This clinical, prospective, randomized, crossover study compared the effects of two different classes of drugs (rosiglitazone, an insulin sensitizer, and nateglinide, an insulin secretagogue) in type 2 diabetes patient. We evaluated the same patient under basal conditions, i.e., while hyperglycemic without medications, and again after 4 months of treatment with nateglinide or rosiglitazone. The major aims of this strategy was to minimize the influence of metabolic control on the specific drug effect. Despite similar improvements on glucose control, changes on lipid profile, insulin response and inflammatory markers were different with therapies.
Both treatment groups achieved similar and significant mean decreases from baseline in plasma glucose and fasting HbA1c levels. Proportions of patients achieving an endpoint HbA1c of <7 % were similar for nateglinide and rosiglitazone groups. Initial insulin response to the 5 h standardized 500 calories breakfast was augmented only with nateglinide treatment. The higher insulin and proinsulin levels, observed during nateglinide therapy, are in line with reports of its stimulatory effects on beta cells function, favoring a quick onset and short duration of insulin secretion, contrasting with the rosiglitazone’s sparing effects on beta cells function [3, 6, 7]. As expected, nateglinide anticipated the insulin peak response, improving mainly post-prandial glucose levels whereas rosiglitazone decreased glucose levels significantly at all times of the curve (Fig. 1).
Similar results were seen with proinsulin levels during the meal test: increased with nateglinide and decreased with rosiglitazone.
So, both treatment affected beta cell function. Despite increasing insulin secretion, the pro-insulin/insulin area under the curve ratio during the 5 h of the breakfast decreased during nateglinide treatment, suggesting that it improved previous secretory dysfunction of beta cells, contrasting with the worsening in beta cells function usually reported to sulphonylureas [18]. The increase in insulin secretion could not be accounted for by changes in body weight—it was unaffected in both groups, probably because of the short duration of post prandial insulin secretion during nateglinide therapy, the frequent ambulatory visits and nutritional counseling of the patients. There was no complains of hypoglycemia with both treatments.
Rosiglitazone also improved beta cells function, attested by the increase in HOMA-B value. Despite causing lower prandial insulin response, rosiglitazone kept total and incremental glucose AUC at similar levels when compared with nateglinide.
Overall changes on plasma lipids levels were different with therapies. Only rosiglitazone decreased post-prandial FFA and of triglycerides levels, both of which probably accounted to the observed amelioration of beta cell function (HOMA-B) and of insulin resistance, reflecting on the glucose-lowering action of rosiglitazone.
By the other side, nateglinide decreased fasting cholesterol levels, that were lower than with rosiglitazone treatment (p = 0.04).
Small changes in lipid metabolism were expected, and previous reports have also been light [3–6]. The near normal triglyceride and cholesterol levels of our patients prior both therapies was probably a factor influencing these modest results. However, neither the increase in insulin production nor the increase in insulin sensitivity were able to decrease fasting or post-prandial glucagon levels, confirming that both the inherent effects of each drugs, allied to the decrease in gluco and lipotoxicity were insufficient to restore alfa cells sensitivity to glucose and insulin levels, favoring the progression of diabetes.
Besides improvements on plasma FFA levels and HOMA beta, rosiglitazone treatment decreased CRP, TGF beta and fibrinogen levels and PAI-1 activity. These data suggest drug specific effects, not dependent on amelioration of the metabolic milieu.
Inflammatory markers and other haemostatic factor (IL-6, TNF alpha, leptin, s-ICAM, platelet aggregation) were unaffected by both treatment, despite the great improvement in glucose profile, Such persistence in inflammation is probably implicated in the poor reduction in cardiovascular disease despite glucose control in type 2 diabetes patients [19].
No changes were observed in GLP-1 levels during both therapies. A reduced incretin effect is a well-known characteristic of patients with type 2 diabetes. Impaired release of glucagon-like peptide-1 (GLP-1) has been reported to be at least partly involved in impairment of early-phase insulin secretion after food intake and postprandial hyperglycemia and hyperlipidemia [20].
High concentrations of several antidiabetic drug classes, namely thiazolidinediones, sulphonylureas, meglitinides and morphilinoguanides have been reported to inhibit the DPP-IV enzyme, being nateglinide the strongest inhibitor. So, besides its effect as a beta-cell K-ATP channel inhibitor [6, 7], nateglinide was reported to act as a prandial insulin-releasing agent, both by inhibiting GLP-1 degradation [21, 22], and by increasing GLP-1 secretion [8] secondary to the increase of intracellular calcium.
We did not confirm these data in our study.
There was no change in blood pressure. Nateglinide, probably due to its little binding to the vascular muscle and cardiac SUR2 receptors [9], was not expected to change blood pressure levels. Overall assessment of safety demonstrated that both drugs were well tolerated, and there were no significant side effects or severe hypoglycemic episodes.
Although metformin has been confirmed as the first line option to treat diabetes, troublesome gastrointestinal intolerance sometimes precludes its use [2]. Thus, glinide remains an important adjuvant for recent onset T2D patients. When compared with rosiglitazone, nateglinide achieved similar efficacy in improving glucose control. Although rosiglitazone had a sparing effect on beta cell function and decrease FFA, triglycerides and PAI-1 levels, it was recently excluded from the marked due to an increase in cardiovascular disease. Despite leading to more insulin secretion, nateglinide did not worsen body weight or beta cell function, measured by the pro-insulin/insulin ratio. Long term studies are needed to ascertain whether it can prevent beta cell exhaustion or apoptosis.