Lessons from glargine trials: What is the goal fasting glucose with basal insulin? (来自甘精胰岛素临床试验的经验教训：使用基础胰岛素治疗的空腹血糖目标是什么？)

Most approaches to the glycemic treatment of type 2 diabetes suggest achieving a level as close to normal as can be achieved without adverse side-effects like weight gain, hypoglycemia, or others. This laudable aim is not, however, readily translated into a specific glucose goal. The American Association of Clinical Endocrinologists consensus recommendations are for fasting glucose below 6.1 mmol/L (110 mg/dL) and HbA1c below 48 mmol/mol (6.5%). The position statement of the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) suggests that HbA1c below 53 mmol/mol (7.0%) “can be achieved with a mean plasma glucose of 8.3–8.9 mmol/L (150–160 mg/dL) . fasting and premeal glucose <7.2 mmol/L” (<130 mg/ dL). Should these goals be used for treatment with basal insulin? We used Pubmed (http://www.ncbi.nlm.nih.gov/ pubmed) to find 13 studies in which insulin glargine was titrated using a “treat to target” approach, with a total of nearly 3000 type 2 diabetic patients, most receiving metformin, as well as a variety of other oral hypoglycemic agents, preprandial insulin and exenatide (Table 1). The blood glucose goals were set at 5.0, 5.5, and 6.0 mmol/L (90, 100, 110 mg/dL) in one, nine, and three of the studies, respectively. It is instructive, then, to observe that the initial and final fasting glucose levels in the treat-to-target studies were 9.8 and 6.7 mmol/L (176 mg/ dL, and 120 mg/dL), respectively, and yet the mean endof-study fasting glucose was 1.1 mmol/L (20 mg/dL) above the prespecified goal. In these studies, carried out by highly skilled investigators, it seems then that the majority of participants failed to achieve a 5.5 mmol/L fasting glucose level with the addition of basal insulin. Is it a quibble to point out that “treat-to-target” studies typically do not lower participants to the desired target? Is it useful, in administering basal insulin, to deliberately employ a seemingly unattainable low fasting glucose “goal”? Undoubtedly, as the studies generally report averages, some patients reach the stated goals while others have levels far above the goals. Recall that in ACCORD an important marker of both the risk of hypoglycemia and, worrisomely, of the risk of mortality was an on-trial HbA1c substantially above the goal. We are left, then, with a dilemma. In non-diabetic populations the fasting glucose is <5.5 mmol/L (100 mg/dL), and even within this range there is continuous increase in the likelihood of diabetes with increasing glucose levels, with fasting glucose levels of 5.5–6.0 having similar specificity for insulin resistance as levels above 6.0 mmol/L. It is certainly reasonable to desire a normal fasting glucose level. However, in a general population, although retinal complications can be seen at a pre-diabetic level of glycemia, their prevalence becomes particularly great when fasting glucose exceeds 7 mmol/L (126 mg/mL), the level also associated with an increase in cardiovascular mortality, suggesting that this accepted cutoff level for the diagnosis of diabetes may not represent an unreasonable therapeutic target. Interestingly, a recent continuous glucose monitoring study showed that mean fasting and premeal glucose levels of 7.9 and 7.7 mmol/L (142– 138 mg/dl) correspond with HbA1c of 48–53 mmol/mol (6.5–7.0%). Furthermore, insulin treatment certainly leads to hypoglycemia and weight gain, and it is often the case that once a patient’s fasting glucose level nears 7 mmol/L (126 mg/dl) there may be considerable increase in insulin dosage for relatively little further improvement in glycemia. Is there, though, some advantage to setting a goal, even if not typically reachable, to encourage greater efforts among physicians and diabetic patients to improve their glucose level – perhaps? Interestingly, the reviewed treat-to-target studies suggest that it is not always the case. Lower fasting blood glucose (FBG) targets did correlate with lower end-study FBG levels (r = 0.257), but there was no relationship between lower FBG targets and attained HbA1c (r = 0.038). Could this reflect low (sometimes excessively low) overnight and fasting glucose levels counterbalanced by daytime hyperglycemia? Does a “treat to target” approach, focused only on controlling fasting glucose, lead to an imbalance, underscoring the need for a balanced approach aiming separately at prandial glucose monitored by premeal glucose levels, which ideally would be below 6.1 mmol/L (110 mg/dL), or below 7.2 mmol/L (130 mg/dL), according to the two sets of recommendations. Realizing that the “Treat to Target” trials were primarily developed to test the efficacy of bs_bs_banner