Endocrinologists offer updated recommendations to increase glycemic control and avoid complications. Here is a quick summary.
The American Association of Clinical Endocrinologists (AACE) has released new guidelines to help the practitioner caring for patients with diabetes mellitus.1 Several well-designed, large-scale trials have demonstrated that tight glycemic control can yield benefits in end-organ/complication prevention. As the guidelines show, these results have given clinicians additional reason to intensify glycemic control in attempts to prevent and/or minimize the severity of microvascular and macrovascular complications. Despite these efforts, only 7% of patients with type 2 diabetes who receive their care in academic centers achieve recommended goals for glycemia, lipids, and BP.
A growing problem
An estimated 7% of the U.S. population has diabetes, and twice that number has prediabetes, which carries with it a risk for progression to full-blown diabetes at the rate of approximately 11% a year. Prevalence is increasing, with lifetime risk of developing diabetes for individuals born in 2000 approaching 33%. And prevalence is increasing at both ends of the age spectrum, with 21% of patients over age 60 affected. In addition, type 2 diabetes is being diagnosed at younger ages. Up to 45% of new diagnoses are being made in children and adolescents in certain high-risk populations.
Because complications are related to degree of hyperglycemia and duration of disease, early diagnosis and screening are the cornerstones of good care. All at-risk patients older than 30 years should be screened; risk factors include family history, cardiovascular disease, obesity, and a sedentary lifestyle. Several ethnic groups are also more susceptible: Latinos, non-Hispanic blacks, Asian Americans, Native Americans, and Pacific Islanders. Also at risk are individuals with a history of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) (i.e., prediabetes), hypertension, elevated triglycerides, and psychiatric illness. Pregnancy, polycystic ovary syndrome, or a history of gestational diabetes increase a woman’s risk.
Acceptable screening tests include fasting plasma glucose or oral glucose tolerance testing (OGTT) using 75 g of Glucola. A fasting plasma glucose of 100-125 mg/dL indicates prediabetes or IFG, while a level ≥126 is diagnostic for diabetes. Patients with a two-hour OGTT plasma glucose of 140-200 have prediabetes or IGT; a post-OGTT glucose >200 is diagnostic for diabetes. The two-hour OGTT is a more sensitive test but less practical in a typical outpatient setting.
For patients at high risk for diabetes or those with prediabetes, a comprehensive diet, education, and exercise program should be prescribed, with emphasis on nutrition goals, exercise goals of 150 minutes per week, and weight reduction of 5%-10% of total body weight. Several well-designed, large-scale studies have shown decreased rates of progression from prediabetes to diabetes as high as 58% with exercise and total body weight loss of 5%-7% compared with little or no intervention.2,3
Controlling blood sugar
Glycemic management of diabetes is the area in which patients look most to primary-care clinicians for medication intervention. The new guidelines call for achieving blood sugar control as near to normal as possible without causing clinically significant hypoglycemia. This will often include a hemoglobin A1c (HbA1c) ≤6.5%, a fasting plasma glucose <110, and a two-hour postprandial blood sugar <140. All patients should be referred for comprehensive education in self-management skills and nutrition therapy. This education should be ongoing and reviewed by all members of the treatment team at patient visits.
Patients should be encouraged to self-monitor blood sugar. Studies show that interventions which include self-monitoring reduce HbA1c by 0.40% (compared with interventions that do not include monitoring) and that if this information is reviewed with the patient, the HbA1c improvement doubles.4
Treating type 1 diabetes
Patients with type 1 diabetes should be offered intensive insulin therapy with a basal-bolus insulin regimen, including a mealtime rapid-acting insulin analog (lispro, aspart, or glulisine) and basal insulin with insulin glargine or detemir. Carbohydrate-counting is an option for select patients to help best estimate rapid-acting insulin needs at meals.
Continuous subcutaneous insulin infusion (CSII) or insulin-pump therapy is an ideal tool for those who can dedicate the time and effort needed to use a pump effectively. In general, patients who are unable to achieve acceptable control using a regimen of multiple daily injections and patients with frequent hypoglycemic episodes or hypoglycemic unawareness should be offered a pump.
CSII is an invaluable tool for pregnant patients whose motivation is often at a lifetime peak and whose success rates for ideal control are therefore high. Patients who are highly insulin-sensitive and those with a dawn phenomenon resulting in high morning blood sugars often benefit from the pump’s capability to alter basal insulin rates hour to hour. The new AACE guidelines also provide for insulin-pump use in patients who are willing and able to comply with prescribed self-care behavior, including frequent monitoring of blood sugar, carbohydrate counting, and insulin adjustment. This last indication implies that CSII is not only appropriate as a last-ditch effort when all else fails in type 1 diabetes, but it is also appropriate for any type 1 patient who is complying with the general recommendations for good care.
Pramlintide, a synthetic analog of amylin being marketed as Symlin, should be considered in insulin-treated patients seeking to enhance glycemic control (specifically postprandial control) and/or trying to control weight. Using Symlin will decrease the amount of insulin required to control blood sugar. The guidelines also indicate that an insulin sensitizer may be used in insulin-resistant type 1 patients.
If glycemic goals are not realized on insulin therapy, more frequent monitoring is recommended, with specific checks done two hours after meals and occasionally at 2 am. Patients should monitor blood sugars anytime they suspect they are at risk for low glucose levels and before driving. Type 1 patients should be instructed to monitor their blood sugar more frequently when they are sick and to check urine ketones if the blood sugar is >250.
Hypoglycemia can limit glycemic control in type 1 patients. Those using insulin analogs (lispro, aspart, glulisine) in physiologic patterns have fewer hypoglycemic episodes than patients using regular insulin. Hypoglycemia unawareness can be reversed in type 1 patients with intensive insulin therapy. Use of an insulin pump has been shown to improve overall control, lessen the frequency of hypoglycemia, improve hypoglycemia awareness, and reduce morning hyperglycemia due to the dawn phenomenon.
Prescribing oral medications
Patients with type 2 diabetes should be assessed at diagnosis for medical nutrition therapy, weight management when appropriate, and medication as needed. On average, type 2 patients are diagnosed 9-12 years after they develop the condition, so prompt and swift medical intervention at the time of formal diagnosis is indicated. Home blood sugar monitoring should include pre-meal and two-hour post-meal levels.
HbA1c will often guide the need for immediate pharmacologic intervention. An HbA1c of 6%-7% indicates a need for monotherapy with metformin, a thiazolidinedione, an insulin secretagogue, a dipeptidyl-peptidase-4 inhibitor, or an α-glucosidase inhibitor. If glycemic goals are not reached within three months, addition of a second medication should be considered. Exenatide (Byetta) may be combined with oral therapies. Treatment regimens should be re-evaluated at two to three months and adjusted appropriately.
An HbA1c >8% in a patient who has been educated about proper diet and exercise should prompt the clinician to consider insulin therapy. An HbA1c >10% may warrant insulin therapy to reverse glucose toxicity.
Particular attention needs to be given to postprandial blood sugar levels in well-controlled patients. The relative contribution of fasting glucose levels to overall glycemia is approximately 70% in patients with HbA1c values >10.2%, whereas it is only 30% in patients with an HbA1c <7.3%; in this latter group, the postprandial levels are much more important, comprising 70% of the HbA1c value. The contributions of pre- and post-meal blood sugar levels are approximately equal in patients with HbA1c values of 7.3%-8.4%.
Many oral agents are available for blood sugar control in type 2 diabetes. Secretagogues (sulfonylureas) will enhance insulin secretion from the beta cell and lower HbA1c 1%-2%. Glinides (nateglinide [Starlix] and repaglinide [Prandin]) employ a similar mechanism of action but have a much shorter half-life.
The primary effect of metformin is to reduce hepatic glucose output in the presence of insulin. Besides lowering HbA1c by 1%-2%, metformin also lowers LDL and triglycerides.
The two thiazolidinediones currently available are pioglitazone (Actos) and rosiglitazone (Avandia). They likely alter transcription of various genes that regulate carbohydrate and lipid metabolism. Adverse effects of thiazolidinediones include weight gain, edema, and peripheral fractures in women. Thiazolidinediones should not be used in patients with NY Heart Association class 3 or 4 heart failure. A meta-analysis of 42 studies reported an increased risk of MI among rosiglitazone users vs. controls (odds ratio 1.43; 95% confidence interval [CI] 1.03-1.98).5 The odds ratio for cardiovascular death was 1.64 (CI 0.948-2.74). Several limitations to this study have been pointed out by the authors and others. The Rosiglitazone Evaluated for Cardiovascular Outcomes (RECORD) study may shed more light on rosiglitazone’s safety, but this is not due until 2009. A recently published interim analysis suggests that RECORD could be underpowered and may not answer the questions about thiazolidinedione safety more definitively.6
The guidelines include discussion of several new drugs for type 2 diabetes: Pramlintide, previously noted in the discussion of type 1 diabetes, is also beneficial for type 2 patients who have failed to achieve desired control with mealtime rapid-acting insulin. Exenatide is the first in a new class of incretin-mimetic drugs that helps improve postprandial blood sugar control and is approved for use with a sulfonylurea and/or metformin and/or the thiazolidinediones. Sitagliptin (Januvia), currently the only available dipeptidyl-peptidase-4 inhibitor, has been shown in large-scale trials to help lower primarily postprandial blood sugars, but it also acts on fasting blood sugars. (The newer antihyperglycemic agents were also discussed in greater detail in “A quick guide to the newest diabetes drugs,” The Clinical Advisor, May 2007)
Using insulin in type 2 diabetes
Basal-bolus insulin regimens are the most physiologic approach for patients with type 2 diabetes. Many are reluctant, however, to begin such intensive therapy. Instead, a long-acting insulin analog alone may be used first. Addition of a rapid-acting insulin at one or more meals may further improve control. Another option is to begin insulin therapy with premixed insulin (intermediate-acting insulin and rapid-acting insulin in a 75/25 or 70/30 ratio). An initial dose of 10 units per injection is a safe starting dose for once-daily or twice-daily insulin injections; most type 2 patients are insulin-resistant, so upward titration of insulin doses may be needed soon after initiation. If the desired drop in HbA1c is not seen after initiation of an insulin regimen, postprandial blood sugars should be measured and targeted in additional therapeutic maneuvers.
Cardiac risk factors
Nonglycemic parameters of cardiovascular risk should be optimized in all diabetic patients. Approximately 25% of type 1 patients and 50% of type 2 patients have hypertension. First-line antihypertensive therapy after diet and exercise should be either ACE inhibitors or angiotensin receptor blockers with or without a diuretic as needed. Calcium channel blockers and third-generation beta blockers can also be used if necessary.
Aggressive management of the dyslipidemic pattern seen in diabetics is critical to lowering overall cardiovascular risk. Goals of LDL <100 (or 40 in men and >50 in women, and triglycerides 400 mg/dL, these agents should be used cautiously with statins because of the risk of rhabdomyolysis; this risk is less with fenofibrate than with gemfibrozil.
Role of nutrition
Medical nutrition management is essential to glycemic control, lipid control, and overall health in patients with diabetes. Total dietary carbohydrate should represent 45%-65% of total daily calories. Protein intake should comprise 15%-20% of dietary caloric intake. Fiber intake of 25-50 g/day is recommended.
This aids with digestion and metabolism of carbohydrates by blunting the glycemic response. Total dietary fat should be <30% of total caloric intake, saturated fat <10% of daily calorie intake, and cholesterol 100, then the goals should be <7% total calories and 200 mg cholesterol, respectively.)
The AACE guidelines provide a comprehensive approach to diabetes, addressing patient and health-care team concerns. The result should be good clinical outcomes and better overall health for patients afflicted with the disease.
Dr. Mitzner is an endocrinologist at the Joslin Clinic and an instructor in medicine at Harvard Medical School, both in Boston.
1. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Management of Diabetes Mellitus. Endocr Pract. 2007;13(suppl 1):1-68.
2. Knowler WC, Barrett-Connor E, Fowler SE, et al; for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Tuomilehto J, Lindstrom J, Eriksson JG, et al; for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350.
4. Jansen JP. Self-monitoring of glucose in type 2 diabetes mellitus: a Bayesian meta-analysis of direct and indirect comparisons. Curr Med Res Opin. 2006;22:671-681.
5. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471.
6. Home PD, Pocock SJ, Beck-Nielsen H, et al; RECORD Study Group. Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med. 2007;357:28-38.