Treatment of Type 2 Diabetes

Lifestyle

Medical nutrition therapy

Weight loss is a critical part of type 2 diabetes treatment. Type 2 diabetes is highly comorbid with obesity,[1] and weight reduction has been associated with decreased insulin resistance,[2] improved glycemic control,[3] and an improvement in cardiovascular risk profile.[4] The goals of medical nutrition therapy for all people with diabetes are to: 1) attain and maintain optimal metabolic control; 2) prevent and treat all diabetes complications; 3) improve health through healthy food choices; and 4) address individual nutritional needs, taking into account personal preferences, cultural preferences, lifestyle, and willingness to change.[5] For all people with diabetes, carbohydrates and monounsaturated fats should comprise 45-65% of daily caloric intake. Despite the increased popularity of the high-protein and low-carbohydrate diet, this approach is not recommended.[5]

Specific recommendations for people with type 2 diabetes include reducing total energy intake in order to decrease overweight and improve insulin resistance and glycemic control, as even modest weight loss can improve insulin sensitivity in the short term.[5] Because people with type 2 diabetes have an increased risk of cardiovascular disease, diets low in saturated fats, cholesterol, and sodium may also be a part of nutrition recommendations for this group.[6] For people who are also obese, structured educational programs that include reduced fat and energy intake, regular physical activity, and regular participant contact are an effective way to promote long-term weight loss.[6]

Physical activity

According to the American College of Sports Medicine (ACSM), every adult should accumulate at least 30 minutes of moderate-intensity physical activity on most or all days of the week in order to promote good health and prevent chronic disease.[7] In addition to the health benefits of physical activity,[8],[9] people with diabetes can also experience diabetes-specific benefits of physical activity, including lowered A1C and reduced insulin requirements.[5],[10]

Before beginning any exercise program, a thorough screening for cardiovascular disease, peripheral arterial disease, retinopathy, nephropathy, and neuropathy should be undertaken.[5] Adequate warm-up, stretching, and proper footwear are essential. Because many people with type 2 diabetes are sedentary, physical activity promotion in this population has switched from an emphasis on structured aerobic activity to an emphasis on lifestyle physical activity. Lifestyle activity interventions have demonstrated efficacy comparable to structured aerobic activity.[11]

Because the improvements in insulin tolerance and glucose sensitivity that accompany physical activity typically deteriorate within 72 hours,[12] regular activity is of great importance. According to ACSM guidelines, people with type 2 diabetes should exercise at least 3 nonconsecutive days per week and should strive for at least 5 physical activity sessions per week.[12] Low to moderate intensity is recommended, as that is what is required to achieve favorable metabolic changes.[12] Physical activity sessions should start at 10 to 15 minutes, with the goal of increasing to 30 minutes.[12] Activities that offer greater control over intensity, have little interindividual variability in energy expenditure, are easily maintained, and require littleskill are recommended.[12] A summary of the ACSM guidelines appears in Table 1.

Table 1. CSM guidelines for exercise and type 2 diabetes[12]

Oral antihyperglycemic agents

Sulfonylureas (SUs)

SUs, also called insulin secretagogues, cause the secretion of insulin at a lower-than-normal glucose threshold. In addition to increasing insulin secretion, these drugs may also increase insulin action and decrease hepatic insulin clearance.[13] SUs generally lower A1C by 1-2 percentage points. The most common adverse reactions include allergic reactions among people who have a sensitivity to sulfa drugs and hypoglycemia.[13]

Meglitinides

Drugs in this class are non-SU insulin sensitizers, generally lower A1C by 1.6-1.9%. The most common side effects include hypoglycemia and allergic reaction.[13]

Biguanides

Biguanides work by decreasing hepatic glucose output, and thus have their greatest effect on fasting plasma glucose levels. Biguanides reduce A1C by 1.5-1.8% and may also beneficially affect lipid profiles.[13]The most common side effects are gastrointestinal, and they are generally mild.[13]

Thiazolidinediones (TZDs)

TZDs work primarily by decreasing insulin resistance in muscle and adipose tissue. They may also affect hepatic glucose production, and generally lower A1C by 0.7-1.75%. Side effects include edema, weight gain, and congestive heart failure, although that is rare.[13]

Alpha-glucosidase inhibitors

This class of medications works by delaying the absorption of carbohydrates and decreasing postprandial hyperglycemia.[14] These drugs have only a modest effect on A1C (0.5-1%) and are generally accompanied by gastrointestinal side effects such as flatulence and diarrhea.[14]

Combination pills

A number of oral medications are now available in the form of combination pills. Available combinations include biguanide and SU combination pills and biguanide and TZD combination pills.[14],[15]

Injectable therapies

Until recently, insulin was the only available injectable therapy for the treatment of diabetes. In addition to insulin (now also available in inhalable form), 2 other hormone-based therapies have recently been approved for use by people with type 2 diabetes. The glucagon-like peptide (GLP)-1 receptor agonist exenatide is approved for use by patients who have failed oral therapy with SUs, metformin, or a combination of the 2 agents, whereas synthetic amylin (pramlintide) is approved for use among people with insulin-requiring diabetes who are not achieving adequate glucose control.

GLP-1 receptor agonists

The newest available treatment for type 2 diabetes is the GLP-1 receptor agonist exenatide. Native GLP-1 has a number of properties that make it a desirable therapy, including theability to suppress glucagon secretion, stimulate insulin secretion in a glucose-dependent manner, slow gastric emptying, increase feelings of satiety, and promote weight loss.

Treatment with exenatide has resulted in improvements in blood glucose control in clinical studies of patients with type 2 diabetes inadequately controlled with SUs, metformin, or combination SU-metformin therapy.[16],[17],[18] Further, because the effects of exenatide are glucose-dependent, exenatide treatment was not associated with an increase in severe hypoglycemia. Patients treated with exenatide also showed a statistically significant weight reduction relative to a placebo group in a study with 82 weeks of follow-up.[19]

Insulin

In healthy individuals, the pancreatic beta cells produce a constant low level of insulin (basal insulin), as well as larger spikes in response to meal ingestion (prandial insulin). The goal of insulin replacement therapy in people with diabetes is to mimic normal pancreatic function as closely as possible.

Insulin pharmacology

Insulins are categorized based on their onset of action: rapid acting (onset of less than 15 minutes), short acting (onset 0.5-2 hours), intermediate-acting/long-acting (onset 2-4 hours).[20] Common insulins and their action profiles appear in Table 2.

Table 2. Insulin action profiles[14]

The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the efficacy of tight glycemic control for the prevention of complications.[21] Because type 2 diabetes is progressive, monotherapy with any one agent is generally only effective for 5 years. Traditionally, initial treatment begins with lifestyle modification, then progresses to a single oral agent, multiple oral agents, and then finally to insulin therapy. This approach is problematic because of the repeated metabolic failures, which increase the likelihood of complications and decrease motivation to adhere to treatment. Accordingly, the addition of a basal insulin to the treatment regimen may be a useful way to prevent complications and achieve tight glycemic control.[22]

Initiation of insulin therapy

There are 3 primary reasons to initiate insulin therapy among people with type 2 diabetes: glucose toxicity, insufficient beta-cell mass, and contraindications to the use of oral medications.[23] The reason for initiating insulin therapy will help determine the appropriate regimen. In the case of glucotoxicity, the need for insulin may be temporary. However, if insulin therapy is needed due to decreased beta-cell mass, then the insulin need is likely permanent.[24] A recent study suggests that substantial resistance among both patients and healthcare providers exists with regard to commencing insulin therapy, and that this may illustrate a larger problem with initiating blood-glucose-lowering medications.[25] Among patients the need to take insulin was associated with self-blame for not achieving adequate control with oral medications or lifestyle changes. Among healthcare providers, resistance toward starting insulin was highest when treating patients who were not adhering to treatment.

Insulin adjustment

A variety of factors affect insulin requirements. Food consumption, glucose level, and activity level should be considered when making decisions about insulin dose.[26] There are also numerous factors that affect the rate at which insulin is absorbed, including factors related to insulin preparation, injection site, and other external factors.[20] A summary of factors affecting insulin absorption and insulin action appears in Table 3.

Table 3. Factors affecting insulin absorption and action[24]

Inhaled insulin

For years, has been available only in injectable form. In January 2006, the first inhalable form of insulin became available.[27] The efficacy and safety of inhaled insulin was compared with that of subcutaneous insulin therapy in patients with type 2 diabetes in a 6-month, randomized, comparative trial.[28] Patients were randomized to receive either premeal inhaled insulin plus a bedtime dose of Ultralente or at least 2 daily injections of subcutaneous insulin (mixed regular/NPH insulin). Inhaled insulin achieved comparable glycemic control to that of the conventional subcutaneous regimen and was well tolerated. Inhaled insulin has also been shown to improve overall glycemic control and hemoglobin A1C level when added to or substituted for oral therapy.[29]

Synthetic amylin

Synthetic amylin (pramlintide) is another recently approved treatment option for insulin-requiring patients with type 2 diabetes. Though it is found in lower plasma levels than insulin, the naturally occurring hormone amylin regulates gastric emptying, working in partnership with insulin to slow glucose entry into the circulation while insulin regulates glucose uptake. Amylin is also known to decrease food intake and increase satiety. In clinical trials, amylin replacement with pramlintide has been shown to improve long-term glycemic control, reduce postprandial glycemic excursions, and promote weight loss among people with insulin-requiring type 2 diabetes.[26],[30] Evidence also suggests that pramlintide contributes to enhanced satiety and reduced food intake and that this may explain the weight loss observed in long-term treatment of patients with this agent.[31]

Combination therapy

Oral medications, due to their differential mechanism of actions, can be used in combination to further improve metabolic outcomes. Specific combinations that have been used appear in Table 4.

Table 4. Oral medication combinations[13]

Additionally, insulin therapy can be used in conjunction with a number of different oral medications, including SUs, biguanides, and TZDs, as well as with multiple oral agents.[32] Triple therapy involving the addition of insulin glargine or rosiglitazone to a maximized combination of metformin and SUs has also demonstrated efficacy.[33] Exenatide treatment is indicated for use in conjunction with SU, metformin, or both. Pramlintide is indicated for use by people with insulin-requiring type 2 diabetes.

Self-monitoring of blood glucose (SMBG)

Self-monitoring of blood glucose (SMBG) is a critical part of self-management, especially for people treated with insulin or insulin secretagogues. However, a large epidemiological study found that 29% of insulin-treated patients, 65% of patients treated with oral medications, and 80% of patients with lifestyle changes have never monitored their blood glucose or monitor less than once per month.[34] A recent 6-year study of patients with type 2 diabetes found that SMBG was associated with decreased diabetes-related morbidity and all-cause mortality, including in people not receiving insulin therapy.[35]

According to ADA guidelines, self-monitoring among people with type 2 diabetes should be performed to reach glycemic goals and minimize hyperglycemia and hypoglycemia, although the optimal frequency of monitoring is not known.[36] Additionally, the benefits of SMBG to patients treated with lifestyle change alone is unknown. Any time a change in treatment plan is initiated, monitoring frequency should be increased.

References

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5. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36.
6. American Diabetes Association. Nutrition principles and recommendations in diabetes. Diabetes Care. 2004;27(suppl 1):S36-S46.
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8. Laaksonen DE, Atalay M, Niskanen LK, et al. Aerobic exercise and the lipid profile in type 1 diabetic men: a randomized controlled trial. Med Sci Sport Exer. 2000;32:1541-1548.
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14. American Association of Clinical Endocrinologists. Guidelines pocketcard: managing diabetes mellitus type 2, version 3.0. Baltimore, Md: International Guidelines Center; 2004.
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27. [No authors listed] First inhaled insulin product approved. FDA Consum. 2006;40:28-29.
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