Dr. Ford is a clinical pharmacy specialist, University of North Carolina Hospitals, Departments of Pharmacy and Family Medicine.
Type 2 diabetes is an important and growing health concern. Of the 20.8 million Americans with type 2 diabetes, it is estimated that 6.2 million are undiagnosed. 1 Additionally, 54 million people have prediabetes (encompassing impaired fasting glucose and impaired glucose tolerance), putting them at high risk of developing type 2 diabetes. 1
Patients with diabetes are at increased risk of cardiovascular disease and are also at risk for microvascular complications of diabetes, such as retinopathy, neuropathy, and nephropathy. Although many medications are available to lower blood glucose and reduce the risk of cardiovascular disease, many diabetes patients continue to have suboptimal glycemic control, and the risk of death from cardiovascular disease remains 2 to 4 times higher. 1
Goals of Therapy
The goals of treatment for patients with type 2 diabetes as defined by the American Diabetes Association (ADA) are listed in the table. 2 The A1C blood test provides a picture of average blood glucose control over a 2- to 3-month period. The ADA recommends a general A1C goal of <7%, although a goal of achieving a near normal A1C (<6%) is recommended for individual patients if this can be accomplished without significant hypoglycemia. Similarly, less stringent A1C goals may be suitable in specific patients, such as those with a history of severe hypoglycemia or those with limited life expectancies. Lowering premeal plasma glucose is recommended as the initial target to reduce A1C, but postprandial glucose is an appropriate target in patients who fail to meet A1C goals despite having premeal glucose levels in the target range.
Management of Type 2 Diabetes
Although many medications are available to lower A1C, there is a lack of prospective data to indicate which medication, if any, is superior to the others, or which combination of medications best lowers A1C and reduces the risk of complications from diabetes with minimal adverse effects.
The UK Prospective Diabetes Study (UKPDS) randomized patients with type 2 diabetes to conventional control aimed at maintaining blood glucose less than 270 mg/dL without symptoms of hyperglycemia, versus intensive control with sulfonylurea, insulin, or metformin aimed at lowering blood glucose to "near normal values" of fasting glucose less than 108 mg/dL. 3,4 Patients in the conventional-control group had a median A1C of 7.9%, compared with an A1C of 7% in the intensivecontrol arm over 10 years of follow-up. This absolute reduction in A1C of 0.9% corresponded to a 25% decrease in microvascular complications; the difference in rates of cardiovascular disease or mortality between the 2 groups was not statistically significant in the overall population. 3
Data from the UKPDS indicate that improved glycemic control, rather than an effect of any one medication, leads to a reduction in complications. Therefore, in the absence of clear evidence of the superiority of one medication over another, treatment regimens to improve glycemic control are made on the basis of anticipated A1C reduction, adverse effects, and cost. 5
Physical activity and diet modification are important in the prevention and control of type 2 diabetes. The ADA recommends lifestyle intervention programs aimed at weight loss and increased activity levels as an integral part of diabetes management. 2,5 These programs, however, have had limited long-term success in maintaining glycemic control, and even patients initially controlled with lifestyle modification alone will likely require medication as their disease progresses.
Metformin works primarily to reduce hepatic gluconeogenesis and produces absolute reductions in A1C of 1% to 2%, mostly due to reductions in fasting glucose. The most common adverse effect of metformin is gastrointestinal upset, especially upon initiation and with dose increases. These effects can generally be minimized by starting at low doses, increasing the dose in 1- to 2-week intervals, and counseling patients to take metformin with a meal. Metformin does not substantially increase the risk of hypoglycemia when used as monotherapy and is weight-neutral or may lead to minimal weight loss. Lactic acidosis is a very rare, but potentially lifethreatening adverse effect. Metformin is commonly used first-line, especially in overweight patients, because of its relatively potent effects on A1C, tolerability, and evidence that it may lower the risk of cardiovascular events in overweight patients with type 2 diabetes. 5
Sulfonylureas are insulin secretagogues that bind to a receptor on the pancreatic beta cell to increase insulin release. They, like metformin, lead to an absolute reduction in A1C of 1% to 2% and are generally well-tolerated. The most common adverse effects of sulfonylureas are weight gain and hypoglycemia. Hypoglycemia experienced with sulfonylureas is generally mild, although uncommonly patients can experience severe hypoglycemia necessitating outside assistance.
Taking insulin is the most effective method of achieving glycemic control. Insulin has no maximum dose at which it loses effectiveness, and the major limitation to increasing the dose is hypoglycemia. Patients with type 2 diabetes may require much higher doses of insulin than patients with type 1 diabetes because of insulin resistance. Weight gain and hypoglycemia, which can be severe, are the most common adverse effects.
Sulfonylureas, metformin, and insulin are the backbone of the treatment of type 2 diabetes because they are known to not only improve glycemic control, but also to reduce complications of diabetes. 2,5 Many other medications are available to lower A1C, however. The thiazolidinediones- rosiglitazone and pioglitazone- primarily increase peripheral insulin sensitivity and lower A1C on average 0.5% to 1.5%. Adverse effects of the thiazolidinediones include weight gain and peripheral edema, and they have been linked to increased rates of heart failure and heart-failure exacerbations. Recently, reports have surfaced concerning other cardiovascular risks associated with thiazolidinedione use, but the true cardiovascular effects of these medications remain unknown. Thiazolidinediones are not recommended in patients with New York Heart Association (NYHA) class III or IV heart failure and should be used cautiously in patients with NYHA class I or II heart failure. 6
Other medications that primarily target postprandial hyperglycemia, including the meglitinides (repaglinide and nateglinide), -glucosidase inhibitors (acarbose and miglitol), sitagliptin, pramlintide, and exenatide, lower A1C by 0.5% to 1%. These medications may be useful in meeting glycemic goals by targeting postprandial hyperglycemia in patients who have met preprandial glucose goals but have failed to achieve the treatment goal level for A1C. Although these medications have been shown to lower A1C, they have not been assessed to determine their effects on microvascular or macrovascular complications of diabetes.
Since patients with diabetes are at a substantially increased risk of cardiovascular disease, other risk factors for cardiovascular disease should be treated aggressively. Blood pressure should be treated to a goal of less than 130/80 mm Hg, and lifestyle and pharmacologic interventions should target a low-density lipoprotein (LDL) cholesterol level of less than 100 mg/dL. 2 A lower target of LDL less than 70 mg/dL is an option in patients with diabetes and overt cardiovascular disease. Additionally, initiation of a statin is recommended regardless of baseline cholesterol levels in patients with diabetes over the age of 40. 2 Aspirin is indicated in all patients with type 2 diabetes older the age of 40 and in those patients younger than 40 years of age with additional risk factors for cardiovascular disease, unless contraindicated. 2 Finally, smoking status should be assessed in all patients, and patients should be advised to quit smoking and offered appropriate behavioral therapy and pharmacotherapy as applicable.
Type 2 diabetes is a major public health concern due to its increasing prevalence and associated morbidity. Improved glycemic control and aggressive management of other risk factors for cardiovascular disease are important to prevent complications of diabetes.
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.
2. American Diabetes Association. Standards of medical care in diabetes-2007. Diabetes Care. 2007;30:S4-S41.
3. 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). Lancet. 1998;352: 837-853.
4. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-865.
5. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963-1972.
6. Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Circulation. 2003;108:2941-2948.