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Treatment of the Patient With Diabetes: Importance of Maintaining Target HbA^Sub 1c^ Levels

Posted on: Friday, 25 February 2005, 15:00 CST

Key words: Diabetes mellitus - Diabetic complications - HbA^sub 1c^ - Insulin - Intensive glycemic control - Oral hypoglycemic agents

SUMMARY

Objective: To review clinical trial evidence supporting treatment of patients to a near-normal HbA^sub 1c^ target level and outline therapeutic strategies that optimize glycemic control.

Research design and methods: The current MEDLINE database and bibliographies were searched for literature relevant to diabetic complications, glycemic control, and the intensive management of diabetes meliitus.

Results: Two randomized trials, the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS), provided evidence that intensive glycemic control obtained with either intensive insulin or oral therapy effectively slowed the onset and progression of diabetic retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. An epidemiologic analysis of the UKPDS results showed a significant correlation between glycemie control and microvascular and cardiovascular disease risk and mortality rates.

Conclusions: ne results of clinical trials confirm that stringent levels of glycemic control can be attained through the use of intensive multiple-injection insulin regimens (administration of insulin 3 or more times daily by injection or an external pump with dosage adjustments as needed), oral monotherapy or combination therapy, or a combination of insulin and oral therapy. The expanded choices for oral agents and the availability of insulin analogs now provide physicians with the tools to tailor therapy to prevent or delay the devastating complications of diabetes. Indeed, newer insulin analogs, both short-acting (insulin lispro, insulin aspart) and long-acting (insulin glargine), are an important part of a treatment strategy to circumvent diabetes complications and overcome the shortcomings of conventional insulin preparations.

Introduction

Approximately 13 million people in the United States have been diagnosed with diabetes mellitus, and an estimated 5.2 million more have the disease but remain undiagnosed1. The incidence of diabetes is increasing at an alarming rate, as is the potential for increased morbidity and premature death in those affected1. Uncontrolled diabetes is associated with long-term microvascular and macrovascular complications2, including a 2- to 4-fold increased risk for adverse cardiovascular events3 and an annual mortality rate 2-3 times higher than that among nondiabetic individuals4. Apart from the burden of human pain and suffering, diabetes impacts the economy and the healthcare system. The direct and indirect costs of diabetes in the United States totaled $132 billion in 20025. In addition, the 2000 National Ambulatory Medical Care Survey indicated that 38% of patients with diabetes are managed by family physicians annually6, and that there are approximately 2800 prescriptions filled per day in the United States for diabetes treatment1.

Stringent treatment goals and the consistent monitoring of patients' glycemic control provide the foundation for establishing, adjusting, and changing treatment to restore metabolic control and, thus, improve long-term clinical outcomes. This article will review the clinical trial evidence supporting the need to treat patients to near-normal glycosylated hemoglobin (HbA^sub 1c^) target levels adhering to stringent standards of care. Therapeutic strategies to optimize glycemic control will be outlined. The current MEDLINE database and bibliographies were searched for literature relevant to diabetic complications, glycemic control, and the intensive management of diabetes mellitus.

Pathophysiology

The pathophysiology of type 1 diabetes results from the autoimmune destruction of the insulin-secreting β-cells in the pancreas7 whereas in patients with type 2 diabetes, the underlying process is the development of insulin resistance and the inability of pancreatic β-cells to adequately compensate for glycemic demands8. This results in an alteration in the normal physiologic biphasic pattern of insulin secretion, with the eventual loss of the first phase of prandial insulin secretion, which normally serves to inhibit hepatic glucose production in response to an intravenous glucose load. In addition, the second (postprandial) phase of insulin secretion is impaired, resulting in postprandial hyperglycemia.

Diagnosis

The current recommendation from the American Diabetes Association (ADA) for the diagnosis of diabetes9 defines a fasting plasma glucose (FPG) level ≤ 100mg/dL (≤ 5.6mmol/L) as normal. A FPG level ≥ 126 mg/dL (≥ 7 mmol/L), measured on 2 separate occasions, indicates diabetes. Subjects with FPG levels > 100 mg/dL but < 126 mg/dL should be diagnosed as having impaired glucose tolerance or prediabetes. In terms of overall glycemic control, the American College of Endocrinology (ACE) recently recommended a targeted HbA1c concentration of ≤ 6.5%10, which is a more rigid goal than that suggested by the ADA (< 7%)9. However, FPG remains the recommended defining value, both in screening for diabetes and as the initial treatment target9.

Treatment

Treatment of Type 1 Diabetes

Intensive glycemic control may be achieved in type 1 diabetes by multiple daily insulin injections (MDI)11, which deliver short- or rapid-acting insulins to prevent excessive meal-related glucose excursions, and intermediate- or long-acting insulin preparations to manage basal glycemia12. The pharmacokinetic parameters of onset, peak action, and duration of action vary among these insulins and are indicated in Table 1.

Prandial insulins are administered before meals to regulate postprandial glycemic levels. This treatment approach typically involves short-acting regular human insulin. Used alone, however, regular insulin rarely achieves the intended level of glycemic control because it diffuses slowly from the injection site, resulting in limited absorption13. Other problems associated with regular insulin include the risks of severe hypoglycemia, coma, and postprandial hyperglycemia14. The rapid-acting insulin analogs insulin lispro15 and insulin aspart16 are associated with a lower incidence of severe hypoglycemia and postprandial hyperglycemia due to their faster absorption rates. Although the time to onset and duration of action of these 2 insulins are similar, insulin aspart attains a peak action more quickly than insulin lispro16.

The goal of basal insulin supplementation is to maintain near- normal glucose levels between meals and overnight. These insulin preparations are administered in the evening or at bedtime in MDI regimens and include the intermediate-acting neutral protamine Hagedorn (NPH) insulin and lente insulin (Humulin* L), split-mixed insulin (Novolint N), the long-acting ultralente insulin (Ultralentet), and the new insulin analog insulin glargine (Lantus).

Significant limitations exist with the 2 intermediateacting insulins and ultralente insulin. The peak-action patterns of NPH and lente contribute to nocturnal hypoglycemia when used as the basal component of an MDI regimen. Also, ultralente is characterized by a wide peak effect and variable duration of action. In addition, these insulin products vary widely with regard to absorption into the systemic circulation and, thus, to reproducibility of effect and outcome17. Alternatively, the pharmacokinetics of insulin glargine exhibit no pronounced plasma peaks or troughs in insulin concentration during a 24-hour period18, allowing for better glycemic control with a lower risk of hypoglycemia19. Also, the more consistent absorption of insulin glargine promotes less variability of effect compared with NPH and ultralente insulins20.

Treatment of Type 2 Diabetes

Initial treatment strategies for patients with type 2 diabetes include diet and exercise. With time, however, these measures alone become insufficient to maintain glycemic control. Studies indicate that only a small percentage of newly diagnosed type 2 diabetes patients achieve near-normal FPG levels (< 6 mmol/L) with dietary modification alone after 3 months21. Monotherapy with an oral agent or combination therapy involving > 1 oral agents plus insulin is eventually required22.

Table 1. Time-action characteristics of available insulins*

Table 2. Hypoglycemic agents used in type 2 diabetes9,11,22-31

Oral Hypoglycemic Agents

The number and type of oral hypoglycemic agents has increased significantly in recent years. These agents differ with regard to drug class, target organ, mechanism of action, efficacy in lowering HbA^sub 1c^ concentration, and associated adverse events (Table 2)9,23-28. Sulfonylureas are secretagogues that augment overall insulin secretion25, while the meglitinides, repaglinide and nateglinide, are secretagogues that augment prandial insulin secretion26,28. Metformin and the thiazolidinediones, rosiglitazone and pioglitazone, enhance insulin action on peripheral and hepatic tissues9,23,27, and acarbose and miglitol decrease the absorption rate of complex carbohydrates from the gut9,24.

Oral agents are initially used as monotherapy. The clinicians' choice of oral hypoglycemic medication must be based on a variety of factors, including patient characteristics and disease stage, the level of glycemic control desired, and treatment contraind\ications and potential adverse reactions (Table 2)11,22-24,26-31. However, the natural history of type 2 diabetes, where β-cell function declines over time, does not allow for maintenance of desirable glycemic control using endogenous insulin and, therefore, often fails. Upon failure of monotherapy, a second oral agent with a complementary mechanism of action should be added to the existing regimen. Such combination regimens address the dual defects present in type 2 diabetes, thus providing additive glucose-lowering efficacy. For example, the combination of metformin and a second oral hypoglycemic agent has been shown to significantly lower mean fasting glucose FPG levels and HbA^sub 1c^ concentrations compared with metformin alone32. Unfortunately, failure of dual oral combination therapy may eventually ensue in > 40% of patients33. Clinical evidence on the usefulness of triple oral combination therapy is limited34.

Insulin/Oral Combination Therapy

The addition of insulin to oral monotherapy or oral combination regimens that no longer control hyperglycemia has been proven effective and safe35-37. Moreover, lower doses of insulin are required to improve HbA^sub 1c^ concentrations when the insulin is given as part of a combination regimen than when it is given alone35.

Several successful strategies exist for combining insulin and oral hypoglycemic agents. A simple approach is to use an intermediate- or long-acting insulin at bedtime to regulate basal glucose levels and a sulfonylurea to control daytime glycemia38. Although NPH insulin is associated with nocturnal hypoglycemia, these regimens often use NPH insulin for basal coverage22. Emerging data confirm the improved safety profile of insulin glargine relative to NPH, with respect to the risk of hypoglycemia36,37,39. Indeed, a study evaluating the comparative efficacy of insulin glargine and NPH in insulin-naive patients with type 2 diabetes poorly controlled with oral therapy (1 or 2 agents) showed comparable improvements in glycemic control but significantly lower rates of hypoglycemia, particularly nocturnal episodes, with insulin glargine36,37. An alternative way to add insulin to an existing regimen of oral agents is to combine prandial insulin (regular insulin or a fast-acting insulin analog such as insulin lispro) with a sulfonylurea, with or without insulin sensitizers, to improve postprandial glycemic control40,41.

Any therapy plan using insulin or agents that target insulin secretion increases the risk of hypoglycemia. Elderly patients who depend on others for meals are at higher risk of hypoglycemia, and therefore special attention is required for these individuals. Patients unable or unwilling to perform glucose self-monitoring are also at higher risk for hypoglycemic reactions. To decrease the risk of hypoglycemic episodes, the patients and their families/ caregivers must be educated on the symptoms of hypoglycemia, the proper use of glucose self-monitoring and the importance of proper and timely nutrition. For hypoglycemic events in insulin-treated patients, most commonly seen in type 1 diabetes, prevention through patient education must be the first goal. Severe hypoglycemia is rare in patients with type 2 diabetes, but it does occur, and when it happens the treatment is as important as if it happened in a patient with type 1 diabetes. If the patient is able to self-treat, the use of glucose tablets or any rapidly absorbed carbohydrate can improve the patient's status. If the patient is impaired and/or unable to self-treat, the ideal treatment is administration of subcutaneous glucagon, but in order to do so, a third person must know how and when to administer the medication. Educating a relative and friends is the recommendation. If the patient has some degree of renal impairment and is being treated with long-acting insulin secretagogues, the recommendation must include hospitalization and observation until glucose levels are stable.

Prognosis

Long-term Complications of Diabetes

Over the past few decades, evidence from epidemiologic studies has established a clear correlation between the level of a patient's glycemic control, as assessed by HbA^sub 1c^ concentration, and the incidence and progression of diabetes-related microvascular and macrovascular disease. Population-based data demonstrated significantly higher 10-year trends for the development and, in some cases, progression of microvascular complications in patients with higher HbAk concentrations at baseline42. In terms of macrovascular sequelae, higher baseline HbA^sub 1c^ concentrations (higher quartiles) strongly predicted the 3.5-year incidence of cardiovascular events, related death, and stroke in a randomly selected Finnish population sample43, while each percentage point increase in HbA^sub 1c^ was accompanied by a 10% increase in mortality from all forms of heart disease and stroke among patients in a large Wisconsin cohort44.

Similarly, the Norfolk cohort of the European Prospective Investigation of Cancer and Nutrition also found HbA^sub 1c^ concentrations predictive of death from cardiovascular disease as well as all-cause mortality across the entire population, with the relative risk following a constantly increasing gradient throughout the entire range of HbA^sub 1c^ categories (< 5%; 5%-5.4%; 5.5%- 6.9%; ≥ 7%). The lowest rates of cardiovascular death were noted among patients with HbA^sub 1c^ concentrations < 5%, and each percentage point increase in HbA^sub 1c^ concentration was associated with a 28% increase in risk for cardiovascular death, even after adjusting for other cardiovascular risk factors. Given the fact that the patient samples in the Finnish and Norfolk cohorts were population-based, the serious clinical implications of these findings may apply to the general population.

Importance of Intensive Glycemic Control: Clinical Research Evidence

The correlation between risk of microvascular complications and blood glucose control was elucidated by the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS), which were powered to detect differences in outcome regarding glycemic goals and the development of complications between conventional and intensive treatments2,11. The results of these studies support the use of intensive glycemic control by treating to target HbA^sub 1c^ percentage as close to normal as possible to reduce the risk of complications and mortality in diabetes patients.

Diabetes Control and Complications Trial

The DCCT, a large, multicenter, randomized, controlled trial, evaluated the effect of intensive therapy (treating to target HbA^sub 1c^ percentage of 6% [normal range, 4%-6%]) on the incidence and progression of complications in patients with type 1 diabetes11. The development and progression of retinopathy and other complications were compared over an average period of 6.5 years in patients who had no (primary-prevention cohort) or mild (secondary- intervention cohort) retinopathy at baseline and were randomized to either conventional or intensive treatment regimens. The conventional regimen consisted of 1 or 2 daily injections of mixed intermediate- and rapid-acting insulins, while the intensive regimen consisted of 3 or more daily insulin injections or insulin provided by an external pump with dosage adjustments made as needed.

Glycemic control, as measured by HbA^sub 1c^, was significantly improved (p < 0.001) with intensive treatment, and was associated with marked reductions in the incidence and severity of microvascular complications. Intensive therapy reduced the risk of retinopathy by 76% (95% CI 62-85) in the primary cohort compared to conventional therapy. In both cohorts, intensive therapy reduced the incidence of nephropathy (defined as a urinary albumin excretion [UAE] of ≥ 40 mg per 24 h) by 39% (95% CI 21-52), albuminuria (UAE ≥ 300 mg per 24 h) by 54% (95% CI 19-74), and neuropathy by 60% (95% CI 38-74)11. Statistical analysis of the results revealed a direct relationship between reductions in HbA^sub 1c^ and the reduced risk of complications such as retinopathy: for every 10% reduction in HbA^sub 1c^ percentage there was a 39% reduction in the risk of retinopathy45.

The results of this study demonstrate the effect of stringent blood glucose control on retinopathy, nephropathy, and neuropathy, and clearly indicate a direct relationship between glycemic control and the occurrence or progression of microvascular complications46. However, the analysis of the relationship between cardiovascular outcomes and mortality revealed only a non-significant trend for a lower incidence of major macrovascular events with intensive treatment46.

UK Prospective Diabetes Study

The objective of this large landmark study (n = 3867) was to evaluate whether intensive therapy to achieve tight glycemic control would result in a greater reduction in the incidence of microvascular and macrovascular complications than would conventional therapy in patients newly diagnosed with type 2 diabetes2. Patients were randomized to intensive therapy (a sulfonylurea or insulin if non-obese, metformin if obese) with FPG targets < 108mg/dL (< 6 mmol/L) and preprandial glucose levels between 72 mg/dL and 126 mg/dL (4 mmol/L and 7 mmol/L), or conventional therapy, which involved dietary modification only.

Over a 10-year follow-up period, intensive treatment significantly reduced mean HbA^sub 1c^ concentrations compared with conventional treatment (7.0% vs. 7.9%; p < 0.0001) and also reduced the risk for kidney failure, amputation, retinopathy, and other microvascular complications by 25%2. Furthermore, a direct relationship was identified between glycemia and the risk of microvascular complications (Figure 1)47. The rate of increased risk of macrovascular disease with hyperglycemia was much lower in the intensively treated patients (Figure 2)47, as were the risks f\or death (Figure 3)47. For every 1% decrease in HbA^sub 1c^, the risk of microvascular complications was reduced by 37% (p < 0.0001), that of amputation or death from peripheral vascular disease by 43% (p < 0.0001), and that of stroke by 12% (p < 0.05). Unlike the DCCT, this trial did find significant cardiovascular benefits and reduced mortality when patients were treated to stringent, near-normal glycemic levels47. The risk of myocardial infarction and all-cause mortality was reduced by 14%, and death from any diabetes-related cause by 21% (p < 0.0001) for every 1% decrease in HbA^sub 1c^.

Mirroring the results of the DCCT for type 1 diabetes patients, the UKPDS found no HbA^sub 1c^ threshold for the risk of microvascular complications, macrovascular events, or mortality in type 2 diabetes patients (Figures 1, 2, and 3)47.

Figure 1. Incidence of fatal and nonfatal microvascular disease as a function of updated HbA^sub 1c^ concentrations (value at each specific follow-up) in patients with type 2 diabetes participating in the UKPOS, who were followed for a mean of 10 years47

Figure 2. Incidence of myocardial infarction by updated HbA^sub 1c^ concentrations (value at each specific follow-up) in UKPDS patients followed for a mean of 10 years47

Figure 3. Incidence of death related to diabetes and all-cause mortality in UKPDS patients followed for a mean of 10 years47

Table 3. Changes over time in guidelines for evaluating hyperglycemia48

Redefining Optimal Glycemic Control

Treatment recommendations have evolved since the 1993 publication of the DCCT results, gradually lowering the HbA^sub 1c^ value for initiating or changing treatment (Table 3)48. The ADA currently recommends target HbA^sub 1c^ values < 7% (Table 4)9. Most recently, the ACE and the European Association for the Study of Diabetes (EASD) have proposed a treatment goal (HbA^sub 1c^ < 6.5%) closer to the normal glycemic range defined by the DCCT (4%-6%) (Table 4)10. Treatment guidelines and specific treatment algorithms have been modified to reflect these updated recommendations.

The need to avoid hyperglycemia has led to more stringent diagnostic criteria for diabetes (Table 5)9, which is essential to prevent or delay early microvascular and macrovascular injury associated with the disease. The high rates of serious complications currently observed in patients with diabetes are due, in part, to the existing pattern of relatively late diagnosis, ineffective treatment, and poor monitoring of glycemic control by the patient and practitioner49.

Table 4. Treatment goals for individuals with diabetes9,10

Table 5. Criteria for the diagnosis of diabetes9

Conclusion

Several landmark studies have provided evidence to link glycemic control and the reduction of risk of diabetic complications. Aggressive treatment is the most effective means of achieving and maintaining near-normoglycemia, which is imperative to prevent or delay the onset and progression of long-term microvascular complications of the disease. Every effort should be made to safely attain HbA^sub 1c^ concentrations ≤ 6.5%, as recommended by ACE and the International Diabetes Federation (IDF). Together with the expanded armamentarium of oral hypoglycemic agents and recent improvements in insulin therapy, including the development of insulin analogs, greater opportunities to safely reach target glycemic goals exist. The expanded choices for oral agents and the availability of insulin analogs now provide physicians with the tools to tailor therapy to prevent or delay the complications of diabetes.

Acknowledgment

This manuscript was supported by an unrestricted educational grant from Aventis Pharmaceuticals, Inc.

* Humulin is the tradename of Eli Lilly and Company, Indianapolis, IN

[dagger] Novolin is the tradename of Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ

[double dagger] Ultralente is the tradename of Eli Lilly and Company, Indianapolis, IN

Lantus is the tradename of Aventis Pharmaceuticals, Inc., Bridgewater, NJ

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2740_5, Accepted for publication: 09 September 2004

Published Online: 11 November 2004

doi:10.1185/030079904X6291

Jaime A. Davidson

Endocrine and Diabetes Associates of Texas, Dallas, TX, USA

Address for correspondence: Jaime A. Davidson, MD, Endocrine and Diabetes Associates of Texas, 7777 Forest Lane, Suite C-204, Dallas, TX 75230, USA. Tel.: +1-972-566-7020; Fax: +1-972-566-7943; email: Endodiab@medicalcitydallas.com

Copyright Librapharm Dec 2004

Source: Current Medical Research and Opinion

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