T1D. Higher baseline HbA1c, family history of diabetes and not being treated with statins were predictors of improvement in HbA1c. Not being treated with statins and higher baseline HbA1c predicted improvement in HbA1c without worsening hypoglycemia. History of hypoglycemia was a predictor of severe hypoglycemia. Family history, higher baseline HbA1c and psychological/psychiatric disorders were predictors of ketoacidosis.

Conclusion

Benefits of insulin pump were independent of sex, age, and duration of T1D. Baseline HbA1c, family history of diabetes, treatment with statins, history of hypoglycemia and psychological/psychiatric disorders were predictors of outcomes and may allow the identification of patients who benefit most from insulin pump therapy or who are at increased risk of complications.

Introduction

Type 1 Diabetes (T1D) represents 10–15% of all diabetes cases [1]. It is a chronic autoimmune disease that results from the interaction of genetic, environmental and immunological factors [2]. T1D is characterized by destruction of pancreatic beta cells, which causes an absolute or almost absolute deficiency in endogenous insulin production [3, 2].

Patients with T1D are at risk of acute (diabetic ketoacidosis and severe hypoglycemia) and chronic complications of diabetes (macrovascular, microvascular and other complications). Proper management of hyperglycemia is essential to decrease the risk of acute and long-term complications [4–6]. Intensive glucose treatment decreases the risk of microvascular complications [7] and may decrease the risk of macrovascular complications on the long-term follow-up. [8] However, most patients with T1D have poor glycemic control [9], and acute and chronic complications are still frequent in patients with T1D [10, 11].

The objective of treatment in T1D is to mimic the physiological secretion of insulin. The insulin dose to be administered must be adjusted considering glycemia, diet and physical activity [12, 13]. Intensive treatment of T1D can be divided in two main strategies: multiple daily injections and insulin pump therapy. The latter is frequently considered the preferred strategy for glycemic control, since it is the one that most accurately can mimic the physiological action of the pancreas [14, 15]. Insulin pump therapy is more expensive but allows more flexible adjustments on basal insulin rates and on the types of insulin bolus [15]. Over the past 20 years, there have been several improvements in insulin pumps, ensuring greater reliability of the technology resulting in an increasing use of insulin pump therapy [16]. However, the evidence showing the superiority of one form of treatment over the other is still limited [17].

Several studies have shown improvements in glycemic control with transition from multiple daily injections to insulin pump therapy [18, 17, 19]. However, this improvement is not observed in all patients [10], and some may worsen or have more acute complications after transitioning to insulin pump therapy [11]. The reason why some patients improve glycemic control with this treatment while others do not improve is not yet fully established. The aim of this study was to determine which predictors are related to the effectiveness of insulin pumps in patients with T1D previously treated with multiple daily injections.

Materials And Methods

Results

Baseline characteristics of the 136 patients included in the analysis are shown in Table 1. The mean (± standard deviation) age was 36 ± 12 years and 57.4% were women. Fifty-nine percent had 12th grade and 29.6% had higher education. The mean duration of the disease was 14 ± 9 years. Thirty-seven percent had a positive family history of diabetes. Regarding microvascular complications, 28.6% had diabetic retinopathy, 18.8% diabetic nephropathy and 9.8% diabetic neuropathy. Fourteen percent had a history of severe hypoglycemia and 6.1% had history of diabetic ketoacidosis.

Baseline characteristics of study population before starting insulin pump therapy. ^a - Body Mass Index. ^b - Low Density Lipoprotein. ^c – High Density lipoprotein. ^d - Estimated glomerular filtration rate calculated using the CKD-EPI equation.

During the follow-up, there was a mean HbA1c variation of -0.9 ± 1.2% (HbA1c of 8.3% ± 1.5 at baseline, 7.3% ± 0.9 at 6 months and 12 months, and 7.4% ± 1.0 at 36 months, p < 0.001) (Fig. 1), 80.0% had improvement of HbA1c, 75.4% had improvement of HbA1c without worsening of hypoglycemia, 23.5% had improvement of hypoglycemia and 18.4% had improvement of hypoglycemia without the worsening HbA1c. Regarding safety outcomes, 72.4% had hypoglycemia after starting insulin pump therapy, 4.5% had severe hypoglycemia after starting insulin pump therapy and 4.5% had diabetic ketoacidosis after starting insulin pump therapy (Table 2).

Predictors of HbA1c Variation (%), using the mean of HbA1c over the follow-up period after starting insulin pump therapy.  ^a- Body Mass Index. ^b - Low Density Lipoprotein. ^c – High Density lipoprotein. ^d - Estimated glomerular filtration rate calculated using the CKD-EPI equation. * Adjusted for variables with P value <0.05 in the unadjusted analysis.

The improvement of HbA1c was independent of sex, age and duration of the disease (Fig. 2). Patients with higher HbA1c before insulin pump therapy had greater reductions of HbA1c (Fig. 3). The presence of family history of diabetes, higher baseline HbA1c, diabetic nephropathy, albuminuria and history of diabetic ketoacidosis were predictors of greater reductions of HbA1c. In the adjusted analysis for HbA1c, only family history of diabetes and baseline HbA1c were predictors of reductions of HbA1c (Table 3).

^a- Body Mass Index. ^b- Low Density Lipoprotein. ^c – High Density lipoprotein. ^d - Estimated glomerular filtration rate calculated using the CKD-EPI equation. * Adjusted for variables with P value <0.05 in the unadjusted analysis.

The outcome improvement in HbA1c without the worsening of hypoglycemia was more common among women, in those with higher HbA1c at baseline, in patients not treated with statins, and in patients with history of hypoglycemia. After adjustment only higher HbA1c at baseline and not being treated with statins were significant predictors of decrease in HbA1c without worsening hypoglycemia (Table 4).

In the adjusted analysis, it was found that higher HbA1c at baseline, family history of diabetes and not being treated with statins as independent predictors of improvement in HbA1c (with or without worsening of hypoglycemia) (Supplementary Table 1). There were no statistically significant predictors of improvement in hypoglycemia or improvement of hypoglycemia without worsening HbA1c (Supplementary Tables 2 and 3).

Regarding the safety outcomes, there were no predictors of hypoglycemia after starting insulin pump therapy (Supplementary Table 4), and hypoglycemia at baseline was a predictor of severe hypoglycemia after starting insulin pump therapy (Supplementary Table 5). The incidence of diabetic ketoacidosis was higher in those with higher HbA1c at baseline, in those with family history of diabetes and in those with history of psychological or psychiatric disorder (Supplementary Table 6).

Discussion

In this analysis of patients with T1D transitioning from multiple daily injections to insulin pump therapy, higher HbA1c and not being treated with statins were independent predictors of improvement of HbA1c without worsening hypoglycemia. Higher baseline HbA1c and family history of diabetes were independent predictors of reduction of HbA1c. And higher baseline HbA1c, family history of diabetes and not being treated with statins were independent predictors of improvement in HbA1c. Having hypoglycemia before insulin pump therapy was a predictor of severe hypoglycemia after starting this treatment, and family history of diabetes, higher HbA1c and psychological/psychiatric disorders were predictors of diabetic ketoacidosis after therapy with insulin pump.

Insulin pump therapy has several advantages over multiple daily injections that have been already highlighted in previous studies [20, 17, 21]. This therapy allows more flexible, programmable and customizable basal insulin rates, with downloadable records and easy adjustment of insulin doses with physical activity. The possibility of using different types of boluses adjusted to the type of meal is also an advantage of insulin pump therapy. In addition, the increased flexibility improves the feeling of well-being and motivation of patients, improving their adherence to therapy [22, 23, 15]. Although more expensive, previous studies have shown that insulin pump therapy is more cost-effective than multiple daily injections [24]. Insulin pump therapy also have disadvantages that may justify why some patients have poorer glycemic control with this therapy. The disadvantages include the risk of potential infection of the site, occlusion of the catheter, or the cosmetic impact of the device, which can be discouraging for patients [22, 23, 25].

Our results are in agreement with previous reports evidencing an improvement in HbA1c levels after start therapy with insulin pump [18, 21, 19]. The association of higher baseline HbA1c values with greater reduction of HbA1c is also in agreement with other studies [26]. This association is probably explained by the greater margin to improve that patients with higher HbA1c have in comparison with patients with HbA1c closer to the target.

In our study, family history of diabetes was a predictor of reduction and improvement of HbA1c after insulin pump therapy. Other studies suggested that having a family history of diabetes may be associated with worse glycemic control and higher HbA1c levels [27–29]. As higher levels of HbA1c are associated with a greater improvement in HbA1c, this may partially explain this finding. However, in the adjusted analysis, family history of diabetes was an independent predictor of reduction of HbA1c, suggesting that additional mechanisms are involved. Having a family history of diabetes is associated with a greater awareness of the disease [30]. Family members with diabetes may be more prepared to help managing the insulin pump system, which may contribute to the improvement of HbA1c [31, 32]. The presence of a family history was also a predictor of diabetic ketoacidosis after insulin pump therapy. This may be justified by the higher levels of HbA1c found in these patients. This finding is in agreement with the study by Vakharia J et al. that found an association between family history of diabetes and a higher risk for diabetic ketoacidosis recurrence in youth with T1D [33, 29].

Patients not treated with statins were more likely to improve HbA1c levels after transitioning to therapy with insulin pump. While several studies have shown an association of treatment with statins and increased HbA1c levels and risk of diabetes in the general population and in type 2 diabetes, [34–36] few studies assessed this association in T1D. In the Thousand & 1 Study, use of statins was independently associated with increased HbA1c in patients T1D. It is uncertain whether the association of statins with HbA1c is causal or simply a marker for another mechanism such a dietary or lifestyle factor.

The improvement in HbA1c was independent of several factors including sex, age, duration of the disease and education level. Most previous studies also reported similar benefits for men and women [37, 38]. Concerning age, previous studies found discordant results. While some studies also found no difference according to age, [39, 38] other studies showed that an younger age at insulin pump initiation was associated with better glycemic controls [40, 37, 41]. Although the education level was not associated with improvement in HbA1c in our study, it should be noted that the population included in our study had higher education levels that the general Portuguese population. This suggests that people with higher education are being more frequently treated with insulin pumps, which was also reported in previous studies [42].

Regarding the safety outcomes, we found that hypoglycemia before therapy with insulin pump was a predictor for severe hypoglycemia after starting this therapy. Previous studies have shown that the main predictor of future severe hypoglycemia is previous occurrence of severe hypoglycemia or the occurrence of frequent hypoglycemia. Our results highlight that preventive measures to avoid severe hypoglycemia with insulin pump therapy are particularly relevant among patients that had hypoglycemia before starting this therapy [43, 33, 18, 44]. Due to the low number of severe hypoglycemias, our study may have been underpowered to identify other predictors. Previous reports have also identified long-standing type 1 diabetes, peripheral neuropathy and smoking as predictors of severe hypoglycemia [45, 46].

One of the most dreaded complications of T1D is diabetic ketoacidosis. As insulin pump therapy uses only fast acting insulins, failure of the device may lead to diabetic ketoacidosis in a few hours if no appropriate intervention is performed [47]. In our study, 4.5% of the population had ketoacidosis during the 3 years of follow-up. Higher baseline HbA1c levels and the presence of psychological/psychiatric disorders was a predictor of having diabetic ketoacidosis after insulin pump therapy, which is in agreement with other studies [48, 49]. This relationship can be attributed to the negative impact of psychopathology on diabetes, since it may influence blood glucose levels indirectly through lower adherence to therapy and directly increasing by promoting the release of catecholamines and corticosteroids [48].

Other studies found other predictors of improvements in HbA1c that were not assessed in our study including increased frequency of blood glucose monitoring [40] and using the bolus calculator feature [41].

Our study has limitations, including the retrospective design which limited our analysis to predictors that are routinely assessed during clinical practice. Furthermore, the study was carried out in a single center and only included adult participants, which may decrease the generalizability of our findings. Our analysis did not include patients with sensor-augmented pump therapy and, as such, our conclusions may not be applicable to this type of pump.

The strengths of our study include the specific questions that we addressed. Although several studies evaluated factors associated with outcomes during treatment with insulin pumps, few studies assessed which baseline predictors were associated with glycemic control and acute complications after transitioning to insulin pump. The identification of predictors of HbA1c improvement and predictors of severe hypoglycemia and ketoacidosis after starting insulin pump therapy is of clinical relevance as it will help to guide clinical practice. This allows a better selection of patients that most benefit from insulin pump therapy and those that are at increased risk of complications during treatment with insulin pumps.

In conclusion, insulin pump therapy was associated with improvement of glycemic control in most patients and a low risk of acute complications of diabetes. Higher baseline HbA1c, family history of diabetes and not being treated with statins were predictors of improvement of HbA1c, while hypoglycemia before insulin pump therapy was a predictor of severe hypoglycemia after starting this therapy. Family history of diabetes, higher HbA1c and psychological/psychiatric disorders were predictors of diabetic ketoacidosis after starting therapy with insulin pump. Future studies evaluating strategies to improve results in patients at risk of worse results after transitioning to insulin pump therapy are warranted.

Declarations

ACKNOWLEDGMENTS

The authors gratefully acknowledge the Department of Endocrinology, Diabetes and Metabolism of Centro Hospitalar Universitário São João for allowing this study to be carried out, providing technical and consultancy support.

Funding: No funding was received for conducting this study.

Conflicts of interest: The authors declare that they have no conflict of interest.

Availability of data and material: The datasets analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Code availability: Not applicable. 

Ethics approval: The authors declare that the procedures followed were in accordance with the regulations of Ethics Committee of the Centro Hospitalar Universitário de São João/ Faculty of Medicine of University of Porto and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).

Confidentiality of Data: The authors declare that they have followed the protocols of their work center on the publication of patient data.

Author contributions: All authors contributed to the study conception. Joana Camões Neves: study design, manuscript design and conception, acquisition and interpretation of data, work draft and critical review, final approval of the manuscript; João Sérgio Neves: study design, manuscript design and conception, analysis and interpretation of data, work draft and critical review, final approval of the manuscript; Celestino Neves: work draft and critical review, final approval of the manuscript; Davide Carvalho: work draft and critical review, final approval of the manuscript.

References

1. Schatz, D.A., Bingley, P.J.: Update on Major Trials for the Prevention of Type I Diabetes Mellitus: The American Diabetes Prevention Trial (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT). Journal of Pediatric Endocrinology and Metabolism 14(Supplement), 619-622 (2001). https://doi.org/10.1515/JPEM.2001.14.S1.619
2. Katsarou, A., Gudbjörnsdottir, S., Rawshani, A., Dabelea, D., Bonifacio, E., Anderson, B.J., Jacobsen, L.M., Schatz, D.A., Lernmark, Å.: Type 1 diabetes mellitus. Nature reviews Disease primers 3(1), 1-17 (2017). https://doi.org/10.1038/nrdp.2017.16
3. Atkinson, M.A., Eisenbarth, G.S., Michels, A.W.: Type 1 diabetes. The Lancet 383(9911), 69-82 (2014). https://doi.org/10.1016/S0140-6736(13)60591-7
4. Gilhotra, R.A., Rodrigues, B.T., Vangaveti, V.N., Kan, G., Porter, D., Sangla, K.S., Malabu, U.H.: Non-traumatic lower limb amputation in patients with end-stage renal failure on dialysis: an Australian perspective. Renal failure 38(7), 1036-1043 (2016). https://doi.org/10.1080/0886022X.2016.1193872
5. Kantharidis, P., Wang, B., Carew, R.M., Lan, H.Y.: Diabetes complications: the microRNA perspective. Diabetes 60(7), 1832-1837 (2011). https://doi.org/10.2337/db11-0082
6. Nathan, D.M., Zinman, B., Cleary, P.A., Backlund, J.-Y.C., Genuth, S., Miller, R., Orchard, T.J., Control, D., Trial, C., Interventions, E.o.D., Group, C.R.: Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Archives of internal medicine 169(14), 1307 (2009). https://doi.org/ 10.1001/archinternmed.2009.193
7. Group, D.R.: Diabetes control and complications trial (DCCT): update. Diabetes care 13(4), 427-433 (1990). https://doi.org/10.2337/diacare.13.4.427
8. Control, D., Group, C.T.R.: Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 75, 894-903 (1995). https://doi.org/ 10.1016/s0002-9149(99)80683-3
9. Leite, S.A.O., Zanim, L.M., Granzotto, P.C.D., Heupa, S., Lamounier, R.N.: Pontos básicos de um programa de educação ao paciente com diabetes melito tipo 1. Arquivos Brasileiros de Endocrinologia & Metabologia 52(2), 233-242 (2008). http://dx.doi.org/10.1590/S0004-27302008000200010
10. Group, R.S.: Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE). bmj 356 (2017). https://doi.org/10.1136/bmj.j1285
11. Guerci, B.: Acute complications of insulin pump therapy. Diabetes Research and Clinical Practice 74, S104-S107 (2006). https://doi.org/10.1016/S0168-8227(06)70009-2
12. Association, A.D.: Insulin administration. Diabetes care 27(suppl 1), s106-s107 (2004). https://doi.org/10.2337/diacare.27.2007.S106
13. Colberg, S.R., Sigal, R.J., Yardley, J.E., Riddell, M.C., Dunstan, D.W., Dempsey, P.C., Horton, E.S., Castorino, K., Tate, D.F.: Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes care 39(11), 2065-2079 (2016). https://doi.org/10.2337/dc16-1728
14. McAdams, B.H., Rizvi, A.A.: An overview of insulin pumps and glucose sensors for the generalist. Journal of clinical medicine 5(1), 5 (2016). https://doi.org/10.3390/jcm5010005
15. Pickup, J.C.: Insulin-pump therapy for type 1 diabetes mellitus. New England Journal of Medicine 366(17), 1616-1624 (2012). https://doi.org/ 10.1056/NEJMct1113948
16. Tauschmann, M., Hovorka, R.: Technology in the management of type 1 diabetes mellitus—current status and future prospects. Nature Reviews Endocrinology 14(8), 464-475 (2018). https://doi.org/10.1038/s41574-018-0044-y
17. Oliveira, S., Neves, C., Esteves, C., Neves, J., Oliveira, A., Pereira, M., Arteiro, C., Costa, A., Redondo, M., Baltazar, R.: Assessing the Effects of the Transition from Multiple Daily Insulin Injections (MDI) to Continuous Subcutaneous Insulin Infusion in the Intensive Treatment of Type 1 Diabetes Mellitus. (2019). https://hdl.handle.net/10216/124961
18. Karges, B., Schwandt, A., Heidtmann, B., Kordonouri, O., Binder, E., Schierloh, U., Boettcher, C., Kapellen, T., Rosenbauer, J., Holl, R.W.: Association of insulin pump therapy vs insulin injection therapy with severe hypoglycemia, ketoacidosis, and glycemic control among children, adolescents, and young adults with type 1 diabetes. Jama 318(14), 1358-1366 (2017). https://doi.org/ 10.1001/jama.2017.13994
19. Scott, E.S., McGrath, R.T., Januszewski, A.S., Calandro, D., Hardikar, A.A., O'Neal, D.N., Fulcher, G., Jenkins, A.J.: HbA1c variability in adults with type 1 diabetes on continuous subcutaneous insulin infusion (CSII) therapy compared to multiple daily injection (MDI) treatment. BMJ open 9(12), e033059 (2019). https://doi.org/10.1136/bmjopen-2019-033059
20. Doyle, E.A., Weinzimer, S.A., Steffen, A.T., Ahern, J.A.H., Vincent, M., Tamborlane, W.V.: A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using insulin glargine. Diabetes care 27(7), 1554-1558 (2004). https://doi.org/10.2337/diacare.27.7.1554
21. Pickup, J.: Insulin pumps. Diabetes technology & therapeutics 16(S1), S-17-S-22 (2014). https://doi.org/10.1089/dia.2014.1503
22. Fuld, K., Conrad, B., Buckingham, B., Wilson, D.M.: Insulin pumps in young children. Diabetes technology & therapeutics 12(S1), S-67-S-71 (2010). https://doi.org/10.1089/dia.2009.0182
23. Maahs, D.M., Horton, L.A., Chase, H.P.: The use of insulin pumps in youth with type 1 diabetes. Diabetes technology & therapeutics 12(S1), S-59-S-65 (2010). https://doi.org/10.1089/dia.2009.0161
24. Roze, S., Smith‐Palmer, J., Valentine, W., de Portu, S., Nørgaard, K., Pickup, J.: Cost‐effectiveness of continuous subcutaneous insulin infusion versus multiple daily injections of insulin in Type 1 diabetes: a systematic review. Diabetic Medicine 32(11), 1415-1424 (2015). https://doi.org/10.1111/dme.12792
25. Ross, P., Milburn, J., Reith, D., Wiltshire, E., Wheeler, B.: Clinical review: insulin pump-associated adverse events in adults and children. Acta diabetologica 52(6), 1017-1024 (2015). https://doi.org/10.1007/s00592-015-0784-2
26. DeFronzo, R., Stonehouse, A., Han, J., Wintle, M.: Relationship of Baseline HbA1c and Efficacy of Current Glucose Lowering Therapies: A Meta‐Analysis of Randomised Clinical Trials. Diabetic medicine, no-no (2009). https://doi.org/ 10.1111/j.1464-5491.2010.02941.x
27. Lebenthal, Y., Shalitin, S., Yackobovitch-Gavan, M., Phillip, M., Lazar, L.: Retrospective comparative analysis of metabolic control and early complications in familial and sporadic type 1 diabetes patients. Journal of Diabetes and its Complications 26(3), 219-224 (2012). https://doi.org/10.1016/j.jdiacomp.2012.03.016
28. Lee, Y.-H., Shin, M.-H., Nam, H.-S., Park, K.-S., Choi, S.-W., Ryu, S.-Y., Kweon, S.-S.: Effect of family history of diabetes on hemoglobin A1c levels among individuals with and without diabetes: the dong-gu study. Yonsei medical journal 59(1), 92 (2018). https://doi.org/10.3349/ymj.2018.59.1.92
29. Vakharia, J.D., Agrawal, S., Molino, J., Topor, L.S.: Family history of diabetes is associated with increased risk of recurrent diabetic ketoacidosis in pediatric patients. Endocrine Practice 26(3), 305-311 (2020). https://doi.org/10.4158/EP-2019-0351
30. Šipetić, S., Vlajinac, H., Kocev, N., Marinković, J., Radmanović, S., Denić, L.: Family history and risk of type 1 diabetes mellitus. Acta diabetologica 39(3), 111-115 (2002). https://doi.org/10.1007/s005920200028
31. Armour, T.A., Norris, S.L., Jack Jr, L., Zhang, X., Fisher, L.: The effectiveness of family interventions in people with diabetes mellitus: a systematic review. Diabetic medicine 22(10), 1295-1305 (2005). https://doi.org/10.1111/j.1464-5491.2005.01618.x
32. Rintala, T.-M., Paavilainen, E., Åstedt-Kurki, P.: Everyday living with diabetes described by family members of adult people with type 1 diabetes. International journal of family medicine 2013 (2013). https://doi.org/10.1155/2013/967872
33. Hanas, R., Ludvigsson, J.: Hypoglycemia and ketoacidosis with insulin pump therapy in children and adolescents. Pediatric diabetes 7, 32-38 (2006). https://doi.org/10.1111/j.1399-543X.2006.00169.x
34. Chogtu, B., Magazine, R., Bairy, K.: Statin use and risk of diabetes mellitus. World journal of diabetes 6(2), 352 (2015). https://doi.org/ 10.4239/wjd.v6.i2.352
35. Seshadri, S., Rapaka, N., Prajapati, B., Mandaliya, D., Patel, S., Muggalla, C.S., Kapadia, B., Babu, P.P., Misra, P., Saxena, U.: Statins exacerbate glucose intolerance and hyperglycemia in a high sucrose fed rodent model. Scientific reports 9(1), 1-9 (2019). https://doi.org/10.1038/s41598-019-45369-8
36. Sukhija, R., Prayaga, S., Marashdeh, M., Bursac, Z., Kakar, P., Bansal, D., Sachdeva, R., Kesan, S.H., Mehta, J.L.: Effect of statins on fasting plasma glucose in diabetic and nondiabetic patients. Journal of Investigative Medicine 57(3), 495-499 (2009). http://dx.doi.org/10.2310/JIM.0b013e318197ec8b
37. Scheiner, G., Boyer, B.A.: Characteristics of basal insulin requirements by age and gender in Type-1 diabetes patients using insulin pump therapy. Diabetes research and clinical practice 69(1), 14-21 (2005). https://doi.org/10.1016/j.diabres.2004.11.005
38. Somali, M., Paschou, S.A., Mouslech, Z.: Insulin pumps use in Greece: efficacy and safety data from 140 patients with type 1 diabetes mellitus. Diabetes research and clinical practice 160, 108026 (2020). https://doi.org/10.1016/j.diabres.2020.108026
39. Matejko, B., Kiec‐Wilk, B., Szopa, M., Trznadel Morawska, I., Malecki, M.T., Klupa, T.: Are late‐night eating habits and sleep duration associated with glycemic control in adult type 1 diabetes patients treated with insulin pumps? Journal of diabetes investigation 6(4), 460-464 (2015). https://doi.org/10.1111/jdi.12320
40. Nabhan, Z.M., Rardin, L., Meier, J., Eugster, E.A., DiMeglio, L.A.: Predictors of glycemic control on insulin pump therapy in children and adolescents with type I diabetes. Diabetes research and clinical practice 74(3), 217-221 (2006). https://doi.org/10.1111/j.1464-5491.2010.03068.x
41. Wilkinson, J., McFann, K., Chase, H.: Factors affecting improved glycaemic control in youth using insulin pumps. Diabetic medicine 27(10), 1174-1177 (2010). https://doi.org/10.1111/j.1464-5491.2010.03068.x
42. Paris, C.A., Imperatore, G., Klingensmith, G., Petitti, D., Rodriguez, B., Anderson, A.M., Schwartz, I.D., Standiford, D.A., Pihoker, C.: Predictors of insulin regimens and impact on outcomes in youth with type 1 diabetes: the SEARCH for Diabetes in Youth study. The Journal of pediatrics 155(2), 183-189. e181 (2009). https://doi.org/10.1016/j.jpeds.2009.01.063
43. Hanas, R., Adolfsson, P.: Insulin pumps in pediatric routine care improve long‐term metabolic control without increasing the risk of hypoglycemia. Pediatric diabetes 7(1), 25-31 (2006). https://doi.org/10.1111/j.1399-543X.2006.00145.x
44. Mecklenburg, R.S., Benson, E.A., Benson, J.W., Fredlund, P.N., Guinn, T., Metz, R.J., Nielsen, R.L., Sannar, C.A.: Acute complications associated with insulin infusion pump therapy: report of experience with 161 patients. JAMA 252(23), 3265-3269 (1984). https://doi.org/ 10.1001/jama.1984.03350230025026
45. Flatt, A.J., Little, S.A., Speight, J., Leelarathna, L., Walkinshaw, E., Tan, H.K., Bowes, A., Lubina-Solomon, A., Holmes-Truscott, E., Chadwick, T.J.: Predictors of recurrent severe hypoglycemia in adults with type 1 diabetes and impaired awareness of hypoglycemia during the HypoCOMPaSS study. Diabetes care 43(1), 44-52 (2020). https://doi.org/10.2337/dc19-0630
46. Pedersen‐Bjergaard, U., Pramming, S., Heller, S.R., Wallace, T.M., Rasmussen, Å.K., Jørgensen, H.V., Matthews, D.R., Hougaard, P., Thorsteinsson, B.: Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection. Diabetes/metabolism research and reviews 20(6), 479-486 (2004). https://doi.org/10.1002/dmrr.482
47. Phillip, M., Battelino, T., Rodriguez, H., Danne, T., Kaufman, F.: Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes care 30(6), 1653-1662 (2007). https://doi.org/10.2337/dc07-9922
48. Liss, D.S., Waller, D.A., Kennard, B.D., McINTIRE, D., Capra, P., Stephens, J.: Psychiatric illness and family support in children and adolescents with diabetic ketoacidosis: a controlled study. Journal of the American Academy of Child & Adolescent Psychiatry 37(5), 536-544 (1998). https://doi.org/10.1097/00004583-199805000-00016
49. Lustman, P.J., Harper, G.W., Griffith, L.S., Clouse, R.E.: Use of the Diagnostic Interview Schedule in patients with diabetes mellitus. Journal of Nervous and Mental Disease (1986). https://doi.org/10.1097/00005053-198612000-00006