Metformin is the 'drug-of-first-choice' in obese patients with type 2 diabetes mellitus (T2DM) due to its antihyperglycaemic and cardiovascular protective potentials. In non-obese patients with T2DM, insulin secretagogues are empirically used as first choice. In this investigator-initiated trial, we evaluated the effect of metformin vs. an insulin secretagogue, repaglinide on glycaemic regulation and markers of inflammation and insulin sensitivity in non-obese patients with T2DM.
A single-centre, double-masked, double-dummy, crossover study during 2 x 4 months involved 96 non-obese (body mass index < or = 27 kg/m(2)) insulin-naïve patients with T2DM. At enrolment, previous oral hypoglycaemic agents (OHA) were stopped and patients entered a 1-month run-in on diet-only treatment. Hereafter, patients were randomized to either repaglinide 2 mg thrice daily followed by metformin 1 g twice daily or vice versa each during 4 months with 1-month washout between interventions.
End-of-treatment levels of haemoglobin A(1c) (HbA(1c)), fasting plasma glucose, mean of seven-point home-monitored plasma glucose and fasting levels of high-sensitivity C-reactive protein and adiponectin were not significantly different between treatments. However, body weight, waist circumference, fasting serum levels of insulin and C-peptide were lower and less number of patients experienced hypoglycaemia during treatment with metformin vs. repaglinide. Both drugs were well tolerated.
In non-obese patients with T2DM, overall glycaemic regulation was equivalent with less hypoglycaemia during metformin vs. repaglinide treatment for 2 x 4 months. Metformin was more effective targeting non-glycaemic cardiovascular risk markers related to total and abdominal body fat stores as well as fasting insulinaemia. These findings may suggest the use of metformin as the preferred OHA also in non-obese patients with T2DM.
"Yajima et al. demonstrated the metformin administration at a dose of 500-750 mg/day to be more effective in non-obese patients (n = 22, mean BMI was 25.6 kg/m2) with type 2 diabetes mellitus than in those treated at a dose of 150-300 mg/day of acarbose, an α-glucosidase inhibitors, in a crossover study conducted with 3-months treatment periods . Lund et al. described that the glycemic regulation was equivalent between metformin and repaglinide, an insulin secretagogue, in a 4-month crossover trial in 96 non-obese (BMI ≤ 27 kg/m2) European patients with type 2 diabetes mellitus . They also reported that the effect of metformin (n = 52) and repaglinide (n = 49) was not significantly different when combined with insulin for the treatment of non-obese patients, according to a randomized prospective study for 12 months . "
[Show abstract][Hide abstract] ABSTRACT: We aimed to investigate the long-term effect of metformin on the blood glucose control in non-obese patients with type 2 diabetes mellitus.
A retrospective study was performed in 213 patients with type 2 diabetes mellitus under the administration of metformin for more than one year. The clinical parameters were investigated for 3 years. The obese and non-obese individuals were defined as a body mass index (BMI) of 25 kg/m2 or over (n = 105) and a BMI of less than 25 kg/m2 (n = 108), respectively.
HbA1c levels were significantly decreased compared with those at the baseline time. The course of HbA1c was similar between the non-obese and the obese groups, while the dose of metformin required to control blood glucose was significantly lower in the non-obese group than in the obese group. The reductions in HbA1c were 1.2% and 1.1% at 12 months, 0.9% and 0.9% at 24 months, and 0.8% and 1.0% at 36 months in the non-obese and obese groups, respectively. BMI did not change during the observation periods. Approximately half of all patients required no additional antidiabetic agents or a reduction in other treatments after the initiation of metformin in either of the two groups.
The present study demonstrated the long-term beneficial effect of metformin in non-obese (BMI < 25 kg/m2) diabetic patients. This effect appears to be maintained even after the observation period of this study, because metformin was limited to a relatively low dose in the non-obese group and the observed worsening in glycemic control over time can probably be attenuated by increasing the dose of metformin.
[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia due to a combination of insulin resistance and impaired insulin secretion. The hyperglycemia is associated with an increased risk for micro- and macrovascular complications, and lowering fasting and postprandial hyperglycemia may be protective against these complications. Repaglinide is an insulin secretagogue that lowers blood glucose levels in patients with T2DM. We review the effects of repaglinide in patients with T2DM, its impact on glycemia and its non-glycemic effects, and its effects when used in special situations or patient populations. Results from randomized controlled trials, observational studies, and safety reports involving humans and published in the English-language through 1 May 2007 identified by a search in PubMed/MEDLINE were evaluated. Present knowledge indicates that repaglinide reduces fasting and postprandial hyperglycemia and the level of glycosylated hemoglobin (HbA1c) in patients with T2DM. It is at least as effective in reducing HbA1c and fasting plasma glucose as sulphonylureas, metformin, or the glitazones and in combination therapy with other drugs, repaglinide is as effective as any other combination. Some studies show a better effect of repaglinide on postprandial glycemia than the comparators. Its propensity to induce hypoglycemia is similar to or a little less than that of sulphonylureas. Repaglinide is associated with less weight gain than sulphonylureas and the glitazones. Repaglinide has primarily a role in the treatment of T2DM when metformin cannot be used due to adverse effects, when metformin fails to adequately control blood glucose levels, when there is a need for flexible dosing (i.e. the elderly or during Ramadan fasting), or when there is a specific wish to lower postprandial glucose. Repaglinide may also have an advantage when an oral agent is needed in diabetic patients with renal impairment. Because of its short duration of action, repaglinide should be taken before each meal, usually at least three times a day. Although no study has investigated whether repaglinide lowers total mortality or cardiovascular endpoints, several studies indicate beneficial effects on cardiovascular surrogate endpoints, such as carotid intima-media thickening, markers of inflammation, platelet activation, lipid parameters, endothelial function, adiponectin, and oxidative stress. In conclusion, repaglinide is a compound that can be used in both mono- and combination therapy for the treatment of both fasting and postprandial hyperglycemia in patients with T2DM. It can be used in patients at different stages of the disease, from uncomplicated to severe renal impairment. Although the drug has been tested in a large number of clinical trials and observational studies, its world-wide use is far less than, for example, sulphonylureas. Repaglinide may offer an additional potential for lowering blood glucose levels in T2DM that until now has not been fully realized by many clinicians.
American Journal of Cardiovascular Drugs 02/2007; 7(5):319-35. DOI:10.2165/00129784-200707050-00002 · 2.42 Impact Factor
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