Combination Therapy for Patients with Type 2 Diabetes: Repaglinide in Combination with Metformin

Robert G Moses


Expert Rev Endocrinol Metab. 2010;5(3):331-342. 

In This Article

Overview of Oral Antidiabetic Medications

Currently, six classes of oral antidiabetic drugs (OADs) are available: biguanides (e.g., metformin), sulfonylureas (e.g., glimepiride), meglitinides (e.g., repaglinide), thiazolidinediones (e.g., pioglitazone), dipeptidyl peptidase IV inhibitors (e.g., sitagliptin), and α-glucosidase inhibitors (e.g., acarbose).[20]


Sulfonylureas (SUs) are the oldest and most widely used medications for the treatment of T2DM. Although SU therapy effectively lowers blood glucose concentrations (average decrease in FPG of 2–4 mmol/l, accompanied by a decrease in HbA1c of 1–2%) by stimulating insulin secretion from β-cells, treatment with SUs is associated with a progressive linear decline in β-cell function.[13,21] Eventual inability to maintain glycemic control reflects an advanced stage of β-cell failure. Hypoglycemia is the most common and most serious adverse event associated with SU therapy, mainly because of insulin release being initiated even when glucose concentrations are below the normal threshold for normal physiologic glucose-stimulated insulin release. Weight gain, regarded as a class effect of SUs, is thought to result from an anabolic effect of increased insulin concentration.[22] Owing to decreased effectiveness of SUs over time and an associated decline in the insulin secretory reserve, combination therapy has focused mainly on adding insulin-sensitizing medications, including metformin and thiazolidinediones.

α-glucosidase Inhibitors

α-glucose inhibitors, including acarbose, are competitive inhibitors of membrane-bound intestinal α-glucosidases that hydrolyze oligosaccharides, trisaccharides and disaccharides to glucose and other monosaccharides in the small intestine and thereby delay postprandial glucose absorption.[23] These agents are available as a first-line treatment in patients with slightly raised basal glucose concentrations and marked postprandial hyperglycemia (average decrease in HbA1c of 0.5–1%).[24] Derosa et al. demonstrated that both repaglinide and acarbose had a similar effect on reducing postprandial glucose levels (-14.9%, p < 0.05; -16.2%, p < 0.05; both vs baseline, respectively).[25] A meta-analysis of seven major studies on the use of acarbose in the treatment of diabetes indicated that acarbose treatment was associated with a 35% risk reduction of cardiovascular disease through diminution of oxidative stress induced by postprandial hyperglycemia.[26] In a nationwide analysis of risk of cardiovascular death according to different glucose-lowering drugs used as monotherapy, it was concluded that, in terms of cardiovascular profile, acarbose, repaglinide and gliclazide were as safe as metformin, while other SUs were associated with higher risk.[27] The use of α-glucosidase inhibitors in combination with SUs, metformin or insulin can improve glycemic control.[28] Despite their good safety record, limited gastrointestinal tolerability has substantially restricted their use. α-glucosidase inhibitors are more commonly used in Europe and Japan than in the USA.


Meglitinides such as repaglinide and nateglinide are prandial insulin releasers that stimulate rapid insulin secretion.[29] Repaglinide (NovoNorm®, Prandin®, GlucoNorm®) is the first clinically available insulin secretagog that specifically enhances early-phase prandial insulin response by increasing the sensitivity of β-cells to elevated glucose levels, producing a greater insulin release under hyperglycemic conditions.[17,30] In this regard, it has been shown in vitro that repaglinide is five-times more potent than glibenclamide in stimulating insulin secretion, with half-maximal stimulation observed at 40 and 200 nmol/l, respectively.[31] Repaglinide is taken orally immediately before a meal and has been shown to particularly reduce postprandial hyperglycemia. Rapid-acting insulin releasers can be suitable for lifestyles where meals are unpredictable or missed. Lower risk of hypoglycemia makes these agents an attractive option for some elderly patients, in particular when other agents may be contraindicated. Repaglinide has been shown to be associated with 60% fewer hypoglycemic episodes compared with a second-generation SU.[32] This could be related to an in vitro finding that repaglinide increases insulin release from β-cells only in the presence of glucose (as seen in the presence of 5 and 10 mmol/l of glucose), whereas glibenclamide stimulates insulin secretion in the absence of glucose.[31]


The thiazolidinediones are insulin-sensitizing drugs that improve whole-body insulin sensitivity through gene regulation.[24] These agents increase glucose uptake via glucose transporter-4 in skeletal muscle and reduce rates of gluconeogenesis in the liver. Reductions in plasma insulin concentration and lowering of circulating triglycerides are additional indirect mechanisms that may help improve whole-body insulin sensitivity. Thiazolidinediones have also been known to improve β-cell function and reduce insulin resistance; however, they are associated with weight gain and can cause peripheral edema.[21]


Metformin, a biguanide that acts directly against insulin resistance, is regarded as an insulin sensitizing drug and is considered to be a cornerstone in the treatment of T2DM.[33] Available formulations include Glucophage®, Glucophage XR®, Riomet®, Fortamet®, Glumetza®, Obimet®, Dianben®, Diabex® and Diaformin®. Because of its safety and efficacy, metformin is the cornerstone of monotherapy, and joint guidelines from the AACE and ACE recommend that metformin be initiated as first line monotherapy unless a contraindication such as renal disease, hepatic disease, gastrointestinal intolerance or risk of lactic acidosis coexists.[4]

Despite being the most widely used OAD in the world, metformin can reach a plateau of effectiveness due to progressive β-cell failure.[34,35] Metformin is only effective when there is sufficient endogenous or exogenous insulin and, because of this, patients are unable to maintain tight glycemic control as their disease progresses.[36]

Metformin also forms the cornerstone of dual therapy and is used extensively in combination with several classes of OADs. The safety and efficacy of SU plus metformin, a commonly prescribed combination, is well documented.[37] Metformin is available in combination with the following agents: rosiglitazone (Avandamet®), pioglitazone (Actoplus Met®), glipizide (Metaglip®), glibenclamide (Glucovance®), sitagliptin (Janumet®), and repaglinide (PrandiMet®). Generic formulations of metformin/glipizide and metformin/glibenclamide are also available. A generic formulation of metformin/rosiglitazone from Teva has received tentative approval from the US FDA and is expected to reach the market in early 2012.

Results from studies investigating the association between combination therapy with metformin and SUs and the risk of cardiovascular disease and mortality have been conflicting. While some studies have reported an increased risk of all-cause and cardiovascular disease mortality,[15,38] others have reported no association.[39,40] In a recent meta-analyses, Rao et al. have shown that combination therapy with metformin and SUs significantly increased the relative risk of cardiovascular hospitalization or mortality (fatal and nonfatal events). However, there were no statistically significant effects of combination therapy on cardiovascular disease mortality or all-cause mortality.[41]

Lund et al. have shown that metformin was more effective in reducing selected biomarkers of inflammation and endothelial dysfunction compared with repaglinide despite providing similar glycemic control.[42] Favorable changes in cardiovascular disease markers (TNF-a, PAI-1-ag, t-PA-ag, vWf, sICAM-1, and sE-selectin, heart rate and Amadori albumin) suggest that combination therapy with repaglinide and metformin may have beneficial effects. Despite the as-yet-unexplained finding of increased mortality in the group of patients randomized to receive metformin plus SUs versus SUs alone,[15] retrospective data published by Monami et al. show that, after adjusting for known confounders related to disease severity and comorbidity, glibenclamide in combination with metformin was associated with a higher mortality compared with repaglinide or other insulin secretagog in combination with metformin.[43] Although this remains an important and currently poorly understood aspect of combination therapy, it is important to evaluate the benefit versus risk prior to treatment decisions.

Dipeptidyl Peptidase-IV Inhibitors

Dipeptidyl peptidase-IV (DPP-IV) inhibitors suppress the degradation of a variety of bioactive peptides, including glucagon-like peptide-1, leading to an enhancement of their action.[19] DPP-IV inhibitors are orally administered drugs with a significant effect on glucose tolerance and lasting improvement of HbA1c. Several agents are in different stages of clinical development. Sitagliptin was approved by the FDA in 2006 as an adjunct to diet and exercise in patients with T2DM.[101] A combination of sitagliptin and metformin was approved in 2007 and is also indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM, when treatment with both sitagliptin and metformin is appropriate.[102] DPP-IV inhibitors are weight-neutral and well tolerated.[44]


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