Which of these is the most helpful in evaluating this patient’s long term glucose management?
Diabetes mellitus is a chronic and devastating disease, affecting 8% of the US population.1 Despite recent advances in diagnostic and therapeutic options, the incidence of diabetes continued to rise in 2007. According to the Centers for Disease Control and Prevention, approximately 24 million Americans are currently diagnosed with diabetes, an increase of 3 million over the past 2 years, and another 57 million are classified as having prediabetes.1 About one third of the people with diabetes remain undiagnosed. Show
Worldwide, the prevalence of diabetes is projected to reach 366 million people by the year 2030.2 Major increases in both macrovascular and microvascular complications can be projected on the basis of this growing prevalence. Indeed, recent studies have reported that life expectancy is reduced in patients with diabetes, with an estimated risk of death about twice that of the general population of similar age.1,3 Men and women who are diagnosed with diabetes before the age of 40 have an average life expectancy reduction of 12 and 19 years, respectively.4 The cost of diabetes to the US healthcare system is staggering; it was estimated to be around $174 billion in direct ($116 billion) and indirect ($58 billion) costs in 2007.1 Data from the United Kingdom Prospective Diabetes Study Group, the Diabetes Control and Complications Trial, and the Kumamoto study have clearly shown that early and aggressive glycemic interventions can reduce the risk of microvascular complications—retinopathy, nephropathy, and neuropathy—of diabetes.5-7 Despite this knowledge, studies continue to show that most Americans with diabetes are not achieving the recommended treatment goals. Recent data from the National Health and Nutrition Examination Survey reported that only one third of diabetic patients are at goal with regard to glycemic and blood pressure control, and only half are meeting their cholesterol goals.8 It is hopeful that the availability of published guidelines and algorithms will aid physicians to bring more patients to the desired glycemic, blood pressure, and lipid goals. Diagnosis
Table 1 Screening
Table 2
PreventionPrevention of progression to diabetes is essential, considering the serious medical and economic consequences of the disease and the lack of cure. Several clinical trials have demonstrated that lifestyle modifications alone or in conjunction with pharmacologic therapies can prevent or delay the development of type 2 diabetes. Individuals who lose 7% of their body weight and maintain 150 minutes of exercise weekly can reduce the rate of progression from impaired glucose tolerance (IGT) to diabetes by 58%.17 Studies have demonstrated that the use of several pharmacologic agents—metformin,17 orlistat,18 acarbose,19 and troglitazone20—can successfully reduce the progression of IGT and impaired fasting glucose (IFG)9 to diabetes, although to a lesser degree than diet and exercise. The ADA endorses lifestyle modifications as the initial treatment for prediabetes. If pharmacologic intervention is required, metformin is the only drug that is recommended in conjunction with diet and exercise in high-risk patients (those with both IGT and IFG).9 Glycemic Control
Table 3 Methods to achieve glycemic goals are lifestyle modifications and pharmacologic treatments. Although lifestyle modifications (ie,
diet, exercise, and/or behavioral interventions) remain the best and first-line treatment, most patients will not be able to follow a rigid diet and exercise regimen and will eventually require the use of antihyperglycemic medications. Treatment Options
Figure Oral Antihyperglycemic Agents Table 4 Biguanides (sensitizers). Metformin is the only biguanide available in the United States. Its main action is to decrease hepatic glucose production and enhance insulin sensitivity. As monotherapy, metformin is very effective in decreasing plasma glucose level, reducing HbA1C by approximately 1% to 2% compared with diet or placebo.22 Aside from its glycemic effect, metformin also lowers triglycerides and low-density lipoprotein cholesterol.23 By itself, it does not cause weight gain nor hypoglycemia.24 Gastrointestinal (GI) discomfort, which usually resolves over time with continuation of the medication or dose reduction, is the most common side effect of metformin. To minimize the risk of lactic acidosis, metformin should not be given to patients with renal dysfunction (serum creatinine ≥1.5 mg/dL in men, ≥1.4 mg/dL in women). Because of its cost and benign side-effect profile, metformin is considered a first-line drug in the treatment of diabetes. It can be used concurrently with lifestyle modifications at the time of diagnosis or even for diabetes prophylaxis.9,22 To date, it remains 1 of only 2 oral antihyperglycemic medications that have been shown to reduce macrovascular complications.23 Sulfonylureas (secretagogues). Sulfonylureas are the oldest class of antihyperglycemic agents, first introduced to the US market in 1946. Their primary action is to promote insulin secretion from the pancreas. Similar to metformin, sulfonylureas are effective at decreasing plasma glucose level, reducing HbA1C by approximately 1% to 2%.22 Hypoglycemia and weight gain are the 2 major side effects of this class. Because they are the least expensive of all antihyperglycemic medications, sulfonylureas—which are second-line agents after lifestyle modifications and metformin—are the drugs of choice for patients with financial considerations. Nonsulfonylurea secretagogues (secretagogues). Repaglinide (a meglitinide) and nateglinide (a phenylalanine) function in the same manner as sulfonylureas, by increasing insulin secretion from the pancreas, and they reduce HbA1C at the same level (–1.5%).22 They are structurally different from the sulfonylureas and have a faster onset of action; thus, they should be taken at mealtime to reduce the risk of hypoglycemia.23 Because these agents are metabolized exclusively by the liver, they can be used in patients with renal insufficiency.25 In head-to-head trials against sulfonylureas, meglitinides and phenylalanines have not been found to be superior in terms of improving postprandial control.26,27 At a cost of 3 to 4 times more than sulfonylureas,23 it is unlikely that these drugs will be widely used. Alpha-glucosidase inhibitors (carbohydrate absorption inhibitors). Alpha-glucosidase inhibitors delay carbohydrate absorption in the small intestine, thereby lowering postprandial blood glucose without causing hypoglycemia.28 They do not cause weight gain but are associated with significant GI side effects (ie, diarrhea, abdominal pain, flatulence)24; thus, long-term compliance is a significant issue with these drugs. Unlike the biguanides, alpha-glucosidase inhibitors are not considered first-line therapy because of their minimal glycemic control (HbA1C –0.5%)22 and higher costs.23 Thiazolidinediones (sensitizers). Thiazolidinediones (TZDs; rosiglitazone and pioglitazone) reduce insulin resistance by binding to peroxisome proliferator–activated receptors-? (PPAR-?) in the peripheral muscles, liver, and adipose tissues. This, in turn, alters the transcription of genes that positively regulate glucose uptake. As monotherapy, they lower HbA1C by 0.5% to 1.4%.22 Their onset of action is slower than that of the sulfonylureas, but they do not cause hypoglycemia.28 In addition to lowering blood glucose, these agents exert beneficial effects on lipid metabolism, as well as improve surrogate markers for pancreatic betacell regeneration and vascular inflammation.15,28 A recent meta-analysis has raised the possibility that rosiglitazone may increase the risk of myocardial infarction (not seen with pioglitazone).29 Because of the methodological limitations of this analysis, numerous studies, including one from the US Food and Drug Administration (FDA),30 were subsequently initiated to reevaluate these findings. Results from these studies were mixed and inconclusive,30-32 prompting the FDA to recommend caution in the use of TZDs and to mandate the inclusion of a black box warning in the package inserts of TZDs relaying the 2-fold increased risk of fluid retention and heart failure with this class.33 The future of TZDs remains strong. But at a cost of 2 to 3 times more than the cost of metformin, TZDs should only be considered after failure of lifestyle modifications and metformin.9 DPP-4 inhibitors. These medications represent the newest class of oral antihyperglycemic medications, introduced to the US market in 2006. This class inhibits the breakdown of endogenous glucagon-like peptide 1 (GLP-1),15 a compound that can control or even reverse some of the metabolic derangements seen in type 2 diabetes. Sitagliptin, the only FDA-approved drug in this class to date, has been shown to lower HbA1C by 0.5% to 0.8%.22 One advantage of this DPP-4 is that it only works when blood glucose is elevated; thus, the risk for hypoglycemia is minimal. Other advantages include once-daily administration, oral availability, and, more important, weight neutrality.34 Sitagliptin is effective and safe in patients with renal insufficiency, including those on hemodialysis; however, dose adjustments will be necessary based on the severity of renal impairment.35 Although the appropriate role of DPP-4 inhibitors is still unclear, sitagliptin's efficacy and safety profile suggests that this class is a reasonable treatment option for type 2 diabetes. Parenteral Antihyperglycemic Agents Table 5 Table 6 Insulins. Insulin is the best agent for reducing blood glucose concentrations. It is mandatory in patients with type 1 diabetes but is a second-line therapy for patients with type 2 diabetes who have failed lifestyle modifications with or without oral antihyperglycemic therapy.22 Patients receiving insulin therapy are more likely to develop hypoglycemia and weight gain than patients taking oral medications.36 However, the recent advent of rapid-acting as well as long-acting insulins has significantly reduced these risks.24 Insulin detemir, the newest long-acting insulin analog in the United States, has consistently shown in clinical trials to be very effective in reducing blood glucose levels with less weight gain than other basal insulins.37 Incretin mimetics. Incretins are hormones that are secreted by cells in the small intestine during an oral nutrient load. GLP-1 is one incretin that has antihyperglycemic effects. In the presence of hyperglycemia, GLP-1 causes the release of insulin from the pancreas, shuts down glucagon secretion, slows down gastric emptying, and acts on the hypothalamus to increase satiety.38 Exenatide is the first synthetic GLP-1 to be introduced in the United States. Possessing many of the properties of endogenous GLP-1, exenatide can lower HbA1C by 0.5% to 1%.22 Aside from its antiglycemic effect, exenatide can also induce weight loss. Patients who were treated with exenatide for 30 weeks had an average weight loss of 4.4 kg,39 which was maintained when the study was extended for another 22 weeks using a longer-acting version of exenatide.40 Nausea is the most common side effect of exenatide, which usually subsides with continuation of this medication.38 The FDA has recently alerted physicians to 6 cases of necrotizing pancreatitis thought to be related to exenatide use41; this is in addition to the 30 cases of nonnecrotizing pancreatitis reported by the FDA in October 2007. Although the exact relationship between pancreatitis and the drug is still unknown, it is recommended that patients receiving exenatide and presenting with abdominal pain be evaluated promptly. Amylin analogs. Amylin is a neuropeptide that is cosecreted with insulin by pancreatic beta-cells in response to food intake. Amylin complements insulin's action by suppressing glucagon release, slowing gastric emptying, and inducing satiety.15,42 Pramlintide is the only amylin analog currently available in the United States. Approved as an adjunctive treatment for patients with type 1 or type 2 diabetes who are not optimally controlled with short-acting insulin (mealtime insulin), pramlintide can lower HbA1C by 0.5% to 1%.22 To lower the risk of hypoglycemia, the dose of premeal insulin should be reduced by 50% when pramlintide is initiated. In clinical trials, the use of pramlintide has been associated with modest weight loss.42 The most common side effect is nausea, which usually subsides with continuation of treatment. The availability of a pen formulation has made pramlintide more user-friendly; however, the future of this drug class is still uncertain because of its cost, need for multiple injections, and relatively modest therapeutic profile. Table 7 In the Pipeline
ConclusionsLifestyle modification is recognized as the mainstay of therapy for diabetes. Metformin is considered the first-line oral antihyperglycemic drug. If immediate lowering of blood glucose level is required, insulin should be used. Exenatide and DPP-4 inhibitors are 2 new classes with favorable weight profiles. Optimal management should focus not only on glycemic control but also on comorbid conditions that often accompany this potentially life-threatening condition, including hypertension, dyslipidemia, and obesity. Disclosure Statement Dr Felicetta is on the Speaker's Bureau of Merck and sanofi-aventis. Drs Nguyen and Nguyen have no potential or apparent conflict of interest to report. References
What is the best measure of long term blood glucose control?Glycated hemoglobin (A1C, hemoglobin A1C, HbA1c), which reflects average levels of blood glucose over the previous two to three months, is the most widely used test to monitor chronic glycemic control. It is used to diagnose diabetes and to monitor the efficacy of treatment.
What test is most effective in evaluating the effectiveness of long term diabetes management?Besides daily blood sugar monitoring, your provider will likely recommend regular A1C testing to measure your average blood sugar level for the past 2 to 3 months. Compared with repeated daily blood sugar tests, A1C testing shows better how well your diabetes treatment plan is working overall.
What is the gold standard for monitoring long term glucose control?HbA1c provides a reliable measure of chronic glycemia and correlates well with the risk of long-term diabetes complications, so that it is currently considered the test of choice for monitoring and chronic management of diabetes.
Which is the most important for the successful management of diabetes mellitus?A key to many diabetes management plans is learning how to count carbohydrates. Carbohydrates often have the biggest impact on your blood sugar levels. For people taking mealtime insulin, it's important to know the amount of carbohydrates in your food, so you get the proper insulin dose.
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