1. Carina Signori, D.O., M.P.H. Penn State Hershey Medical Center Ceriello, Antonio. Diabetes Care August 2010;33,8.

2. Introduction NAVIGATOR Trial (NEJM 2010; 362: 1477-90) Looked at Nateglinide and Valsartan in patients with impaired glucose tolerance. Nateglinide lowers postprandial hyperglycemia by increasing the first phase of insulin secretion. Conclusions of study: There was not a significant decrease in new cases of diabetes nor new cardiovascular events with use of nateglinide. Valsartan reduced onset of DM (but no change in CV events).

3. Introduction Postprandial hyperglycemia has been linked to increased risk of CVD, so its treatment (in this case with nateglinide) was expected to decrease CV events. The negative result of the NAVIGATOR trial suggested that postprandial hyperglycemia treatment may not improve CV risk in diabetes.

4. Background Evidence suggests that type 2 DM occurs from both: 1.) impaired pancreatic beta-cell glucose sensitivity and whole body insulin sensitivity 2.) defects in acute insulin secretion First phase insulin secretion (FPIS) FPIS is impaired early on in the progression from normal glucose tolerance to diabetes. It first becomes impaired or sluggish until eventually it is lost in diabetes. The end result is postprandial hyperglycemia.

5. Background Importance of postprandial hyperglycemia: Hemoglobin A1C Postprandial glucose affects overall glycemic control. HgA1C is affected by postprandial glucose especially in tight glycemic control (HgA1C <7.5%). To achieve tight control, postprandial glucose ultimately needs to be under control.

6. Background Cardiovascular Disease Many studies have supported a linear relationship between postprandial hyperglycemia and risk of CVD death. However, these studies mainly looked at postprandial glucose following oral glucose tolerance test. This finding was questioned because the OGTT is not an a meal and it was felt that actual food would not show the same relationship. Another study did show correlation between 2 hour postprandial levels after OGTT as well as after a meal 2.

7. Postprandial hyperglycemia and CVD Is there evidence that treating postprandial hyperglycemia reduces risk of CVD? The Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) showed that new CV events (secondary endpoint) may be reduced by treating postprandial hyperglycemia in impaired glucose tolerance patients 3. This was confirmed in diabetic patients in a meta- analysis with acarbose 4. The HEART2D 5 trial and NAVIGATOR study failed to comfirm this.

8. Postprandial hyperglycemia and CVD Limitations of the NAVIGATOR Trial: It only showed that nateglinide does not reduce cardiovascular events. The nateglinide group did not have improved postprandial hyperglycemia. The nateglinide group had higher postprandial glucose levels 2 hours after OGTT compared to placebo. The incidence of new DM was higher in nateglinide group than placebo.

9. Limitations of Navigator Trial: Multiple studies (ACCORD, ADVANCE, VADT, UKPDS) have shown that control of overall hyperglycemia if started too late in CVD loses its beneficial effect. The NAVIGATOR subjects in the primary prevention who had hx of CV event were pooled together which could have affected the end results. Also, there was a very high drop out rate.

10. Conclusions The effect of postprandial hyperglycemia on CVD is still unclear. The Acarbose Cardiovascular Evaluation (ACE) is a large trial that may give more information. Postprandial hyperglycemia is becoming part of the treatment targets and is the most important contributor to A1C, especially if lower than 7.5%. One study showed that further reducing strict glycemic control (HgA1C 6.5 to 6.1% ) in diabetes reduced carotid intima-media thickness in diabetes 7.

11. Conclusions Oxidative stress has been thought to be the cause of diabetic complications with hyperglycemia 6. Postprandial hyperglycemia likely produces oxidative stress resulting in endothelial damage. Irbesartan reduces oxidative stress and valsartan may have worked in the NAVIGATOR study for this reason. There is significant evidence that widely fluctuating glucose is associated with worsening prognosis and diabetic complications.

12. Conclusions In nondiabetics, glucose is very closely maintained within in a small range suggesting also that postprandial hyperglycemia needs to be controlled. Therefore, the NAVIGATOR study did not help clarify the issue and only suggests that nateglinide did not reduce risk of cardiovascular disease in this study.

13. References 1. NAVIGATOR Study group, McMurray JJ et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. NEJM 2010; 362: 1477-1490. 2. Meier, JJ et al. Excess glycaemic excursions after an oral glucose tolerance test compared with a mixed meal challenge and self-measured home glucose profiles: is the OGTT a valid predictor of postprandial hyperglycaemia and vice versa? Diabetes Obes Metab 2009; 11: 213-222. 3. Chiasson JL et al. STOP-NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP- NIDDM trial. JAMA 2003; 290; 486-494. 4. Hanefeld M, et al. Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies. Eur Heart J 2004; 25: 10-16. 5. Raz I et al. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Diabetes Care 2009; 32: 381-386. 6. Nishikawa T et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404: 787-790. 7. Mita T et al. Nateglinide reduces carotid intima-media thickening in type 2 diabetic patients under good glycemic control. Arterioscler Thromb Vasc Biol 2007; 27:2456-2462.