Abstract
Context
Despite the available evidence showing the vital role of glycemic control in the management of type 2 diabetes, a significant proportion of patients are not achieving a good glycemic control.
Objective
Here we present the results of the Diabetes Unmet Need with basal insulin Evaluation (DUNE) study for patients enrolled in Romanian centers with the aim to describe the proportion of participants who achieved individualized HbA1c targets at 12 weeks following basal insulin therapy initiation.
Design
Prospective, observational study.
Subjects and Methods
355 consecutive adults with type 2 diabetes, who were newly initiated with basal insulin therapy (Newly initiated group) or had been treated for less than 12 months with basal insulin prior to study enrollment (Previously initiated group) were enrolled and followed for 12 weeks.
Results
The individualized HbA1c target was achieved by 22.7% of the patients in the Newly initiated group and by 25.0% of the patients in the Previously initiated group. During the study period, in the Newly initiated group mean basal insulin dose increased from 16.2 U at baseline to 27.6 U at 12 weeks. In the Previously initiated group, the insulin dose increased from 27.4 U at baseline to 33.1 U at 12 weeks. In both groups, 9.7% and 12.8% of the patients reported at least 1 episode of symptomatic hypoglycemia.
Conclusions
In real-world settings, despite insulin initiation a large number of patients fail to achieve their individualized glycemic targets. One of the reasons appeared to be linked to the insufficient basal insulin titration.
Keywords: insulin therapy, type 2 diabetes, real-life, efficacy, safety
INTRODUCTION
Type 2 diabetes is one of the most prevalent chronic non-communicable disease and its frequency is on the rise mainly led by increasing incidence of obesity (1, 2). Type 2 diabetes is associated with increased costs at both individual and society level and these costs are mainly driven by associated chronic complications (3). Previous landmark clinical trials have clearly established that good glycemic control plays a key role in the prevention of diabetes chronic complications (4-7).
Despite of the available evidence showing the vital role of good glycemic control in the management of type 2 diabetes and the increasing number of available medications, a significant proportion of patients are not achieving a good glycemic control, as assessed by HbA1c and hence these patients are at increased risk of complications (8). Among reasons for not achieving a good glycemic control that have been identified is fear of hypoglycemia, clinical inertia in adding new hypoglycemiant medication once glycemic control starts to deteriorate and sub-optimal dosing (8, 9). A higher frequency of hypoglycemia is typically associated with a good or improved glycemic control and may occur with various hypoglycemia therapies. Undoubtedly the antihyperglycemic therapeutic approach which has the highest risk of hypoglycemia is insulin therapy. Hence it is not surprising that there is a high level of reluctance from both physicians and patients to initiate therapy and optimize the applied therapeutic regime in case of insulin therapy (9). This has been observed even in case of the simplest approach, which is the basal insulin therapy in type 2 diabetes (8, 9).
Diabetes Unmet Need with basal insulin Evaluation (DUNE) study was an international, multicentric, prospective observational study with the main objective to describe the proportion of participants who achieved individualized HbA1c targets at 12 weeks following basal insulin therapy initiation, and to evaluate the impact of symptomatic hypoglycemia on the achievement of HbA1c target (10). Here we present the results of this study for patients enrolled in Romanian centers.
MATERIALS AND METHODS
Study design and patients
DUNE study was conducted between February 2015 and July 2016 in 28 countries. Of the all centers, 39 were in Romania and 355 participants from these centers were enrolled. The study design and participants’ inclusion and exclusion criteria were previously described in the paper presenting the main study results (10). Briefly, consecutive adults with type 2 diabetes, who were newly initiated with basal insulin therapy or had been treated for less than 12 months with basal insulin prior to study enrollment, with an HbA1c of 7.5% to 11.0% for those newly initiated and an HbA1c of 7.5% to 10.0% for those previously treated with basal insulin, willing to perform self-monitoring of blood glucose (SMBG) and keep a diary (SMBG results, insulin dose, hypoglycemia) were enrolled. Patients were eligible whether they had associated therapy with an oral antihyperglycemic drug or a GLP-1 receptor agonist or no associated therapy (Table 1). Patients treated with rapid acting or premixed insulin, those with a suspicion of type 1 diabetes (start of insulin therapy within 1 year after diabetes diagnosis in a patient under 40 years), and pregnant women or those who intended to become pregnant were excluded.
Table 1.
Baseline characteristics of patients enrolled
| Variable |
Newly initiated basal insulin
(N=207) |
Previously initiated basal insulin
(N=148) |
All
(N=355) |
|---|---|---|---|
| Age, years | 60.1 ± 8.7 | 61.4 ± 8.2 | 60.7 ± 8.5 |
| Women, n (%) | 113 (54.6%) | 83 (56.1%) | 196 (55.2%) |
| BMI, kg/m2 | 31.8 ± 5.7 | 31.7 ± 5.1 | 31.8 ± 5.4 |
| Baseline BMI categories, n (%) | |||
| <25 | 15 (7.2%) | 8 (5.4%) | 23 (6.5%) |
| 25-30 | 68 (32.9%) | 54 (36.5%) | 122 (34.4%) |
| 30-40 | 106 (51.2%) | 77 (52.0%) | 183 (51.5%) |
| ≥40 | 18 (8.7%) | 9 (6.1%) | 27 (7.6%) |
| Baseline estimated GFR (mL/min/1.73m2) | 83.4 ± 25.7 | 80.8 ± 23.0 | 82.3 ± 24.6 |
| Duration of diabetes, years | |||
| <1 year | 20 (9.7%) | 20 (13.5%) | 40 (11.3%) |
| 1-5 years | 53 (25.6%) | 30 (20.3%) | 83 (23.4%) |
| 5-10 years | 80 (38.6%) | 49 (33.1%) | 129 (36.3%) |
| >10 years | 54 (26.1%) | 49 (33.1%) | 103 (29.0%) |
| Time since first antidiabetic medication (years) | 6.95 ± 4.84 | 7.03 ± 5.15 | 6.98 ± 4.96 |
| Duration of basal insulin, n (%) Without insulin prior to inclusion | |||
| ≤2 weeks | 3 (1.4%) | 0 | 3 (0.8%) |
| <6 months | 204 (98.6%) | 0 | 204 (57.5%) |
| 6-12 months | 0 | 82 (55.4%) | 82 (23.1%) |
| 6-12 months | 0 | 66 (44.6%) | 66 (18.6%) |
| Concomitant antihyperglycemic medication, n (%) | |||
| Metformin | 168 (81.2%) | 119 (80.4%) | 287 (80.8%) |
| Sulfonylureas | 127 (61.4%) | 71 (48.0%) | 198 (55.8%) |
| Alpha-glucosidases inhibitors | 20 (9.7%) | 11 (7.4%) | 31 (8.7%) |
| DPP-IV inhibitors | 16 (7.7%) | 9 (6.1%) | 25 (7.0%) |
| GLP1-R agonists | 7 (3.4%) | 4 (2.7%) | 11 (3.1%) |
| Meglitinides | 3 (1.4%) | 7 (4.7%) | 10 (2.8%) |
| Thiazolidinediones | 1 (0.5%) | 1 (0.7%) | 2 (0.6%) |
| SGLT-2 inhibitors | 1 (0.5%) | 0 | 1 (0.3%) |
| Type of current basal insulin, n (%) | |||
| Human intermediate-acting insulin | 11 (5.3%) | 3 (2.0%) | 14 (3.9%) |
| Long-acting basal analogue | 196 (94.7%) | 145 (98.0%) | 341 (96.1%) |
| Current total basal insulin daily dose, units | 16.18 ± 7.93 | 27.41 ± 13.25 | 20.86 ± 11.84 |
| Insulin dose/kg body weight, units | 0.2±0.1 | 0.3±0.2 | 0.2±0.1 |
| Number of injections per day, n (%) | |||
| 1 | 206 (99.5%) | 144 (97.3%) | 350 (98.6%) |
| 2 | 1 (0.5%) | 4 (2.7%) | 5 (1.4%) |
| Individual HbA1c targets (%) set by the physician at baseline | |||
| <6.5 | 4 (1.9%) | 0 | 4 (1.1%) |
| 6.5 to <7.0 | 16 (7.7%) | 18 (12.2%) | 34 (9.6%) |
| 7.0 to <7.5 | 143 (69.1%) | 102 (68.9%) |
245 (69.0%) |
| 7.5 to <8.0 | 37 (17.9%) | 26 (17.6%) | 63 (17.7%) |
| 8.0 to <8.5 | 7 (3.4%) | 2 (1.4%) | 9 (2.5%) |
| ≥8.5 | 0 | 0 | 0 |
N/n (%)=number (percentage) of patients; BMI=body mass index; GFR=glomerular filtration rate; DPP-IV= Dipeptidyl peptidase-IV; GLP1-R= Glucagon-like peptide-1 receptor; SGLT-2=sodium-glucose cotransporter-2.
Patients were followed for 12 weeks, by their physician (all specialists in diabetes, nutrition and metabolic diseases in the Romanian sample). No interim study visits were scheduled per protocol and investigators were free to choose the number and type of visits performed during these 12 weeks. Also, investigators were free to titrate the basal insulin and use concomitant antihyperglycemic therapy as per local standard of care. Data collected at baseline included medical history, history of severe hypoglycemia and type and dose of basal insulin used, last HbA1c, fasting plasma glucose and estimated glomerular filtration rate value available in patients’ medical files and performed within 1 month prior to study enrollment, weight, height and demographic information.
Clinical study protocol and all study-related documents were approved by institutional review boards or independent ethics committees and the study was conducted in accordance with good clinical practices guidelines, the Declaration of Helsinki. All patients were informed about the investigational nature of the study and provided a written informed consent before any study-related procedures.
Efficacy assessment
The primary efficacy endpoint was the achievement of individualized HbA1c target at 12 weeks. Secondary efficacy endpoints included: 1) achievement of the general HbA1c target of <7.0% at week 12 (for patients with individual target as well); 2) HbA1c change from baseline to 12 weeks (week 12 – baseline); 3) decrease of at least 0.5 and 1.0% of HbA1c improvement from baseline to week 12.
At baseline each investigator was required to agree with the patient an individualized long-term HbA1c target. If no individual target was set, a general HbA1c target of <7.0% was defined. All HbA1c assessments were performed at local laboratories using standardized commercially available methods.
Safety assessment
The primary safety endpoint was the assessment (frequency and severity) of symptomatic hypoglycemia during the study.
Severe hypoglycemia was defined as any event which required third party assistance regardless of blood glucose level availability. Non-severe symptomatic hypoglycemia was defined as any event which was associated with hypoglycemic symptoms and which did not require third party assistance regardless of blood glucose level availability.
Statistical analysis
Data was presented as mean and standard deviation for quantitative variables and number and percentage for qualitative variables, for the whole sample and separately for the group newly initiated with basal insulin therapy (Newly initiated group; for which the insulin was initiated at study inclusion) and for the group with prior basal insulin therapy (Previously initiated group, for which the insulin therapy was initiated prior to study enrollment, but who had been treated for less than 12 months with basal insulin prior to study enrollment). Patients with missing data for HbA1c or hypoglycemia at weeks 12 visit were not included in the analysis.
RESULTS
Baseline characteristics
In the 39 study centers from Romania were enrolled 355 eligible patients, of which 207 newly initiated with basal insulin therapy and 148 with a prior basal insulin therapy within 12 months prior to study inclusion. Mean age was 60.7 years and 55.2% were women. Mean baseline BMI was 31.8 kg/m2 and most participants were obese (59.1%). 65.3% of the participants had a mean duration of diabetes >5 years and 80.8% were treated with metformin. At study inclusion, the mean time since first basal insulin intake was 0.66 days for the Newly initiated group (ranging between -7 and 14 days) and 159.7 days for the Previously initiated group (ranging between 15.0 and 364 days). Also, current basal insulin administered at inclusion was a long acting basal analogue for 96.1% of the patients with a mean daily dose of 20.9 U (Table 1). During the study period, in the Newly initiated group mean basal insulin dose increased from 16.2 U (0.2 U/kg body weight) at baseline to 27.6 U (0.3 U/kg body weight) at 12 weeks (mean difference 11.4 U). In the Previously initiated group, the insulin dose increased from 27.4 U (0.3 U/kg body weight) at baseline to 33.1 U (0.4 U/kg body weight) at 12 weeks (mean difference 5.7 U).
Glycemic control
Mean HbA1c decreased from 9.3% at baseline to 7.9% at week 12 in the Newly initiated group and from 8.5% at baseline to 7.7% at week 12 in the Previously initiated group. Mean HbA1c change from baseline to week 12 was -1.4% in the Newly initiated group and -0.75% in the Previously initiated group. An HbA1c <7.0% was achieved by 20.3% of the patients in the Newly initiated group and by 24.3% of the patients in the Previously initiated group. At week 12, 22.7% of the patients in the Newly diagnosed group and 25.0% of the patients in the Previously diagnosed group achieved the individualized targets set by their physicians (Table 2).
Table 2.
Changes in glycemic control from baseline to study end and targets achievement
| Variable |
Newly initiated basal insulin
(N=207) |
Previously initiated basal insulin
(N=148) |
All
(N=355) |
|---|---|---|---|
| Baseline HbA1c, % | 9.3±1.0 | 8.5±0.7 | 8.9±1.0 |
| Week 12 HbA1c, % | 7.9±1.1 | 7.7±1.1 | 7.8±1.1 |
| Patients with HbA1c <7.0% at 12 weeks | 42 (20.3%) | 36 (24.3%) | 78 (22.0%) |
| Reason for setting the target | |||
| Age | 143 (69.1%) | 110 (74.3%) | 253 (71.3%) |
| Comorbidities | 131 (63.3%) | 81 (54.7%) | 212 (59.7%) |
| History of previous severe hypoglycemia | 0 | 0 | 0 |
| Acceptability patient | 67 (32.4%) | 68 (45.9%) | 135 (38.0%) |
| Other | 7 (3.4%) | 7 (4.7%) | 14 (3.9%) |
| Patients achieving the individualized target at 12 weeks | |||
| Overall | 47 (22.7%) | 37 (25.0%) | 84 (23.7%) |
| HbA1c <7.0% | 42 (20.3%) | 36 (24.3%) | 78 (22.0%) |
| HbA1c <8.0% | 114 (55.1%) | 93 (62.8%) | 207 (58.3%) |
N (%)=number (percentage) of patients; HbA1c=glycated hemoglobin.
Frequency of hypoglycemia
In both groups, 9.7% and 12.8% of the patients, respectively, reported at least 1 episode of symptomatic hypoglycemia. A symptomatic hypoglycemia with a glucose level ≤54 mg/dL was reported by 3.4% of the patients in the Newly initiated group and by 2.0% of the patients in the Previously initiated group (Table 3).
Table 3.
Frequency of symptomatic hypoglycemia during the study period
| Variable |
Newly initiated basal insulin
(N=207) |
Previously initiated basal insulin
(N=148) |
All
(N=355) |
|---|---|---|---|
| Patients with symptomatic hypoglycemia, n (%) | 20 (9.7%) | 19 (12.8%) | 39 (11.0%) |
| Patients with symptomatic hypoglycemia ≤70 mg/dl, n (%) | 15 (7.2%) | 12 (8.1%) | 27 (7.6%) |
| Patients with symptomatic hypoglycemia ≤54 mg/dl, n (%) | 7 (3.4%) | 3 (2.0%) | 10 (2.8%) |
| Patients with severe hypoglycemia, n (%) | 0 | 1 (0.7%) | 1 (0.3%) |
| Frequency of severe symptomatic hypoglycemia events, n (%) | |||
| 0 to 1 | 207 (100%) | 147 (99.3%) | 354 (99.7%) |
| 2 to 5 | 0 | 1 (0.7%) | 1 (0.3%) |
| More than 5 | 0 | 0 | 0 |
| Frequency of non-severe symptomatic hypoglycemia events, n (%) | |||
| 0 to 1 | 196 (94.7%) | 138 (93.2%) | 334 (94.1%) |
| 2 to 5 | 8 (3.9%) | 10 (6.8%) | 18 (5.1%) |
| More than 5 | 3 (1.4%) | 0 | 3 (0.8%) |
N/n (%)=number (percentage) of patients.
DISCUSSION
The aim of the DUNE study was to assess the achievement of HbA1c targets in real-world settings and their relationship with the occurrence of hypoglycemia. Results for Romania, presented here, showed a low achievement of the HbA1c targets – only 23.7% of the whole study population enrolled in Romania achieved the targets set by their treating physician at baseline. The figures are slightly higher in those in which basal insulin therapy was initiated prior to study enrollment. These figures are similar to the ones reported in the whole DUNE study, in which only 27% of the patients achieved their individualized target at 12 weeks (10). Similar results were reported by other previous observational studies which also showed a low percentage of patients achieving the HbA1c targets (11). The main reasons incriminated in not achieving the HbA1c targets outside of clinical trials settings are clinical inertia, with delays in therapy intensification, and insufficient titration of insulin doses once insulin therapy is initiated (11). The SOLVE study, which aimed to assess the timing of insulin therapy initiation in patients with type 2 diabetes, showed significant delays in diabetes therapy intensification and insulin initiation decided only when diabetes was poorly controlled, with HbA1c values >9.0% in a significant proportion of patients (11). Furthermore, until commencing insulin therapy, a patient usually accumulates 10 years with HbA1c values >7.0% and 5 years with HbA1c values >8.0% (8). In line with these findings the HbA1c in the Romanian patients initiating basal insulin enrolled in the DUNE study was as high as 9.3%.
Insufficient titration of insulin doses is another problem observed in the DUNE study. During the 12-weeks follow-up, in the Romanian sample, the insulin doses increased with 11 U in the Newly initiated group and with 6 U in the Previously initiated group. Results are similar to the ones reported in the whole DUNE cohort with 9 U and 5 U increase in the insulin dose in the newly initiated and previously initiated insulin therapy, respectively (10). In the DUNE study no data on the insulin titration algorithms used or on the person who performed the titration were collected (10). Given the insufficient titration of insulin doses observed, we can assume that if any algorithm was used the adherence to that titration algorithm was limited. This, despite data from real-world practice that showed that both physician-led titration and patients-led titration of insulin doses based on titration algorithms and supported by patients’ education are effective in improving glycemic control (12,13).
Fear of hypoglycemia may represent another obstacle in achieving a good glycemic control, especially in populations at risk for complications related to the occurrence of severe hypoglycemia (10, 14-18). In the Romanian sample analyzed here, the frequency of hypoglycemia was low, with only 11.0% of the patients reporting at least one episode of symptomatic hypoglycemia and 2.8% of the patients reporting an episode of symptomatic hypoglycemia with a glycemia <54 mg/dL. These numbers may be understood in the context of low achievement of HbA1c targets and thus a poor glycemic control seen in our sample. Also, the frequency of hypoglycemia in the Romanian sample was lower as compared to the whole DUNE sample in which a frequency of 16% of patients with symptomatic hypoglycemia was reported (10). Previous research showed that experiencing a hypoglycemic episode may result in consequent fear of hypoglycemia with low adherence to hypoglycemic therapy and poor glycemic control (14-18). Real-Life Effectiveness and Care Patterns of Diabetes Management (RECAP-DM) Study which enrolled 2146 patients with type 2 diabetes from 7 European countries pointed to an association between hypoglycemic episodes, lower satisfaction and lower adherence to diabetes therapy (15). An online survey on 1329 patients with type 2 diabetes from the UK showed that higher HbA1c values were associated with a higher fear of hypoglycemia and higher healthcare resources use (14). DUNE study and the analysis presented here has several limitations that should be acknowledged. First, the number of Romanian patients enrolled was limited and the selected centers may not be representative for the whole Romanian diabetes clinical practice. However, this study provides a first picture of insulin initiation practices in Romania. Another limitation is the observational nature of the study, the lack of detailed information on titration algorithm used and the collection of data on hypoglycemic episodes only at the end of the study based on patient diaries. This may have resulted in lower rates of hypoglycemia.
In conclusion, in real-world settings, a large number of patients fail to achieve their individualized glycemic targets despite insulin initiation. Results underline the huge gap between existing guidelines and the real-world situation in terms of glycemic control. These results also point towards the need for education of both patients and physicians managing patients with diabetes on glycemic targets and insulin titration algorithms with the aim to overcome clinical inertia and insufficient titration of insulin doses identified in our sample.
Conflict of interest
AC received fees from AstraZeneca, Boehringer Ingelheim, Sanofi, Servier, MSD, Novo Nordisk, and Eli Lilly; ARP declares fees from Eli Lilly, Sanofi, Novo Nordisk, MSD, Servier, Terapia, Worwag, Abbott; GC declares fees from Eli Lilly, Sanofi, Novo Nordisk, AstraZeneca, Roche, TrustMed, Bayer; DC declares fees from Eli Lilly, Sanofi, Novo Nordisk, AstraZeneca, Roche, MSD, Boehringer Ingelheim, Servier; EA declares fees from Astra Zeneca, Sanofi, Novo Nordisk, Eli Lilly, Boeringer, MSD, Servier , Mylan, Berlin Chemie; MM is an employee of Sanofi Romania.
Funding
This study was funded by Sanofi.
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