Glycated hemoglobin, better known as hemoglobin A_1c, which provides an overall measure of a patient's plasma glucose levels during the previous 2 to 3 months, has been acknowledged in several treatment guidelines as the gold standard for assessing glycemic control in patients with diabetes. Hemoglobin A_1c represents the effects of fasting plasma glucose and postprandial plasma glucose levels, and their relative contributions to overall glycemic control depend on the patient's current hemoglobin A_1c level. Because fasting plasma glucose and postprandial plasma glucose contribute to the microvascular and macrovascular complications of type 2 diabetes, the treatment of diabetic patients should address these 2 components of hyperglycemia. This article discusses the impact of fasting plasma glucose and postprandial plasma glucose on hemoglobin A_1c levels and outlines a stepwise approach for correcting fasting and postprandial hyperglycemia.

An estimated 20.8 million people in the United States have diabetes, and the vast majority (90%-95%) of those diagnosed with the disease have type 2 diabetes.¹ Despite the increasing number of treatment options, including several types of insulin and insulin analogues, the various oral drug classes, and the new incretin mimetics, many patients do not achieve the recommended glycemic goals (Table 1). In one survey conducted between 1999 and 2002, approximately 50% of US adults with diabetes had glycated hemoglobin (HbA_1c values above 7.0%, nearly 30% of whom had HbA_1c values above 8.0%.² Mean fasting plasma glucose (FPG) was also elevated, at 150 mg/dL.²

Understanding the risks associated with poor glycemic control can encourage patients to reach their individual glycemic targets. According to the recent position statement of the American College of Endocrinology and the American Association of Clinical Endocrinologists (ACE/AACE), "A_1c remains the 'gold standard' for assessing glycemic control."³ Since HbA_1c represents the sum of FPG and postprandial plasma glucose (PPG) levels,³ both should be considered for optimum diabetes management.

HbA_1c as a Marker for Glycemic Control

HbA_1c is a minor subtype of hemoglobin A that binds plasma glucose; measuring HbA_1c levels in the individual patient will reveal the patient's glycemic control during the past 2 to 3 months. Because HbA_1c is only eliminated when red blood cells (RBCs) are replaced, HbA_1c values are a weighted average of blood glucose levels over the lifespan of the RBC (averaging 90-120 days). As a result of the constant turnover of RBCs in the body, plasma glucose levels during the past 30 days contribute to approximately 50% of the final HbA_1c measurement, whereas plasma glucose levels from 90 to 120 days earlier contribute only 10% of that measurement. Clinically meaningful changes in HbA_1c can therefore be detected in less than 120 days after a major change in plasma glucose level.⁴ Nevertheless, HbA_1c values are not subject to the day-to-day fluctuations characteristically seen in daily blood glucose monitoring.

The primary benefit of HbA_1c as a measure of long-term glycemic control lies in its ability to predict the risk for diabetes-related complications. Epidemiologic data, including data from the United Kingdom Prospective Diabetes Study (UKPDS), of patients with type 2 diabetes have demonstrated the strong correlation between poor glycemic control and the development of microvascular and macrovascular complications.^5,6 In the UKPDS, each 1% reduction in mean HbA_1c was associated with a 21% risk reduction in any diabetes-related end point, a 37% reduction in microvascular complications, a 14% reduction in myocardial infarction, and a 21% reduction in diabetes-related mortality (P for all <.001).⁶

HbA_1c values are a complex function of FPG and PPG levels,⁷ and measurement of these values alone does not discriminate between the contributions of these 2 factors. To achieve maximal reductions in HbA_1c, preprandial and postprandial glucose levels must be assessed.⁸

Role of FPG and PPG in Glycemic Control

The FPG level is determined by hepatic glucose production and hepatic sensitivity to insulin, whereas PPG levels are influenced by the preprandial glucose level, meal-related glucose load and insulin secretion, as well as peripheral tissue sensitivity to insulin. FPG and PPG are correlated with HbA_1c values to varying degrees. The relative contribution of FPG and PPG to overall glycemic control depends, in part, on a patient's current HbA_1c level.⁷ In a study of 290 patients with type 2 diabetes, a progressive shift was seen in the contribution of PPG to HbA_1c, with PPG levels playing the greatest role in overall hyperglycemia in patients with well-controlled diabetes and the smallest role in patients with poor glycemic control.⁷

It is well recognized that prolonged elevations in FPG levels are correlated with increased risk for microvascular and macrovascular diabetes-related complications.^5,9,10 Often overlooked, however, is the role of PPG levels in the risk of cardiovascular disease (CVD). Evidence indicates that elevated PPG levels increase the risk for CVD, even when FPG and HbA_1c levels are within the normal range.¹¹ Therefore, more aggressive glycemic therapy, including treatment of postprandial hyperglycemia, may be needed to reduce the risk for CVD in patients with type 2 diabetes.

A meta-analysis of 22 studies involving almost 96,000 individuals showed that, compared with a glucose level of 75 mg/dL, a fasting glucose level of 110 mg/dL was associated with a relative risk for a cardiovascular (CV) event of 1.33 (95% confidence interval [CI], 1.06-1.67); the relative risk with a 2-hour postprandial glucose level of 140 mg/dL was 1.58 (95% CI, 1.19-2.10).¹² In the Hoorn Study, a population-based cohort study conducted in the Netherlands, FPG was a predictor of CV mortality only in the diabetic range, but increased PPG and HbA_1c levels were associated with increased risk of CV mortality even within the nondiabetic range (P for linear trend <.05).¹³ The investigators of the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study concluded that postprandial 2-hour blood glucose levels were a better predictor of CV and all-cause mortality than were FPG levels; the largest excess mortality occurred in individuals who had impaired glucose tolerance but normal FPG levels.¹⁴

These data suggest that a lower glycemic threshold exists for macrovascular disease than for microvascular diabetic complications, highlighting the importance of achieving HbA_1c levels of 7.0% or lower in patients with type 2 diabetes.¹⁵ Because PPG elevations play a larger role in overall hyperglycemia at lower HbA_1c values, control of PPG in addition to FPG may be needed to achieve further glucose reductions as patients approach target HbA_1c levels.

A Stepwise Approach to Treating Fasting and Postprandial Hyperglycemia

Most patients with type 2 diabetes will eventually require insulin therapy to achieve or maintain target glycemic values because of the progressive nature of this disease. Current ACE/AACE guidelines recommend the earlier use of regimens that approximate physiologic insulin secretion or combination therapies (insulin plus oral agents) to address the many abnormalities associated with diabetes. A recent joint consensus statement from the ACE/AACE emphasizes that insulin, used in combination with oral agents or with basal-bolus regimens, should be administered in an uncompromising treat-to-target approach early in the course of the disease to reach or sustain glycemic control.³

Insulin options
Insulin options include short-acting insulins, as well as the rapid-acting insulin analogues and are available as prandial therapy (Table 2). The quick onset of action of the rapid-acting insulin analogues allows their administration between 5 and 15 minutes before a meal. Insulin glulisine may be injected within 20 minutes after a meal. Inhaled insulin, although not an insulin analog, also has a fast onset of action, but with a short duration, making it a potential therapeutic option for postprandial glucose control.¹⁶

Premixed insulin formulations, such as 70% insulin aspart protamine/30% insulin aspart, may also be used as basal-prandial insulin therapy. These are administered twice daily (morning and bedtime), but their pharmacokinetic profiles do not result in true basal and prandial coverage (ie, they do not provide physiologic insulin replacement). These formulations also do not allow for mealtime flexibility and pose an increased risk for hypoglycemia if meals are skipped or delayed. Combining insulin therapy and oral agents is an effective approach to therapy that can address fasting and postprandial hyperglycemia.

Patients with type 2 diabetes may be reluctant to initiate insulin therapy, in part because of concerns about using complex regimens, fear of hypoglycemia, or anxiety about performing self-injections. A stepwise approach that starts with adding basal insulin therapy to an existing oral antidiabetic drug regimen and progresses to the addition of rapid-acting prandial insulin as needed, initiated with the largest meal of the day, is a simple method that allows patients to achieve their glycemic targets (Figure).

Figure—Steps in advancing insulin therapy in patients with type 2 diabetes.

Such an approach allows patients to begin insulin therapy with a single daily injection. Evidence indicates that FPG levels influence PPG levels¹⁷; therefore, lowering FPG with basal insulin therapy may also lower PPG levels for many patients and will allow them to reach target HbA_1c values.

Basal therapy
Oral agents, alone or in combination with basal insulin therapy, may not be sufficient to reduce HbA_1c values to target levels in some patients, and the progression of disease may require advancement of therapy to maintain glycemic targets. If HbA_1c values remain above target after the addition of basal insulin therapy (or increase above target over time), prandial insulin may be needed to address postprandial glucose excursions. Although upward titration of the basal insulin dose to meet target glycemic goals is limited only by hypoglycemia, the physician should monitor the patient's progress and note when glycemic improvement substantially slows or stops, especially as the patient approaches target HbA_1c values and PPG levels play a larger role in overall hyperglycemia.

If prandial insulin is required, it should be initiated at the largest meal and then added to remaining meals only if HbA_1c remains above target. This approach minimizes the complexity of the regimen and the number of injections required, while providing a plan for more intensive therapy if needed. When prandial insulin is added to a patient's regimen, metformin HCl (Glucophage) and insulin sensitizers (ie, thiazolidinediones) should be continued, but the dose of insulin secretagogues (ie, sulfonylureas) may be reduced as the patient approaches glycemic control.

The efficacy of adding basal therapy—once-daily insulin glargine or neutral protamine Hagedorn (NPH) insulin—to existing oral therapy in patients with type 2 diabetes was demonstrated in the Treat-to-Target Trial, in which the insulin dose was titrated using a forced weekly titration schedule (Table 3) until a defined FPG target (≤100 mg/dL) was achieved.¹⁸ In this study, a greater proportion of patients in the insulin glargine group achieved the glycemic target, without associated nocturnal hypoglycemia (33.2% versus 26.7% in the NPH group, P <.05).¹⁸ Mean HbA_1c at study end was similar in the NPH and the insulin glargine treatment groups (6.97% and 6.96%, respectively), with approximately 60% of patients in each group achieving HbA_1c levels of 7.0% or lower. The significant reduction in nocturnal hypoglycemia observed with insulin glargine compared with NPH insulin potentially alleviates one of the primary barriers to insulin use in patients with type 2 diabetes.

A similar study using a forced-titration algorithm to evaluate the addition of basal insulin to existing oral antidiabetic drug regimens compared twice-daily insulin detemir with twice-daily NPH insulin for 24 weeks.¹⁹ Insulin detemir and NPH insulin resulted in similar reductions in HbA_1c, but weight gain and hypoglycemia, including nocturnal hypoglycemia, were significantly reduced with insulin detemir compared with NPH insulin (P <.001).

Insulin detemir, a long-acting insulin analog, can be used once or twice daily for basal insulin therapy. A recent study of patients with type 2 diabetes, however, demonstrated that the majority of patients who received insulin detemir required twice-daily injections to achieve glycemic control.²⁰ Insulin detemir has also been associated with a lower risk of nocturnal hypoglycemia compared with NPH insulin.²¹

Incretin mimetics
The first agent in the new drug class known as incretin mimetics, exenatide (Byetta), is a new option for intervention early in the progression of type 2 diabetes. Exenatide reduces hyperglycemia through enhancement of glucose-dependent insulin secretion and regulation of glucagon release and gastric emptying; it also promotes satiety, thereby reducing caloric intake and body weight. Exenatide is indicated for use in combination with oral therapy (a sulfonylurea and/or metformin) in patients who have not achieved adequate glycemic control with oral therapy alone.

In a 26-week, open-label, randomized trial comparing the effects of exenatide and insulin glargine as add-on therapy in 551 patients with poorly controlled type 2 diabetes despite combination therapy with a sulfonylurea plus metformin, similar reductions in HbA_1c were seen in both treatment groups; exenatide had a greater effect on PPG, whereas insulin glargine had a greater effect on FPG.²² Nocturnal hypoglycemia occurred more frequently in the insulin glargine group, but nausea was considerably more common in the exenatide group. In that group, 9.5% of patients withdrew from the study because of adverse events, compared with 0.7% of patients in the insulin glargine group.

Exenatide is an effective addition to current oral therapy for patients who initially fail to achieve glycemic control; its use does not preclude the need for insulin as diabetes progresses. Exenatide and basal insulin appear to have complementary actions as adjuncts to oral therapy, although they have not been approved to be used together. Therefore, basal insulin may be the more appropriate choice when fasting glucose levels remain greatly elevated, as seen in patients with HbA_1c levels above 8.0%. Exenatide may be more beneficial in patients with HbA_1c levels under 7.5%, when PPG levels play the dominant role in determining HbA_1c value.^7,22,23

Conclusion

Recent practice guidelines confirm that HbA_1c measurement is the gold standard for assessing and monitoring glycemic control in patients with type 2 diabetes. However, FPG and PPG levels contribute to the overall HbA_1c value, and measurement of HbA_1c alone does not distinguish between the respective contributions of fasting and postprandial hyperglycemia.

Disclosure statement
Dr Nelson is a consultant to and receives honoraria from Sanofi-Aventis.

SELF-ASSESSMENT TEST

1. The ADA's recommended glycemic target in patients with type 2 diabetes is:

1. ≤ 6.0% HbA_1c
2. ≤ 6.5% HbA_1c
3. < 7.0% HbA_1c
4. < 7.5% HbA_1c

2. Which of the following statements about PPG is true?

1. Elevated PPG level increases the risk for CVD only when FPG and HbA_1c are also elevated
2. Elevated PPG level increases the risk for CVD, even when FPG and HbA_1c are normal
3. Elevated PPG level does not increase CVD risk in patients with normal FPG
4. Elevated PPG level does not increase CVD risk in patients with normal HbA_1c

3. All the following statements about insulin therapy in patients with type 2 diabetes are correct, except:

1. The ACE/AACE recommend combining insulin with oral agents early in the course of type 2 diabetes to achieve glycemic control
2. Insulin therapy is usually begun with 2 injections daily
3. Rapid-acting insulin is initiated with the largest meal of the day
4. Basal insulin may lower both FPG and PPG levels

4. Which of these agents is most often associated with nocturnal hypoglycemia?

1. NPH insulin
2. Insulin glargine
3. Insulin detemir
4. Insulin aspart

5. All these agents have been associated with weight gain, except:

1. Inhaled insulin
2. Insulin detemir
3. Exenatide
4. Insulin aspart

(Answers at end of references list)

References

1. Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, 2005. Atlanta, Ga: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2005. Available at www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf.
2. Resnick HE, Foster GL, Bardsley J, et al. Achievement of American Diabetes Association Clinical Practice Recommendations among US adults with diabetes, 1999-2002: the National Health and Nutrition Examination Survey. Diabetes Care. 2006;29:531-537.
3. American Association of Clinical Endocrinologists. Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement, February 2, 2005. Available at www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed April 13, 2007.
4. Rohlfing CL, Wiedmeyer HM, Little RR, et al. Defining the relationship between plasma glucose and HbA_1c: analysis of glucose profiles and HbA_1c in the Diabetes Control and Complications Trial. Diabetes Care. 2002;25:275-278.
5. UK Prospective Diabetes Study (UKPDS) group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) [published correction appears in Lancet. 1999;354: 602]. Lancet. 1998;352:837-853.
6. Stratton IM, Adler AI, Neil HA, et al, for the UK Prospective Diabetes Study group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405-412.
7. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA_1c. Diabetes Care. 2003;26:881-885.
8. American College of Endocrinology. American College of Endocrinology consensus statement on guidelines for glycemic control. Endocr Pract. 2002;8(suppl 1):5-11.
9. Tanne D, Koren-Morag N, Goldbourt U. Fasting plasma glucose and risk of incident ischemic stroke or transient ischemic attacks: a prospective cohort study. Stroke. 2004;35:2351-2355.
10. Goldberg RB, Mellies MJ, Sacks FM, et al, for the CARE Investigators. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 1998;98:2513-2519.
11. Gerich JE. Clinical significance, pathogenesis, and management of postprandial hyperglycemia. Arch Intern Med. 2003;163:1306-1316.
12. Coutinho M, Gerstein HC, Wang Y, et al. The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233-240.
13. de Vegt F, Dekker JM, Ruhe HG, et al. Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study. Diabetologia. 1999;42:926-931.
14. The DECODE Study Group, for the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001; 161:397-405.
15. Schrot RJ. Targeting plasma glucose: preprandial versus postprandial. Clin Diabetes. 2004;22:169-172.
16. Rave K, Bott S, Heinemann L, et al. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care. 2005;28:1077-1082.
17. Carroll MF, Izard A, Riboni K, et al. Fasting hyperglycemia predicts the magnitude of postprandial hyperglycemia: implications for diabetes therapy. Diabetes Care. 2002;25:1247-1248.
18. Riddle MC, Rosenstock J, Gerich J, for the Insulin Glargine 4002 Study Investigators. The Treat-to-Target Trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086.
19. Hermansen K, Davies M, Derezinski T, et al, for the Levemir Treat-to-Target Group. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes [published correction appears in Diabetes Care. 2007;30: 1035]. Diabetes Care. 2006;29:1269-1274.
20. Raslová K, Bogoev M, Raz I, et al. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes [published correction appears in Diabetes Res Clin Pract. 2006;72:112]. Diabetes Res Clin Pract. 2004;66:193-201.
21. Chapman TM, Perry CM. Spotlight on insulin detemir in type 1 and 2 diabetes mellitus. BioDrugs. 2005;19:67-69.
22. Heine RJ, Van Gaal LF, Johns D, et al, for the GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005; 143:559-569.
23. Kennedy L. Exenatide versus glargine—complementary therapies rather than competing [electronic letter; Rapid Response]. Ann Intern Med [serial online]. November 21, 2005. Available at www.annals. org/cgi/eletters/143/8/559. Accessed April 10, 2007.

Answers: 1. B; 2. B; 3. A; 4. D; 5. C.