To assess the safety and efficacy of a basal-plus (BP) regimen with insulin glargine (as basal insulin) and insulin glulisine (as prandial insulin) with the main meal for elderly patients with type 2 diabetes mellitus (DM2) and high cardiovascular risk, following standard clinical practice.
Patients and methodsAn observational, retrospective study was conducted in 21 centers of internal medicine in Spain. The study included patients aged 65 years or older with DM2, undergoing treatment with a BP regimen for 4 to 12 months before inclusion in the study and a diagnosis of cardiovascular disease or high cardiovascular risk. The primary endpoint was the change in glycated hemoglobin (HbA1c) from the introduction of the glulisine to inclusion in the study.
ResultsThe study included 198 patients (mean age, 74±6.4 years; males, 52%). After at least 4 months of treatment with the BP regimen, started with the addition of glulisine, the mean HbA1c value decreased significantly (9±1.5% vs. 7.7±1.1%; P<.001), and almost 24% of the patients reached HbA1c levels of 7.5–8%. Furthermore, blood glucose levels under fasting conditions decreased significantly (190.6±73.2mg/dl vs. 138.9±38.2mg/dl; P<.001). A total of 35 patients (17.7%) had some hypoglycaemia during the month prior to the start of the study, and 2 cases (1.01%) of severe hypoglycaemia were detected.
ConclusionsThe BP strategy could significantly improve blood glucose control in patients 65 years of age or older with DM2 and high cardiovascular risk and is associated with a low risk of severe hypoglycaemia.
Evaluar la eficacia y seguridad de una pauta basal plus (BP) con insulina glargina como insulina basal, e insulina glulisina como insulina prandial en la comida principal, en pacientes ancianos con diabetes mellitus tipo 2 (DM2) y alto riesgo cardiovascular, siguiendo la práctica clínica habitual.
Pacientes y métodosEstudio observacional, retrospectivo, realizado en 21 centros de medicina interna en España. Se incluyeron sujetos de edad ≥65 años con DM2, en tratamiento con pauta BP durante 4 a 12 meses antes de la inclusión en el estudio, y diagnóstico de enfermedad cardiovascular o elevado riesgo cardiovascular. La variable principal fue el cambio en la hemoglobina glucosilada (HbA1c) desde la introducción de la glulisina hasta la inclusión en el estudio.
ResultadosSe incluyeron 198 pacientes (edad media de 74±6,4 años; hombres: 52%). Tras al menos 4 meses de tratamiento con la pauta BP, iniciada con la adición de glulisina, el valor medio de HbA1c descendió significativamente (9±1,5% vs. 7,7±1,1%; p<0,001) y casi el 24% de los sujetos alcanzaron niveles de HbA1c del 7,5-8%. Asimismo, la glucemia en ayunas descendió significativamente (190,6±73,2mg/dl frente a 138,9±38,2mg/dl; p<0,001). Un total de 35 pacientes (17,7%) presentaron alguna hipoglucemia durante el mes previo al inicio del estudio, y se detectaron 2 casos (1,01%) de hipoglucemia grave.
ConclusionesLa estrategia BP podría mejorar significativamente el control glucémico en pacientes ≥65 años con DM2 y alto riesgo cardiovascular, y se asocia a un bajo riesgo de hipoglucemia grave.
Patients with type 2 diabetes mellitus (DM2) have a high risk of presenting cardiovascular diseases.1 Moreover, the aging of the population is causing a marked increase in the prevalence of DM2 among elderly patients.2
Elderly patients with diabetes present certain characteristics, such as high comorbidity, a shorter life expectancy, geriatric syndromes and polypharmacy, which determine the treatment.3 In this context, the Veterans Affairs Diabetes Trial (VADT),4 the Action to Control Cardiovascular Risk in Diabetes (ACCORD)5 and the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE)6 studies have shown that strict metabolic control in middle-aged patients (60–66 years), with long-standing DM2 (8–10 years) and high vascular risk, does not reduce the associated cardiovascular morbidity and mortality and could result in an increase in mortality and the number of hypoglycemic episodes. For this reason, glycemic control objectives for elderly individuals should be individualized, based on each patient's characteristics.7 Although there is currently no agreement on the glycated hemoglobin (HbA1c) objective for elderly patients, a value between 7% and 9% is considered acceptable. The European Diabetes Working Party for Older People 20118 and the Spanish Consensus for the Treatment of DM2 in the Elderly2 recommend an HbA1c objective of 7–7.5% for the elderly without complications and 7.6–8.5% for frail elderly patients. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consider an HbA1c value between 7.5% and 8.5% as acceptable, based on life expectancy, morbidity and polypharmacy, among other variables.9
The current recommendations for antidiabetic treatment in elderly patients is based on clinical judgment, because there is very little scientific evidence on the risk-benefit ratio of intensive treatment and its long-term administration.10
For elderly patients who require insulin, the safest option is the introduction of basal insulin, typically combined with 1 or 2 oral diabetes drugs (ODD). If the patient does not achieve the HbA1c objective with basal insulin, the current guidelines2,8,9 recommend intensifying the treatment by adding a single dose of prandial insulin before the main meal, which is the meal that causes the greatest increase in postprandial blood glucose. This therapeutic strategy, which is known as basal-plus (BP) therapy, attempts to imitate the physiological profile and promote a gradual approach toward the basal-bolus regimen.2 However, there is little evidence on the use of BP therapy in elderly patients with high vascular risk in clinical practice. This observational study was therefore conducted to evaluate the safety and efficacy of this BP therapy.
Patients and methodsAn observational, retrospective study was conducted in 21 internal medicine departments in centers distributed throughout Spain. The study was conducted according to the Declaration of Helsinki and current legislation. The study was evaluated and approved by the Regional Committee of Galicia (SERGAS), and all patients granted their written informed consent.
Patient selectionWe included patients 65 years of age or older with DM2 and a diagnosis of cardiovascular disease (ischemic heart disease, acute stroke or peripheral arterial disease) or a high cardiovascular risk. The latter condition was defined as the presence of at least 2 of the following risk factors: active tobacco consumption, microalbuminuria (30–300mg/24h), macroalbuminuria (>300mg/24h), renal failure (creatinine>1.4mg/dL in women and >1.5mg/dL in men or a glomerular filtration rate <45mL/min/1.73m2), neuropathy or diabetic retinopathy, heart failure, arterial hypertension, obesity (body mass index ≥30kg/m2) and dyslipidemia. Furthermore, the patients had to be undergoing treatment with a BP regimen, with insulin glargine administered once a day and insulin glulisine at lunch (the main meal), for a minimum of 4 months and a maximum of 1-year before enrolling in the study, in combination or not with ODD. We excluded patients with other types of diabetes (type 1 DM, latent autoimmune diabetes in adults, steroid diabetes or pancreatic diabetes), mental disease or terminal-phase disease.
Patient evaluationThe information was collected retrospectively at the start of treatment with the BP regimen and in the clinical visit during which the patients were enrolled (at least 4 months after starting the BP regimen). The information collected at both times consisted of demographic and anthropometric data, medical history and glucose control values (HbA1c and capillary blood glucose self-monitoring profile). We recorded the diabetic treatment-related data (ODD, type of insulin and total daily dose of insulin), adverse reactions, number of hypoglycemic episodes reported during the month after the BP regimen was introduced and the type of diabetes education, if received. This last point was assessed at the same time as the blood extraction for the HbA1c reading by asking whether the patient had received diabetes education. The response could be yes or no. If yes, the following options were selected: “Exercise, self-analysis of capillary blood glucose (implementation/interpretation), self-adjustment of rapid insulin dose and correct use of the injection device”. We also documented the number of patients who were checked; in other words, who achieved an HbA1c value of 7.5–8%.2,8,9
Asymptomatic hypoglycemia was defined as an asymptomatic episode of hypoglycemia, associated with a capillary blood glucose value <70mg/dL. Symptomatic hypoglycemia was defined as the presence of hypoglycemic symptoms, along with the detection of a capillary blood glucose value <70mg/dL. Severe symptomatic hypoglycemia was established as a hypoglycemic episode whose recovery depended on the help of another individual who administered carbohydrates, glucagon or other measures due to a state of confusion or loss of consciousness in the patient. Lastly, nocturnal hypoglycemia was that which occurred when the patient was sleeping, after going to bed and before waking up in the morning.
Statistical analysisA descriptive analysis of the study variables was conducted, using measures of centralization and dispersion for quantitative variables (mean, median, standard deviation [SD] and interquartile range [IQR]) and frequencies and percentages for the qualitative variables. Two logistic regression analyses were performed to determine the patient profile with the best HbA1c control and the factors associated with the presence of hypoglycemia. A p≤.05 was considered a statistically significant difference. All analyses were performed using the SPSS (version 21.0, Chicago, USA) statistical program.
ResultsPatientsFrom June 2013 to July 2014, 200 patients were included, 2 of whom were excluded for being younger than 65. A total of 198 patients were evaluable; the mean age was 74±6.4 years, and the majority were men (52%). Table 1 shows a summary of the demographic and clinical characteristics of the study population.
Baseline characteristics of the study population (N=198).
| Characteristics | Values |
|---|---|
| Mean age, years±SD | 74.0±6.4 |
| Men, n (%) | 103 (52) |
| Mean weight, kg±SD | 79.9±13.3 |
| Mean BMI, kg/m2±SD | 29.7±5 |
| Mean time from insulinization to study inclusion, months±TD | 23.4±29.5 |
| Mean duration of diabetes, years±SD | |
| Patients with HbA1c <7.0% | 9.2±8.6 |
| Patients with HbA1c >7.0% | 14.0±8.8 |
| Smokers, n (%) | 46 (23.4) |
| Cardiovascular disease, n (%) | 150 (77.3) |
| Ischemic heart disease | 80 (40.4) |
| Stroke | 52 (26.3) |
| Peripheral arterial disease | 53 (26.8) |
| Other | 11 (5.6) |
| Comorbidities, n (%) | |
| Hypertension | 180 (90.9) |
| Dyslipidemia | 158 (79.8) |
| Obesity | 94 (47.5) |
| Other | 11 (7.3) |
| None | 5 (2.5) |
| Risk factors, n (%) | |
| Microalbuminuria | 79 (39.9) |
| Macroalbuminuria | 7 (3.5) |
| Renal failure | 42 (21.1) |
| Neuropathy | 27 (13.6) |
| Retinopathy | 45 (22.7) |
| Atrial fibrillation | 12 (6.1) |
| Heart failure | 23 (11.6) |
Abbreviations: BMI, body mass index; HbA1c, glycated hemoglobin; SD, standard deviation.
At the time of their inclusion, all patients were undergoing treatment with insulin glargine (median dosage [IQR], 24 [16–34]IU/day) and insulin glulisine (6 [5–8]IU/day). At the same time, 144 (72.7%) patients were treated with at least one ODD: metformin (88.2%), sulfonylurea (6.3%), dipeptidildipeptidasa-4 inhibitors (3.5%) and glinides (2.1%). Some 76.8% of the patients took glulisine during lunch, and the others took the glulisine dose before breakfast or dinner.
At the inclusion visit, 156 (78.8%) patients indicated that they had participated in some diabetes education activity: diet control for 143 patients (91.7%), exercise for 131 (84%), capillary blood glucose self-analysis (implementation/interpretation) for 83 (53.2%), care and/or self-hygiene for 72 (46.2%), correct use of the injection device for 53 (34%), self-adjustment of the insulin dose for 46 (29.5%) and other types for 3 (1.9%).
Changes in glycated hemoglobin and capillary blood glucoseWe observed a 1.32% reduction in the mean HbA1c levels, going from 9% (±1.5) at the time the BP regimen was started to 7.7±1.1% (p<.001). Thus, 44 (23.9%) patients had achieved the metabolic control established for this patient group (HbA1c, 7.5–8%) at the study's inclusion visit. Based on the logistic regression analysis, adjusted for the initial HbA1c level, the patients with better HbA1c control were those who stated having undergone diabetes education based on the self-analysis of capillary blood glucose (OR, 3.5; 95% CI 1.4–8.5, p=.005) and who had a more advanced age at the diagnosis of the DM2 (OR, 1.1; 95% CI 1.1–1.1).
We also observed a significant reduction in mean plasma blood glucose levels under fasting conditions from the start of the BP strategy to at least 4 months of treatment (190.6±73.2mg/dL vs. 138.9±38.2mg/dL; p<.001). With regard to the last 3 self-analysis profiles of capillary blood glucose, we obtained lower mean values under fasting conditions and in the mornings; however, we obtained similar values for the measurements performed 2h after lunch. The mean values for the 3 capillary blood glucose self-analysis profiles at the various times of day are listed in Fig. 1.
Adverse events
During the study, 35 (17.7%) patients presented a total of 62 hypoglycemic episodes (Table 2). Only 2 cases (1%) of severe hypoglycemia were detected (one of them nocturnal).
DiscussionThe results of this study show that the administration of a BP regimen to patients 65 years or older with DM2 and high cardiovascular risk, in real clinical conditions, is associated with improved glycemic control, obtaining a mean HbA1c reduction of 1.32%. However, only 24% of this patient group achieved HbA1c levels of 7.5–8%, the recommended therapeutic range for these cases.2,8,9
Several studies have evaluated the beneficial effect of the BP strategy. The results of the Proof of Concept11 and Oral Plus Apidra and Lantus studies12 support a simplified approach for the progressive intensification of treatment with prandial insulin. Both studies were randomized and open and included a broad group of patients with DM2 that was poorly controlled with basal insulin and ODD, for whom treatment intensification was achieved through dose titration of the insulin glulisine for 6 months11 or with the addition of a single bolus of insulin glulisine.12 The addition of a single dose of prandial insulin during the main meal was observed to be an effective strategy for achieving the HbA1c objective.11,12
Insulin glargine was selected as the basal insulin due to its extensive use in our setting and for showing an early and sustained benefit with a minimum risk of hypoglycemia, not only in patients poorly controlled with ODD13 but also in elderly dependent patients (Barthel index<20) who are frail and have comorbidities (age-adjusted Charlson comorbidity index, 8±2.3).14 To implement the BP strategy, insulin glulisine was administered before lunch, which is when its greatest efficacy is observed.15
In this study, a marked reduction in plasma glucose under fasting conditions was observed, while the mean capillary blood glucose values obtained 2h after lunch remained above those recommended by the ADA. Therefore, the improved HbA1c values seemed to be due not only to the addition of the bolus of prandial insulin but also to the fact that during the study period the basal insulin dose continued to be titrated instead of optimizing the rapid insulin dose, perhaps because of an excessive concern about an increase in the incidence of severe hypoglycemia. Elderly patients are especially vulnerable to the onset of hypoglycemia.16 It is worth noting the results of the ACCORD17 and VADT studies,4 which demonstrated that the onset of severe hypoglycemia is an independent predictor of mortality. Consequently, the essential treatment objective for elderly patients with DM2 should be preventing hypoglycemic episodes.2 Although almost 1 of every 5 patients in our study showed an episode of hypoglycemia, the rate of severe hypoglycemia was very low. These results are consistent with those from the combination of 4 multicenter randomized studies of 711 patients with DM2 poorly controlled with ODD who started BP therapy.18 The BP regimen helped achieve good glycemic control and a low risk of hypoglycemia or weight gain, regardless of the patient's age or body mass index.18
An alternative in the therapeutic intensification process for patients with poorly controlled DM2 is the combination of basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), which provides a glycemic control similar or superior to that of BP therapy, with a lower risk of hypoglycemia and no weight gain.19,20 A study by Rosenstock et al. showed that lixisenatide (a short-acting GLP-1 RA) combined with insulin glargine (with or without ODD) administered to patients with obesity and poorly controlled DM2 was more effective in achieving the glycemic objectives, with a lower rate of hypoglycemic episodes and no weight gain, compared with the addition of insulin glulisine to treatment with insulin glargine (combined or not with ODD).21 Moreover, the combined therapy of basal insulin and GLP-1 RAs could be a good alternative to intensification with the insulin regimen in elderly patients with DM2 and a high risk of hypoglycemia.22 Despite the potential of GLP-1 RAs in combination with basal insulin in this patient group, clinical trials that demonstrate this potential are still needed.
This study has a number of limitations. Firstly, this was an observational, retrospective uncontrolled study that did not have a uniform insulin dosage protocol or blood glucose self-monitoring. The hypoglycemic events were self-reported by the patients, which entails a bias of underdiagnosis. Furthermore, the information on the patients’ diabetes education could differ from one center to another, depending on the protocols and dedication employed in the various centers. However, the implementation of this type of study is of utmost importance for understanding the conditions resulting from standard clinical practice.
In conclusion, the results of this research study suggest that the BP insulin strategy (with insulin glargine as basal insulin and insulin glulisine as prandial insulin at the main meal) for patients 65 years or older with DM2 and high cardiovascular risk, following the conditions of standard clinical practice, seems to significantly improve glycemic control while maintaining a low risk of severe hypoglycemia.
FundingThe study was funded by Sanofi España.
Conflicts of interestG Romero Meliá works for Sanofi. The other authors declare that they have no conflicts of interest regarding this study.
The authors of the study would like to thank Ana López Ballesteros and Antonio Torres Ruiz of Dynamic SL for their contribution to the medical drafting of the manuscript.
Please cite this article as: Gómez-Huelgas R, Sabán-Ruiz J, García-Román FJ, Quintela-Fernández N, Seguí-Ripoll JM, Bonilla-Hernández MV, et al. Eficacia y seguridad de una pauta basal plus con insulina glargina e insulina glulisina en pacientes ancianos de alto riesgo cardiovascular con diabetes mellitus tipo 2. Rev Clin Esp. 2017;217:201–206.
