The goal of this study was to assess the safety, tolerability, and metabolic effects of nateglinide in a prediabetic population and to thereby establish the feasibility of using nateglinide for a long-term study to determine whether an insulinotropic agent could delay or prevent the occurrence of type 2 diabetes, as has recently been established for concerted lifestyle modification and for metformin, acarbose, and troglitazone monotherapy. It was found that nateglinide elicited a dose-dependent increase of early prandial insulin levels and reduction of prandial glucose excursions -- both the amplitude of the basal to peak spikes and the 3-h AUCs. This has been observed previously in patients with type 2 diabetes and in healthy volunteers. Since the present study population represents a midpoint between the populations studied previously, this finding is not in itself unexpected. However, it does highlight the power of early insulin release. Thus, the lowest dose tested (30 mg) had no effect on overall insulin exposure, as assessed by the 3-h AUC, but produced more than half the maximal glucose-lowering effect. Thus, by restoring a physiologic insulin profile, nateglinide essentially normalized glucose tolerance -- precisely what would be desired in an agent to be tested in a diabetes prevention study.
It would also be necessary to have an exceptionally "clean" safety and tolerability profile, since the agent would be taken for a prolonged period of time in subjects with minimal hyperglycemia. In the present study, as described previously, nateglinide was very well tolerated. The incidence of AEs other than hypoglycemia in nateglinide-treated subjects was indistinguishable from that in subjects who took a placebo. The non-hypoglycemia-related AEs that occurred more frequently in nateglinide than in the subjects who took a placebo were in no way dose related or suspected to be related to study medication.
With regard to hypoglycemia, it is noteworthy that no severe hypoglycemia (requiring assistance from an outside party) occurred with any dose of nateglinide, likely due to its rapidly reversible and glucose-dependent insulinotropic action. No hypoglycemia occurred in any patient receiving the 30 mg dose of nateglinide, and all hypoglycemia that occurred in subjects given 60 mg was accompanied by a plasma glucose >3.1 mmol/l. In contrast, of the patients in the 120-mg group that did have confirmed hypoglycemia (26.7%), nearly half had one or more episodes during which plasma glucose levels fell below 3.1 mmol/l. In light of the increased incidence and severity of hypoglycemia in subjects receiving 120 mg nateglinide, and given the minimal additional metabolic benefit it provides, this highest dose does not appear to be a good option in subjects with IGT.
The 120 mg dose of nateglinide is used safely and effectively in the vast majority of patients with type 2 diabetes treated with nateglinide, and it was recently reported that in a 24-week study in patients with only moderately elevated FPG (≤7.8 mmol/l), 120 mg nateglinide preprandially normalized HbA1c levels (≤6.0%) in 40% of subjects, with an acceptable incidence of hypoglycemia (5.3%, plasma glucose ≤3.3 mmol/l). However, it is not surprising that a lower dose would be appropriate in nondiabetic subjects with IGT. From the present findings, it appears that either 30 or 60 mg would be acceptable for a long-term study to determine whether this rapid-onset/short-duration insulinotropic agent can delay or prevent manifest diabetes in a prediabetic population and reduce the increased mortality and morbidity associated with IGT[17,18].
Although the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes and the U.K. Prospective Diabetes Study (UKPDS) in patients with type 2 diabetes have convincingly established the benefits of tight glycemic control to reduce microvascular complications[19,20], macrovascular complications were not significantly reduced by insulin or oral secretagogues. Many correlative studies have suggested that postprandial hyperglycemia, or glucose spikes rather than total glycemic exposure, may play a key role in the cardiovascular morbidity and mortality associated with IGT and diabetes[13,17,21,22]. Indeed, it has been reported that postprandial hyperglycemia, but not impaired fasting glucose, is a risk factor for cardiovascular disease. Since early insulin release and the resultant suppression of hepatic glucose production is a major determinant of postprandial glucose levels, an agent such as nateglinide, which selectively augments early insulin release, may be a particularly effective approach to reducing cardiovascular morbidity and mortality.
Accordingly, a diabetes prevention study using nateglinide, which was shown here to substantially reduce postprandial hyperglycemia in subjects with IGT, may allow prospective assessment of the role of glucose spikes, not only in the development of overt diabetes, but also in the risk of macrovascular disease. The promise of this approach was demonstrated many years ago by a small study in which none of the 23 men with IGT who continued treatment with the short-acting SU, tolbutamide, and diet developed diabetes during the 10-year follow-up, whereas 13% of the 98 subjects who maintained diet therapy without tolbutamide developed diabetes.
In summary, augmenting early insulin secretion is a remarkably effective mechanism to control postprandial hyperglycemia. Low-dose nateglinide could be used to determine the potential of this mechanism to prevent or slow the progression of type 2 diabetes and may well become a therapeutic option for prediabetic subjects with only moderately disturbed glucose homeostasis.
The authors gratefully acknowledge the participating investigators (listed below) and their patients:
Spain: Prof. Ramon Gomis (Barcelona), Dr. Pedro De Pablos (Las Palmas), Dr. Domingo Acosta (Sevilla), Dr. Concha Sanabrina (Cividad Real), Dr. Bernardo Costa (Mora d'Ebre), Dra Josefina Olivan (Sevilla). Germany: Prof Markolf Hanefeld (Dresden), Dr. Scholz (Leipzig), Dr. Ernest Schell (Nurnberg), Dr. Michael Panijel (Frankfurt), Prof Ulrich Foelsch (Kiel), Dr. Alexander Mann (Hamburg). Italy: Prof. Mario Maioli (Sassari), Prof. Georgia Pagani (Bergamo), Prof. Antonio Tiengo (Padova), Dr. Giuseppe Seghieri (Pistoia), Dr. Felice Paleari (Monza), Dr. Lamberto De Giorgio (La Spezia). The Netherlands: Dr. MGAAM Nijpels (Zwaag). Sweden: Prof. Leif Groop (Malmö), Dr. Jan Eriksson (Umea), Dr. Oerjan Johansson (Valdermarsvik). Finland: Prof Sinikka Aijänseppä (Helsinki), Dr. Carola Saloranta (Helsinki), Dr. Carol Forsblom (Helsinki), Dr. Bo Isomaa (Jakobstad), Dr. Kaj Lahti (Vaasa), Dr. Bjorn Forsen (Narpes), Dr. Pasi Vanhala (Pieksamaeki).Funding information
C.G. and E.P. hold stock in, C.S. has received funds from, and P.d.P.-V. has received honoraria from Novartis.
Diabetes Care. 2002;25(12) © 2002 American Diabetes Association, Inc.
Cite this: Nateglinide Improves Early Insulin Secretion and Controls Postprandial Glucose Excursions in a Prediabetic Population - Medscape - Dec 01, 2002.