A Prospective,Randomized,Open-Label Study Comparing the Efficacy and Safety of Preprandial and Prandial Insulin in Combination with Acarbose in Elderly,Insulin-Requiring Patients with Type 2 Diabetes Mellitus

Abstract

Background:

By delaying absorption of carbohydrates, acarbose can reduce preprandial hyperglycemia and delay the emergence of postprandial hyperglycemia.

Patients and Methods:

To evaluate whether acarbose can shorten the desirable time interval between insulin injection and meals, 60 elderly (≥60 years) patients with unsatisfactorily controlled type 2 diabetes mellitus despite insulin use were enrolled in a randomized, open-label study of 16 weeks' duration. Two groups (n=20 each) were randomized to receive isophane protamine biosynthetic human insulin 70/30 injections twice daily 30 min before meals plus acarbose 50 mg once daily (Group A) or three times daily (Group B) before meals, whereas the third group (n=20) received isophane protamine biosynthetic human insulin 70/30 injections twice daily immediately before meals plus acarbose 50 mg three times daily before meals (Group C).

Results:

The required insulin dosage at study end was significantly less in Groups B and C than in Group A. Both continuous glucose monitoring data and the patients' self-monitoring data indicated that blood glucose variability parameters were significantly improved in Groups B and C in comparison with Group A, but there were no significant differences between Groups B and C. The incidence of hypoglycemia was low in all three groups.

Conclusions:

The absence of a significant difference in glucose variability between Groups B and C suggests that the addition of acarbose permitted adjustment of the insulin administration time from 30 min before meals to immediately before meals—which may be more convenient for patients—without affecting glycemic control.

Introduction

T he incidence of type 2 diabetes mellitus is increasing rapidly worldwide, and China is no exception. A recent epidemiological survey has shown that the current prevalence of diabetes in China is 9.7%¹; the prevalence increases with age, and in elderly people over 60 years of age it is now 25% or more.² Controlling the occurrence and development of diabetes is therefore a demanding task facing healthcare providers. In treating type 2 diabetes, insulin therapy has an important role in achieving glycemic control, especially in elderly patients, due to the longer disease history, poor islet function, and organ dysfunction in this age group. Isophane protamine biosynthetic human insulin 70/30 is a commonly used insulin in clinical practice and is routinely administered 30 min before meals. However, problems in its use are often seen in clinical practice, including unsatisfactory glycemic control in some patients, frequent occurrences of hypoglycemia before the next meal, and blood glucose variability. In addition, a significant proportion of patients experience difficulties in adhering strictly to subcutaneous administration 30 min before meals. In this regard, a survey of injection-meal intervals has shown that 75% of patients begin a meal less than half an hour after insulin administration, and some do so immediately after insulin administration.³ In view of the pharmacokinetic characteristics of insulin, this type of administration would be expected to influence both the efficacy and safety of treatment in lowering blood glucose.

A common difficulty encountered in clinical practice is how to achieve more stable glycemic control in elderly patients with type 2 diabetes who use isophane protamine biosynthetic human insulin 70/30 and how to improve their medication compliance. Acarbose, an α-glucosidase inhibitor, has a unique mechanism of action in the treatment of diabetes. Carbohydrates in food are decomposed into oligosaccharides (glucose, fructose) under the action of α-amylase in saliva and pancreatic enzymes and then further decomposed into monosaccharides by α-glucosidase at the brush border of small intestinal mucosal cells, which are then absorbed into the circulation via upper small intestinal epithelial cells. The chemical structure of acarbose is similar to that of oligosaccharides, but its α-glucosidase binding capacity is 10⁴–10⁵ times greater than that of oligosaccharides, and it therefore competitively inhibits the decomposition of oligosaccharides and delays that of disaccharides, oligosaccharides, and polysaccharides into glucose. Additionally, α-glucosidase inhibitors can retard the decomposition of food in the upper small intestine. As the diet of elderly diabetes patients in China contains a relatively high proportion of carbohydrates, acarbose can provide a useful antihyperglycemic effect, and it is now widely used in elderly diabetes patients in China. By delaying the absorption of carbohydrates, acarbose can reduce preprandial hyperglycemia and delay the emergence of postprandial hyperglycemia, thereby reducing the “peaks and troughs” in blood glucose. Studies have shown that twice daily subcutaneous administration of isophane protamine biosynthetic human insulin 30 min before meals together with the α-glucosidase inhibitor acarbose can decrease the required insulin dosage, reduce the incidence of hypoglycemia, provide better postprandial glycemic control, and reduce blood glucose variability.⁴ Theoretically, by delaying the peak postprandial blood glucose (PBG) level, acarbose may offset differences in the effect of insulin caused by its injection immediately before a meal before rather than 30 min before a meal.

The present study was designed to verify this assumption by evaluating the efficacy and safety of premixed insulin twice daily combined with acarbose in the treatment of elderly type 2 diabetes patients, specifically focusing on whether the addition of acarbose can reduce blood glucose variability and shorten the desirable time interval between insulin injections and meals.

Patients and Methods

Study design

Sixty elderly patients with type 2 diabetes were enrolled in a randomized, open-label study. Inclusion criteria were as follows: type 2 diabetes mellitus diagnosed in accordance with the 1999 World Health Organization criteria⁵ more than 6 months previously, age ≥60 years; glycemic control not satisfactory despite the use of insulin for more than 3 months (i.e., fasting blood glucose [FBG] ≥7 mmol/L and/or 2-h PBG ≥10 mmol/L and/or glycosylated hemoglobin [HbA1c] ≥6.5%). Exclusion criteria were patients with known cancers, known allergies to insulin or acarbose, serious systemic disease, acute diabetes complications within the last 6 months, poor medication compliance, and an assessment by the researchers as not suitable to participate. The study was approved by the Research Ethics Committee of the PLA General Hospital, Beijing, China.

Study procedures

Eligible patients were hospitalized for treatment for about 2 weeks, during which they were randomly assigned to one of three groups: Group A received isophane protamine biosynthetic human insulin 70/30 (Novo Nordisk, Bagsvaerd, Denmark) injected subcutaneously 30 min before breakfast and dinner plus acarbose (Glucobay™; Bayer HealthCare, Leverkusen, Germany) 50 mg once daily at noon for 16 weeks; Group B received isophane protamine biosynthetic human insulin 70/30 (Novo Nordisk) injected subcutaneously 30 min before breakfast and dinner plus acarbose (Glucobay) 50 mg three times daily for 16 weeks; and Group C received isophane protamine biosynthetic human insulin 70/30 (Novo Nordisk) injected subcutaneously immediately before breakfast and dinner plus acarbose (Glucobay) 50 mg three times daily for 16 weeks. Patients were instructed to chew the acarbose tablets at the beginning of meals. Height, weight, blood pressure, FBG, 2-h PBG, and HbA1c were measured at baseline in all patients. Education on diabetes was provided for all subjects, including guidance on diet and exercise, the correct insulin injection site and method, the blood glucose self-monitoring method, and the recognition and management of hypoglycemia.

Treatment and follow-up were divided into three stages: Stage 1 (adjusted treatment phase) involved monitoring of blood glucose four to eight times per day (pre-breakfast, pre-lunch, pre-dinner, 2 h post-breakfast, post-lunch, and post-dinner, at bedtime, and at 2 a.m.) to enable adjustment of the insulin dosage to achieve glycemic control with an FBG of <7 mmol/L and PBG of <10 mmol/L and recording of the time to achieve glycemic control, the daily insulin dosage, and the incidence of hypoglycemic events. Stage 2 (continuous blood glucose monitoring) involved continuous monitoring via a continuous glucose monitoring system (CGMS) (model 22342-1A6 continuous blood glucose monitor; Medtronic Inc., Northridge, CA) that was performed 3 days after stable glycemic control was achieved, and the insulin dosage was maintained or adjusted according to the monitoring results. Stage 3 (follow-up stage) involved continued treatment for 12 weeks with monitoring of liver and renal function, HbA1c, FBG, PBG, fasting and 2-h postprandial C-peptide levels, and the albumin/creatinine ratio at 2 weeks, 4 weeks, and 12 weeks.

During follow-up, self-monitoring of blood glucose at home was carried out by patients (using the Ascensia^® BRIO^® blood glucose monitoring meter [Bayer HealthCare]) on 2 days per week at seven times (pre-breakfast, pre-lunch, pre-dinner, 2 h post-breakfast, post-lunch, and post-dinner, and at bedtime). Patients were instructed to record in a diary their insulin dosages, measured blood glucose concentrations, information on diet and exercise levels, any discomfort experienced, and if there were any hypoglycemic symptoms. Telephone follow-ups were done once a week, and the treatment regimen was adjusted by clinicians according to the blood glucose levels recorded.

Efficacy assessment

To compare the improvement of FBG, PBG, HbA1c, and other parameters before and after treatment in each group, to compare differences in the times to achieve glycemic control, insulin dosages at glycemic goal, and blood glucose and HbA1c levels post-treatment among the groups, and to evaluate the stability and variability of glycemic control by CGMS, the following parameters were assessed:

• Between-day glycemic variability: (a) mean of daily differences (MODD)^6,7 and (b) coefficient of variation (CV) of FBG.

• Within-day glycemic excursions: (a) number of glycemic excursion, (b) mean amplitude of glycemic excursions (MAGE),^8,9 (c) area under the curve (AUC) for effective excursions, calculated as the sum ([hyperglycemia blood glucose value − baseline value]×5 min)÷24 h, where the baseline value was the mean plus SD, (d) the proportion of the time hyperglycemia was present, (e) the largest amplitude of glycemic excursion, and (f) the M-value, calculated as defined previously.^10,11 Statistical conversion was performed for each blood glucose level versus the amplitude of the glycemic excursion from the target blood glucose level, and the mean value was then obtained.

• Postprandial glucose variability: (a) postprandial glucose spike, (b) time to postprandial glucose spike (Δt), (c) postprandial glucose excursion,¹² (d) effective glucose excursion time, defined as the duration of PBG fluctuations above the mean plus SD blood glucose value, and (e) AUC for postprandial glucose above preprandial glucose, calculated as sum ([postprandial hyperglycemia blood glucose value−baseline value]×5 min)÷24 h, where the baseline value was the average blood glucose level half an hour pre-meal, and postprandial hyperglycemia was defined as blood glucose values above the preprandial level measured from after a meal to the next meal (or at bedtime), which reflects post-meal blood glucose variability.

• Hypoglycemia (blood glucose values less than 3.9 mmol/L): (a) Low Blood Glucose Index (LBGI),^13
–15 calculated from nocturnal blood glucose values to assess the risk of hypoglycemia, (b) number of nocturnal hypoglycemia events, (c) duration of nocturnal hypoglycemia, (d) AUC for hypoglycemia, calculated as sum ([hypoglycemia blood glucose value−3.9]×5 min)÷24 h, and (e) the proportion of the time hypoglycemia was present.

• Self-monitoring of blood glucose (to compare glycemic control at each time point among the groups): (a) CV of overall blood glucose, (b) CV of FBG, and (c) average daily risk range (ADRR).¹⁶

Safety assessment

Safety was assessed by determining the incidence of hypoglycemia in the three groups and monitoring patients for the occurrence of other adverse events.

Statistical analysis

All measured parameters were determined as mean±SD values. The normality of the data was tested by SPSS version 10.0 software (SPSS, Inc., Chicago, IL). For each parameter, differences before and after treatment were analyzed using paired t tests (for normally distributed variables) or the Wilcoxon rank sum test (for non-normally distributed variables) and compared among the three groups using analysis of variance (for normally distributed variables) or the Kruskal–Wallis H test (for non-normally distributed variables). Two independent samples t tests were used to compare each parameter between any two of the patient groups. Statistical analyses were performed using SPSS version 10.0 software.

Results

Baseline characteristics

Twenty patients were randomized to each of the three treatment groups. Their demographic characteristics and the duration of the disease course at baseline are shown in Table 1. The three groups showed good comparability at baseline, with no significant differences among them. No patients were withdrawn from the study.

Table 1.

Baseline Characteristics of the Patients

Parameter	Group A (n=20)	Group B (n=20)	Group C (n=20)	P value ^a
Age (years)	71.00±8.02	73.15±9.97	70.07±6.83	0.12
Gender (M/F)	12/8	12/8	12/8
Disease course (years)	20.90±8.41	21.30±8.59	19.95±5.47	0.13
BMI (kg/m²)	24.92±2.15	25.04±2.85	24.78±3.47	0.96

Data are mean±SD values, except for gender.

There were no statistically significant differences among the groups.

BMI, body mass index; F, female; M, male.

Overall glycemic control

At the end of the study, FBG, PBG, and HbA1c levels in the three groups were all significantly reduced compared with baseline, but there were no significant differences in the changes of these parameters among the groups (P=0.99, P=0.57, and P=0.97, respectively). There were no significant differences in the changes of body weight among the groups (P=0.53). However, there was a significant difference in insulin dosages among the groups (P=0.0027), with Groups B and C requiring a significantly smaller increase from baseline compared with Group A (P<0.05 and P<0.01, respectively). There was no significant difference between Groups B and C for the change in insulin dosage (Table 2).

Table 2.

Glycemic Control Parameters and Insulin Dosages

	Group A (n=20)			Group B (n=20)			Group C (n=20)
Parameter	Baseline	End point	Difference	Baseline	End point	Difference	Baseline	End point	Difference
FBG (mmol/L)	7.58±2.29	6.89±2.25	0.41±2.64	7.64±2.36	6.79±1.55	0.92±1.46	7.61±1.61	7.22±1.71	0.43±1.46
PBG (mmol/L)	11.7±3.16	10.1±2.26	1.56±3.45	11.5±2.86	8.90±2.27	1.46±2.68	10.61±3.11	9.75±2.31	0.7 8±3.32
HbA1c (%)	7.31±1.51	6.79±0.93	0.42±0.83	7.24±1.13	6.73±0.84	0.45±0.61	7.16±0.76	6.67±0.59	0.49±0.75
Insulin dosage (units)	31.4±10.36	37.7±13.89	22±25%	36.7±11.49	40.8±11.50	8±10%^a	36.7±9.30	38.7±7.91	7±14%^b
Body weight (kg)	67.2±7.19	67.0±7.37	0.18±1.2	69.0±9.73	69.4±10.2	0.43±0.96	66.8±9.93	66.6±9.79	0.19±1.72

Data are mean±SD values, except for gender.

P<0.05, ^b P<0.01 compared with Group A.

FBG, fasting blood glucose; HbA1c, glycosylated hemoglobin; PBG, 2-h postprandial blood glucose.

CGMS data analysis

Overall glycemic control

The time to achieve glycemic control, overall mean blood glucose level, and peak blood glucose level were not significantly different in the three groups (P>0.05) (Table 3).

Table 3.

Overall Glycemic Control in the Three Treatment Groups (Continuous Glucose Monitoring System Data)

Parameter	Group A (n=20)	Group B (n=20)	Group C (n=20)	P value
Time to glycemic control (days)	14.20±8.72	11.65±7.95	12.70±6.69	0.58
Mean blood glucose (mmol/L)	7.84±1.01	7.61±1.18	7.26±1.17	0.32
Peak blood glucose (mmol/L)	14.81±2.79	13.7±2.96	14.1±2.95	0.71

Data are mean±SD values.

Between-day glycemic variability

The MODD and CV of FBG were both significantly lower in Groups B and C compared with Group A (P=0.032 and P<0.001, respectively) (Table 4). However, there were no significant differences in these parameters between Groups B and C.

Table 4.

Glycemic Variability, Glucose Excursions, and Hypoglycemic Events in the Three Treatment Groups

Parameter	Group A (n=20)	Group B (n=20)	Group C (n=20)	P value ^a	P values for AB, AC, and BC group comparisons ^b
CGMS data
Between-day glycemic variability
MODD (mmol/L)	2.16±0.88	1.67±0.52^*	1.66±0.54^*	0.032	0.04/0.03/0.98
CV-FBG (mmol/L)	5.07±2.26	2.85±1.53^**	3.02±1.45^**	<0.001	<0.001/<0.001/0.63
Within-day glucose excursions
MAGE (mmol/L)	6.28±1.93	5.45±1.25^*	5.33±1.91^*	0.005	0.04/0.04/0.82
NGE (time/day)	4.63±1.01	4.00±1.00	4.00±1.25	0.25	0.06/0.09/0.99
AUC-SD	13.34±5.05	11.00±3.88^*	10.79±5.26^*	0.01	0.03/0.04/0.86
LAGE (mmol/L)	8.39±2.68	8.31±2.14	8.28±2.93	0.79	0.89/0.75/0.78
Hyperglycemia time (%)	21.3	15.0^**	12.5^**	<0.001	<0.001/<0.001/0.88
M-values (mmol/L)	5.60±3.73	4.10±2.05^*	3.99±2.81^*	0.04	0.04/0.04/0.85
Postprandial glucose excursions
PGS breakfast (mmol/L)	11.43±2.45	10.27±1.50^*	10.07±2.46^*	0.02	0.04/0.02/0.72
PGS dinner (mmol/L)	11.22±2.59	10.49±2.30^*	10.00±1.98^*	0.04	0.03/0.02/0.33
Δt breakfast (min)	125.53±37.97	144.58±32.43^*	157.56±55.37^**	0.006	0.04/0.004/0.3
Δt dinner (min)	103.55±37.70	130.63±44.31^*	147.31±49.06^**	<0.001	0.01/<0.001/0.18
PPGE breakfast (mmol/L)	5.85±2.41	4.79±2.26^*	4.79±2.60^*	0.019	0.04/0.03/0.93
PPGE dinner (mmol/L)	4.66±2.93	3.23±1.65^*	3.62±1.39^*	0.02	0.02/0.049/0.28
T-SD morning (min)	75.66±47.48	41.97±45.72^**	42.50±44.55^**	0.002	0.003/0.003/0.96
T-SD evening (min)	92.39±63.50	56.77±52.50^*	44.44±49.80^**	0.001	0.012/0.006/0.32
AUC-prebreakfast	27.70±15.95	18.73±8.66^**	16.69±7.88^**	<0.001	0.005/0.004/0.31
AUC-predinner	24.51±21.80	11.62±7.60^**	12.82±5.23^**	<0.001	0.002/<0.001/0.20
Hypoglycemia
AUC-low	2.50±5.57	2.02±4.46	2.19±3.74	0.56	0.78/0.84/0.91
Hypoglycemia time (%)	5.0	1.6^**	3.9^**	<0.001	<0.001/<0.001/0.17
Number of nocturnal events	0.55±0.89	0.34±0.67	0.36±0.67	0.78	0.19/0.24/0.88
Duration of nocturnal hypoglycemia (min)	36.28±89.06	24.79±30.82	23.40±48.29	0.43	0.12/0.38/0.31
Nocturnal LBGI (mmol/L)	1.85±3.70	1.34±1.99	1.64±2.49	0.65	0.41/0.74/0.52
Self-monitoring data
Overall blood glucose level
Mean (mmol/L)	7.99±2.10^††	8.05±2.33^††	7.23±2.18	<0.001	0.29/<0.001/<0.001
Blood glucose variability
CV total	25±4.21	26±4.13	28±6.02	0.65	0.33/0.54/0.76
CV-FBG	13.38±3.79	11.35±2.61	9.92±2.81^**	0.04	0.09/0.007/0.16
ADRR	12.34±4.20	9.72±2.59^*	9.72±2.22^*	0.03	0.047/0.04/0.99

Data are mean±SD values.

For comparisons of Groups B and C with Group A.

For comparisons of Group A with Group B, Group A with Group C, and Group B with Group C, respectively.

P<0.05, ^** P<0.01 compared with Group A.

††

P<0.01 compared with Group C.

Δt, time to postprandial glucose spike; ADRR, average daily risk range; AUC-preprandial (pre-breakfast/pre-dinner), area under the curve for postprandial glucose above preprandial glucose; AUC-low, area under the curve for hypoglycemia; AUC-SD, area under the curve for effective excursions; CGMS, continuous glucose monitoring system; CV-FBG, coefficient of variation of fasting blood glucose; CV total, total coefficient of variation of overall blood glucose; LAGE, largest amplitude of glycemic excursions; LBGI, Low Blood Glucose Index; MAGE, mean amplitude of glycemic excursions; MODD, mean of daily differences; NGE, number of glycemic excursions; PGS, postprandial glucose spike; PPGE, postprandial glucose excursion; T-SD, effective glucose excursion time.

Within-day glycemic excursions

The MAGE, AUC for effective excursions, proportion of the time hyperglycemia was present, and the M-value were all significantly lower in Groups B and C compared with Group A (Table 4), but there were no significant differences in the number of glycemic excursions or the largest amplitude of glycemic excursion between the groups (P>0.05). No significant differences between Groups B and C were observed for any of these parameters (Table 4).

Postprandial glucose excursions

Morning and evening postprandial glucose spikes, morning and evening postprandial glucose excursions, morning and evening effective glucose excursion times, and AUC for morning and evening postprandial glucose above preprandial glucose values were significantly lower and the times to morning and evening postprandial glucose spikes (Δt) were significantly higher in Groups B and C compared with Group A (Table 4). However, there were no significant differences in any of these parameters between Groups B and C.

Hypoglycemia

The proportion of the time hypoglycemia was present was significantly lower in Groups B and C compared with Group A (P<0.001), but there were no significant differences in the AUC for hypoglycemia, the number, maximum amplitude, and duration of nocturnal hypoglycemia events, and the nocturnal LBGI among the three groups (P>0.05) (Table 4). No significant differences in any of these parameters were observed between Groups B and C.

Self-monitoring data

Overall blood glucose level

Three months of self-monitoring records showed that the overall mean blood glucose level was significantly lower in Group C compared with Groups A and B (P<0.01) (Table 4), but there was no significant difference between Groups A and B (P>0.05).

Blood glucose variability

Although the CV of overall blood glucose (CV total) was not significantly different in the three groups, the CV of FBG was significantly lower in Group C compared with Group A, and the ADRR was significantly lower in both Groups B and C compared with Group A (Table 4). No significant differences between Groups B and C were observed for these three parameters (Table 4).

Adverse events

Liver and renal function tests showed no changes from baseline to the end of treatment. The most common adverse events recorded in the three groups were abdominal distension and increased exhaustion (Table 5). No severe hypoglycemic events occurred during follow-up.

Table 5.

Adverse Events (Numbers of Events)

Event	Group A (n=20)	Group B (n=20)	Group C (n=20)
Abdominal distension	6	9	5
Increased exhaustion	5	10	7
Constipation	0	1	1
Diarrhea	0	1	0
Bitter taste in mouth	1	2	1

Discussion

The combination of isophane protamine biosynthetic human insulin 70/30 administered subcutaneously twice daily 30 min before meals and acarbose is a standard treatment regimen for patients with type 2 diabetes, but whether the time interval between insulin administration and meals can be shortened without affecting glycemic control is not clear. In this study, two groups of patients received isophane protamine biosynthetic human insulin 70/30 twice daily 30 min before meals together with acarbose 50 mg once daily (Group A) or three times daily (Group B) before meals, whereas a third group received isophane protamine biosynthetic human insulin 70/30 twice daily immediately before meals together with acarbose 50 mg three times daily before meals (Group C).

The findings of the study indicated that mean fasting plasma glucose, postprandial plasma glucose, and HbA1c levels were all significantly decreased after 12 weeks of treatment with insulin and acarbose compared with baseline, but there were no significant differences among the groups in the magnitude of the decreases, suggesting that the three treatment regimens had comparable antihyperglycemic effects. However, the increases in the required insulin dosage in Groups B and C were significantly less than those in Group A, indicating that the addition of acarbose 50 mg three times daily in elderly type 2 diabetes patients reduces insulin requirements to a greater extent than acarbose 50 mg once daily.

Decreases in blood glucose and HbA1c levels alone do not fully reflect the clinical benefit of treatment. In recent years, the impact of blood glucose variability, especially PBG variability, on chronic vascular complications of diabetes has been increasingly recognized. Kilpatrick et al.¹⁷ have shown that the amplitude of blood glucose excursions is an independent risk factor for diabetic retinopathy; PBG variability can lead to endothelial cell dysfunction, fibrinolytic system dysfunction, and increased oxidative stress products and is also an important predictor of cardiovascular disease in diabetes patients. Assessment of blood glucose variability is therefore important, and to do this, continuous glucose monitoring is necessary as it provides more usable data than conventional monitoring.

Many studies have confirmed the advantages of premixed insulin combined with acarbose in the treatment of diabetes. For example, Kelley et al.,⁴ who assessed the efficacy and safety of adding acarbose 50 mg three times daily to 145 type 2 diabetes patients inadequately controlled with insulin and diet, showed that the average HbA1c reduction was 0.69% and that the average insulin dosage reduction was 15–20%. A study of type 1 diabetes subjects indicated that combined insulin and acarbose therapy can reduce both hypoglycemic episodes before the next meal and blood glucose variability.¹⁸ Other studies have reported the successful treatment of postprandial reactive hypoglycemia in an oldest-old (>80 years of age) patient with low-dose acarbose¹⁹ and decreased glycemic variability and hypoglycemic events in patients with type 2 diabetes treated with combined premixed insulin twice daily and acarbose therapy.²⁰

In our study, CGMS data showed that either for day-to-day glucose variability (MODD, CV of FBG), within-day blood glucose variability (MAGE, AUC for effective excursions, the M-value, proportion of time hyperglycemia was present), or PBG fluctuation, Groups B and C showed superior results to Group A, but there were no significant differences in any of these parameters between Groups B and C. This suggests that the addition of acarbose three times daily to twice daily premixed insulin therapy in elderly patients with type 2 diabetes can reduce blood glucose variability compared with the addition of acarbose once daily and, importantly, that adjustment of the insulin administration time from 30 min before meals to immediately before meals had no influence on blood glucose variability when acarbose 50 mg three times daily was added to the insulin regimen. Monitoring via CGMS suggested that the incidence of hypoglycemia was low in all three treatment groups, and there were no significant differences in the number, duration, and amplitude of nocturnal hypoglycemia events and the LBGI, although the proportion of the time hypoglycemia was present was significantly lower in Groups B and C than in Group A. However, there was no significant difference between Groups B and C for the proportion of the time hypoglycemia was present, suggesting that the insulin injection time adjustment did not increase the risk of hypoglycemia.

To achieve optimum control of type 2 diabetes, self-monitoring of blood glucose levels by patients is important to assess both blood glucose control and compliance with treatment. In the present study in which patients were followed up for 3 months, self-monitoring data indicated that the average blood glucose level in Group C was significantly lower than that in Groups A and B, and this may have reflected better patient compliance with treatment, particularly as an end-of-study questionnaire indicated that the patients in this group found that adjustment of the insulin injection time to immediately before meals was more convenient. It should be noted that ADRR is an parameter that reflects self-monitoring of blood glucose variability, and studies have shown that ADRR predicts the likelihood of both hyperglycemia and hypoglycemia.¹⁶ The fact that ADRR in Groups B and C in our study was significantly lower than in Group A further confirms the benefit of adding acarbose three times daily to premixed insulin therapy in reducing blood glucose variability.

In terms of safety, only a few patients experienced mild hypoglycemic reactions, which were relieved by eating food. The most commonly encountered adverse effects of acarbose were abdominal distension and increased exhaustion, the incidence of which was similar in the three groups. Most patients were able to tolerate these adverse effects.

Conclusions

In elderly patients with type 2 diabetes treated with twice daily injections of isophane protamine biosynthetic human insulin 70/30, the addition of acarbose 50 mg three times daily improved glycemic variability, reduced the required insulin dosage, and shortened the duration of hyperglycemia and hypoglycemia compared with acarbose 50 mg once daily. Among patients who received acarbose three times daily in addition to twice-daily isophane protamine biosynthetic human insulin 70/30, a change of the insulin injection time to immediately before meals was equally effective and safe as injection 30 min before a meal. Such a change in the insulin administration time is more convenient for patients, which may improve their compliance with treatment and hence the likelihood of long-term glycemic control.

Footnotes

Acknowledgments

This study was supported by Bayer HealthCare, which provided foundational assistance.

Author Disclosure Statement

None of the authors has any conflict of interest to declare for the collection, analysis, and interpretation of data or for the writing of the report and the decision to submit for publication.

References

Yang

, Lu

, Weng

, Jia

, Ji

, Xiao

, Shan

, Liu

, Tian

, Ji

, Zhu

, Ge

, Lin

, Chen

, Guo

, Zhao

, Li

, Zhou

, Shan

, He

. China National Diabetes and Metabolic Disorders Study Group: Prevalence of diabetes among men and women in China. N Engl J Med, 2010; 362:1090–1101.

Pan

, Tian

, Xu

, Lu

. Prevalence and incidence of diabetes in the elderly in Beijing Army [in Chinese] Chin J Geriatr, 2003; 6:364–367.

Overmann

, Heinemann

. Injection-meal interval: recommendations of diabetologists and how patients handle it. Diabetes Res Clin Pract, 1999; 43:137–142.

Kelley

, Bidot

, Freedman

, Haag

, Podlecki

, Rendell

, Schimel

, Weiss

, Taylor

, Krol

, Magner

. Efficacy and safety of acarbose in insulin-treated patients with type 2 diabetes. Diabetes Care, 1998; 21:2056–2061.

Gabir

, Hanson

, Dabelea

, Imperatore

, Roumain

, Bennett

, Knowler

. The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care, 2000; 23:1108–1112.

Molnar

, Taylor

, Ho

. Day-to-day variation of continuously monitored glycaemia: a further measure of diabetic instability. Diabetologia, 1972; 8:342–348.

Muggeo

, Zoppini

, Bonora

, Brun

, Bonadonna

, Moghetti

, Verlato

. Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care, 2000; 23:45–50.

Abe

, Inoue

, Yamada

, Irie

, Nojima

, Tsuyusaki

, Usui

, Atsuda

, Yamanouchi

. Two-way crossover comparison of insulin glargine and insulin detemir in basal-bolus therapy using continuous glucose monitoring. Diabetes Metab Syndr Obes, 2011; 4:283–288.

Rodbard

. Interpretation of continuous glucose monitoring data: glycemic variability, quality of glycemic control. Diabetes Technol Ther, 2009; 11,Suppl 1:S-55–S-67.

10.

Schlichtkrull

, Munck

, Jersild

. The M-value, an index of glycemic control in diabetics. Acta Med Scand, 1965; 177:95–102.

11.

Takita

, Matsumoto

, Noguchi

, Shimoda

, Chujo

, Itoh

, Sugimoto

, Sorelle

, Onaca

, Naziruddin

, Levy

. Cluster analysis of self-monitoring blood glucose assessments in clinical islet cell transplantation for type 1 diabetes. Diabetes Care, 2011; 34:1799–1803.

12.

Kohnert

, Augstein

, Zander

, Heinke

, Peterson

, Freyse

, Hovorka

, Salzsieder

. Glycemic variability correlates strongly with postprandial beta-cell dysfunction in a segment of type 2 diabetic patients using oral hypoglycemic agents. Diabetes Care, 2009; 32:1058–1062.

13.

Kovatchev

, Cox

, Gonder-Frederick

, Clarke

. Symmetrization of the blood glucose measurement scale and its applications. Diabetes Care, 1997; 20:1655–1658.

14.

Kovatchev

, Cox

, Gonder-Frederick

, Young-Hyman

, Schlundt

, Clarke

. Assessment of risk for severe hypoglycemia among adults with IDDM: validation of the Low Blood Glucose Index. Diabetes Care, 1998; 21:1870–1875.

15.

Cox

, Gonder-Frederick

. Progressive hypoglycemia's impact on driving simulation performance. Occurrence, awareness and correction. Diabetes Care, 2000; 23:163–170.

16.

Kovatchev

, Otto

, Cox

, Gonder-Frederick

, Clarke

. Evaluation of a new measure of blood glucose variability in diabetes. Diabetes Care, 2006; 29:2433–2438.

17.

Kilpatrick

, Rigby

, Atkin

. Effect of glucose variability on the long-term risk of microvascular complications in type 1 diabetes. Diabetes Care, 2009; 32:1901–1903.

18.

Garg

. Noninsulin pharmacological management of type 1 diabetes mellitus. Indian J Endocrinol Metab, 2011; 15,Suppl 1:S5–S11.

19.

Tamura

, Araki

, Chiba

, Horiuchi

, Mori

, Hosoi

. Postprandial reactive hypoglycemia in an oldest-old patient effectively treated with low-dose acarbose. Endocr J, 2006; 53:767–771.

20.

, Wang

, Chen

, Jin

. Glycemic variability in insulin treated type 2 diabetes with well-controlled hemoglobin A1c and its response to further treatment with acarbose. Chin Med J (Engl), 2011; 124:144–147.