Adherence to insulin treatment in diabetes: can it be improved?

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1 bs_bs_banner Journal of Diabetes 7 (2015) REVIEW ARTICLE Adherence to insulin treatment in diabetes: can it be improved? Sheila Anne DOGGRELL 1 and Vincent CHAN 2 1 School of Biomedical Sciences and 2 School of Clinical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia Correspondence Sheila Anne Doggrell, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Gardens Point, Brisbane, GPO2434, QLD 4001, Australia. Tel: Fax: sheila.doggrell@qut.edu.au Received 16 March 2014; revised 20 August 2014; accepted 24 August doi: / Abstract Insulin is used in all subjects with Type 1 diabetes, and when Type 2 diabetes is not controlled by oral anti-diabetic medicines, insulin is also used in Type 2 diabetes. However, despite this use, there is still increased mortality and morbidity in subjects with diabetes, compared to subjects without diabetes. One of the factors, which may be involved in this increased mortality and morbidity in subjects with diabetes, is nonadherence to insulin. Nonadherence rates to insulin are in the range of 20 38%, and many factors contribute to the nonadherence. The major aim of the review was to determine whether interventions to improve adherence to insulin do actually improve adherence to insulin. Most studies have shown that adherence to insulin was improved by changing from the vial-and-syringe approach to prefilled insulin pens, but not all studies have shown that this translated into better glycemic control and clinical outcomes. The results of studies using automatic telephone messages to improve adherence to insulin to date are inconclusive. There is limited and variable evidence that an intervention by a nurse/educator, which discusses adherence to medicines, does improve adherence to insulin. In contrast, there is little or no evidence that an extra intervention by a doctor or an intervention by a pharmacist, which discusses adherence to insulin, does actually improve the measured adherence to insulin. In conclusion, rather than assuming that an intervention by a health professional discussing adherence to insulin actually improves adherence to insulin, long-term studies investigating this are required. Keywords: adherence, diabetes, health professional, insulin, telephone. Introduction Diabetes is a leading cause of mortality and morbidity, and this is due to the development of optic renal, neuropathic and cardiovascular disease. Type 1 diabetes accounts for far fewer cases of diabetes mellitus than Type 2 diabetes. Insulin is the major medicine used in the treatment of Type 1 diabetes. When other medicines become inadequate in subjects with Type 2 diabetes, insulin is added. As a consequence high numbers of subjects with diabetes use insulin injections, e.g. 30% of subjects with diabetes in the US. 1 Any prevention of the progression of diabetes with insulin will require good adherence to insulin. Prior to insulin treatment, subjects with Type 1 diabetes had low life expectancy and high mortality, and when insulin was introduced as the standard treatment for Type 1 diabetes, life expectancy increased and morbidity decreased. However, despite the use of insulin, the prognosis for young subjects with Type 1 diabetes is still not ideal with a recent longitudinal study having shown retinopathy, proteinurea, and neuropathy progressed over 11 years. 2 Furthermore, a recent study, between 2005 and 2007, showed that mortality in subjects with Type 1 diabetes had declined since earlier studies, but that this cohort still had a higher mortality rate than those without diabetes, and this predominantly is due to cardiovascular mortality

2 Adherence to insulin can it be improved? One of the factors that may be involved in this continuing increased mortality and morbidity in diabetes may be nonadherence to insulin, and adherence/ nonadherence to insulin is the subject of this review. This review also discusses whether changes/interventions to improve adherence to insulin do actually improve adherence to insulin. Finally, there is a commentary, as to whether the methods to improve adherence to insulin are adequate, and future directions. Methods The databases searched were PubMed, CINAHL, PsychINFO and Health and Medicine Complete. For the review of the importance of adherence, rates of adherence and factors affecting adherence to insulin, the search was of insulin with adherence, compliance, persistence, concordance or omission. For the section on administration methods and improving adherence to insulin, there was an additional search of insulin with administration or injection. For the section on automatic telephone messages and improving the adherence to insulin, the additional search was of insulin with telephone or SMS. For the section on interventions by health professionals to improve adherence to insulin, the additional search was of insulin with doctor, physician, pharmacist, nurse or educator. The authors read the abstracts, which were written in English, and when it was clear that the adherence being discussed was not to insulin, but to other aspects of adherence to the management of diabetes, the abstract was not downloaded. For the other references, full papers were downloaded or collected via interlibrary loan. The authors extracted and included all papers that specifically addressed adherence to insulin and had a measure of adherence to insulin. Studies referenced in the retrieved studies on adherence to insulin that were relevant, were also collected and included. Adherence/nonadherence to insulin and its relationship to HbA1c levels, morbidity and mortality The importance of adherence to insulin has been established both in studies measuring HbA1c levels and in trials of morbidity and mortality in subjects taking insulin for diabetes. HbA1c levels are often used as an indicator for both the management of diabetes and for the clinical outcomes. As one would predict, low adherence to insulin, measured as the medicine possession ratio (MPR), which is the number of days for which the medicine has been prescribed divided by the number of days for which prescriptions have been fulfilled, is associated with higher HbA1c values, than observed with high adherence to insulin in adolescents with Type 1 diabetes 4 and insulinusing adult subjects with Type 2 diabetes. 5 Perhaps, rather surprisingly, a recent review that included studies of adherence to insulin and HbA1c failed to find any studies attempting to link the rate of adherence to insulin with HbA1c in adults with Type 1 diabetes. 6 However, a study has shown that women with Type 1 diabetes, who restrict their insulin use, have higher HbA1c levels than nonrestrictors. 7 In 234 women with Type 1 diabetes, and a mean age of 34 years, 30% self-reported insulin restriction. 7 Over 11 years, there was an increased rate of death in these restrictors (10 of 71, 14%), compared to appropriate insulin users (16 of 163, 10%). 7 Insulin restrictors also had higher rates of nephropathy (25% vs 10%) and foot problems (25% vs 12%). 7 As HbA1c is only a surrogate marker for clinical outcomes, when considering adherence to insulin, it is important to determine the relationship between adherence to insulin and clinical outcomes, and this is discussed below. Morbidity studies have shown that nonadherence to insulin is associated with more diabetic ketoacidosis, hypoglycemia, and hospital admissions. The Diabetes Audit and Research in Tayside Scotland Medicines Monitory Unit (DARTS/MEMO) collaboration showed that in 89 subjects with Type 1 diabetes attending a teaching hospital or young-adults diabetes clinic, there was a significant association between this nonadherence to insulin and hospital admissions for diabetic ketoacidosis, which was responsible for 15 admissions in 10 subjects in a year, and hypoglycemia (21 admissions from eight subjects) and all hospital admissions for acute complications of diabetes. 4 Nonadherence to insulin is also associated with increased mortality. In adult subjects with Type 2 diabetes, nonadherence to insulin, defined as <80% adherence measured by MPR, occurred in 21.3% of subjects. 8 Over 16 months, this nonadherence was associated with an increased rate of all-cause mortality (5.9% in nonadherent group vs 4.0% in adherent group) and allcause hospitalizations (23.2% vs 19.2%), compared with those with good adherence. 8 Rates of adherence to insulin Children and adolescents S.A. DOGGRELL and V. CHAN In a short-term study of 144 adolescent subjects with Type 1 diabetes and a mean HbA1c of 8.0% (64 mmol/ mol), within 10 days of a clinic visit, 25% admitted to missing at least one injection of insulin. 9 In the longer DARTS/MEMO collaboration, it was shown that in

3 S.A. DOGGRELL and V. CHAN adolescent subjects with Type 1 diabetes, 28% collected less than 365 days worth of insulin prescriptions per annum (mean 250 days). 4 Insulin pumps that give a bolus injection prior to eating are used in children/adolescents who required intensive treatment with insulin. Of 48 adolescent subjects with Type 1 diabetes using these pumps, 31 (65%) missed 3 boluses per week. 10 Another study, of 100 adolescent subjects, showed that 10% skipped mealtime boluses. 11 In a recent study of 90 adolescent subjects with Type 1 diabetes using continuous subcutaneous insulin infusion, 38% had missed a bolus dose on the previous day. 12 Adults In a systematic review of adherence with medications for diabetes performed in 2004, Cramer only found two retrospective insulin studies in subjects with type 2 diabetes 13 and the nonadherence rates ranged from 20% 14 to 37/38%. 15 Subsequently, much larger studies showed rates of nonadherence to insulin in subjects with Type 2 diabetes of 23% in 6222 subjects from the Veterans Affairs regional database, 16 and 29% in 1099 subjects in the DARTS/MEMO collaboration. 5 In the Veterans Affairs regional database, insulin adherence was similar at 77% of prescribed amounts, whether it was being used alone or in combination with oral hypoglycemic agents. 16 A recent study by Peyrot et al. used an international telephone survey of 1530 insulin-treated subjects (180 with Type 1 and 1530 with Type 2 diabetes) and reported that 33% of subjects reported insulin omission/ nonadherence with a mean of 3.3 days in the last month. 17 Nonadherence was highest in Japan (44%) followed by the USA (42%), UK (41%) Germany (40%), China (33%), Turkey (24%), Spain (23%), and France (19%). 17 Adherence can also differ for preparations of insulin. Humulin U-500R (500 units/ml) is 5-times more concentrated than conventional U-100 insulin, and the use of U-500R has increased in recent years. 18 Adherence in 711 subjects with Type 1 or 2 diabetes (mean age 56 years) requiring high dose insulin, >200 units/day, was measured as PDC (proportion of days covered). 18 Only 33% and 18% of subjects taking U-500R and U-100 insulin, were 80% adherent, and adherence <20% was observed in 3% and 37% of subjects respectively. 18 Factors affecting adherence to insulin Although there are many studies of the factors that affect components of the treatment for diabetes, there are few Adherence to insulin can it be improved? studies of the factors specifically affecting adherence to insulin. We identified only one study in adolescent subjects, and this showed that in adolescent subjects who missed injections of insulin, forgetting was the most cited reason by the adolescent subjects for missing the injections, followed by being away from home and forgetting to bring the insulin with them. 8 In 1994, Polonsky et al. reported that intentional insulin omission occurred in 31% of female subjects with Type 1 diabetes, and that omissions occurred across the age range. 19 Omitters had more disordered eating habits, associated insulin use with weight gain, and feared hypoglycemia. 19 In a review, higher adherence for insulin in Type 2 diabetes was observed with those 65 years, compared to <65 years, and Caucasians compared to African American or Hispanic. 13 In a recent Internet survey of 502 subjects, recruited by , taking insulin by injection for Type 1 or 2 diabetes, Peyrot et al. reported intentional insulin omission in over 57% and regular omission reported by 20%. 20 Nonadherence to insulin is more common among subjects who are nonadherent to other aspects of management of diabetes. 20 The risk factors for nonadherence included younger age, low income, and subjects who took more injections. 20 Respondents who planned daily activities around insulin injections, those who said that taking injections interfered with activities of daily living, and those who reported injection-related pain or embarrassment intentionally, all skipped insulin injections more often. 20 Peyrot et al. did not find any racial/ethnic differences in intentional insulin omission in their Internet survey. 20 This contrasts with previous findings that African Americans and Hispanics subjects were less adherent than Caucasians. 13 Peyrot et al. suggests that this may be because they only had a small percentage of African American and Hispanic subjects compared to Caucasian subjects or because they controlled their regression analysis for income and education. 20 A recent telephone survey by Peyrot et al. of 1530 subjects reported the main reasons for insulin omission/ nonadherence were: too busy (19%), followed by travelling (16%), skipped meal (15%), stress or emotional problems (12%), embarrassing to inject in public (10%), challenging to take it at the same time everyday (9%), forgot (7%), too many injections (6%), avoid weight gain (4%), regimen is too complicated (3.8%), and injections are painful (3%). 21 Insulin omission/nonadherence was more common among those who were male, younger, had Type 2 diabetes or more frequent hypoglycemia, were less successful with other treatment tasks, regarded insulin adherence as less important, had more practical/ 317

4 Adherence to insulin can it be improved? logistic barriers and difficulties with insulin adherence, and were concerned that insulin treatment required lifestyle changes or were dissatisfied with the flexibility of injection timing. 22 From the discussion in sections 3 and 5, it is clear that there are morbidity and mortality consequences from not adhering to insulin, and that a variety of factors influence adherence to insulin. For the remainder of this review, we discuss whether changes/interventions to improve adherence to insulin, do actually improve adherence to insulin. Insulin pens and adherence Insulin pen devices were first introduced in 1987 and were important in overcoming the barriers to adherence to insulin caused by the vial-and-syringe approach, e.g. difficulty of transportation, anxiety about self-injection, fear of injection, lengthy training time, and social embarrassment. 23 In the pens, the insulin cartridge and syringe are combined as a single unit, and this improves dosing accuracy, increases mealtime flexibility and convenience of insulin delivery. 23 Prefilled insulin pens are also less painful to use than vial-and-syringe, and this improved user confidence, reduced training time, and made them more stable when handling. 23 In a study of 1156 subjects with Type 2 diabetes converting from vial-and-syringe approach to prefilled insulin pens in the US in , adherence, defined as a medication possession ratio of 80%, was measured. 23 With the vial-and-syringe approach, adherence was 36.1%, and this was increased to 54.6% with the prefilled pens. 23 This increase in adherence was associated with a reduced occurrence of hypoglycemia, hospital visits due to hypoglycemia, physician visits, and the costs associated with the hypoglycemia. 23 In a study of subjects with Type 2 diabetes and private insurance, the adherence was 59% with the vial-and-syringe approach, and increased to 68% with the prefilled insulin pens. 24 This increase in adherence to insulin was associated with less hypoglycemia, emergency visits due to hypoglycemia, physician visits, and the costs associated with the hypoglycemia. 24 Other studies have shown increased adherence with pen than vial, but have not investigated whether this is associated with better glycemic control or outcomes. Thus, a 2010 study confirmed that there was increased adherence with the prefilled insulin pens over the vial and syringe in 1064 subjects using insulin, and also showed that this was not associated with increased healthcare costs. 25 Also, in 4088 subjects with Type 2 diabetes initiating insulin treatment, adherence was higher with a pen than with vial/syringe (proportion of days covered, 54.6% vs 45.2%, respectively). 26 A study that specifically investigated changing from the vial-and-syringe approach to a pen containing insulin glargine showed that persistence and adherence was higher with the pen than vial in 3893 subjects with type 2 diabetes. 27 However, in this study, the amount of insulin used and the glycemic control was similar in both groups, 27 and thus it is unlikely that there were any clinical benefits from changing from vial to pen. Automatic telephone messages to improve adherence To date, studies using automatic telephone messages to improve adherence to insulin have only been reported with adolescent subjects, and these are inconclusive. Sweet Talk used text messages on mobile phones to encourage 92 young people with Type 1 diabetes to adhere to insulin injections, and to other aspects of diabetes management. 28 Adherence to insulin was assessed using a visual analogue adherence scale, and improved adherence with conventional therapy from 70% to 77% (P = 0.042), but this was not associated with an improvement in diabetes management assessed by HbA1c. 28 There was a third group in this trial of intensive insulin therapy with Sweet Talk, which had adherence of 79%, 28 but this group did not have an intensive insulin therapy control group, and consequently it was not able to determine what effect Sweet Talk has in intensive insulin therapy. From this paper, we were unable to determine how long the Sweet Talk intervention was for, and it is not known whether it is effective long-term. A short-term intervention (14 days) of a once daily short messaging service (SMS) text message to a small cohort (10) of young adults with Type 1 diabetes, who self-reported their insulin use, suggested that there may have been an increased injection rate in the evening by some of the children (P = 0.08). 29 However, this study is probably too small and short to provide good evidence. Interventions by health professionals to improve adherence S.A. DOGGRELL and V. CHAN It is well established that intervention or care by nurses/ educators/pharmacists can improve HbA 1c levels in subjects with diabetes, 30 but this does not necessarily mean there is improved adherence to insulin, as improvement of many other aspects of the management of diabetes can lead to improved HbA 1c levels. However, our review shows there is limited and variable evidence that an intervention by a nurse/educator that discusses adherence to insulin does improve this adherence (see below). There have been many who have suggested that intervention/ education by a pharmacist is likely to improve adherence to insulin (e.g. 31,32 ). However, there is little or no evidence (to our knowledge) that an extra intervention by a doctor 318

5 S.A. DOGGRELL and V. CHAN Adherence to insulin can it be improved? or an intervention by a pharmacist, which discusses adherence to insulin, does actually improve the measured adherence to insulin. There have been four studies of interventions by health professionals to improve adherence to insulin, and these are summarized in Table 1, with three studies showing no improvement in adherence to insulin Although the OPENING (Organization Program of DiabEtes INsulIn ManaGement) study showed that adherence to insulin was improved by nurse education (Table 1), this improvement in adherence was only associated with a small benefit in glycemic control (0.16%). 36 Thus, in the control group, the baseline HbA1c was 9.46% and this was reduced to 7.38% by the start of insulin with normal care, whereas in the education group, the HbA1c was reduced from 9.38% to 7.22%. 36 Over the 16 weeks of the trial, the education group had their insulin dosage adjusted more often (83%) than the control group (77%), and at the end of the trial, the education group were taking a higher dose of insulin (30.4 IU) than the control group (19.1 IU). 36 It is possible that this higher dose of insulin in the education than the control group may have contributed to the small benefit in glycemic control in the education group. In a 2012 pilot study of 10 adults with type 1 diabetes and depression, it was shown that an intervention that offered two visits with a certified diabetes nurse educator, three visits with a registered dietitian, and sessions of cognitive-behavioral therapy for adherence and depression improved adherence in the seven subjects who completed. 37 Adherence was self-reported of how often they took their insulin, and increased from 77% before to 87% after the intervention. 37 In addition, there was a decrease in depression severity, insulin monitoring, and a modest decrease in HbA1c from 9.6% (81 mmol/ mol) to 9.0% (75 mmol/mol). 37 There are several problems with this study including the lack of a control group, low numbers of subjects, and high self-reported adherence. Commentary Underestimate of nonadherence The rates of adherence to insulin, reported in this review, have been reported in three ways: self-reporting (e.g. 7 ), visual analogue scale 27 and MPR/pharmacy/medical records. 4,5,8,10,23 All of these methods have limitations. Self-reporting has been shown to overestimate adherence and to underestimate nonadherence. 38 The validity of prescription refill dates relies on the completeness of databases, and does not actually measure medication taking, which could be less than that for which there was Table 1 Effect of intervention by health professionals on adherence to insulin in subjects with type 2 diabetes Year: ref number Participants Baseline HbA1c Intervention Adherence/nonadherence to insulin 40% nonadherent after 3 months 2009: %, 95 mmol/mol Introduction of insulin treatment with education from physician and diabetes nurse educator for 3 months 27 low income from tertiary health care center in Mexico city No change in adherence 2010: %, 64 mmol/mol Reciprocal peer support versus nurse care management for 6 months 244 men from a Department of Veterans Affairs health care facilities with HbA1c >7.5% for last 6 months; 55% were taking insulin No change in adherence 2011:35 8.6%, 70 mmol/mol Telephone calls by a health education, trained by a certified diabetes nurse educator, compared to print information over 1 year The Improving Diabetes Outcomes study of 526 low-income Spanish and English speakers in New York, with HbA1c >7.5%; 24% taking insulin 2013:36 Education group had improvement in adherence 9.4%, 79 mmol/mol Started on insulin therapy with trained nurses delivered education program versus normal care over 16 weeks The Organization Program of DiabEtes Insulin ManaGement study of 1511 subjects at 48 centres throughout China, with HbA1c >7.5% 319

6 Adherence to insulin can it be improved? prescription refills. 38 Thus, it is possible that the rates of nonadherence to insulin given in this review are underestimated, and the problem is more serious than has been reported. Better methods of measuring adherence, including adherence to insulin, are needed to get a definitive answer to this. Automatic telephone messaging To date the evidence with automatic telephone messaging to improve adherence to insulin is not conclusive. Sweet Talk showed a small improvement in adherence to insulin without improvement in HbA 1c, 28 and a separate small short-term study suggested improvements in injections of insulin in the evening. 29 Thus, there is a need for a larger, longer trial of automatic telephone messaging to determine its effects on insulin adherence. Conclusions relating to interventions by health professionals One of the most interesting findings of this review was that there is no conclusive evidence that an intervention by a health professional that discusses adherence to insulin actually improves adherence to insulin. There is some evidence that an intervention by a nurse/educator that discusses adherence to insulin may improve this adherence, but this is not found in all studies. However, there is little or no evidence (to our knowledge) that an extra intervention by a doctor or an intervention by a pharmacist, which discusses adherence to insulin, does actually improve the measured adherence to insulin. Rather than assuming that this is the case, long-term studies investigating whether adherence to insulin can be improved by interventions by health professionals are required. Acknowledgement There was no funding of this article. Disclosure The authors have no conflicts of interest. References 1. Percentage of adults with diagnosed diabetes receiving treatment with insulin or oral medication, United States, Available from: pubs/pdf/factsheet11_figures.pdf (accessed 23 October 2014). S.A. DOGGRELL and V. CHAN 2. Bryden KS, Dunger DB, Mayou RA, Peveler RC, Neil HA. Poor prognosis of young adults with type 1 diabetes: A longitudinal study. Diabetes Care. 2003; 26: Livingstone SJ, Looker HC, Hothersall EJ et al. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish Registry Linkage Study. PLoS Med. 2012; 9: e Morris AD, Boyle DI, McMahon AD et al. Adherence to insulin treatment, glycaemic control, and ketoacidosis in insulin-dependent diabetes mellitus. The DARTS/ MEMO collaboration. Diabetes audit and research in Tayside Scotland. Medicines Monitoring Unit. Lancet. 1997; 350: Donnelly LA, Morris AD, Evans JM, DARTS/MEMO collaboration. Adherence to insulin and its association with glycaemic control in patients with type 2 diabetes. QJM. 2007; 100: Asche C, Lafleur J, Conner C. A review of diabetes treatment adherence and the association with clinical and economic outcomes. Clin Ther. 2011; 33: Goebel-Fabbri AE, Fikkan J, Franko DL et al. Insulin restriction and associated morbidity and mortality in women with type 1 diabetes. Diabetes Care. 2008; 31: Ho PM, Rumsfeld JS, Masoudi FA et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006; 166: Weisserg-Benchell J, Glasgow AM, Tynan WG, Wirtz P, Turek J, Ward J. Adolescent diabetes management and mismanagement. Diabetes Care. 1995; 18: Burdick J, Chase HP, Slover RH et al. Missed insulin meal boluses and elevated haemoglobin A 1c levels in children receiving insulin pump therapy. Pediatrics. 2004; 113: e PańKowska E, Skórka A, Szypowska A, Lipka M. Memory of insulin pumps and their record as a source of information about insulin therapy in children and adolescents with type 1 diabetes. Diabetes Technol Ther. 2005; 7: 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: Cramer JA. A systematic review of adherence with medications for diabetes. Diabetes Care. 2004; 27: Brown JB, Nichols GS, Glauber HS, Bakst A. Ten-year follow-up of antidiabetic drug use, nonadherence, and mortality in a defined population with type 2 diabetes mellitus. Clin Ther. 1999; 21: Rajagopalan R, Joyce A, Smith D, Ollendorf D, Murray FT. Medication compliance in type 2 diabetes patients: Retrospective data analysis (Abstact). Value Health. 2003; 6: Cramer JA, Pugh MJ. The influence of insulin use on glycemic control: How well do adults follow prescriptions for insulin? Diabetes Care. 2005; 26: Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence behaviours and barriers in the 320

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