A Practical Guide for Aggressive Management of Type 2 Diabetes

Article Outline

• Abstract
• Epidemiology of Diabetes Mellitus
• Metabolic Syndrome and Insulin Resistance
• Treatment Failure
• Management of Type 2 Diabetes
• Guideline Recommendations
• Principles of OAD Therapy
• Case Study
  • Follow-up Visit 2
• Benefits of Combination Therapy
  • Follow-up Visit 3
• Summary on Hypoglycemia
  • Follow-up Visit 4
  • Follow-up Visit 5
• Note on Triple OAD Therapy
• Insulin Therapy
• Barriers to Insulin Therapy
• Initiating Insulin Therapy
  • Follow-up Visit 5 continued
  • Follow-up Visit 6
• Insulin Dose Titration
  • Follow-up Visit 7
• Basal-Bolus Regimen
• Newer Therapies
• Summary
• References
• Copyright

Abstract 

The incidence of diabetes mellitus is increasing at alarming rates in the United States which presents a management challenge for primary care practitioners. Evidence from landmark trials such as the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study has shown that tight glycemic control markedly reduces long-term diabetic complications. However, practitioners are often hesitant to institute measures such as multiple drug regimens, insulin therapy, or both. This article offers practitioners an evidence-based guide for managing patients with diabetes while maintaining the clinical practice guidelines as outlined by the American Diabetes Association and the American Association of Clinical Endocrinologists.

Keywords:  aggressive control , clinical practice guidelines , evidence-based practice , insulin management , type 2 diabetes mellitus

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Diabetes remains a significant public health problem in the United States because of the increasing burden of disease, particularly among younger persons. Patients today will subsequently live longer with diabetes; vast evidence shows that strict glycemic control is necessary to avoid long-term complications.¹, ² Therefore, many patients will require aggressive management of their disease that includes earlier initiation of insulin therapy. In our current health care system, primary care providers will be summoned to meet these escalating needs and will need to initiate insulin therapy for a significantly larger number of patients.

Unfortunately, too many patients live for years with unacceptably high hemoglobin A1c (A1C) values and endure preventable diabetic complications because their hyperglycemia is poorly controlled with only oral agents. The reasons for the delay in transitioning patients from oral agents to insulin are many and include provider reluctance, patient hesitation, and patient noncompliance. However, the evidence from rigorous clinical trials such as the Diabetes Control and Complications Trial (DCCT)¹ and the United Kingdom Prospective Diabetes Study (UKPDS)² has indicated that aggressive management of hyperglycemia is vital to prevent long-term diabetic complications and to improve health care outcomes.

The purpose of this article is to provide the practical tools necessary for primary care providers to assist patients with achieving euglycemia. General guidelines as proposed by the American Diabetes Association (ADA) and the American Colleges of Endocrinology (ACE) are integrated into a patient case study to illustrate the many options providers have when managing complicated patients.

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Epidemiology of Diabetes Mellitus 

Despite advances in diabetes management, diabetes mellitus still remains a significant cause of morbidity and mortality in the United States. The estimated number of persons who have diabetes exceeds 20 million in the United States, 14 million are diagnosed and 6 million are undiagnosed. This means that approximately 7% of the population in the United States has diabetes. Diabetes is the sixth leading cause of death and the number one cause of acquired blindness, kidney disease leading to dialysis, and lower limb amputation unrelated to trauma. Diabetes contributes to the development of cardiovascular disease (CVD), which is the number one cause of death. Sixty-five percent of patients with diabetes die of CVD.³

The UKPDS determined that patients with type 2 diabetes who maintained A1C less than 7.0% with monotherapy had a 25% risk reduction of microvascular complications, 21% risk reduction of retinopathy, and 33% risk reduction of albuminuria than patients with A1C of 7.9% that were treated with diet alone.⁴ Monotherapy included either insulin, the sulfonylureas, or metformin. All groups taking monotherapy had similar reductions of microvascular risk; however, metformin had a greater effect on reducing the risk of any diabetes-related effect, all-cause mortality, and stroke than did the sulfonylureas and insulin group.⁵ In general, there was a 14% reduction of macrovascular complications for every 1% reduction of A1C in patients receiving intensive treatment.⁶

The average patient with type 2 diabetes withstands 5 years of A1C greater than 8% from the time of diagnosis until starting insulin. That time includes the progression from lifestyle modifications to sulfonylureas or metformin monotherapy, to finally combination oral therapy. Those same patients endured 10 years of A1C greater than 7%.⁷ Also, studies show that practitioners intensify therapy when A1C is 9% or greater.⁸

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Metabolic Syndrome and Insulin Resistance 

Type 2 diabetes is characterized by early insulin resistance, followed by the gradual deterioration of pancreatic β-cell function.⁹ Visceral (central) obesity is now recognized as one of the responsible factors for triggering a series of chemical reactions that leads to insulin resistance and eventually the development of metabolic syndrome and type 2 diabetes. Excess adipocytes are broken down in a process called lipolysis. The free fatty acids that are released during lipolysis promote hepatic and skeletal muscle insulin resistance.¹⁰ Initially, the pancreas is able to compensate for insulin resistance by increasing insulin production. Normally, hepatic glucose production is suppressed with sufficient serum insulin concentrations. However, as insulin resistance continues, increased hepatic glucose production leads to impaired fasting plasma glucose (100-125 mg/dL) and eventually the development of type 2 diabetes.¹¹

Hyperglycemia is responsible for the destruction of pancreatic β-cells and increased cardiovascular risk. Butler et al¹² concluded that by the time type 2 diabetes is diagnosed, patients have lost approximately 50% of β-cell function primarily because of hyperglycemia-induced apoptosis or cell death. Also, patients with prediabetic hyperglycemia (impaired fasting glucose or impaired glucose tolerance) had increased cardiovascular risk than patients with normal glycemia when adjusted for age, sex, and body mass index (BMI; in kg/m²).¹³

The pathogenesis of macrovascular complications is complex and involves the interplay between all components of the metabolic syndrome. Adipokines, released by adipocytes, are involved in the process of dyslipidemia, inflammation, hypertension, microalbuminuria, and impaired thrombolysis.¹⁰

The mechanism of microvascular complications is not well understood. Two theories attempt to describe the negative effects of hyperglycemia on small blood vessels. One theory suggests that excess glucose has a direct toxic effect on blood vessel tissue. Another theory suggests that blood vessel–destroying free radicals are released as a result of faulty glucose metabolism.¹⁴

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Treatment Failure 

In evaluating the UKPDS² and other studies, it is apparent that patients newly diagnosed with diabetes were unable to maintain target A1C (<7%) within the first 3 years of diagnosis when treated with oral antidiabetic agents (OADs) or insulin, because of progressive decline of β-cell function. Patients taking monotherapy consisting of metformin, sulfonylureas, or insulin needed multiple therapies after 3 years to achieve target A1C. Only 21% of patients treated with sulfonylureas achieved targeted A1C after 3 years.¹⁵ Thirty-three percent of patients taking maximum doses of sulfonylureas and metformin achieved targeted A1C after 3 years.¹⁶ Patients on insulin only had better fasting plasma glucose (FPG) outcomes than patients taking OADs; however, there was no statistically significant reduction in A1C values to less than 7%. Researchers attributed this finding to the inability of the long-acting insulin used to cover prandial blood glucose levels. Patients were unable to remain compliant when short-acting insulin was recommended.¹⁵ Patients on insulin needed progressively higher basal doses and 24% required short-acting insulin to cover meals.¹⁷ The researchers concluded that near-normal glycemia was not attained as a direct result of hypoglycemic attacks. Note that insulin analogs were not available at the time of these studies.

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Management of Type 2 Diabetes 

Mainstream management is to start patients newly diagnosed with type 2 diabetes on a trial of lifestyle modifications, including dietary changes, weight loss, and exercise.¹⁸ The challenge for most practitioners is determining when to initiate OAD therapy, which agent and dose to use, and when to intensify treatment. Refer to the text box for management tips.

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Guideline Recommendations 

The ADA and the ACE have different glycemic guidelines (Table 1). Most of the larger studies have focused on outcomes of target A1C of 7% or less. However, because no evidence shows that patients will not continue to have better outcomes when A1C is 6.5% or less, the ACE guidelines are considered as the standard throughout this article.

Table 1. Comparison of ADA¹⁸ and ACE⁶ Glycemic Guidelines

* Plasma equivalent

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Principles of OAD Therapy 

Initiating OAD therapy involves the appropriate selection of an agent, titration, and follow-up. A reference guide for OAD therapy is given in Table 2. In general, monotherapy with insulin secretagogues or metformin reduces A1C by 1.5% to 2.0%. Nateglinide, a shorter-acting insulin secretagogue, and α-glucosidase inhibitors have less of an effect on the lowering of A1C (0.5%-1.0%). Thiazolidinediones reduce A1C by 0.75% to 2.0%.²⁰

Table 2. Reference Guide to Oral Anti-Diabetic Agents

SU indicates sulfonylurea; PP, postprandial; CHO, carbohydrate; SA, short-acting; LA, long-acting; CI, contraindicated

It is generally an accepted practice to start metformin in obese patients. However, the A1C at the time of diagnosis can affect the decision-making process. Riddle²⁰ suggests starting sulfonylureas in patients with baseline A1C greater than 8% because of the faster onset of action. Also, the risk of hypoglycemia increases as A1C moves closer to goal. Metformin may be the better option for patients with A1C of 7% to 8% because these patients may not have the typical diabetes symptoms and are more able to tolerate gastrointestinal side effects from the medication. Patients with A1C of 8% or less may also be successful with α-glucosidase inhibitors or nateglinide as monotherapy.²⁰ Thiazolidinediones would be appropriate as first-line therapy in patients with baseline A1C of 8% or less, dyslipidemia, or decreased renal function. This class of antidiabetic agents also appears to have the greatest effect with obese patients that have sufficient β-cell function (early in diagnosis).¹¹ Once an agent is selected, the next challenge is dose titration and determining the appropriate follow-up to evaluate the effect.

A case study is presented to assist with the application of principles discussed thus far. Hsueh et al¹¹ designed an algorithm for the evaluation and management of glycemic control. This algorithm offers an aggressive approach that reduces the amount of time patients experience glucotoxicity (hyperglycemia).

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Case Study 

Ms. Cook, a 40-year-old obese white woman, is being followed for an elevated FPG (210 mg/dL).

Past medical history: positive for hypertension and dyslipidemia

Medications: Toprol-XL and Lipitor

Family history: positive for type 2 diabetes, coronary artery disease, and hypertension

Social history: nonsmoker and 2 alcoholic drinks/month

Review of systems: no complaints and denies polyuria, polydipsia, and polyphagia

Vital signs: BMI, 34; weight, 200 pounds; height, 64 inches; blood pressure, 134/86 mm Hg

Laboratory values: FPG, 210 mg/dL

Plan: Ms. Cook was instructed to walk three times a week for at least 30 minutes and to decrease carbohydrate intake. A pamphlet about metabolic syndrome with diet information was given to the patient. She is highly motivated because her mother has type 2 diabetes and complications. Follow up in 2 months with FPG and A1C.

Follow-up Visit 2 

Ms. Cook has been making lifestyle changes.

Weight: 195 pounds

Laboratory values: FPG, 195 mg/dL; A1C, 8.5%

Assessment: type 2 diabetes

Plan: Add aspirin 81 mg/day. Start metformin one 500 mg tablet/day and increase to twice daily after 2 to 3 days. Continue to increase in increments of 500 mg/day every week as tolerated. Repeat FPG in 4 to 6 weeks and continue lifestyle changes.

Patient education: Self blood glucose monitoring (SBGM) several times per week, vary time of testing (ie, fasting, after meal, or before supper) and keep log. Refer to a registered dietician for medical nutrition teaching and to a certified diabetes educator for continued teaching, support, and assistance in the use of the glucometer.

Rationale: According to Riddle,²⁰ a sulfonylurea would be a better choice because her baseline A1C is greater than 8%. However, because there is no evidence that sulfonylureas decrease the risk of macrovascular complications, metformin may be a better option for this patient with established hypertension, hypercholesterolemia, and obesity. Either agent used as monotherapy would have an A1C-lowering effect of 1.5% to 2.0%. We recommend that patients test fasting after a meal and before supper several times a week to track glucose patterns. This schedule also facilitates treatment decisions.

Note: If Ms. Cook could not tolerate the gastrointestinal side effects before reaching the maximum effective dose of metformin, a sulfonylurea could be substituted.

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Benefits of Combination Therapy 

Combination therapy has additive glucose and lipid-lowering effects without additional side effects.¹¹ Therefore, smaller doses of each drug can be given when given as a combination. The thiazolidinediones have the most effect on the lipid profile when added to metformin and sulfonylureas (Table 3). As mentioned earlier, thiazolidinediones can be first-line therapy when A1C is 8% or less or with renal dysfunction.

Table 3. Comparison of the Lipid-Lowering Effects of Combination Therapies

Follow-up Visit 3 

Ms. Cook could not tolerate metformin's gastrointestinal side effects beyond 2000 mg/day.

Weight: 190 pounds

Laboratory values: FPG, 182 mg/dL

SBGM averages: postprandial (PP) test taken 1 to 2 hours after meals

Plan: Discontinue metformin. Start antidiabetic combination of glipizide and metformin (Metaglip), one 5/500 mg tablet twice daily with meals. Follow up in 1 month for FPG and evaluation of SBGM log.

Patient education: hypoglycemia

Rationale: The addition of a long-acting secretagogue will help to lower the basal (FPG and before supper) glucose and ultimately PP levels. If she had mild FPG and presupper levels but consistently high PP levels, an α-glucosidase inhibitor instead of a secretagogue could be an alternate option (25 mg with meals three times daily). As mentioned previously, a benefit of combination therapy is that lower doses of each drug can be given to achieve efficacy without the same risk of side effects. If Ms. Cook's basal readings were lower, a lower dose of glipizide (ie, 2.5 mg) could be started to avoid hypoglycemia. Titrating up to an effective dose is reasonable.¹³, ²²

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Summary on Hypoglycemia 

Although the frequency of iatrogenic hypoglycemia is much lower in patients with type 2 diabetes, serious hypoglycemic episodes are still possible. Serious hypoglycemic episodes that required medical attention were reported by patients during a 6-year follow-up of the UKPDS.² Patients taking metformin, sulfonylureas, and insulin experienced serious hypoglycemia 2.4%, 3.3%, and 11.2%, respectively.²⁴

Patients with advanced or long-standing type 2 diabetes may have an impaired neuroendocrine response to hypoglycemia (hypoglycemia unawareness). This is a dangerous situation because these patients do not experience protective symptoms when blood glucose approaches 65 to 70 mg/dL. Nighttime hypoglycemia is especially serious in these patients because their epinephrine response is impaired. It has been suggested that 2 to 3 weeks of hypoglycemia avoidance can help patients return to a normal response and experience protective symptoms.²⁴

All patients and caregivers should be instructed on the signs and symptoms of hypoglycemia, proper use and interpretation of the glucometer, and the appropriate responses to hypoglycemia. Patients with hypoglycemia unawareness should test before bed and before driving. Practitioners may need to adjust glycemic targets to manage these patients safely.

When patients are on combination OAD therapy with metformin and sulfonylureas, hypoglycemia may occur. When A1C is less than 7.4%, there is a significantly higher risk of hypoglycemia. Many factors contribute to hypoglycemia such as the use of long-acting sulfonylureas, A1C values close to goal, and when PP blood glucose is mostly high when basal glucose level is normal. This situation can be remedied by substituting sulfonylureas with the short-acting meglitinides, α-glucosidase inhibitors, or thiazolidinediones.

Follow-up Visit 4 

Weight: 193 pounds

SBGM averages:

Plan: Increase dose of combined metformin and sulfonylurea incrementally every 2 weeks. Ms. Cook is to call if FPG is less than 80 mg/dL or if she experiences symptoms of hypoglycemia. She was encouraged to continue weight loss. Reevaluate in 4 to 6 weeks and repeat A1C.

Follow-up Visit 5 

Ms. Cook is taking the maximum tolerable dose of metformin and sulfonylurea and has been consistent with lifestyle changes.

Weight: 180 pounds

Laboratory values: A1C, 7.5%

Ms. Cook decides she would rather start insulin than add a third oral medication. She understands that insulin is inevitable and wants to learn how to self-inject, but she also feels overwhelmed by multiple daily injections.

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Note on Triple OAD Therapy 

If A1C is not at goal with combination therapy, triple OAD therapy is a consideration. However, adding premixed insulin to metformin is less costly than triple OAD therapy. Also, a recent study concluded that 16.3% of patients trying triple OADs were not able to continue because of side effects or because of not reaching target A1C.⁸

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Insulin Therapy 

When prescribing insulin therapy, it is important to understand how insulin works naturally in the body. Normally, there is a continuous secretion of small amounts of insulin known as basal insulin. According to Heller,²⁵ basal insulin covers hepatic glucose production that occurs during sleep, as well as any glucose surges between meals. A meal-related secretion also covers PP glucose excursions. Normally, glucose peaks 1 hour after the start of a meal, returns to normal within 2 to 3 hours, and rarely exceeds 140 mg/dL.⁶

Conventional insulin therapy (human and pork) attempted to match normal insulin actions; however, many problems prevented tight glycemic control. Refer to Table 4 for a comparison of the time-action profiles of different insulin types.

Table 4. Onset, Peak, and Duration of Insulins

* Assumes 0.1-0.2 u/kg injection. Onset and duration may vary significantly by injection site.

** Time to steady state. Copyright” 2005 American Diabetes Association. From Clinical Diabetes, Vol. 23, 2005; 78-86 Reprinted with permission from The American Diabetes Association

Rapid-acting regular insulin must be injected 30 minutes before mealtime. Delays in the premeal injection lead to PP hyperglycemia. An injection of regular insulin to cover an evening meal can lead to hypoglycemia during sleep, especially if patients do not eat an evening snack. The intermediate-acting NPH is given twice daily to attempt to cover basal and mealtime glucose. However, because of the wide duration of action, there is increased risk of hypoglycemia.²⁰

Insulin therapy is more manageable for patients and providers since the advent of insulin analogs (ie, insulin glargine, insulin lispro, insulin aspart, and insulin glulisine [Apidra]). Analogs are chemically engineered with recombinant DNA technology to closely mimic physiological secretion insulin.²⁵ When compared with human insulin, (rapid-acting) analogs, such as insulin aspart, insulin lispro, and insulin glulisine, have a shorter onset and duration of action. Apidra, approved in 2004, has a similar physiologic profile to insulin aspart and insulin lispro. Apidra does have a quicker onset, earlier peak, and shorter duration (0.3 hour, 1 hour, and ≤5 hours, respectively). The long-acting basal insulin analog, insulin glargine, begins to work in approximately 2 to 4 hours and is effective up to 24 hours. Also available are premixed analogs consisting of rapid-acting and intermediate-acting insulins. These combinations cover PP and basal glucose levels.²⁰, ²⁵

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Barriers to Insulin Therapy 

Many barriers exist that delay the initiation of insulin therapy. Attitudes on the part of patient and provider affect this decision. Patient-related barriers include fear of needles, pain from the injections, hypoglycemia, or being treated differently by family and friends; weight gain; belief that insulin causes complications; and adverse effect on lifestyle.¹⁸ Health care providers may be hesitant to start insulin because of fear of hypoglycemic events and concerns about the patient's ability to inject insulin and may be reluctant to manage insulin for fear that it is too complex and time-consuming in a primary care practice.¹⁹

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Initiating Insulin Therapy 

Once the decision is made to start insulin therapy, many factors are considered when determining the most appropriate regimen type and dose. Patient comfort level with self-injection, predictability of mealtimes, frequency of SBGM, and motivation for portion control all contribute to the decision. Hirsch et al⁸ developed a tool that assists in the selection of an insulin regimen based on patient profile (Table 5).

Table 5. Patient-Based Insulin Regimens

Copyright 2005 American Diabetes Association. Clinical Diabetes, Vol. 23, 2005; 78-86 Reprinted with permission from The American Diabetes Association

There are many ways to initiate insulin. Once-daily insulin (insulin glargine or NPH given at bedtime) can be started when metformin and sulfonylureas are continued. If sulfonylureas are discontinued but metformin is continued, twice daily insulin can be initiated. If all OADs are discontinued, twice daily insulin should be started.²⁰

Studies indicate that insulin used in combination with metformin results in less weight gain, lower insulin doses, and less hypoglycemia than insulin alone or insulin with sulfonylureas. Insulin and sulfonylureas are still effective (ie, lowering insulin doses with little weight gain), but this combination is more expensive. Once-daily insulin glargine had fewer hypoglycemic episodes and better after dinner control than NPH. Insulin with thiazolidinediones results in significant weight gain along with higher costs.²⁶ Several generalizations are related to standard insulin dosing.

Follow-up Visit 5 continued 

Review: Maximum doses of sulfonylurea and metformin, with A1C of 7.5% and weight of 180 pounds. Insulin therapy is the best option.

Ms. Cook verbalizes that she wants to start slowly with insulin therapy and that she is overwhelmed. She does not want to be as concerned with nighttime hypoglycemia and decides to start with daily insulin glargine even though it is double the cost of NPH insulin.

Plan: Start Lantus 10 units at bedtime. Continue metformin and sulfonylurea as directed. Continue SBGM as directed and call office with any problems. Follow up in 2 months.

Rationale: According to Hirsch et al,⁸ patients on daily insulin need only to check daily FPG. Patients should check PP and before supper readings several times per week to get a better picture of the glucose pattern. It is standard practice to continue OADs when initiating daily insulin. Basal insulin and secretagogues provide continuous low-level insulin.

Follow-up Visit 6 

Ms. Cook has changed jobs. She has not been eating lunch most days because of meetings and has increased her breakfast and dinner portions.

Weight: 180 pounds (∼82 kg)

Laboratory values: FPG, 180 mg/dL

SBGM averages:

Plan: Discontinue sulfonylurea and insulin glargine. Start 0.1 units/(kg/day) (4 units twice daily) of premixed analog (75% NPL/25% insulin lispro [Humalog] or 70% APS/30% insulin aspart [NovoLog]). Advise SBGM fasting and before supper. Because of her busy schedule, Ms. Cook requests that she call in her readings. She is to call the office with results of average SBGM readings from 1 week.

Rationale: Because of lifestyle changes, it is appropriate to change to premixed twice daily insulin. Because she rarely eats lunch or lunch is small, a rapid-acting analog/intermediate-acting analog twice daily would cause less hypoglycemia than NPH/regular insulin twice daily. Hirsch et al⁸ recommend that the patient check glucose levels before breakfast and before dinner when on twice daily insulin therapy. Premixed NPH/regular insulin would have been an option if three meals a day were isocaloric, if lunch was the largest meal of the day, or if cost was a consideration.

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Insulin Dose Titration 

Hirsch et al⁸ designed a dose titration schedule that applies to all insulin types (Table 6).

Table 6. Dosage Titration for Once-Daily or Twice-Daily Insulin Regimens

Adjust prebreakfast dose based on presupper/evening meal Adjust presupper (premixed)/bedtime (basal) dose based on pre-breakfast/morning value DO NOT increase dose if hypoglycemia (<70 mg/dl) or symptoms are present

Copyright2005 American Diabetes Association. Clinical Diabetes, Vol. 23, 2005; 78-86

Reprinted with permission from The American Diabetes Association

Follow-up Visit 7 

Ms. Cook's average readings for most days of last week were before breakfast, 150 to 160s; before supper, 120 to 130s.

Plan: Increase before supper dose to 8 units and increase before breakfast dose to 6 units.

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Basal-Bolus Regimen 

Patients with consistently high PP glucose values require either meal modifications or basal-bolus regimen. This regimen is manageable but complex. Usually, 1 basal injection (insulin glargine) is given and a bolus of rapid-acting analog covers every meal. Bolus dosing is given before each meal and is calculated according to planned carbohydrate intake. Patients will require regular visits to the dietician and the practitioner initially for close follow-up.

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Newer Therapies 

Some exciting new therapies have recently been approved for the treatment of type 2 diabetes that mimic the hormones responsible for glucose metabolism. Exenatide (Byetta; jointly manufactured by Eli Lilly and Amylin) became available in June 2005. Byetta mimics glucagon-like peptide 1 (GLP-1) that is found in the small intestine. The main effects of GLP-1 are to stimulate glucose-dependent insulin release, decrease gastric emptying, inhibit inappropriate glucagon release, stimulate β-cell proliferation and differentiation, and increase satiety. It is thought that GLP-1 is deficient in people with type 2 diabetes.²⁷

A 30-week study was done to compare the efficacy of Byetta (5 units twice daily or 10 units twice daily) added to either metformin monotherapy or metformin and sulfonylurea combination therapy. The metformin, sulfonylurea, Byetta (10 mcgs twice daily) group had a significant reduction (1%) of A1C from the baseline.²⁸ The metformin and Byetta (10 mcgs twice daily) group had a similar reduction of 0.78%.²⁹ All groups were able to achieve A1C less than 7% at the end of 30 weeks. All groups receiving Byetta had significant weight loss; however, the metformin and Byetta (10 mcgs twice daily) group lost the most weight (∼3%). Weight loss did not plateau at the end of 30 weeks and was independent of nausea that is common in the first few weeks.²⁹ Mild-to-moderate hypoglycemia occurred in all groups but increased as a dose-related response to Byetta. Fasting blood glucose reductions were modest in all groups, and no significant improvement was seen when Byetta was added. Approximately 200,000 patients already take Byetta, and the cost per patient is estimated at $1500 to $2000 per year as compared with $1200 per patient for injectable insulin.³⁰

Vildagliptin (Galvus; Novartis) and sitaglipitin (Januvia; Merck) are two other GLP-1 drugs. Galvus and Januvia do not appear to be quite as potent at lowering blood glucose as metformin, the existing first-line diabetes drug. Because of their mild side effects, they will probably be given as an adjunct to metformin, replacing sulfonylureas.³¹ Januvia was released in 2006 and Galvus is expected to be released soon.

Pramlintide (Symlin; Amylin), approved in March 2004, mimics the hormone amylin. Symlin is approved for use in type 1 and type 2 diabetes as an adjunct to insulin when A1C is less than 9%. Amylin is normally secreted with insulin in response to meals and is thought to be deficient in type 1 and type 2 diabetes. Amylin regulates glucagon production, decreases gastric emptying, and is involved in the central regulation of food intake and body weight. Patients injecting Symlin (120 μg twice daily) had significant A1C lowering and weight loss as compared with placebo. The weight loss was more significant in patients with baseline BMI greater than 40 and those taking metformin (3.2 kg and 2.5 kg, respectively) after 26 weeks. Hypoglycemia occurred, especially in patients with type 1 diabetes.³²

Exubera (Pfizer) is the first inhaled insulin to be approved by the Food and Drug Administration for the adult population. It has a unique inhalant delivery system that provides predispensed amounts of dry powder insulin via a blister pack that does not need refrigeration. There is no need for special inhalation instructions. Exubera achieves significant A1C control in clinical trials and has a similar pharmocodynamic profile to regular injectable insulin. It is contraindicated for patients who smoke or have chronic lung disease, and pulmonary function tests are recommended before starting treatment and periodically thereafter. Transient cough and hypoglycemia are the most commonly reported side effects.³¹

Insulin detemir (Novo-Nordisk) is the second long-acting analog made available in 2006. For patients with type 1 diabetes, it will need to be given twice daily for basal coverage, but it may be able to be used for once-daily injection for patients with type 2 diabetes who need basal insulin coverage. Several trials that compared NPH insulin to insulin detemir have shown that NPH is associated with weight gain, whereas insulin detemir was either neutral or caused a small weight loss. Further studies that compare insulin detemir with insulin glargine need to be conducted.³³

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Summary 

There is an urgent need to manage diabetes mellitus efficiently particularly when considering the rapid rise in incidence of the disease and the economic burden on the health care system. The Institute of Medicine³³ identifies diabetes as a prime candidate for interventions to improve outcome for several reasons. Evidence is convincing that (1) clinical practice guidelines are effective, (2) a set of robust measures exist to assist with evaluation of interventions, and (3) verified ways of improving delivery of care already exist. When coupled with the increased prevalence (33% increase during the 1990s) of diabetes, the Institute of Medicine has made diabetes a model for improving quality of care for other chronic diseases such as CVD, hypertension, and renal disease.³³

Landmark trials such as the DCCT¹ and UKPDS² provided the evidence-based foundation for the strict management of type 2 diabetes. It has been widely accepted that strict glycemic control offers the best reassurance against long-term complications; yet, clinicians are sometimes hesitant to manage patients with diabetes aggressively for fear of hypoglycemic complications or discomfort with new treatment modalities. This article can help the advanced practice nurse overcome the hesitations and choose appropriate pharmacologic agents to maintain normal blood glucose levels. Also several algorithms of care are included to assist with further navigation, especially when considering that combinations and newer options have made treatment more challenging.

Note that patients with chronic illnesses such as diabetes often benefit from disease management. Diabetes is a classic example of reaching positive patient outcomes when clinical practice guidelines are followed. Nurse practitioners should actively engage a multidisciplinary team approach to manage the patient most effectively. Teaming with the patient will also make positive outcomes more likely.

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References 

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