Lifestyle Interventions

Nutritional therapy is essential in management of both type 1 and type 2 diabetes. A registered dietitian is crucial in helping to individualize a meal plan and to teach the patient and family about healthy nutrition.^7,8 The goal of nutritional therapy for diabetes and prediabetes is the development of the meal plan, balancing insulin with food intake and activity to achieve glycemic control. The nutrition goal for patients with type 1 diabetes is to promote normal growth and development during childhood, adolescence, pregnancy, and lactation; to balance energy intake and expenditure; and to achieve near-normal blood glucose levels. Matching insulin doses to carbohydrate intake is necessary. For patients with type 2 diabetes, the nutrition goals are the achievement and maintenance of a healthy weight, adequate blood pressure control and lipid levels, and good glycemic control (Box 206-4). To promote recovery from a severe illness, special dietary adjustments may be necessary and can be individualized with the help of a registered dietitian.

Exercise and physical activity have been shown to improve glycemic control.⁹ Exercise causes increased glucose uptake in skeletal muscles as well as improved insulin sensitivity. All of the other benefits of exercise for the heart, lungs, and state of mind help reduce the risk of diabetes complications. It is important for the individual with type 1 diabetes to make appropriate adjustments in food intake and/or insulin doses to balance the effects of exercise. Postexercise hypoglycemia or hyperglycemia may occur. The exercise lag effect refers to the low blood glucose concentration that may happen many hours after exercise. To prevent hypoglycemia during exercise, the individual must balance activity with adequate food and appropriate insulin doses. High blood glucose levels after exercise may result from decreased circulating insulin and glucose uptake and increased hormonally regulated hepatic glucose. In the setting of exercise without adequate circulating insulin, ketosis is increased as fatty acids are broken down for energy, resulting in higher blood glucose levels and possible ketosis.⁹

In the individual with type 2 diabetes, exercise decreases insulin resistance and increases glucose uptake. Increased insulin sensitivity, contributing to the exercise lag effect, can last up to 48 hours after exercise. Thus, food intake and medication, especially insulin, need to be adjusted for the activity or exercise. A reduction in the insulin that is peaking at the time of exercise and perhaps the basal insulin as well may be necessary. In the patient with type 2 diabetes, it would be desirable to decrease the medication rather than increasing food consumption so as to promote weight loss.⁹ Exercise has been shown to prevent or delay the progression from prediabetes to diabetes. Guidelines for exercise in diabetes are reviewed in Box 206-5.

The most physiologic regimen is basal/bolus insulin. This can be accomplished with multiple daily injections or with an insulin pump, also known as continuous subcutaneous insulin infusion. Exogenous insulin requirements vary from one patient to another and, for an individual, from day to day. Physiologic insulin secretion for adults who do not have diabetes is approximately 20 to 40 units/day.¹⁰ Thus, most adults with type 1 diabetes will need to inject approximately this much insulin every 24 hours. One unit of any kind of insulin will cause the same reduction in blood glucose concentration in a given individual for the duration of that type of insulin. For example, 1 unit of a rapid-acting insulin may drop one patient’s blood glucose level 60 mg/dL in 2 to 3 hours, and 1 unit of a long-acting insulin will reduce the glucose level 60 mg/dL for over 12-24 hours. A patient who is much more resistant to insulin will experience a drop of only 10 mg/dL in glucose concentration in 2 to 3 hours after 1 unit of rapid-acting insulin and a drop of 10 mg/dL for 24 hours after 1 unit of basal insulin.

When insulin treatment is initiated, body weight, morphologic development (obese versus muscular), age (adolescent versus elderly), and activity (sedentary versus athletic) must be considered. The type of insulin prescribed depends on the patient’s needs and the provider’s preference. Therapy should begin with conservative starting doses and continuously titrated to achieve the desired blood glucose levels. On the basis of the patient’s weight, an initial total daily dose (TDD) may be calculated as 0.5 unit/kg. The TDD is then divided into basal and bolus doses. Fifty percent of the TDD is basal insulin, and 50% is divided among the mealtime doses. Frequent premeal and postmeal blood glucose monitoring will guide dose adjustments.

Glargine and detemir, true long-acting insulins, are typically given once daily, often at bedtime, and last for up to 24 hours, mimicking the basal secretion of insulin.¹⁰ Basal insulin may be given at a different time of day, if it is more convenient for the patient, to maintain a consistent routine. Large doses may be divided into twice-daily injections given 12 hours apart. Some individuals notice a peak from their basal insulin, so they may split their dose into two daily injections to minimize this. The dose of basal insulin is not determined with a sliding scale, so as not to make a decision with 24-hour implications based on a single blood glucose value. Rather, the dose of basal insulin should be adjusted every 2 or 3 days until the fasting blood glucose level is less than 110 mg/dL. The basal insulin should be increased by increments of 2 to 5 units in an obese, insulin-resistant individual or by 1 to 2 units in an insulin-sensitive patient with a thin body frame or in patients with frequent episodes of hypoglycemia.¹⁰ If the fasting glucose concentration is consistently lower than 80 mg/dL, the dose of basal insulin should be reduced.

To prevent high postprandial glucose levels, a rapid-acting insulin analogue should be injected just before, during, or immediately after the meal. A low premeal blood glucose level, unpredictable food intake, and delayed gastric emptying are common reasons for waiting until after the meal to inject the bolus dose. Most often, mealtime insulin is injected 10 minutes before eating. A bolus dose with meals allows more flexibility in mealtimes, prevention of postprandial hyperglycemia, and fewer episodes of hypoglycemia.¹⁰ Initially, mealtime doses are the TDD, but they can later be fine-tuned on the basis of postprandial blood glucose monitoring. The best approach to determination of mealtime insulin doses is counting the amount of carbohydrate to be consumed and calculating the dose on the basis of an individualized carbohydrate-to-insulin ratio.

The goal of the diabetes plan is to attain glycemic control with appropriate insulin doses but without symptoms of hypoglycemia or hyperglycemia. Intensive insulin therapy is defined as four or more insulin injections each day or use of an insulin pump. This comprehensive strategy requires collaboration among the individual patient and family, the health care provider or diabetes specialist, and the diabetes education team of a nurse educator and dietitian. The more the patient knows about diabetes, the better and safer the diabetes management will be.

Hypoglycemia is the most serious side effect of insulin. Fear of hypoglycemia prevents some individuals from embracing intensive insulin therapy. To prevent both hypoglycemia and hyperglycemia, factors such as exercise and activity, meal composition, mealtimes, sleep patterns, illness, and psychological well-being must be considered in adjusting insulin doses. The most important tool for control of day-to-day variations and prevention of hypoglycemia is home blood glucose monitoring. For a patient using an insulin pump, co-management with an endocrinologist and diabetes care and education team is strongly recommended. Intensive insulin therapy is not appropriate for all patients, including those with hypoglycemia unawareness, those who are poorly motivated and unwilling to monitor their blood glucose levels frequently, older adults, and those who have a limited life expectancy.¹⁰

Basal/bolus insulin treatment is complex and more expensive than a twice-daily regimen of regular and NPH insulin or premixed insulin. This treatment regimen is an alternative for patients who cannot or will not take multiple daily injections. The patient using twice-daily insulin must eat meals on a schedule and be aware of the risk of nocturnal hypoglycemia. Regular insulin may be used as a less expensive alternative to a rapid-acting analogue but does not offer the immediate mealtime coverage, resulting in hyperglycemia postprandially and then hypoglycemia before the next meal. The four prepared insulin mixtures—Humalog 75/25, NovoLog 70/30, and mixtures of NPH and regular 70/30 (Novolin, Humulin)—offer ease and convenience for the individual. Dose adjustments, however, change both the short-acting and longer-acting insulin.

Insulin products are available in both a vial (to be drawn into a syringe) and a prefilled, disposable pen. A prescription for insulin must be accompanied by a second prescription for either syringes or insulin pen needles. Syringes are available in several different sizes, and needles come in several different lengths. NPH and regular insulin may be mixed in one syringe and injected together. Glargine and detemir cannot be mixed with another insulin (Box 206-6).

Requirements for insulin increase during illness, surgery, and growth spurts and in patients with ketoacidosis. Insulin absorption from subcutaneous tissues varies about 25% among patients. The practitioner should be aware of a possible “honeymoon” phase in the patient with newly diagnosed type 1 diabetes with recovering beta cell function. Insulin requirements may decrease to 0.2 to 0.5 unit/kg body weight per day during this short-term phase.⁴

Medications for Type 2 Diabetes

Treatment of type 2 diabetes includes management of dyslipidemia, hypertension, obesity, insulin resistance, and hypercoagulability as well as glycemic control.¹¹ The mainstays of therapy are education, diet, exercise, and achievement and maintenance of a desirable body weight. These therapies have no side effects, although they are difficult to sustain over time. Hyperglycemia may be reversed with weight loss of as little at 4 kg.¹¹ Early diagnosis and prompt initiation of treatment are associated with better sustained glycemic control and fewer long-term complications. Treatment of diabetes should be individualized to achieve an HbA_1c level as close to the nondiabetic range as possible, and a value of 7% or greater should be a “call to action.”¹¹ This target should be modified for patients with a significant risk for dangerous hypoglycemia or with a limited life expectancy.

While recommendations for diet and exercise are being maximized, pharmacologic intervention should be considered. Consideration of the patient’s place along the continuum of the natural progression of type 2 diabetes and the mechanisms¹² that are contributing to hyperglycemia, will guide the selection of medication(s). Individualization of medications should be determined on the basis of effectiveness, safety, tolerability, and cost. The reduction of risk for complications of diabetes has been shown to be related to the level of glycemic control over time rather than to the use of any single medication or combination.¹¹ Some agents used to improve glycemic control also have beneficial or detrimental effects on related conditions (e.g., obesity, elevated lipids).

The variety of diabetes medications to supplement lifestyle changes enables treatment individualization for improved glycemic control, targeting each patient along the continuum of type 2 diabetes. Agents with different mechanisms can be combined to achieve greater glucose reduction. Metformin (Glucophage), a biguanide, is commonly the first-line oral medication for type 2 diabetes. The mechanism of action is suppression of hepatic glucose production, which typically results in lower fasting glucose levels. A reduction of approximately 1.5% can be expected in the HbA_1c level. Side effects are typically mild and include temporary nausea and diarrhea. Metformin does not cause hypoglycemia and may promote weight loss. There is the rare but serious risk of lactic acidosis. For this reason, metformin must be held before the intravenous administration of contrast material and temporarily discontinued (up to 48 hours) after radiologic studies involving intravenous contrast dye. In addition, metformin should be discontinued if the serum creatinine concentration exceeds 1.4 mg/dL in women or 1.5 mg/dL in men. This creatinine threshold has been debated as being too conservative and thus restricts the use of metformin for many patients who might benefit. Use of the estimated glomeruler filtration rate (eGFR) instead has been recommended by professional societies and has been proposed to the FDA.¹²

Sulfonylureas help reduce blood glucose by stimulating insulin secretion and can also reduce the HbA_1c level by approximately 1.5%. The most common side effects are weight gain and hypoglycemia. Persistent hypoglycemia is more frequent in older adults. The second-generation medications in this class are glyburide (Micronase, DiaBeta, Glynase), glipizide (Glucotrol), and glimepiride (Amaryl). They are once- or twice-daily medications. Meglitinides (repaglinide [Prandin], nateglinide [Starlix]) are nonsulfonylurea insulin secretagogues. These are shorter-acting agents that must be taken with each meal and should be withheld if the patient is omitting a meal. The risk for weight gain exists, but these medications are less likely to cause hypoglycemia because of their shorter duration.

α-Glucosidase inhibitors (acarbose [Precose], miglitol [Glyset]) act in the small intestine, delaying the digestion of polysaccharides. The inhibition of starch and the sucrose enzyme causes lower postprandial glucose levels. To be effective, the pill must be taken with the first bite of a meal that contains carbohydrate. Alone, these medications will not cause hypoglycemia; but if they are used in combination with another medication and hypoglycemia occurs, glucose (not sucrose) is necessary for treatment. Sucrose would be blocked by the action of these agents, so patients are advised to carry glucose tablets or gel. Contraindications include inflammatory bowel disease, colonic ulceration, obstructive bowel disease, gastroparesis, and creatinine levels above 2 mg/dL. α-Glucosidase inhibitors typically result in a 0.5% reduction in HbA_1c.

The thiazolidinediones (TZDs) pioglitazone (Actos) and rosiglitazone (Avandia) are peroxisome proliferator-activated receptor γ (PPAR-γ) modulators. These agents improve the sensitivity of liver, fat, and muscle to both endogenous and exogenous insulin. Ultimately, this works to decrease insulin resistance, thereby improving insulin sensitivity and decreasing insulin levels. In addition, the TZDs reduce hepatic glucose output. Improvement of both fasting and postprandial blood glucose levels occurs over time and without stimulating insulin secretion. Side effects include weight gain and edema; thus, congestive heart failure is a contraindication. TZDs should not be used as first-line therapy if the patient is glucose toxic because it takes 4 to 8 weeks for the full effect. Advantages include the delay of beta cell exhaustion, decrease in insulin resistance, no hypoglycemia (if used alone), and improvement of triglyceride and HDL levels. Some studies have revealed a slight increase in low-density lipoprotein (LDL) levels with rosiglitazone. A disadvantage of this class is a possible increase in liver function enzymes. However, the recommendation is to monitor liver function test (LFT) results and to stop the drug if serum transaminase exceeds 2.5 times the upper limit of normal. LFTs should then be monitored until the results return to normal. Caution is to be exercised when TZDs are used with insulin because they may cause more peripheral edema and, in cardiac patients, congestive heart failure.

In July 2010, an FDA advisory panel reviewed evidence citing the increased risk of heart attack with rosiglitazone. The panel voted not to withdraw the drug but to continue to market it with additional restrictions and warnings. Subsequently, in response to the findings of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, which showed no elevated risk of myocardial infarction (MI) or death in patients taking rosiglitazone compared with standard-of-care diabetes medications, the FDA lifted the restrictions.¹³ The FDA has been conducting a safety review of a reported association between long-term pioglitazone exposure and bladder cancer. A history of bladder cancer is a contraindication to pioglitazone use.

The incretin mimetics glucagon-like peptide 1 (GLP-1) agonists are a class of noninsulin injectable medications indicated for treating type 2 diabetes that is inadequately controlled with healthy diet, regular exercise, and metformin. The GLP-1 peptide, produced in the small intestine, stimulates insulin secretion in the fed state. It acts to stimulate insulin secretion, to suppress glucagon secretion, and to slow gastric emptying. Gastrointestinal side effects are common and related to the effect on gastric motility. Weight loss is also common, but hypoglycemia is not.

Exenatide (Byetta) is given as a twice-daily subcutaneous injection 0 to 60 minutes before breakfast and dinner, starting with 5 µg and titrating to 10 µg after a month if needed. Liraglutide (Victoza) is a once-daily subcutaneous injection, taken without respect to mealtime. There are three once-weekly GLP-1 receptor agonists: exenatide (Bydureon), dulaglutide (Trulicity), and albiglutide (Tanzeum). The GLP-1 receptor agonists have been shown to contribute to weight loss and a reduction in systolic blood pressure, in addition to a reduction in HbA_1c. Combination therapy with insulin is an area of active investigation.

A higher dose of liraglutide is now marketed as Saxenda and is indicated as a treatment for weight loss, as an adjunct to diet and exercise. Side effects at the higher dose include nausea and hypoglycemia.

A related class of medications is the dipeptidyl peptidase 4 (DPP-4) inhibitors. They work to release insulin and to decrease glucagon levels by slowing the inactivation of incretin hormones. These medications help to regulate insulin by affecting both alpha and beta cells in response to elevated glucose levels. This process then helps decrease preprandial and postprandial glucose levels.

The newest class of oral agents to treat type 2 diabetes is the sodium-glucose cotransporter-2 (SGLT2) inhibitors. This class includes canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga). These once-daily pills cause increased excretion of glucose in the urine and thereby reduce plasma glucose concentration and may contribute to weight loss. The side effects include an increased risk for urinary tract infections (UTIs), genital infections in females, and hypotension.

If a single agent does not result in adequate glycemic control, a second agent may be added and then a third. Many different combinations have received FDA approval, and several two-medication tablets are available. The use of a combination tablet may reduce insurance copayments and may improve compliance because of the convenience. All medications have side effects, and many of the newer agents are expensive. An ADA position statement summarizes the current treatment recommendations.¹²

When a patient who is taking several diabetes medications in addition to medications for other conditions is not achieving the glycemic targets, insulin must be considered. Many patients find the switch from pills to insulin to be daunting. Thoughtful discussion of their concerns, reassurance, and a relaxed environment in which to practice injections can ease the transition. Insulin, given in adequate doses, can reduce any glucose level to the desired range. Individuals with type 2 diabetes may need large doses (1 unit/kg or more per day) to achieve desired glycemic control. An evening dose of intermediate-acting (NPH) or long-acting (glargine or detemir) insulin may be added to one or more oral medications. In some cases, other medications are discontinued and a split-mixed regimen of NPH and regular insulin or NPH and a rapid-acting analogue is recommended. Other patients will use basal/bolus insulin treatment alone. In addition to the insulin products used in type 1 diabetes, U-500 regular insulin may be used in type 2 diabetes. This is five times as concentrated as other insulins, allowing a patient with severe insulin resistance to inject a smaller volume. The use of U-500 insulin concentrate requires careful documentation and communication of the doses in actual units as well as in volume of insulin, to avoid overdosage or underdosage by a factor of five.

Insulin may be used as first-line treatment of the patient with type 2 diabetes in the following situations: HbA_1c level greater than 10% or glucose range above 250 mg/dL, severe illness with associated complications, gestational diabetes, and fragile older adults. However, the most common reason for use of insulin in type 2 diabetes management is failure to respond to the oral antihyperglycemic agents.

Combination therapy allows a more individualized regimen aimed at optimal glycemic control. Despite all the medications, however, a healthy diet and regular exercise remain the cornerstones of management of diabetes.