Open Journal Systems

ORIGINAL CONTRIBUTIONS

Received: June 26^th 2014

Accepted: July 15^th 2014

Efficacy and safety of inicitial treatment with glimpeiride versus sitagliptin in type 2 diabetes

Héctor Eloy Tamez-Pérez^a y el Grupo de Estudio SUMER

^aSubdireccion de Investigación, Facultad de Medicina, Hospital Universitario “Dr. José Eleuterio González”, Monterrey, Nuevo Leon, México.

Grupo de estudio SUMER

Aldrete Jorge, Alpizar Melchor, Anaya Celia, Barrientos Margarita, Beltrán Teresa, Benítez Nicolas, Bran Sergio, Cano Ruben, Cervantes Ma. Carmen, Chavarría Leticia, Córdova Carlos, Echeverri Jorge, Escalante Miguel, Garza Alejandro, Grover Fernando, Jimenez Marisela, Luna Rosa Isela, Mauricio Gilberto, Moreira Juan Pablo, Nevarez Leticia, Núñez Andrés, Palencia Julio, Pascoe Sara, Pérez Cristina, Quezada Ma. Irene, Ramírez Santiago, Robles José Antonio, Rodríguez Hiromi, Rodríguez Jorge, Rodríguez Luis, Salinas Saúl, Sánchez José, Sandoval Blanca, Secchi Nikos, Siekavizza Juan, Torres Andrés, Vázquez Cristian, Vázquez Jorge, Vega Adriana, Vidrio Maricela.

Communication with: Héctor Eloy Tamez-Pérez

Telephone and fax: 01 (81) 8329 4050, extensions 2870-74

Email: hectoreloytamez@gmail.com

Background: Diabetes mellitus type 2 (DM2) is a multifactorial disease that can be treated with oral antiglycemic medication or with insulin. The antiglycemic drugs glimepiride and sitagliptin have different mechanisms of action, and have not been directly compared in a Latin-American population with recent DM2 diagnostic.

Methods: The primary objective in this randomized (1:1), multicentric, two arms, open study with adult patients, was to compare the efficacy of glimepiride with sitagliptin in a DM2 population naïve to treatment. Secondary objectives had been the effect on fasting and postprandial glycemia, hypoglycemia, weight modification, safety, percentage of patients quiting the trial, vital signs and laboratory results.

Results: Glimepiride and sitagliptin were equally effective in glycemic control and all other parameters, and the only difference found has been the frequency of hypoglycemic events reports, wich has been reported as higher and statistically significant in the in the glimepiride group. No fatalities where reported in either group.

Conclusions: Glimepiride or sitagliptin monotherapy are equally effective in control of HbA1c.

Keywords: Diabetes mellitus; Hypoglycemia; Hb A1c

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Type 2 diabetes mellitus (DM2) is a chronic disease of multiple causes whose incidence is increasing and which, when not treated properly and promptly, causes serious health complications:¹ The World Health Organization (WHO) estimates that there are 366 million people with diabetes in the world.² In Mexico, DM2 is one of the leading causes of death, whose prevalence in patients over 20 years old was 7% in 2007 and 9.17% in 2012.³ There are 400,000 new cases and about 60,000 deaths each year; this disease reduces life expectancy in our country by up to 10 years despite more than 80% of diagnosed diabetics in Mexico receiving treatment.^3-5 Treatment for diabetes is a challenge. Changing lifestyle with a healthy eating plan and increasing physical activity is a part of the treatment, but the impact of these is not always as desired for levels of glycosylated hemoglobin (HbA1c),⁶ also taking into account the restrictions on physical activity for patients due to cardiovascular risks. In addition, patients often do not follow these regimens properly, so that oral hypoglycemic therapy is one of the most effective strategies of glycemic control for the diabetic patient.¹

Among the drugs used to treat DM2, there is more recent second generation sulfonylurea (SU) and glimepiride.⁷ Glimepiride acts on functional beta cells where it blocks potassium-dependent ATP channels, promotes cell depolarization and calcium influx, stimulates insulin secretion, and lowers the concentration of blood glucose.⁸ Glimepiride can be used as initial therapy, as monotherapy, or in combination with other oral agents for controlling diabetes.^7,9 Sitagliptin inhibits the enzyme dipeptidyl peptidase-4 (DPP-4) whose substrate is incretins that stimulate the release of insulin.^10,11 The primary objective of this study was to determine the superiority of sitagliptin over glimepiride in reducing the percentage of HbA1c after 24 weeks of treatment in patients with newly diagnosed DM2, previously untreated with oral antidiabetic agents. Secondary objectives were to evaluate the effect of both drugs on fasting glucose levels, postprandial glucose, percentage of patients with HbA1c < 7%, rate of symptomatic hypoglycemia, changes in body weight, percentage of patients who withdrew from the protocol, and percentage of patients with salvage therapy. Another secondary objective was to evaluate the safety of glimepiride over sitagliptin with respect to adverse events (AE) and serious adverse events (SAE).

Methods

This was a comparative, multicenter, 24-week clinical trial with two arms, randomized (1:1) and open, in 306 adult patients. It included DM2 patients, men and women between 18 and 70 years of age who had not received prior treatment with antidiabetic agents, and with HbA1c > 8.5% and up to 11%. Subjects on lipid-lowering, antihypertensive, or hormone replacement therapy and/or using contraceptive hormones were admitted as long as their dose remained stable during the study period. The study excluded patients with diabetes other than type 2, pregnant or lactating women, diabetics treated with oral antidiabetic agents or insulin, with a history of ketoacidosis, with a history of hypersensitivity to SU or DDP-4, with renal dysfunction (serum creatinine = 1.5 mg/dL for men, y = 1.4 mg/dL for women), with liver dysfunction, low systemic corticosteroid treatment three months before or during the study, with a history of alcohol or drug abuse, a history of acute coronary syndrome within 3 months previous, with neoplasia or with any medical, psychological, social or geographic condition present or past that in the investigator's opinion could jeopardize the safety or restrict the patient's participation in this study. Only subjects who provided the signed letter of consent participated in the study. The selection was made in Week 1. Eligible patients were divided randomly into two groups. Group 1 received oral glimepiride (starting at a dose of 2 mg daily and allowed up to 4 or 6 mg daily as needed) as investigational treatment. Titration was performed to maintain fasting plasma glucose < 100 mg/dL. Group 2 received oral sitagliptin (100 mg daily) as the reference treatment. Randomization was done centrally through envelopes sent to the research centers. The efficacy data in the population by intention to treat (ITT) (defined as patients enrolled in the study who received at least one dose of study or reference drug), were evaluated with the following parameters: change in the average baseline HbA1c level and at 12 and 24 weeks, changes in mean levels of glucose at baseline and at the end of treatment, levels of fasting plasma glucose (FPG) and average postprandial blood glucose. Safety throughout the study and in the PIT was estimated by the frequency of hypoglycemic events and severe hypoglycemic events, AE, SAE-according to global definitions for pharmaceutical surveillance-, vital signs, and laboratory results. Hypoglycemia was defined as blood glucose values ​​of = 70 mg/dL (3.9 mM/L) with or without symptoms, and severe hypoglycemia was defined as blood glucose values ​​of = 50 mg/dL (2.8 mM/L). 

Statistical methods

To calculate the sample size a scenario was chosen with a = 5% and a potency of 80% to detect an absolute difference of 0.39% in HbA1c levels between the two treatments. The required N was 324 analyzable patients. To compare proportions and determine the degree of association between discrete variables researchers used:

• Pearson chi-squared test to compare variables in percentages of units of magnitude and independence tests of maximum likelihood, and the Z test of two proportions.
• To compare the average values ​​of the variables analyzed in the modality of intragroup comparison, we calculated arithmetic mean, median, SD, and the maximum and minimum values. For intragroup comparison Student’s t test was used for dependent or paired samples as well as for independent samples. To evaluate homogeneity between samples, Levene’s and Brown-Forsythe tests were used.
• To compare both groups and determine the significance of the differences in basal means versus means at week 24 in HbA1c and postprandial glucose, analysis of variance of one and two factors was used. To make multiple comparisons and define differences in baseline HbA1c values ​​versus week 24 in both groups, the Tukey test was used. The results were considered statistically significant when the significance level was less than 5%.

Treatment and measurements

At weeks 1, 2, 4, 12, and 24 researchers determined weight, height, body mass index (BMI), fasting and postprandial blood glucose, HbA1c, blood pressure, and serum creatinine. Enzymatic techniques were used for the determination of glucose, HbA1c, serum creatinine, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), low density (LDL) and high density lipoprotein (HDL), and triglycerides, determined by Quest Diagnostics, Mexico DF.  

Results and discussion

Characterization of population

Of the 400 patients initially registered, 200 for each group, 94 withdrew from the study for various reasons such as: absence at patient appointments, voluntary withdrawal of the patient, protocol violation, noncompliance, pregnancy or stopping birth control for procreative purposes, failure to meet laboratory criteria, and hypoglycemia. A total of 29 patients were excluded for not having HbA1c values ​​at week 24. The protocol population (PP) consisted of 306 patients. Table I shows the baseline laboratory characteristics of the volunteers in each study group. Clinical features (not shown) and initial laboratory profile were similar for both groups without significant differences.

Superiority of glimepiride over sitagliptin after 24 weeks of treatment

Both drugs significantly reduced the mean percentage of HbA1c at the end of treatment compared to baseline in each group (p < 1 x 10^-6) (Table II). There were no significant differences in the reduction of HbAc1 comparing the two treatments.

Glimepiride induced a reduction of 2.06% between the baseline and final values ​​compared to a reduction of 1.69% for sitagliptin. The absolute difference of reduction (2.06-1.69) was 37%, which is lower when accepting the hypothesis of superiority at 39% as defined above. With a more detailed characterization of the percentages of HbA1c (> or < 7%), no significant differences were found either. Table III shows the number of patients in the range of HbA1c = 7.1%, and = 7% at the end of treatment. No significant differences between treatments were found upon performing this analysis. This study required the titration of glimepiride, which is a common procedure for starting treatment with this medicine. By analyzing changes in HbA1c levels for different doses of glimepiride at the end of treatment, significant differences between 2 mg, 4 mg, and 6 mg doses were found (Table IV). The lowest percentage of HbA1c at this point was found with the smallest dose, which was received by a low proportion of group 1 (17.6%).

Secondary objectives

The results of the secondary objectives of this study did not indicate significant differences between treatment in the two groups, although both treatments significantly reduced levels of fasting glucose (group 1 = 27.54 mg/dL; group 2 = 22.28 mg/dL, p = 0.23). Postprandial blood glucose was also reduced at the end of both treatments without significant differences between groups. On average, group 1 showed a reduction of 33.26 mg/dL and group 2 28.59 mg/dL in postprandial glycemia. There were no significant differences when comparing breakfast, lunch or dinner (p > 0.05). The change in weight of patients in group 1 was -0.216 kg (down 0.27%) and group 2 -0.892 kg (down 1.12%), p = 0.695 (week 12). There were no differences between groups in the number of patients who withdrew (total = 42 patients, p = 0.66). The two patients who received salvage therapy belonged to the sitagliptin group. There was no significant difference when comparing the average systolic and diastolic pressure in the PP, nor were changes observed in these parameters or pulse at the beginning and end of protocol. It is important to note that during the course of this study there were no fatalities.

Safety

To assess safety in the ITT, incidence of AE and SAE, hypoglycemia, significant changes in vital signs, and results of laboratory studies were considered. Table V shows that the number of AE and SAE in both treatment groups was statistically significant (chi-squared = 31.58, p < 0.1 x 10^-7), with a greater number of events in the group receiving glimepiride. Hypoglycemia is often seen during diabetes treatment.^7,10 The same table shows reports of symptomatic hypoglycemia (blood glucose = 70 mg/dL) and severe hypoglycemia (blood glucose = 50 mg/dL). It also shows that the number of reports of symptomatic hypoglycemia in group 1 is higher (and statistically significant, chi-squared = 29.0, p < 0.1 x 10^-6). The incidence of hypoglycemic events in this category averaged 3.32 events/patient in the glimepiride group and 2.28 in the sitagliptin group. These averages also have a significant difference (p <0.001). In the category of severe hypoglycemia, the sitagliptin group reported no event (chi-squared = 0.29, p, 1 x 10^-6). There were no lethal events in either group.

Discussion

DM2 has become one of the leading causes of death in the country, even in individuals 20-39 years of age, which can be explained by the fact that many factors that favor its development are increasingly common in Mexican society. The diagnosis and monitoring of the patient is done by measuring HbA1c as recommended by the WHO.^13,14 To control it, the patient requires the use of medication, because the lifestyle changes are difficult to implement and have moderate impact on the disease and its development.¹ The oral antidiabetic drugs often used, have efficiencies similar to each other,¹⁵ and drugs such as SU and incretin mimetics are in widespread use. The use of sitagliptin and glimepiride to treat diabetes is well documented: while these two drugs differ in their mechanism of action, efficacy, pharmacokinetics, pharmacodynamics and side effects, both are able to control the patient with DM2,^7,10 although its effectiveness in newly diagnosed untreated Mexican patients had not previously been compared, we found data only in multicenter studies but without subgroup analyses. The dose of glimepiride was graduated according to the patient and progress of their condition, and in general terms the most used is 4 mg, which could be considered suboptimal, since 8 mg have been recommended for higher efficacy and safety. Its AE are moderate, with a higher risk of hypoglycemia in the first weeks of treatment.^8,16 Although the efficacy of sitagliptin is similar to other oral agents in diabetes control, it is recommended to be prescribed in combination or as a second-line agent,¹² which is a common strategy for effective control of the disease;⁷ a dose of 100 mg/day is effective.¹⁷ The primary objective of this study was to establish differences in efficacy between treatment with glimepiride (2, 4 and 6 mg daily) and sitagliptin (100 mg daily). The glimepiride dosages used here were based on previous publications.8,18,19 This study found that glimepiride even at submaximal doses (< 8 mg) significantly reduced HbA1c levels from 9.84 ± 0.74% to 7.78 ± 1.90%. Effectiveness of sitagliptin monotherapy at a dosage of 100 mg has been previously established for moderate levels of HbA1c (< 8%).^17,20 The dose used here (100 mg daily) was effective in reducing HbA1c significantly from an average of 9.81 ± 0.71 ± to 8.12% ± 2.08% (Table II). Although the percentage of reduction obtained with glimepiride (2.06% reduction in the average) is higher than that obtained with sitagliptin (1.69% reduction in the average), the difference was not significant. One factor that may have influenced this result is that in the end the number of patients was 306, i.e., a lower figure than planned. Upon doing a more detailed analysis of the effect of these drugs on different final blood sugar levels (less than 7% and 7.1%, Table III) no significant differences in effectiveness between the two treatments was observed, either. However, 88 patients in the sitagliptin group had HbA1c = 7.1%, compared with only 78 patients in the glimepiride group. Similarly, a larger number of patients with glimepiride achieved HbA1c levels less than 7% (75 patients compared with 65 patients with sitagliptin).

Different doses of glimepiride had different effects on patients, the efficacy being directly dose-dependent (Table IV). However, the majority (110) of the patients in this group (Table IV) received the highest dose (6 mg/day). Therefore we conclude that at the doses used in this study (2, 4, or 6 mg/day), the efficacy of glimepiride, even submaximal doses, and that of sitagliptin are similar and could be an alternative initial therapy for patients with intolerance to metformin, a frontline drug recommended for controlling these patients.15 Glimepiride had a low risk of developing hypoglycemia.16 The results indicate that 39.88% of group 1 patients developed non-severe hypoglycemia (= 70 mg/dL), whereas 13.96% of patients treated with sitagliptin have this condition (chi-squared 0.29, p < 1 x 10^-6) (Table V). Also the glimepiride group reported significantly more severe symptomatic hypoglycemia events compared with the sitagliptin group (chi-squared 0.29, p < 1x10-6) (Table V). The pharmacological behavior related to hypoglycemia was expected according to what described in literature.

Conclusions

The primary objective of this study was to compare the superiority of glimepiride over sitagliptin in their ability to reduce HbA1c levels at 24 weeks of treatment. Although glimepiride tended to have a greater reduction in HbA1c than sitagliptin, the differences were not statistically significant. The trend in the efficacy of glimepiride was an absolute reduction of 37% against an assumption of superiority of 39%, so the alternative hypothesis of superiority was not demonstrated. Safety results indicate that the glimepiride group had significantly more hypoglycemic events than the sitagliptin group. No fatalities occurred in either group.

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