Abstract
Aims/Introduction: To evaluate glucose excursions and hypoglycemia frequency in patients with type 2 diabetes treated with the combination drug mitiglinide/voglibose versus glimepiride as add-on therapy to dipeptidyl peptidase-4 inhibitor.
Materials and Methods: This is a randomized cross-over trial involving 20 patients with type 2 diabetes. After receiving vildagliptin 100 mg, patients were randomized to have add-on therapy as either the fixed-dose combination drug mitiglinide/voglibose 10 mg/0.2 mg three times daily for a few days followed by glimepiride 1 mg once daily for several subsequent days, or vice versa. Glycemic excursions and the frequency of hypoglycemia were measured using 24-hour continuous glucose monitoring. Metabolic profile changes were evaluated using a meal tolerance test.
Results: The mean glucose levels in the mitiglinide/voglibose and glimepiride groups were almost identical (7.9 vs. 8.1 mmol/L, respectively). However, the mitiglinide/voglibose group exhibited a significantly lower standard deviation of glucose (1.2 vs 2.0 mmol/L; P<0.001), mean amplitude of glycemic excursions (3.4 vs 5.2 mmol/L; P<0.001), M-value (24.6 vs 70.0; P<0.001), continuous overlapping net glycemic action-1 value (22.6 vs 31.0; P<0.001), and area under the curve >10 mmol/L (0.1 vs 0.5 mmol/L*hr; P<0.001) than the glimepiride group. Hypoglycemia (glucose level <3.8 mmol/L) was not observed with mitiglinide/voglibose, whereas it was observed 0.35 times per day with glimepiride. The meal tolerance test demonstrated higher pre-meal and lower post-meal glucose levels in the mitiglinide/voglibose group.
Conclusions: Adding the combination drug mitiglinide/voglibose to vildagliptin therapy results in more efficient postprandial glucose control and fewer hypoglycemia than adding glimepiride.
Clinical trial registry: University hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000024817.
Keywords: Continuous glucose monitoring, Glucose variability, Oral antidiabetic agents
Main text
Introduction
Chronic uncontrolled hyperglycemia is related to diabetes complications1. Cardiovascular complications are associated with postprandial glucose excursions and hypoglycemia, in addition to high glycated hemoglobin (HbA1c) levels. Clinical studies such as the Diabetes Epidemiology Collaborate Analysis of Diabetic Criteria in Europe (DECODE) study2 and Funagata study3 have found that postprandial or postload hyperglycemia is associated with the development of cardiovascular disease. In addition, many large cohort studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD)4 and the Action in Diabetes and Vascular Disease (ADVANCE)5 studies, have shown that hypoglycemia also poses a risk of cardiovascular disease and mortality. Therefore, the approach to control glycaemia should aim to reduce glycemic excursions by lowering postprandial glucose levels while avoiding hypoglycemia.
Many current reports and guidelines place great significance on HbA1c levels, but HbA1c does not always reflect exact glycemic excursions. Recently, several methods or markers have been developed to assess the glycemic excursions; these are based on continuous glucose monitoring (CGM), and have been applied clinically6. In addition, detection of hypoglycemia in clinical trials, generally assessed by casually measured blood glucose levels or based on patient’s symptoms, is often suboptimal, particularly if hypoglycemic events are asymptomatic. CGM may contribute to convenient and accurate recording of glycemic trends and to improvements in detection of hypoglycemia in clinical trials.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in clinical practice. They stimulate insulin secretion in a glucose-dependent manner; hence, DPP-4 inhibitor monotherapy rarely causes hypoglycemia. However, DPP-4 inhibitor monotherapy is often associated with inadequate glucose control, and additional medications such as insulin or other oral antidiabetic drugs are required. Adding sulfonylureas to DPP-4 inhibitor therapy is a choice in terms of cost effectiveness and simplicity; however, it may increase the risk of hypoglycemia. Among the oral antidiabetic drugs, glinides, α-glucosidase inhibitors (αGIs), and DPP-4 inhibitors mainly reduce postprandial glucose levels. Considering the actions of these drugs, combinations of glinides and αGI may be reasonable for patients with postprandial hyperglycemia. However, since glinides have insulinotropic actions similar to sulfonylureas, there is some concern about the possibility of hypoglycemia.
In Japan, a fixed-dose combination tablet consisting of mitiglinide 10 mg and voglibose 0.2 mg was approved for use in 2011. To our knowledge, no studies have compared the effects of mitiglinide/voglibose versus glimepiride on glucose variability and hypoglycemia using CGM. Therefore, in this study, we evaluated glucose excursions and the frequency of hypoglycemic episodes in patients using mitiglinide/voglibose compared with those using glimepiride when these drugs were used as add-on therapy to DPP-4 inhibitor therapy.
Materials and Methods
Patients
This open-label, single-center, randomized cross-over trial was conducted between April 2013 and May 2014. We recruited adult patients (aged over 20 years) with type 2 diabetes who were taking DPP-4 inhibitors and were admitted to the general hospital for glycemic control. The target number of patients to investigate efficiently was defined as 20. Exclusion criteria were: patients with insulin dependent diabetes, defined by serum c-peptide level <0.5 ng/mL; known allergies to mitiglinide, voglibose, or glimepiride; hepatic dysfunction (serum aspartate aminotransferase or alanine aminotransferase levels more than two times the normal limit); renal dysfunction (creatinine clearance <40 mL/min); use of corticosteroids; existing pregnancy; alcoholism; a history of severe hypoglycemic episodes requiring other’s assistance; a history of diabetic ketoacidosis; diabetic retinopathy with a high risk of hemorrhage; and physician’s judgment that the patient was inappropriate for the study. The patients’ data were obtained from medical records. The protocol was approved by the ethics committee of the institute at which the study was conducted, in accordance with the principles of the Declaration of Helsinki. All study participants provided written informed consent at enrolment. This study was registered with UMIN Clinical Trials Registry (UMIN000024817).The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.
Study design
This study, designed as a prospective, randomized, cross-over trial, aimed to investigate glucose excursions and episodes of hypoglycemia in patients with type 2 diabetes treated with mitiglinide/voglibose or glimepiride. Individuals who met the criteria for inclusion and who provided written informed consent to participate in this study were randomly assigned to the “mitiglinide/voglibose first, glimepiride second” or the “glimepiride first, mitiglinide/voglibose second” arm by simple randomization with sequentially numbered papers. Random allocation was made by authors and concealed from everyone until interventions were assigned. The subjects were given a CGM system, iPro2 (Medtronic MiniMed, Inc., Northridge, CA, USA), to use throughout the study period. Patients were administered in advance with DPP-4 inhibitor vildagliptin (100 mg). Thereafter, they were randomized to have either the combination drug mitiglinide/voglibose 10 mg/0.2 mg (Kissei Pharma Co. Ltd., Matsumoto, Japan), dosed at one tablet three times daily before meals, or glimepiride (Sanofi, Gentilly, France), dosed at 1 mg in the morning, added to the treatment regimen. Other antidiabetic medicines used before the trial were discontinued, with the exception of metformin and pioglitazone.
First, treatment was continued for a few days. Thereafter, patients were switched to another medication for several subsequent days. Considering the possible effects of improved glucotoxicity in the latter period, a subgroup analysis of drug use order was performed. Correlation analysis of the standard deviation (SD) ratio at both periods (SD glimepiride : SD mitiglinide/voglibose) and clinical parameters (including age, BMI [body mass index], duration of diabetes, HOMA R [homeostasis model assessment ratio], HOMA β [homeostasis model assessment beta], estimated glomerular filtration rate [eGFR], and pre-medication) were performed to reveal the characteristics of patients who experienced lower glucose fluctuations with mitiglinide/voglibose therapy than with glimepiride therapy. The subjects were given a standard meal tolerance test (MTT) which contained about 500 kilocalories (60% carbohydrate, 20% protein, and 20% fat) in the fasting state on the last day of both periods. Metabolic profile changes during MTT in both periods were evaluated. The study strategy is illustrated in Figure 1.
Efficacy parameters
The primary efficacy points were glycemic excursions and the frequency of hypoglycemic episodes. These were evaluated using 24-h CGM on the last day of both periods. More than 2 days were provided between each CGM period to avoid possible carry over effects. The following efficacy measures were assessed: Glycemic variability, which included the SD of sensor glucose levels measured through CGM; the mean amplitude of glycemic excursions (MAGE); M-value; continuous overlapping net glycemic action-1 (CONGA-1) value; and area under the curve (AUC) >10 mmol/L. The MAGE is obtained by calculating the arithmetic mean of the differences between consecutive peaks and nadirs, only including changes greater than one SD; this method has been widely used to assess glycemic fluctuation and variability7. The M-value is calculated for each glucose value using a formula; and is then divided by the total number of values to produce a mean8. CONGA-1 value represents the SD of differences between the current observation and the observation one hour earlier9. The mean glucose level was calculated as the average of 288 sensor values during the 24-h CGM period. Hypoglycemia frequency was defined as the number of times during the 24-h CGM period that the glucose level measured through CGM was <3.8 mmol/L. Metabolic profile changes during MTT were determined with plasma glucose levels, insulin levels, and glucagon levels measured by standard radioimmunoassay procedures at pre-meal and 120 min post-meal
Diet and exercise
The diet during the study was designed to provide a total daily calorie intake of 25–30 kcal/kg/day, with about 60% of calories coming from carbohydrates, 20% from proteins, and 20% from fats. The meals were served at 07:30 h (breakfast), 12:00 h (lunch), and 18:00 h (dinner). Each patient exercised equally during the study, according to their capability.
Statistical analysis
Normally distributed data are presented as the mean ± standard error (SE) except for baseline characteristics which are presented as the mean ± SD. The differences between the groups in the parameters evaluated were analyzed by two-tailed paired t-test or chi-square test, and associations were assessed using simple linear or logistic regression analysis. Statistical analyses were performed using SPSS version 20 (IBM Corp., Armonk, NY, USA). Statistical significance was declared for P < 0.05.
Results
A total of 20 patients were enrolled in this study and no one lost the trial. The baseline characteristics of the study population are shown in Table 1. About half of the patients were treated with sulfonylureas and/or DPP-4 inhibitors before this trial.
Glucose fluctuations in 24-h CGM are shown in Figure 2. The mean glucose levels of the mitiglinide/voglibose and glimepiride groups were very similar (7.9 ± 0.3 mmol/L vs 8.1 ± 0.3 mmol/L, respectively). However, the mitiglinide/voglibose group exhibited significantly lower postprandial glucose levels than the glimepiride group, with a lower SD of glucose (1.2 ± 0.1 mmol/L vs 2.0 ± 0.1 mmol/L, respectively; P < 0.001), MAGE (3.4 ± 0.2 mmol/L vs 5.2 ± 0.3 mmol/L, respectively; P < 0.001), M-value (24.6 ± 6.1 vs 70.0 ± 13.8, respectively; P < 0.001), CONGA-1 value (22.6 ± 1.7 vs 31.0 ± 2.0, respectively; P < 0.001), and AUC >10 mmol/L (0.1 ± 0.0 mmol/L*hr vs 0.5 ± 0.1 mmol/L*hr, respectively; P < 0.001) (Table 2). Furthermore, regardless of drug order, the mean glucose level was almost identical in the mitiglinide/voglibose and glimepiride groups (mitiglinide/voglibose first: 8.1 vs 8.0 mmol/L, respectively; glimepiride first: 7.7 vs 8.3 mmol/L, respectively). The SD of glucose was lower in the mitiglinide/voglibose group, irrespective of drug order (mitiglinide/voglibose first: 1.3 vs 2.2 mmol/L; P < 0.005, glimepiride first: 1.2 vs 1.9 mmol/L; P < 0.005). Hypoglycemia was not observed during treatment with mitiglinide/voglibose, but was observed 0.35 times per day with glimepiride treatment. We performed regression analysis with the SD ratio (SD glimepiride : SD mitiglinide/voglibose) as the dependent variable and clinical parameters as independent variables. The SD ratios were not related to age, BMI, duration of diabetes, HOMA R, HOMA β, eGFR, or pre-medication.
Analysis of the MTT results showed higher pre-meal glucose levels (7.5 ± 0.3 mmol/L vs 6.9 ± 0.3 mmol/L; P < 0.001) and lower post-meal glucose levels at 120 min (8.7 ± 0.3 mmol/L v. 12.0 ± 0.6 mmol/L; P < 0.001) in the mitiglinide/voglibose group than in the glimepiride group, respectively. Although pre-meal insulin level did not differ between the groups (mitiglinide/voglibose group: 50.7 ± 4.2 pmol/L and glimepiride group: 54.9 ± 4.2 pmol/L), post-meal insulin level at 120 min was significantly lower in the mitiglinide/voglibose group (258.4 ± 38.2 pmol/L) than in the glimepiride group (312.5 ± 34.0 pmol/L; P < 0.005). Similarly, while pre-meal glucagon levels were almost identical in both arms (mitiglinide/voglibose group: 86.7 ± 6.1 ng/L; glimepiride group: 89.9 ± 5.2 ng/L), post-meal glucagon level at 120-min was slightly higher in the mitiglinide/voglibose group (99.6 ± 4.7 ng/l vs. 85.1 ± 5.0 ng/l; P < 0.005) (Table 3).
Discussion
In this study we revealed that, in patients with type 2 diabetes, adding the combination drug of mitiglinide/voglibose to DPP-4 inhibitor therapy achieved less glucose excursions and fewer episodes of hypoglycemia than adding glimepiride. Although the mean glucose levels were almost identical in participants in the mitiglinide/voglibose and glimepiride groups, glucose variability was significantly less in those receiving mitiglinide/voglibose.
Sulfonylureas are known to increase hypoglycemic risk, especially in patients with renal failure. Prolonged hypoglycemia and consequent weight gain are the most frequent adverse effects of sulfonylureas, and are considered major issues. It is conceivable that the higher post-prandial glucose levels associated with glimepiride were due to delayed stimulation of insulin secretion, resulting in the inter-meal hypoglycemia and the diurnal glycemic fluctuations observed in this study. Glinides are insulin secretagogues with a similar mechanism of action to sulfonylureas. They bind to the sulfonylurea receptors of β-cells and close voltage-dependent potassium channels; this results in insulin secretion. Because of the rapid time to maximum drug concentration and short half-life of glinides, they provoke rapid insulin secretion to reduce the postprandial glucose spike and rarely cause prolonged insulin secretion. We used mitiglinide as the glinide in this study, which has been reported to be safe, even in patients with renal failure10.
In terms of postprandial effect, αGI reduces postprandial hyperglycemia and insulin secretion by delaying the digestion of complex carbohydrates in the small intestine. Thus, both glinides and αGIs may have synergistic effects for treating postprandial hyperglycemia and sparing additional insulin secretion11. This combination is certainly rational because it may address the clinical issue that impaired early insulin secretion is the main pathogenesis of patients with type 2 diabetes. It may be especially suitable for Asian populations because diabetes in Asian patients is characterized by severely attenuated insulin secretion compared with Caucasians12, and because the Asian diet includes carbohydrates-rich meals such as polished rice. Furthermore, treating postprandial hyperglycemia with an αGI does not stimulate excess insulin secretion; delayed absorption of glucose may prevent subsequent pre-meal hypoglycemia induced by glinides.
Importantly, this study showed that mitiglinide/voglibose therapy reduced glucose fluctuations more effectively than did glimepiride therapy, not only in the postprandial period but also during the whole course of the day. This was despite its use as add-on therapy to a DPP-4 inhibitor, whose effects of enhancing glucose-dependent insulin secretion and glucagon suppression over the whole day are established. A synergistic effect between αGIs and DPP-4 inhibitors may account for that underlying mechanism. Increased amounts of undigested food stimulate the lower small intestine and enhance postprandial glucagon-like peptide-1 (GLP-1) secretion in patients with type 2 diabetes13. These findings suggest that the combination of glinide and αGI therapy is potentially the preferred add-on incretin treatment to DPP-4 inhibitor therapy. However, in this study, postprandial (120 min) blood glucose levels were significantly lower in the mitiglinide/voglibose group than in the glimepiride group, with slightly higher glucagon levels and significantly lower levels of insulin. An animal study reported that mitiglinide elicits glucagon secretion from α-cells directly14. However, the relatively higher postprandial glucagon levels observed in mitiglinide/voglibose therapy might be secondarily caused by lower postprandial glucose and insulin levels, considering that postprandial glucose variations were smaller in mitiglinide/voglibose therapy than in glimepiride therapy.
Postprandial glucose fluctuations provoke more oxidative stress than sustained hyperglycemia15, decrease vasodilator response16, damage endothelial cells17, and are associated with cognitive decline18 in patients with type 2 diabetes. Clinically, it is reported that wide glucose fluctuations can predict better than HbA1c the risk of major adverse cardiac events in patients with acute myocardial infarction19, although large studies found no relation between glucose variability and cardiovascular events20, 21. In terms of hypoglycemia, a few studies have demonstrated that glycemic variability is greater in patients who experience hypoglycemia, in particular severe hypoglycemia22, 23. Hypoglycemia is known to be associated with cardiovascular-related death24 and dementia25, and prolonged hypoglycemia sometimes provokes sustained brain damage26. Our CGM data showed sporadic hypoglycemic episodes with glimepiride therapy, although the mean glucose levels were almost identical between both treatment arms, suggesting that evaluating the glucose control of patients using only a mean glucose or HbA1c level is inadequate. The concept of measuring glucose levels at various meaningful times, in addition to measuring HbA1c levels, should be evaluated. Although combination therapy with a DPP-4 inhibitor and mitiglinide/voglibose was associated with low glucose excursions and low hypoglycemic risk in this study, it is unknown whether this therapeutic approach can prevent cardiovascular events in patients with type 2 diabetes. The results of the Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial showed that glinides were not effective in decreasing either new onset diabetes or cardiovascular events in a population at high risk27, whereas αGI had the potential to prevent cardiovascular events28. Mitiglinide was reported to decrease oxidative stress and inflammation29 and to improve endothelial function30. Although further investigation is required, the combination drug mitiglinide/voglibose has the potential to prevent cardiovascular events.
The strengths of current study include that it is the first randomized study investigating the glucose excursions associated with mitiglinide/voglibose or glimepiride using CGM. In addition, we highlighted the risk of unnoticed hypoglycemic episodes associated with the use of sulfonylureas. However, this study also has several limitations. First, it was conducted in one hospital and the sample size was small. However, significant differences and benefits of mitiglinide/voglibose were observed despite the small study sample. Second, the observation period was short and no long-term evaluation of effectiveness was performed. Trials conducted over a longer period and with a larger number of subjects are needed to address this issue. Third, both mitiglinide and voglibose need to be taken immediately before each meal. This may lead to failure of accurate administration of the drugs and may negatively affect adherence to the drugs; this was not taken into account in this study. However, using a “combination” drug should offer advantages in terms of adherence. Motivating patients’ perceptions through education and encouragement may also be helpful in resolving this issue.
In conclusion, adding the combination drug mitiglinide/voglibose to vildagliptin resulted in more efficient postprandial glucose control and fewer hypoglycemic episodes than adding glimepiride. Improvements in postprandial hyperglycemia may be crucial for preventing cardiovascular events. The therapeutic option of mitiglinide/voglibose as add-on therapy to vildagliptin is considered suitable for achieving ideal and attentive glycemic control.
Acknowledgement
This research did not receive any specific grant from funding agencies. The authors thank the volunteer patients for their participation, and the nurses and laboratory technologist for their professional support for and during this study.
Disclosure
The authors declare no conflict of interests relevant to this study.