By Betsy B. Dokken, PhD, NP, CDE. Keywords: diabetes mellitus, insulin analogues, insulin therapy

Transcription

1 How insulin analogues can benefit patients Abstract: Primary care providers offer diabetes care for many patients in the United States. Primary care nurse practitioners can benefit from an understanding of effective administration of insulin therapy. This review will outline suggestions for the effective use of insulin analogues in clinical practice. A pproximately 65% of patients with diabetes receive care for their condition from a primary care provider. 1 By definition, patients with type 1 diabetes require insulin therapy. In addition, most patients with type 2 diabetes may require insulin therapy during stress (such as hospitalization) and throughout the later stages of the disease. Since the development and FDA approval of the first insulin analogue in 1997 (insulin lispro), insulin therapy has evolved rapidly. This brief review will outline the purpose of insulin analogues and suggestions for their effective use in clinical practice to help patients achieve glycemic control. Why insulin analogues? Insulin analogues were developed to provide a strategy for the delivery of exogenous insulin to mimic the physiologic By Betsy B. Dokken, PhD, NP, CDE Keywords: diabetes mellitus, insulin analogues, insulin therapy release of insulin, improve effectiveness, and increase flexibility for patients. Regular insulin has a delay to onset of action of 30 to 60 minutes. In order to match carbohydrate absorption and insulin bioavailability, it must be injected 20 to 30 minutes before eating. In addition, regular insulin is active in the circulation between 5 and 8 hours. 2 If enough regular insulin is taken to control postprandial glucose, hypoglycemia may occur several hours after the injection. Neutral protamine Hagedorn insulin (isophane insulin suspension; NPH) is regular insulin with the addition of protamine (which results in the dose being absorbed slowly). The onset of action of NPH insulin is 2 to 4 hours after the injection. The peak is variable, can occur between 4 and 10 hours after the injection, and can last up to 16 hours. 3 One of the most important limitations of insulin therapy with NPH and regular insulin is the requirement 44 The Nurse Practitioner Vol. 38, No. 2 Photo by Marcela Barsse/istockphoto

2 for patients to eat on a fixed schedule. A patient taking a mixture of NPH and regular insulin must inject, wait up to 30 minutes to eat, and eat again during the peak of NPH action 4 to 10 hours after the injection. A missed or delayed meal results in hypoglycemia. This schedule must be repeated in the evening, and patients taking NPH with regular insulin before the evening meal risk nocturnal hypoglycemia during the peak action of the NPH. Insulin analogues were engineered to provide peakless basal coverage and rapid/short-acting insulin action for coverage of meals and quick correction of hyperglycemia. The human insulin molecule was modified by amino acid substitution or the addition of side-chains in order to produce the desired effect. Long-acting insulin analogues include insulin glargine and insulin detemir. Rapid-acting insulin analogues include insulin lispro, insulin aspart, and insulin glulisine. They have a shorter duration of action, and provide increased insulin action faster than regular insulin. These analogues have slight differences, but for the purposes of this article, they will be grouped together interchangeably. Advantages of insulin analogues Rapid-acting insulin analogues blunt the rise of postprandial blood glucose and decrease the risk of late postprandial hypoglycemia. Long-acting insulin analogues decrease the variability of blood glucose levels and also mitigate the risk of hypoglycemia during the postprandial state especially overnight. 4 Disadvantage of insulin analogues The major disadvantage of insulin analogues is the cost. 5 Analogues on an average cost twice as much as NPH or regular insulin. Most health plans cover analogues, but patients must pay a higher co-pay. Some health plans deny coverage for analogues but will authorize payment provided medical necessity is justified. 6 One example of justifying a switch from NPH to a long-acting analogue would be a patient with fasting hyperglycemia on evening NPH who becomes hypoglycemic during the night when the dose is increased. This patient would clearly benefit from a long-acting, peakless insulin analogue. Individualized goals are critical Patients with type 1 diabetes are typically sensitive to insulin and require lower doses than their type 2 counterparts. However, this is not always the case. Due to the high prevalence of obesity, many patients with type 1 diabetes may have components of the metabolic syndrome and its associated insulin resistance. 7 Insulin therapy and goals should be individualized for every patient. In addition, patients on insulin therapy should be frequently evaluated for glycemic control and the presence of the most commonly associated adverse reaction hypoglycemia. Blood glucose monitoring is important. Patients must know the target ranges for fasting, preprandial, and postprandial blood glucose levels in addition to having specific guidance on a testing schedule. Insulin therapy in type 1 diabetes Since the results of the Diabetes Control and Complications Trial (DCCT) were published, 8 clinicians have been convinced of the value of near-normal control of blood glucose. This landmark study demonstrated unequivocally that the common complications of diabetes retinopathy, nephropathy, and neuropathy could be significantly decreased by glycemic control. 8 Type 1 diabetes results in the absolute destruction of pancreatic beta cells. 9 For this reason, the goal of insulin therapy is to mimic the pattern of insulin secretion from a healthy pancreas. The healthy pancreas provides a low concentration of insulin during the hours of fasting and between meals (basal insulin) and a higher concentration for a short duration during meals (bolus insulin). Physiologic insulin therapy in type 1 diabetes is attempted by using multiple daily insulin injections (MDII) or by using continuous subcutaneous insulin infusion (CSII, or an insulin pump). Successful basal-bolus insulin therapy is dependent on predictable absorption and action of the insulin. Traditional insulin preparations are fraught with variability in both absorption and action. In addition, the longeracting insulin preparations have been associated with a peak action that was not necessarily beneficial. Insulin analogues have been developed to facilitate improved basal-bolus insulin therapy with minimal risk of hypoglycemia. 10 Basal-bolus insulin therapy The goal of basal-bolus insulin therapy is to replace insulin in as physiologic a manner as possible. Basal (long-acting) insulin is provided for the patient s metabolic requirements during periods of fasting and between meals, while bolus (rapid-acting) insulin is provided to either rapidly correct hyperglycemia or compensate for the predicted glycemic excursion after a meal. Initiating insulin therapy in type 1 diabetes Initiate insulin therapy as soon as possible in patients diagnosed with type 1 diabetes in order to prevent diabetic ketoacidosis. Most adult patients can be started on a total daily dose of 0.4 to 1.0 unit of insulin/kg/day, 11 although most will ultimately require more. Approximately 50% of The Nurse Practitioner February

3 the total dose should be given as basal insulin, preferably a long-acting analogue (glargine or detemir). The remaining 50% of the insulin should be given as rapid-acting insulin (lispro, aspart, or glulisine) in divided doses. 11 Since the onset of action of rapid-acting insulin analogues is within 10 minutes, patients should generally be instructed to dose and eat ; this means to take the injection and eat immediately (refer to prescribing information for specific details on each analogue). Thus, the correction dose must be individualized according to each patient based on his or her responses to a conservative starting point. However, the use of slidingscale prandial insulin based solely on the premeal blood glucose concentration is usually not effective, as this type of insulin regimen does not compensate for carbohydrates in the patient s diet. Accurate dosing of prandial bolus insulin should result in a peak postprandial blood glucose level less than 180 mg/dl. 12 Adjusting insulin therapy in type 1 diabetes Since the purpose of basal insulin is to provide metabolic requirements during fasting and between meals, the dose should be adjusted based on the pattern of fasting blood glucose readings. The goal for fasting blood glucose should be individualized based on the patient s age, ability to sense Rapid-acting insulin analogues compensate for dietary carbohydrate intake and correct hyperglycemia. early warning signs of hypoglycemia, and the presence of cardiovascular complications. For most patients, the fasting blood glucose should be maintained between 70 and 130 mg/dl most of the time. 12 Basal insulin can be safely adjusted by 10% every 3 to 7 days. If the patient is competent, self-titration is very effective If not, frequent (at least weekly) review of blood glucose results, and insulin adjustments by the provider are recommended. This can be done via fax, , or very brief follow-up visits. Bolus insulin Ideally, rapid-acting insulin analogues are administered precisely to compensate for dietary carbohydrate intake as well as to correct hyperglycemia when necessary. Hyperglycemia correction is an important factor to consider when prescribing insulin therapy. Patients with type 1 diabetes are typically quite sensitive to insulin. 17 Correction of hyperglycemia with rapid-acting insulin analogues Rule : 1. Divide 1800 by the total daily dose of insulin. 2. The number reflects an estimate of the amount (blood glucose in mg/dl) that 1 unit of insulin will decrease. 3. Example: Total daily dose is 60 units. 1800/60 = unit of a rapid-acting insulin analogue would be expected to decrease blood glucose by 30 mg/dl. Importance of dietary carbohydrate intake Unlike dietary fat or protein, approximately 100% of carbohydrates eaten are likely to be absorbed into the circulation as blood glucose. Because of this, the amount of carbohydrates ingested during a meal may have a major impact on the postprandial blood glucose concentration. Patients who report erratic blood glucose levels often are not aware of the influence of dietary carbohydrates. Patients with type 1 diabetes (and many with type 2 diabetes) should be trained in carbohydrate counting, in addition to a dosing algorithm or formula for hyperglycemia correction (see Correction of hyperglycemia with rapid-acting insulin analogues), and should be taught to take insulin to compensate for dietary carbohydrates. In clinical practice, this is typically called the insulin- to-carbohydrate ratio. Registered dietitians can help educate patients to quantify dietary carbohydrate intake and limit if necessary. Although the amount of carbohydrates determines the primary response of the blood glucose, the type of carbohydrate may also be important for some patients. A detailed review is available through the American Diabetes Association. 18 Insulin pumps Insulin pumps provide an alternate delivery system for basalbolus insulin therapy. Basal insulin is supplied in the form of a continuous infusion with premeal bolus doses administered to minimize postprandial glycemic excursions. Only rapid-acting insulin analogues are used in pumps. Patients are taught to program the basal rate(s) and the bolus doses into the pump. The basal rate typically ranges from 0.3 to 1.2 units/hour and can be adjusted to compensate for periods of the day when more or less insulin is required. 19 Bolus doses are based on preprogrammed formulas for correcting hyperglycemia and for compensating for intake of carbohydrate. Certified insulin pump trainers are usually available to initiate patients on pumps and to provide support and dose adjustments during the first few weeks of therapy. 46 The Nurse Practitioner Vol. 38, No. 2

4 Advantages Insulin absorption is less variable from day-to-day using insulin pumps, and so, glucose profiles may be more predictable. In addition, patients with a significant dawn phenomenon, in which blood glucose is increased during the early morning hours compared to the remainder of the day, benefit from the ability to deliver more insulin during this time period. Moreover, patients who are physically active and have exercise-induced hypoglycemia have the ability to deliver less basal insulin during and after exercise to prevent hypoglycemia. However, taken together, studies evaluating superior efficacy of insulin pump therapy are inconclusive. 20,21 Disadvantages Insulin pumps are expensive. Although covered by many plans when justified as medically necessary, the cost of CSII with an insulin pump far exceeds the cost of MDII with insulin delivered via syringes or insulin pens. In addition, patients must be willing and able to learn the technical skills necessary for programming the pump and changing the insertion set/tubing every 3 days. 19 There is a slight risk of skin infection due to the indwelling catheter. In addition, because insulin pumps use only rapid-acting insulin analogues, the duration of action of any given basal rate or bolus is only several hours. If insulin infusion is interrupted and the patient is not aware, diabetic ketoacidosis from insulin deficiency can develop very rapidly within hours. Therefore, the decision for insulin pump therapy should be made by the provider (along with the patient) after careful consideration of the advantages and disadvantages by all parties involved in the patient s care. Diabetes education Rapid initiation of insulin therapy in type 1 diabetes can prevent a hospitalization for diabetic ketoacidosis. However, once insulin therapy is initiated, the goal becomes optimizing therapy to promote excellent glycemic control while preventing hypoglycemia. In order to successfully achieve this goal, patient self-management education and participation in care are critical. If the patient is a child, education of the parent(s) is essential. Nurse practitioners (NPs) who are not experts themselves would benefit from establishing relationships with their colleagues in diabetes education. Certified Diabetes Educators (CDEs) are experts in patient self-management education and training. Many CDEs are also NPs who manage their own patients. Clarify on the referral if you are sending the patient for education only or for diabetes management and education. To find an educator in a specific area, refer to the American Association of Diabetes Educator website: org/diabeteseducation/find.html. Insulin therapy in type 2 diabetes Although initially developed to treat insulin-deficient type 1 diabetes, insulin has been used for decades to control blood glucose in patients with type 2 diabetes. Due to the progressive nature of beta-cell dysfunction in type 2 diabetes, most patients with this disease will eventually require insulin for glycemic control. 22 Unlike other blood-glucose-lowering agents indicated for use in type 2 diabetes, insulin has no maximum dose, and when administered in adequate doses, has the potential to promote glycemic control in virtually any patient with diabetes. 23 In clinical practice, insulin therapy in type 2 diabetes is usually started with a single daily injection of basal insulin (glargine or detemir). Due to the presence of insulin resistance, patients with type 2 diabetes typically require substantially more insulin than patients with type 1 diabetes. Weight-based Insulin absorption is less variable from day-to-day using insulin pumps, so glucose profiles may be more predictable. estimates of insulin requirements in type 2 diabetes tend to be inaccurate. A common practice is to start basal insulin at a dose of 10 units daily or 0.2 units/kg body weight. 24 These doses will virtually always need to be increased. Dose titration by educated patients is a very effective method for achieving fasting blood glucose. A safe rule of thumb is a 10% dosage increase every 3 to 7 days until the fasting blood glucose goal is achieved. Protocols used in the Treat-to-Target studies are available Once the fasting blood glucose target is consistently achieved, the need for prandial insulin must be considered. Unlike patients with type 1 diabetes, patients with type 2 diabetes may not require prandial insulin to achieve glycemic control. Depending on their ability to secrete prandial insulin, these patients may be able to control postprandial blood glucose through the use of a prudent diet. Again, dietary carbohydrate intake plays a major role. Patients who are able and willing to limit (not eliminate) dietary carbohydrates can minimize the glucose excursion after meals. In addition, other prandial pharmacologic therapies (beyond the scope of this article) are available for postprandial glucose control in type 2 diabetes The Nurse Practitioner February

5 Patients with type 2 diabetes are often overweight and want to lose weight. Therefore, particularly in overweight patients, it is important to give them the opportunity to control postprandial glucose by restricting carbohydrate (thus, also caloric) intake. Providing prandial insulin for large meals will increase the risk of weight gain. In addition, a patient on prandial insulin who accidentally delays or skips a meal will likely experience hypoglycemia, providing tacit reinforcement to eat frequently. Therefore, it is important to determine the need for prandial insulin in patients with type 2 diabetes prior to prescribing it. If necessary, one approach to the addition of prandial insulin is to start with the largest meal of the day, usually the evening meal. 26 Typically, start with 4 units of a rapid-acting analogue, and adjust by 2 units every 3 to 4 days to keep the 2-hour postprandial blood glucose less than 160 mg/dl. 26 Additional doses of prandial insulin should then be added as necessary. Patients with type 2 diabetes who demonstrate the need for prandial insulin (even when carbohydrate intake is limited) should be given the option of using an insulinto-carbohydrate ratio. Many patients with type 2 diabetes are producing such limited amounts of endogenous insulin that they benefit from basal-bolus insulin therapy identical to that of a patient with type 1 diabetes. In fact, many patients with type 2 diabetes benefit from insulin pump therapy. Moving forward Insulin analogues provide many advantages over older insulin formulations. Insulin therapy is most effective when tailored to the individual patient s needs. In addition, attention to lifestyle behaviors (such as diet) is critical for the success of virtually any insulin regimen. NPs can stay abreast of current recommendations by frequently consulting the American Diabetes Association Standards of Medical Care. 17 Diabetes educators and dietitians are very important and helpful members of the diabetes care team and can help providers and patients achieve mutual, positive health outcomes. REFERENCES 1. Schappert S, Rechtsteiner E. Ambulatory medical care utilization estimates for Vital Health Stat. 2011;13(169): Hirsch IB, Bergenstal RM, Parkin CG, Wright E Jr, Buse JB. A real-world approach to insulin therapy in primary care practice. Clin Diabetes. 2005; 23: Duckworth W, Davis SN. Comparison of insulin glargine and NPH insulin in the treatment of type 2 diabetes: a review of clinical studies. J Diabetes Complications. 2007; 21(3): Bolli GB. Insulin analogues. In: Stehouwer C, Schaper N, eds. Therapeutic Strategies in Diabetes. Oxford, England: Clinical Publishing; 2010: Brixner DI, McAdam-Marx C. Cost-effectiveness of insulin analogs. Am J Manag Care. 2008;14(11): Monami M, Marchionni N, Mannucci E. Long-acting insulin analogues vs. NPH human insulin in type 1 diabetes. A meta-analysis. Diabetes Obes Metab. 2009;11(4): Thorn LM, Forsblom C, Fagerudd J, et al. Metabolic Syndrome in Type 1 Diabetes. Diabetes Care. 2005;28: The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. New Engl J Med. 1993;329(14): Notkins AL, Lernmark A. Autoimmune type 1 diabetes: resolved and unresolved issues. J Clin Invest. 2001;108: Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care. 2000;23(5): Kaufman FR. Medical Management of Type 1 Diabetes. Alexandria, Virginia: American Diabetes Association; American Diabetes Association. Standards of Medical Care in Diabetes Diabetes Care. 2012;35:S11-S Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008;51(3): Fogelfeld L, Dharmalingam M, Robling K, Jones C, Swanson D, Jacober S. A randomized, treat-to-target trial comparing insulin lispro protamine suspension and insulin detemir in insulin-naive patients with type 2 diabetes. Diabet Med. 2010;27(2): Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006; 29(6): Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26(11): American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2012;35:S11-S63. Supplement_ American Diabetes Association, Bantle JP, Wylie-Rosett J, Albright AL,et al. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care. 2008;31 (suppl 1):S61-S Pickup JC. Insulin-pump therapy for type 1 diabetes mellitus. N Eng J Med. 2012; 366: Bode BW. Use of rapid-acting insulin analogues in the treatment of patients with type 1 and type 2 diabetes mellitus: insulin pump therapy versus multiple daily injections. Clin Ther. 2007;29:S135-S Retnakaran R, Hochman J, DeVries JH, et al. Continuous subcutaneous insulin infusion versus multiple daily injections: the impact of baseline A1c. Diabetes Care. 2004;27(11): DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA. 2003;289(17): Mayfield JA, White RD. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Am Fam Physician. 2004; 70: Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2008; 31(1): Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2009;32(1): Henske JA, Griffith ML, Fowler MJ. Initiating and titrating insulin in patients with type 2 diabetes. Clin Diabetes. 2009;27: Hirsch IB, Trence D. Optimizing Diabetes Care for the Practitioner. Philadelphia, PA: Lippincott Williams & Wilkins; 2003:43. Betsy B. Dokken is an Assistant Professor of Medicine/Endocrinology at the University of Arizona in Tuscon, Ariz. The author has disclosed that she has no financial relationships related to this article. DOI /01.NPR The Nurse Practitioner Vol. 38, No. 2