Deficit of endogenous insulin secretion progresses over time in patients with type 2 diabetes mellitus (T2DM). Because of the progressive deterioration in pancreatic β-cell function, oral antidiabetic medications (OAMs) are often unable to sustain control of hyperglycemia. Thus, insulin remains the foundation of antihyperglycemic therapy (1). Although it is generally agreed that insulin therapy should be started in a timely manner in these patients, many health care professionals delay insulin therapy for various reasons, including concern over hypoglycemia and weight gain (2). Additionally, patients are reluctant to begin insulin therapy due to a variety of reasons, including fear of injections, fear of hypoglycemia, and complexity/inconvenience of insulin regimens (3).
Premixed insulin analogues, typically composed of a combination of a rapid-acting insulin analogue for prandial coverage and a protamine suspension of the analogue for basal coverage, may help mitigate the reluctance to initiate insulin therapy by eliminating potential errors due to patient self-mixing of insulin, minimizing the number of injections required, and providing greater flexibility in timing of dose relative to meal time (4,5). Nevertheless, hypoglycemia remains a potentially serious complication of any insulin regimen, and patients with T2DM have been shown to be at higher risk of severe hypoglycemia with insulin treatment compared with other treatments (6).
Several clinical trials of premixed insulin analogues have been conducted in patients with T2DM (7-11), but little information exists regarding the real-world risk of severe hypoglycemia in these patients. In addition, the choice of insulin regimen after OAM failure remains controversial (10, 11). Therefore, we undertook the present analysis of a Turkish subpopulation from a multinational observational study to assess the risk of severe hypoglycemia (primary objective) and to examine glycemic measures routinely available in clinical practice (secondary objective) with insulin therapy initiation using premixed insulin analogues in patients with T2DM suboptimally controlled with OAMs (12).
The original study was a 12-month multinational, multicenter, open-label, prospective, observational study in patients with suboptimal glycemic control who initiated a commonly prescribed premixed insulin analogue (12). At baseline (insulin initiation), patients either continued or discontinued OAM therapy. Consistent with an observational design, patients were treated in outpatient settings by general practitioners, internists, or diabetes specialists. Treatment for diabetes was prescribed according to the usual standard of care, and treatment pattern and initiation of changes were solely at the discretion of the physician and patient in the course of standard clinical practice. Data were collected at 0 months (baseline, visit 1), 4 (±1) months (visit 2), 8 (±1) months (visit 3), and 12 (±1) months (visit 4). Only the results for the Turkish patients who participated in the study are provided in this report.
Patients aged ≥18 years with T2DM (according to the World Health Organization (WHO) classification) and a body mass index (BMI) <40 kg/m2, receiving at least one OAM without insulin for at least 3 months immediately before the study and, in the opinion of the physician, requiring insulin therapy to achieve proper metabolic control were enrolled. Patients were not allowed to participate if they had taken the following medications for more than 2 weeks within 3 months before entering the study or during the observation period: chronic systemic glucocorticoid therapy excluding topical and inhaled preparations, any prescription drug to promote weight loss, or thiazolidinediones.
Premixed insulin treatment, as monotherapy or in combination with OAMs, was initiated by the administration of insulin lispro mix 25 (25% insulin lispro, 75% insulin lispro protamine suspension or biphasic insulin aspart 30/70 (30% insulin aspart and 70% insulin aspart protamine suspension, twice daily, before morning and evening meals.
The primary assessment was the risk of severe hypoglycemia, as determined by the number of patients with at least one severe hypoglycemic episode during 1 year of observation, and the rate (number of episodes per patient-year) of severe hypoglycemia. A severe hypoglycemic episode was defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and was associated with either a blood glucose level <70 mg/dL or a prompt recovery attributable to the restoration of plasma glucose to normal. Secondary measures included mean changes from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose levels (measured in the clinic), self-monitored postprandial whole blood glucose levels, BMI, and total daily insulin dose after starting therapy with premixed insulin analogues.
Estimates for the study population size for the original study were based on the incidence of severe hypoglycemia reported in the United Kingdom Prospective Diabetes Study (UKPDS) trial (6). The original study enrolled 1150 patients of whom 1139 received at least one dose of insulin (12). In the current study, a subset of 154 Turkish patients who received at least one dose of insulin was included in the analyses; data from the two insulin therapies were combined.
The frequency of severe hypoglycemia between insulin groups was compared using Fisher’s exact test. Changes (intrapatient) from baseline in HbA1c levels, fasting plasma glucose levels, postprandial blood glucose levels recorded 2 hours after the morning and evening meals, BMI, and total daily insulin dose were calculated. Differences between mean baseline and 12-month values were assessed for glycemic indices using a paired t-test, with a p-value <0.05, indicating a significant difference from baseline; 95% confidence intervals (CIs) were constructed for the mean differences.
Of the 155 Turkish patients enrolled, 154 patients received insulin (138 insulin lispro and 16 biphasic insulin aspart) and 1 patient was not treated. Of the 154 treated patients, 35 (23%) discontinued and 118 (77%) completed the study; 1 (0.6%) patient had no follow-up data beyond visit 1. Reasons for discontinuation included physician decision (n=17), lost to follow-up (n=15), death (n=2), and subject decision (n=1).
The characteristics of the patients are summarized in Table 1. The mean (standard deviation [SD]) age was 56 (10) years, and the duration of diabetes mellitus was 8.9 (5.4) years (Table 1). The most common OAM at baseline was metformin (46.7% of 242 medications administered); 70 (45.5%) patients stopped OAMs from baseline.
Of the 154 insulin-treated patients, 12 (7.8%) reported 16 severe hypoglycemic episodes (8 with 1 episode each and 4 with 2 episodes each). No significant difference (p=1.000) was found in the frequency of severe hypoglycemia between patients treated with biphasic insulin lispro (8.0%, 11 of 138 patients) and those treated with biphasic insulin aspart (6.3%, 1 of 16 patients). The rate of severe hypoglycemia over the 12-month study was 0.14 episodes per patient-year. All hypoglycemic episodes were confirmed by blood glucose readings. Eight episodes (50.0% of total episodes) occurred between the morning mean and lunch, 1 (6.3%) occurred between lunch and the evening meal, 3 (18.8%) occurred between the evening meal and bedtime, and 2 (12.5%) occurred between waking and the morning meal; the timing of 2 episodes was unknown (Table 2). Most events (11 of 16) were reported in Visit 2 (Table 2). There were no reported nocturnal severe hypoglycemic episodes. Two episodes (12.5%) resulted in changed insulin regimens and 1 (6.3%) resulted in hospitalization. During 12 episodes (75.0%), the patients were aware of hypoglycemic symptoms, and during 4 episodes (25.0%), the patients were unaware of symptoms.
Secondary measures are summarized in Table 3 and Figures 1 and 2. The mean change from baseline in HbA1c was -2.7% (95% CI -3.0% to -2.4%; p<0.0001). Fasting plasma glucose and self-monitored 2-hour postprandial blood glucose after the morning meal also showed significant improvement with premixed insulin analogue therapy, with mean changes from baseline of -115.9 mg/dL (95% CI -135.2 mg/dL to -96.6 mg/dL; p<0.0001) and -163.3 mg/dL (95% CI -228.6 mg/dL to -98.0 mg/dL; p<0.0001), respectively. Only 1 patient had both baseline and 12-month values for the 2-hour postevening meal time point. Over the 12-month period, the mean (SD) BMI increased from baseline by 1.4 (1.8) kg/m2, and the mean total daily insulin dose increased by 4.2 (11.9) IU.
Less than half of the patients in this observational study performed self-monitored blood glucose determinations. The time point with the highest rate of patient participation was the baseline 2-hour post morning meal blood glucose measurement, with 55 of 154 (36%) patients recording values. This number decreased to 25 patients (16%) by the end of the 12-month observational period, with only 17 patients (11%) having both baseline and 12-month recorded values. The rate of performance of the 2-hour post evening meal blood glucose measurement was even lower than that of the post morning meal blood glucose determination, with 18 (12%) patients performing the measurement at baseline and 8 (5%) patients performing the measurement at 12 months.
Hypoglycemia is still a significant barrier to adequate glycemic control in patients with T2DM treated with insulin. In this analysis of a Turkish subpopulation with T2DM from a multinational observational study (12), the rate of severe hypoglycemia is consistent with many population-based studies of insulin-treated patients with T2DM (0.12 to 0.28 episodes/patient-year) (13-17), and higher than typically reported in controlled clinical trials of premixed insulin analogues (0.00-0.10) (7-11). The modest increase in BMI observed was not unexpected and in keeping with previous studies of premixed insulin regimens in insulin-naive patients (7-11, 18-21).
A possible explanation for the higher rate of severe hypoglycemia found in this real-world study compared with those in controlled clinical trial settings could be a lack of or minimal patient education and engagement regarding insulin therapy and management of hypoglycemia in routine clinical practice. By comparison, patients in controlled clinical trials are typically monitored by clinical staff and engaged in dialogue regarding their therapy to a degree that is often difficult to achieve in a average specialist center, and even more so in general practice settings. Thus, controlled clinical trial environments may not be fully applicable to the real-world setting (22).
Similar to the current study, a retrospective medical records analysis of Turkish patients with T2DM who received conventional insulin therapy on an outpatient basis reported a rate of severe hypoglycemia of 0.15 episodes/patient-year (13). In that study, the authors reported that only 10% of patients with T2DM regularly attended a diabetes teaching program and only 5% of patients performed self-monitoring of blood glucose. Patient-reported reasons for severe hypoglycemic episodes, which were not collected in the current study, included dietary mistakes (65.5%), exercise (27.5%), and insulin overdose (7%) (13).
Intensification of diabetes therapy to include insulin is often delayed until patients have markedly high HbA1c values (23,24). This occurs for a variety of reasons on the part of both physicians and patients (25). Indeed, the current study population had a mean HbA1c of 10.4% at the time of insulin initiation, an indication that T2DM had progressed significantly in these patients. Although the mean duration of diabetes at baseline (8.9 years) was similar to, or less than other populations reported to have lower baseline HbA1c levels (26-28), it is important to note that the diabetes duration value was obtained from patient recall of the date of diagnosis, which could be prone to error. In addition, patients could have gone undiagnosed for some time. Thus, there appears to be an important opportunity within the Turkish diabetes community to screen and treat patients with T2DM sooner.
Despite the apparent advanced progression of their disease, the patients in this study responded well in terms of glycemic control to relatively low insulin doses and small insulin dose increases, with significant improvement in HbA1c, fasting plasma glucose, and self-monitored postprandial blood glucose recorded 2 hours after morning meal. This may suggest that, in this patient population, insulin resistance may play a minor role in patients with T2DM (29), and may indicate an opportunity to bring patients into glycemic control without the need for high insulin doses.
A limitation of this study includes the potential for patient recall bias, which could have resulted in underreporting or overreporting of hypoglycemia. In addition, if the patients were not clear on the reporting criteria for hypoglycemia, it is possible that there may have been confusion regarding the severity of their hypoglycemic events. However, the patients were asked to recall severe hypoglycemic episodes rather than mild hypoglycemia, and it has been shown that unlike mild hypoglycemia, retrospective recall of severe hypoglycemia is relatively robust (14,30). Another possible limitation is that patient participation in self-monitoring of blood glucose was low, especially at the 2-hour postevening meal. Thus, results for postprandial blood glucose values represent only a portion of the patient population. For these reasons, the results of the present study should be interpreted with caution. The lack of a requirement for the study design to record possible complications of diabetes such as, diabetic neuropathy or nephropathy, also represents a possible limitation.
In conclusion, initiation of insulin therapy with premixed insulin analogues in Turkish patients with T2DM in normal clinical practice significantly improves glycemic control during the first year of treatment, but comes with a risk for severe hypoglycemia. An important opportunity exists to better educate Turkish patients regarding self-monitoring of blood glucose and strategies to avoid hypoglycemia. As with all patients with T2DM, education regarding diet and exercise to help control weight gain, manage hyperglycemia and hypoglycemia, and improve insulin sensitivity is of great importance.
We thank all site personnel for contributing to this observational trial. The authors thank Edit Nadasi, Primo Scientific Corporation, Panama, Rep. of Panama for writing assistance.
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