Diabetes mellitus in the young: Gliptins or sulfonylurea after metformin?

Abstract

Introduction:

Diagnosis and initial management of diabetes mellitus (DM) in the young are clinical dilemma. Gliptins may be a safer and more effective option than sulfonylureas. Few Indian studies have addressed this issue of clinical relevance.

Aim:

To compare the use of sitagliptin and glimepiride as early add-on drugs along with metformin in young patients with DM to achieve optimum glycemic targets.

Methods:

This was a prospective, open-label, cohort study set in a tertiary care hospital in North India. Newly diagnosed patients of DM ≤35 year of age were initially treated to pre-defined glycemic goals (Fasting plasma glucose (FPG) 70-130, post prandial glucose (PPG) < 180 mg/dl) with insulin and metformin 1 g for 8 weeks. Insulin was discontinued and metformin increased to 2 g daily for next 4 weeks. Thereafter, glimepiride 1 mg or sitagliptin 100 mg was randomly added to those who were not maintaining the set glucose targets. Dose of glimepiride was uptitrated every 4 weeks upto a maximum of 4 mg. Three groups (Gp A: Metfromin 2 g/d, Gp B: Metformin 2 g + Glimepiride 1-4 mg/d, and Gp C: Metformin 2 g + sitagliptin 100 mg/d) were followed up over next 24 weeks. They were compared for glycemic control and weight change. Those failing therapy on these drugs (FPG > 180, PPG > 250 mg/dl with/without catabolic symptoms/ketosis) were withdrawn.

Results:

Sitagliptin with metfromin and metfromin alone group fared better than the glimepiride group for glycemic control, lesser treatment failures, and less weight gain.

Conclusion:

In this limited study, we found that sitagliptin is a safer and more effective option in young, newly diagnosed patients with DM. Findings of this study are relevant for clinical practice in Indian setting.

INTRODUCTION

Young patients with diabetes mellitus (DM) present as a dilemma to the treating clinician as to the exact type of diabetes (Type 1 or Type 2) and the management protocol to be followed (insulin or oral anti-diabetic drugs [OADs]). Although the efficacy of OADs in the initial stages of the disease is often noted, there is a fear of rapid beta-cell degeneration, weight gain, and hypoglycemia with the use of sulfonylureas in this setting. Dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) with their glucose-dependent insulin secretion and glucagon suppression, weight neutrality, and probable positive effect on beta-cell health are likely to be a better option in this setting. There is little data in literature regarding their usage in the initial period after diagnosis in young Indian patients with DM.[1,2]

We compared the use of sitagliptin and glimepiride as early add-on drugs along with metformin in young patients with DM to achieve optimum glycemic targets.

METHODS

This study was conducted as a prospective, uncontrolled, open-labeled, cohort study in a tertiary care hospital setting on newly diagnosed young patients with DM. Patients of age <35 years who were diagnosed with DM in the period from February 2009 to January 2012 were included in the study. Detailed history and clinical examination including the assessment of autoimmune markers, markers of insulin resistance, goiter, testing for neuropathy and retinopathy were done. Baseline investigations included fasting and pre-meal, post-prandial blood glucose, hemoglobinA1c (HbA1c), lipid profile, blood urea nitrogen, creatinine, bilirubin, transaminases and urinary ketones and microalbumin were made. All patients were counseled regarding diet and exercise by a qualified diabetes educator. They were treated with insulin (Glargine or Detemir) along with metformin 1 g daily for a period of at least 8 weeks to obtain optimum glycemic control (fasting FPG and pre-meal glucose, 70-130 mg/dl; PPG <180 mg/dl). Patients who presented initially with diabetic ketoacidosis and had low post-meal C-peptide levels after initial period of 8 weeks on insulin were excluded from the study.

After initial period of 8 weeks on insulin and optimum glycemic control, dosage of metformin was increased to 2 g for next 4 weeks. Glimepiride 1 mg or a sitagliptin 100 mg was randomly introduced as add-on to metformin if desired glycemic targets were not achieved. Patients were seen at the interval of 4 weeks. History of hypoglycemic symptoms was obtained. Dosage of glimepiride was increased (1 mg every 4 weeks) to a maximum of 4 mg daily if the desired targets were not achieved during the 4-week visits. In case of worsening of glycemic control (FBG >180 mg/dl, PPBG >250 mg/dl), catabolic features or ketosis at any stage on the existing therapy, additional OADs, or insulin were introduced and the patient was withdrawn from the study. Patients were followed up on OADs in three groups (Gp A: Metformin alone, Gp B: Metformin + glimepiride, and Gp C: Metformin + sitagliptin) and re-assessed at 24 weeks for glycemic control. All three groups were matched for baseline age, weight, body mass index (BMI), and HbA1c [Table 1]. At 24t6-point blood glucose profiles (fasting, post-breakfast, pre-lunch, post-lunch, pre-dinner, and post-dinner) were tested over 24-h period. HbA1c, weight change, maintenance of satisfactory glycemic control at 24 weeks were compared between the three groups [Table 2].

Table 1.

Groupwise baseline characteristics of the patients include in the study

Table 2.

Assessed groupwise parameters at 24 weeks of follow-up on oral anti-diabetic drugs

RESULTS

A total of 57 patients of age ≤35 years were diagnosed to have DM during the period of the study. All were males and their mean (±SD) age was 31.8 (±2.5) years. Five were obese (BMI ≥25 kg/m²) and eight were overweight (Body mass index (BMI): 23-24.9 kg/m²). At diagnosis, all were treated with basal insulin (Glargine or Detemir) starting at a dose of 10 U, titrated every 72 h with FPG and metformin 1000 mg daily for the initial period of 8 weeks. Out of 10 patients who presented with Diabetic ketoacidoses (DKA) at onset, eight were excluded from the study as post-meal C-peptide in them was low (<1.1 ng/ml) after the initial period of 8 weeks on insulin. After the initial period of 8 weeks, 49 patients were included for the next phase of study. Insulin was discontinued and dose of metformin was increased to 2 g daily. After a further period of 4 weeks, 35 patients who did not achieve the desired FPG and PPG targets were randomly assigned to the addition of glimepiride (Gp B: 20 cases) or sitagliptin (Gp C: 15 cases).

Patients who continued to remain in acceptable glycemic targets at 24 weeks were 9 (64.3%) in Gp A, 6 (30%) in Gp B, and 11 (73.3%) in Gp C. The difference was statistically significant between Gp C and the other two groups while that between Gp A and Gp C were not significant.

One patient each from Gp A and C and nine from Gp B had to be withdrawn as they developed hyperglycemia beyond set limits (FPG > 180, PPG > 250 mg/dl) with or without catabolic symptoms requiring additional OADs or insulin.

HbA1c reduction at 24 weeks was 0.9%, 1.2%, and 1% in the three groups, respectively. FPG reduction was 19, 34, and 26 mg/dl and PPG reduction was 78, 46, and 82 mg/dl in the three groups, respectively.

Weight change from baseline significantly greater in the sulfonylurea group compared to the other two groups, while the sitagliptin group was better than the metfromin group although not statistically significant.

DISCUSSION

We studied the glycemic control with the early use of sitagliptin along with metformin and compared it to glimepiride in newly diagnosed young males with DM. Over a period of 24 weeks on OADs, comparison revealed greater number of failures (withdrawal due to additional OADs or insulin requirement) on glimepiride than metformin with or without sitagliptin. FPG reduction was significantly greater for glimepiride than for the other two groups. PPG reduction was significantly greater for the sitagliptin and metformin groups compared to the glimepiride group. Weight gain was greater in the glimepiride group.

In the initial period after diagnosis of DM in a young individual, there is always a clinical practice dilemma whether to use insulin or OADs as initial line of management. Rapid beta-cell failure with the use of sulfonylureas in the initial stages of type 2 DM and more so in the honeymoon phase of Type 1 DM or latent autoimmune diabetes of adults (LADA) is always fraught with the future risk of early insulin dependence and complications. Risk of hypoglycemia and weight gain is a major factor while considering the treatment options at this stage of disease.

DPP-4 inhibitors with their glucose-dependent insulin secretion, glucagon suppression, and weight neutrality may be ideally suited as initial options in this setting. Their proposed beta-cell preserving effects may also play a beneficial role as a disease-modifying agent.

Greater efficacy and lesser failure rates within such a short period of its use in this young subset of newly diagnosed diabetics suggest that sitagliptin is a safer option in the initial stage of the disease.

The limitations of this study are its small sample size, only male subjects, and lack of clear differentiation at diagnosis regarding type of DM. The basis for dosage modification, treatment response and failure used in our study was FPG and PPG not HbA1c as in most studies and guidelines. This was done due to short duration of follow-up, the practical utility of FPG and PPG values in day-to-day patient management, and their greater availability.

Our study suggests that sitagliptin would be a better option as first add-on drug after Metfromin in newly diagnosed young patients of DM where the type of DM was not clearly characterized.