Reduction in Fear of Hypoglycemia in Subjects With Sub-optimally Controlled Diabetes Using a Glargine Insulin-based Treatment Regimen

Transcription

1 fear of hypoglycemia with insulin glargine 101 Reduction in Fear of Hypoglycemia in Subjects With Sub-optimally Controlled Diabetes Using a Glargine Insulin-based Treatment Regimen Richard E. Gilbert MD PhD 1,2 and Greg Fulcher MD 3 1 Keenan Research Centre, Li Ka Shing Knowledge Institute and Division of Endocrinology, St. Michael s Hospital and University of Toronto, Toronto, Ontario, Canada 2 University of Melbourne Department of Medicine, St. Vincent s Hospital, Victoria, Australia 3 Department of Endocrinology, Royal North Shore Hospital, New South Wales, Australia Objective Fear of hypoglycemia is a major obstacle to achieving good glycemic control. While insulin glargine has been shown to reduce the frequency of severe and nocturnal hypoglycemia in subjects with diabetes, whether it also attenuates the fear of nocturnal hypoglycemia is unknown. Methods We conducted a multicentre, open-label clinical trial to assess fear of hypoglycemia (Hypoglycemia Fear Survey) and anxiety/depression (Hospital Anxiety and Depression Scale) in patients with type 1 (n=244) or type 2 (n=168) diabetes before and after a 24-week treatment with insulin glargine according to defined algorithms. Results When compared with baseline, 24 weeks of treatment in type 1 or type 2 subjects with diabetes was accompanied by reductions in the fear of hypoglycemia, including both worry and behavioural components (all p<0.05). Similar improvements in anxiety/depression were also noted. These changes were seen in the setting of improved glycemic control, with glycosylated hemogobin decreasing by 0.44 and 0.89% in type 1 and 2 subjects with diabetes, respectively. ConclusionS A B S T R A C T These findings suggest that therapy with an insulin glarginebased treatment algorithm is associated with reductions in fear of hypoglycemia and anxiety/depression in subjects Address for correspondence: Richard E. Gilbert St. Michael s Hospital Room Queen Street East Toronto, Ontario Canada M5C 2T2 richard.gilbert@utoronto.ca Objectif La crainte de l hypoglycémie est un obstacle majeur au contrôle de la glycémie. On a démontré que l insuline glargine réduisait la fréquence des hypoglycémies graves et des hypoglycémies nocturnes chez les sujets atteints de diabète, mais on ne sait pas si elle calme la crainte des hypoglycémies nocturnes. Méthodes Nous avons mené un essai clinique multicentrique ouvert pour évaluer la crainte de l hypoglycémie (Hypoglycemia Fear Survey) et l anxiété et la dépression (Échelle d anxiété et de dépression en milieu hospitalier) chez des patients atteints de diabète de type 1 (n = 244) ou de type 2 (n = 168) avant et après un traitement de 24 semaines par l insuline glargine selon des algorithmes prédéfinis. Résultats R É S U M É Le traitement de 24 semaines administré à des sujets atteints de diabète de type 1 ou de type 2 a calmé la crainte de l hypoglycémie, tant du point de vue des inquiétudes que du comportement (valeur p globale < 0,05). Nous avons également observé une atténuation de l anxiété et de la dépression. Ces changements accompagnaient une amélioration du contrôle de la glycémie, l hémoglobine glycosylée ayant baissé de 0,44 % et 0,89 % chez les sujets atteints de diabète de type 1 et de type 2, respectivement. ConclusionS Ces constatations semblent indiquer que le traitement par l insuline glargine selon des algorithmes prédéfinis est associé à une baisse de la crainte de l hypoglycémie, de l anxiété et de la dépression chez les sujets atteints de diabète de type 1 ou de type 2, ainsi qu à une amélioration apparente du contrôle de la glycémie. CANADIAN JOURNAL OF DIABETES. 2008;32(2):

2 CANADIAN JOURNAL OF DIABETES 102 with both type 1 and type 2 diabetes in the setting of apparently improved glycemic control. keywords Basal insulin analogues, insulin glargine, fear of hypoglycemia, anxiety/depression Mots clés Analogues de l insuline basale, insuline glargine, crainte de l hypoglycémie, anxiété, dépression INTRODUCTION Despite the robust evidence base that good glycemic control reduces the risk of complications in both type 1 (1) and type 2 diabetes (2), achieving targets proposed by national guidelines remains a challenge. While increasing doses of insulin effectively lower plasma glucose concentrations, the greater likelihood of hypoglycemia associated with this strategy remains a major limiting factor (3). For patients with diabetes, significant hypoglycemia, frequently accompanied by substantial physical, cognitive and emotional disturbances, is a major cause of morbidity and mortality. Indeed, hypoglycemia is feared to the same extent as nephropathy and retinopathy among patients with type 1 diabetes (4). Insulin glargine, a long-acting basal insulin analogue with a flat, stable absorption profile (5), has been shown to reduce the frequency of severe and nocturnal hypoglycemia in subjects with diabetes with equivalent if not better glycemic control than NPH insulin (6,7). However, whether the use of a glargine-based insulin regimen might also attenuate the fear of hypoglycemia, particularly while insulin doses are being increased in an attempt to improve glycemia, is not known. Accordingly, we assessed fear of hypoglycemia and patient well-being in a substudy of a large, multicentre, open-label trial that employed an algorithm-based titration regimen to establish the optimal method for initiating and maintaining good glycemic control with insulin glargine in subjects with type 1 or type 2 diabetes. METHODS Study design The Hypoglycemia Avoidance with Lantus Trial (HALT) is a substudy of ATLANTUS (A Trial Comparing Lantus Algorithms to Achieve Normal Blood Glucose Targets in Subjects with Uncontrolled Blood Sugar), a prospective, multinational, multicentre, randomized study that compared an investigator-initiated with a patient-led titration algorithm for initiating and maintaining insulin glargine therapy in subjects with type 1 or type 2 diabetes mellitus. The study design and outcome of ATLANTUS have recently been published (8). In brief, following a screening period of 1 to 4 weeks, patients with suboptimal glycemia were treated with insulin glargine according to the 2 defined treatment algorithms for a period of 24 weeks (Table 1). The main objective of the HALT substudy was to quantify fear of hypoglycemia while attempting to improve glycemic control with insulin glargine. Instruments At baseline and study end, participants were asked to complete the Hypoglycemia Fear Survey (HFS-98) and the Hospital Anxiety and Depression Scale (HADS). HFS-98 consists of a series of 33 questions, each scoring from 0 to 4, and comprises 2 domains: the behaviour domain (questions 1 to 15) and the worry domain (questions 16 to 33). HADS consists of a series of 14 questions, each scoring from 0 to 3. In both cases, high scores indicate most worries/avoidance behaviour in relation to hypoglycemia and high anxiety/depression, respectively. Each participating country used translated versions. Information in relation to patient characteristics, glycated hemoglobin (A1C) and hypoglycemic episodes was extracted from the AT.LANTUS database, with symptomatic, nocturnal and severe hypoglycemia defined as described in the AT.LANTUS study (8). Table 1. Increases in daily insulin glargine dose (IU) Fasting glucose meter readings, mmol/l Insulin adjustment algorithm 1 (IU increase) Insulin adjustment algorithm 2 (IU increase) 5.5 and < (at investigator discretion) 0 2 (at investigator discretion) 6.7 and < and < (at investigator discretion) 2 Algorithms for increases in daily insulin glargine dose (IU) according to mean fasting glucometer recordings for the previous 3 consecutive days, with a target fasting glucometer reading of 5.5 mmol/l. For algorithm 1, titration was managed by the investigating physician and occurred at every visit. For algorithm 2, titration was undertaken by the patient every 3 days according to the regimens above.

3 Statistical methods Analyses were performed as intention to treat, examining change from baseline. The change from baseline in the HFS-98 (overall and for each of its behaviour and worry domains), HADS and A1C were each assessed by analysis of covariance (ANCOVA); the frequency of hypoglycemic episodes was assessed using a Poisson model with overdispersion and adjustment for baseline covariates where significant. A p value of 0.05 was regarded as statistically significant. RESULTS Baseline characteristics Demographic and baseline characteristics of the 2 patient populations are summarized in Table 2. Two hundred and forty-four subjects with type 1 and 169 patients with type 2 diabetes participated in the study. Patients were mainly recruited in Australia, which contributed 356 patients (22 centres); the Netherlands contributed 57 patients (5 centres). Twenty-six patients withdrew from the study (15 type 1 patients, 11 type 2 patients). All received at least 1 dose of study medication but 1 patient (who withdrew). The intention-to-treat population is therefore comprised of 244 patients with type 1 diabetes and 168 with type 2 diabetes. Reasons for withdrawal were as follows: not wishing to continue in the study (12/26), protocol violation (7/26), perceived lack of efficacy (2/26), lost to follow-up (2/26), adverse event (1/26) and problems using the injection device (Optipen) (1/26). Post-baseline data were missing for 8 patients (4 with type 1 diabetes and 4 with type 2 diabetes). Baseline characteristics of the patient populations involved in this substudy were similar to those described for the entire AT.LANTUS cohorts (8). Glycemic control and hypoglycemia In patients with type 1 and type 2 diabetes, A1C decreased by 0.44% [95% CI: 0.54 to 0.33] and 0.89% [95% CI: 1.05 to 0.72], respectively, by the end of the treatment period (Figure 1A). Unlike the main AT.LANTUS study, the HALT substudy was not powered to assess changes in the frequency of hypoglycemia. Nevertheless, in subjects with type 1 diabetes the frequency of severe hypoglycemia decreased following treatment with insulin glargine (Table 3), as did the frequency of symptomatic hypoglycemia, reaching borderline significance only (p=0.06). Fear of hypoglycemia In subjects with type 1 diabetes, overall fear of hypoglycemia was reduced by 7.53 arbitrary units (AU) [95% CI: 9.60 to 5.46, p<0.05], with changes in both the behaviour and worry domains of HFS-98 ( 2.72 AU [95% CI: 3.66 to 1.79] and 4.69 AU [95% CI: 6.11 to 3.28], respectively, p<0.05 in both cases). Similarly, in type 2 diabetes, institution of the glargine-based treatment algorithm was fear of hypoglycemia with insulin glargine 103 also accompanied by a reduction in the overall fear of hypoglycemia ( 3.47 AU [95% CI: 5.37 to 1.57], p<0.05), with statistically significant improvements in each of the behaviour and worry domains of the questionnaire ( 1.95 AU [95% CI: 2.87 to 1.04] and 1.73 AU [95% CI: 2.93 to 0.52], respectively, p<0.05 in both cases) (Figure 1B). Table 2. Demographics and baseline characteristics of subjects with type 1 or type 2 diabetes included in the HALT dataset (intention to treat population) Characteristics Type 1 diabetes (n=244) Type 2 diabetes (n=168) Male/female, % 45.5/ /44.6 Age, years 42.7 ± ± 9.6 Disease duration, years 17.5 ± ± 7.1 Age at onset, years 24.2 ± ± 9.2 Duration of treatment with insulin, years Duration of treatment with OHAs, years 17.2 ± ± 4.7 NA 8.8 ± 6.1 BMI, kg/m ± ± 5.3 A1C, % 8.1 ± ± 1.1 HFS-98 Overall score 35.3 ± ± 19.3 Behaviour domain 14.7 ± ± 9.6 Worry domain 20.5 ± ± 11.9 HADS Overall score 8.3 ± ± 6.8 Patients with anxiety and depression, % Patients with definite depression, % Results are presented as mean±standard deviation unless otherwise stated Defined as HADS score 8 points Defined as HADS score 11 points A1C = glycated hemoglobin BMI = body mass index HADS = Hospital Anxiety and Depression Scale HALT = Hypoglycemia Avoidance with Lantus Trial HFS = Hypoglycemia Fear Survey NA = not applicable OHAs = oral antihyperglycemic agents CANADIAN JOURNAL OF DIABETES. 2008;32(2):

4 CANADIAN JOURNAL OF DIABETES 104 Anxiety and depression Patients with type 1 diabetes experienced a reduction in mean HADS score relative to baseline, decreasing by 1.45 points (95% CI: 2.06 to 0.84) (Figure 1C), with attenuation in the proportion of patients suffering from anxiety/ depression (mean HADS score 8) from 45.5 to 37.7% (p<0.05). The proportion of patients suffering from definite depression (mean HADS score 11) was also reduced by the end of the study, decreasing from 26.2 to 20.6% (p=0.05). In patients with type 2 diabetes, mean HADS score also decreased ( 1.36 AU [95% CI: 2.05 to 0.66], p<0.05) as did the proportion of patients suffering from anxiety/ depression (decreased from 53.6 to 46.8%), though not quite reaching statistical significance in the latter (p=0.06). The proportion of patients suffering from definite depression was essentially unchanged, decreasing from 35.7 to 33.3%. DISCUSSION The psychological impact of diabetes is immense, necessitating major changes in diet and lifestyle, along with fears of acute problems such as hypoglycemia and long-term end-organ complications. Although tight glycemic control is a key component of reducing the latter, many patients prefer to maintain higher-than-recommended blood glucose levels in order to avoid hypoglycemia (9). The results of this 24-week study show that an insulin glargine-based treatment algorithm leads not only to apparently better glycemic control but also significant reductions in fear of hypoglycemia in patients with both type 1 and type 2 diabetes. The Hypoglycemia Fear Survey (HFS) is a previously validated tool with 2 domains that assess worry (HFS-W) and behaviour (HFS-B) related to hypoglycemia (10). The HFS-W enables the anxiety of possible hypoglycemia to be quantified using a summed 18-item questionnaire in which patients respond to each item on a scale of never to very often (11), while the 15-item HFS-B examines behaviours designed to avoid hypoglycemia. In the present study, improvements in both domains were noted. The improvement in both domains was not just statistically significant, but also appeared clinically relevant, with relative changes in the order of 18 to 23% and 15 to 19% in patients with type 1 and type 2 diabetes, respectively. The improvement in the worry domain is consistent with the notion that patients who experience hypoglycemia are fearful of it and that with fewer episodes the fear of it diminishes. Furthermore, the reduction in the behaviour score suggests that the demonstrated improvement in A1C may be in part due to a lessening of hypoglycemia-avoiding behaviours. As might be expected from the higher rates of hypoglycemia when compared with subjects with type 2 diabetes, patients with type 1 diabetes also had a greater fear of hypoglycemia in the present study. Psychological distress is a common comorbidity in subjects with diabetes. In the present study we used the Hospital Anxiety and Depression Scale (HADS) associated morbidity, Figure 1. Glycemic control, fear of hypoglycemia and anxiety/depression A B C A1C (%) HFS-98 overall score HADS overall score p A1C at baseline Study end in patients with type 1 or type 2 diabetes; Type Type 2 Type 1 Type 2 anxiety/depression at baseline Study end in patients with type 1 and type 2 diabetes; fear of hypoglycemia at baseline Study end in patients with type 1 and type 2 diabetes; Type 1 Type 2 HFS = Hypoglycemia Fear Survey HADS = Hospital Anxiety and Depression Scale

5 fear of hypoglycemia with insulin glargine 105 Table 3. Hypoglycemia at baseline and on treatment Patients with type 1 diabetes Baseline (screening period) On treatment On treatment/baseline risk ratio (95% CI), p value Exposure, patient days NA Symptomatic hypoglycemia events, n (0.73, 1.01), p=0.06 Nocturnal hypoglycemia events, n (0.67, 2.32), p=0.48 Severe hypoglycemia events, n (0.34, 0.99), p=0.04 Patients with type 2 diabetes Exposure, patient days NA Symptomatic hypoglycemia events, n (0.63, 1.64), p=0.95 Nocturnal hypoglycemia events, n 3 27 Severe hypoglycemia events, n 2 12 Nocturnal hypoglycemia includes only events with BG <2.8 mmol/l but without symptoms, identified from available fasting BG measurements BG = blood glucose NA = not applicable noting symptomatology in almost half of subjects studied. These findings concur with previous reports of the high prevalence of anxiety and depression among a wide range of patients with diabetes (12-14). In subjects with type 1 or type 2 diabetes, the use of a primarily non-psychological intervention was associated with a substantial reduction in the severity of symptoms, consistent with improved well-being. The HALT substudy was designed to assess the psychological aspects of hypoglycemia in a treatment setting with subjects compared with their own baselines. The substudy was not designed to assess changes in A1C or incidence of hypoglycemia. The absence of a non-glargine comparator group is an important limitation of the study. Thus, it is possible that the improvements noted reflect the patients participation in a trial rather than being the result of any specific treatment. In summary, treatment with an insulin glargine-based treatment algorithm was associated with reductions in fear of hypoglycemia and anxiety/depression in subjects with type 1 or type 2 diabetes in the setting of apparently improved glycemic control. ACKNOWLEDGEMENTS The authors are grateful to Josette Dangain for her excellent statistical advice and analysis, and to Sue Hopkins for her helpful advice. This trial was sponsored by Sanofi-Aventis. AUTHOR DISCLOSURES REG and GF have each received financial support for travel to scientific meetings and honoraria for speaking engagements from Sanofi-Aventis, the manufacturers of insulin glargine. AUTHOR CONTRIBUTIONS REG contributed substantially to conception and design, analysis and interpretation of data, drafted the article and gave final approval of the version to be published. GF contributed substantially to conception and design, analysis and interpretation of data, revised the article critically for important intellectual content and gave final approval of the version to be published. REFERENCES 1. Diabetes Control and Complications Trial Research Group. 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: UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352: Cryer PE. Hypoglycemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia. 2002;45: Pramming S, Thorsteinsson B, Bendtson I, et al. Symptomatic hypoglycemia in 411 type 1 diabetic patients. Diabet Med. 1991; 8: Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long- CANADIAN JOURNAL OF DIABETES. 2008;32(2):

6 CANADIAN JOURNAL OF DIABETES 106 acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49: Rosenstock J, Dailey G, Massi-Benedetti M, et al. Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care. 2005;28: Porcellati F, Rossetti P, Pampanelli S, et al. Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin. Diabet Med. 2004;21: Davies M, Storms F, Shutler S, et al. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28: Irvine AA, Cox D, Gonder-Frederick L. Fear of hypoglycemia: relationship to physical and psychological symptoms in patients with insulin-dependent diabetes mellitus. Health Psychol. 1992;11: Cox DJ, Irvine A, Gonder-Frederick L, et al. Fear of hypoglycemia: quantification, validation, and utilization. Diabetes Care. 1987;10: Ebos JM, Tran J, Master A, et al. Imatinib mesylate (sti-571) reduces bcr-abl-mediated vascular endothelial growth factor secretion in chronic myelogenous leukemia. Mol Cancer Res. 2002;1: Peyrot M, Rubin RR. Levels and risks of depression and anxiety symptomatology among diabetic adults. Diabetes Care. 1997;20: Gary TL, Crum RM, Cooper-Patrick L, et al. Depressive symptoms and metabolic control in African-Americans with type 2 diabetes. Diabetes Care. 2000;23: Lloyd CE, Dyer PH, Lancashire RJ, et al. Association between stress and glycemic control in adults with type 1 (insulindependent) diabetes. Diabetes Care. 1999;22: