PRINCIPLES OF INSULIN THERAPY

Transcription

1 08 PRINCIPLES OF INSULIN THERAPY 8.1 GENERAL PRINCIPLES Indications of Insulin Therapy The classical type 1 diabetes mellitus and LADA cases Hyperglycemic emergencies (DKA, HHS) Some cases of type 2 diabetes mellitus GDM not controlled with diet and physical activity Mechanism of Insulin Action Stimulates entry of glucose into the cells Increases glycogen storage Inhibits hepatic glucose output Inhibits the degradation of fat and protein Insulin Sources Recombinant DNA technique (human insulin, insulin analogues) Traditional bovine and porcine insulins Semi-synthetic insulin obtained from porcine insulin (not used in our country) Insulin Absorption Insulin absorption may be different on individual basis due to the reasons listed below: Insulin source: Compared to animal insulin, human insulin has a shorter duration of action. There are some differences depending on manufacturer (NovoNordisk, Eli Lilly and Sanofi-Aventis) Injection site: From the fastest to the slowest absorbing site: insulin could be injected s.c. into upper abdomen (epigastrium), upper arms, thighs, and buttocks. Environmental temperature: The warm temperature is associated with higher insulin absorption compared to cold temperature. Exercise, systemic fever and massage to the injection site increase insulin absorption. 40

2 Turk JEM 2010; 14: Suppl 40-6 The Principles of Insulin Therapy Insulin Preparations A. Insulin Strength Insulin preparations available in Turkey and used globally contain 100 IU insulin in 1 ml and called as U-100-insulins. Also U-500 insulins can be used in patients with marked insulin resistance and insulin requirement in some European countries and USA). B. Types and Action Profile of Insulins The following table shows currently available insulin preparations and their action profiles (Table 8.1). Although insulin does not pass through the placenta, there is not enough data available about the use of long-acting insulin analogs in pregnancy. Table 8.1 Types and action profiles of insulin preparations Insulin type Generic name Trade name Onset of Peak action (h) Duration action (min) of action (h) Short-acting (Regular) insulin Human regular insulin Actrapid HM, Humulin R Rapid-acting insulins Glulisine insulin Apidra (Prandial analogs) Lispro insulin Humalog Aspart insulin NovoRapid Intermediate -acting (NPH) insulin NPH human insulin Humulin N Insulatard HM Long-acting insulins (*) Glargine insulin Lantus (Basal analogs) Detemir insulin Levemir 60 Peakless (**) Premixed (biphasic) human insulin 30% regular + 70% Humulin M 70/30 (Regular + NPH) NPH human insulin Mixtard HM Variable Premixed analogs 25% insulin lispro + Humalog Mix25 (Biphasic lispro + NPL) 75% insulin lispro protamin 50% insulin lispro + Humalog Mix Variable % insulin lispro protamin Premixed analogs 30% insulin aspart + NovoMix Variable (*) Long-acting (basal) analogs are not equivalent in efficiency. When used as basal insulin the requirement for glargine is at least 10 to 15% less than that for detemir. Insulin detemir shows slightly less day to day variation and less weight gain effect (0.5-1 kg) than glargine. The duration of action of insulin detemir shortens at low doses, therefore especially type 1 diabetes patients with <0.35 IU/kg/day basal insulin requirement may need a second basal dose Routes of Insulin Delivery Insulin is normally injected subcutaneously. In case of emergency rapid- or short-acting insulins can be given intramuscularly or intravenously Insulin Dose Adjustment Aim To mimic normal basal insulin secretion in people with type 1 diabetes (insulin replacement) Some cases with type 2 diabetes may need (basal) insulin support, and the need for insulin replacement arises over time Insulin Indications in Type 2 Diabetes Failing to obtain good metabolic control with submaximal doses of OADs Excessive weight loss Severe hypoglycemia symptoms

3 42 The Principles of Insulin Therapy Turk JEM 2010; 14: Suppl 40-6 Acute MI Acute diseases with fever, systemic diseases Hyperosmolar hyperglycemic state (HHS) and ketotic coma (DKA) Major surgical operation Pregnancy and lactation Kidney or liver failure Severe allergy or side-effects to any OADs Severe insulin resistance (with acanthosis nigricans) Complications of nsulin Treatment Hypoglycemia: The main and most frequent complication during therapy with insulin is hypoglycemia. It is associated with strict glycemic control and longer duration of diabetes. It is more frequent in type 1 diabetic patients treated with basal-bolus insulin regimen. In DCCT study the frequency of hypoglycemia is 3 times higher in intensive insulin therapy group compared to conventional treatment group. Risk of hypoglycemia with insulin analogues is slightly lower than human insulins. Weight gain: At the beginning of insulin therapy few kilograms of weight gain is expected due to the regaining of previously lost adipose and muscle tissue, and the disappearance of glucosuria. Then the fear of hypoglycemia and unbalanced diet may cause continued weight gain. Massive hepatomegaly: It is associated with excessive glycogen storage in the liver, and is rare nowadays. Edema: Increased sodium reabsorption and decreased osmotic diuresis due to insulin may increase body fluid volume at the beginning of treatment. Anti-insulin antibodies and allergy to insulin: Both are rare complications nowadays with availability of human insulins and new insulin analogues. Lipoatrophy: It is a rare immunological event with newer pure insulins. Lipohypertrophy: It occurs when the same injection site is used too frequently, and can be treated by rotating the injection sites. Bleeding, leakage and pain: Bleeding can be prevented by administrating injection to a region which is not rich in capillary vessels. Leakage is minimized by using long needle and by releasing the pinch 5 to 10 seconds before removing the needle from the skin. Especially acid insulins, such as glargine, may cause slight and unimportant pain at the injection site. Relationships between hyperinsulinemia and insulin resistance and risk of atherosclerosis and cancer: Although experimental studies have pointed to the relationship between atherosclerosis and hyperinsulinemia, clinical evidence is not sufficient. Insulin is an anabolic hormone. Insulin receptors are structurally similar to that of insulin-like growth hormone (e.g. IGF-1). The power of insulin correlates with its receptor affinity. Powerful insulins have higher affinity for insulin and IGF-1 receptors. Therefore the relationship between insulin and cancer risk has been considered for many years. However, because of conflicting data based on cross-sectional studies, the discussions about this issue still continue. But randomized clinical studies on this issue are lacking. 8.2 INSULIN TREATMENT PROTOCOLS Basal-Bolus Insulin Replacement Basal-bolus insulin replacement should be recommended in type 1 diabetes, GDM that cannot be controlled with diet and type 2 diabetes with decreased endogenous insulin reserve. It can be applied in the following ways: A. Multiple Subcutaneous Insulin Injections (MSII) Rapid/short-acting (bolus) insulin three times in a day preprandial plus intermediate/long-acting (basal) insulin (preferably in the evening) as a single dose. Rapid/short-acting (bolus) insulin three times in a day preprandial plus intermediate/long-acting (basal) insulin two times in a day. Premixed (biphasic) insulin analogs should be considered in patients with type 2 diabetes who have difficulty to implement basal bolus insulin therapy with two different insulin preparations. B. Continuous Subcutaneous Insulin Infusion (CSII) Continuous subcutaneous insulin infusion, using basal, bolus and adjustment doses via external pump, could be a solution to improve glycemic control (see Chapter 10).

4 Turk JEM 2010; 14: Suppl 40-6 The Principles of Insulin Therapy Insulin Supplement Therapy It is recommended in elderly patients with type 1 diabetes with complications or at high risk of hypoglycemia, GDM that cannot be controlled with diet, and some cases with type 2 diabetes. A. Biphasic Insulin Mixtures Intermediate/long-acting + rapid/short-acting premixed insulins two times in a day: Premixed insulin preparations can be used. Alternatively, patients may inject two different insulin. B. Basal insulin support Intermediate/long-acting (basal) insulin support once or twice a day (in type 2 diabetic patients and some GDM cases). There is not enough evidence about the safety of long-acting insulin analog during pregnancy, therefore glargine and detemir insulin should not be used in cases of pregestational diabetes and GDM Insulin Dose Calculation and Adjustment Initially it is adjusted per kilogram of body weight. Moreover, phenotype and physical activity status of individuals with diabetes, and presence of diabetes complications should be taken into consideration. Recommendations for calculation of insulin dose are given in Table 8.2. In general, maintenance of insulin dose for individuals with type 1 and type 2 diabetes is as follows: Type 1 diabetes; IU/kg/day Type 2 diabetes; IU/kg/day In basal bolus insulin regimen about half of daily requirement (40-60%) is calculated as basal and the remaining half (40-60%) as bolus dose. Basal insulin support; IU/kg/day can be given initially. Insulin injection time It depends on the type of insulin. Rapid-acting insulins are administered 5 to 15 minutes and short-acting insulins 30 minutes before meal. Insulin injection time can be changed according to blood glucose levels. For example, a meal may be delayed if preprandial PG level is higher than the targeted value. Insulin injections may be delayed to postprandial to avoid hypoglycemia in diabetic patients with extremely prolonged gastric emptying time. Table 8.2 Calculation of the insulin dose Phenotype Insulin dose (IU/kg/day) Normal weight patients Intense physical activity 0.3 Moderate physical activity 0.4 Mild physical activity 0.4 Obese patients Intense physical activity 0.5 Moderate physical activity 0.6 Mild physical activity 0.8 Renal failure Conditions with high risk of hypoglycemia Frequent, binge eaters Newly onset type 1 diabetes (<30 years of age) 0.3

5 44 The Principles of Insulin Therapy Turk JEM 2010; 14: Suppl Injection Methods A. Insulin Pens It allows safe and correct application of insulin, therefore it is more preferable. Most pens contain 300 IU (3 ml) of insulin and some of them are disposable, while others use replaceable cartridges. Insulin pens are calibrated for 1 IU, moreover pens calibrated for 0.5 IU are available for children. Insulin pen needles are in three lengths as 4 mm, 6 mm, 8 mm and 12 mm. Generally, 4, 6 or 8 mm needles are used. Obese individuals may require 12 mm-length needles. B. Insulin Syringes This method is used less frequently in most developed countries as well as our country. Insulin syringes are available in three different sizes; 0.3, 0.5, and 1 ml. They are calibrated for 1 IU, and syringes calibrated for 0.5 IU are available for children and for patients more sensitive to insulin. In general syringes with 8 mm needles are in use but also 6 and 12 mm needles are available. Ten ml vials (containing 1000 IU insulin) are used for syringes. C. Insulin Pump Continuous subcutaneous insulin infusion (CSII) or insulin pump therapy will be discussed in detail in the following sections (see Chapter 10 The Principles of CSII) Insulin Storage Guidelines Unopened vials and cartridges can be stored at 2-8 o C in the refrigerator until the expiration date. Opened vials and cartridges can be used at room temperature up to 30 days. Intermediate/long-acting or premixed insulin preparations may lose their biological activity slightly 15 days after they have opened. This should be considered if glycemic control begins to deteriorate although patient s health condition has not changed Mixing of Insulin Preparations Short-acting and NPH insulins should be used immediately after mixing (However, some authors suggest that these mixtures can be kept in the refrigerator up to 2 weeks). Glargine and detemir insulins should not be mixed with other insulins Drugs that Interact with Insulin Given that some drugs in Table 8.3 may lead to hypoglycemia by increasing the effect of insulin whereas some others to hyperglycemia by reducing the effect of it (some of them by inducing insulin resistance) they require insulin dose adjustments.

6 Turk JEM 2010; 14: Suppl 40-6 The Principles of Insulin Therapy 45 Table 8.3 Drugs that Interact with Insulin A. Drugs increasing the hypoglycemic B. Drugs reducing the hypoglycemic effect and lowering glycemia effect and increasing glycemia β-blockers (*) Acetazolamide ACE-I Albuterol Alcohol Antiviral agents used in AIDS Anabolic steroids Asparaginase Calcium Calcitonin Chloroquine Corticosteroids Clofibrate Cyclophosphamide Clonidine Danazol Disopyramide Dextrothyroxine Fluoxetine Diazoxide Guanitidine Diltiazem Lithium carbonate Diuretics Mebendezole Dobutamine Monoamine oxidase inhibitors Epinephrine OADs Estrogen hormones Pentamidine (**) Ethacrynic acid Phenylbutazone Isoniazid Piridoxine Lithium carbonate Propoxyphene Morphine sulphate Salicylate Niacin Somatostatin analogs (Octreotide) Nicotine Sulfonamides Oral contraceptives Sulphynpirazone Phenytoin Tetracycline Somatropin Terbutaline Thiazide diuretics Thyroid hormones (*) They may delay the recovery from hypoglycemia. (**) Hypoglycemia is sometimes followed by hyperglycemia SEMT APPROACHES TO INSULIN TREATMENT AND RECOMMENDATIONS Basal-bolus (intensive) insulin therapy should be preferred to provide glycemic control in adults with type 1 diabetes, and in patients with type 2 diabetes whose beta cell reserves were depleted [For type 1 diabetic patients: Class A, Level 1A evidence; For type 2 diabetic patients: Class D, evidence-based consensus]. Insulin analogues are not superior to human insulin to obtain good glycemic control (A1C) [Class A, Level 1 evidence (2,3)]. Basal insulin can be used together with rapid-acting insulin analogues (aspart, glulisine, lispro) to reduce the risk of hypoglycemia and to provide PPG control while lowering A1C [Class B, Level 2 evidence (3,4)]. Long-acting insulin analogues (glargine, detemir) can be used as an alternative to NPH insulin for basal insulin support [Class B, Level 2 evidence (5-8)]. Long-acting insulin analogues (glargine, detemir) should not be used in pregnancy (Class D, evidence-based consensus). It has been shown in clinical trials that the risks of severe hypoglycemia and nocturnal hypoglycemia with basal insulin analogeus are slightly lower compared to NPH insulin: - to reduce the risk of severe hypoglycemia [For glargine: Class B, Level 2 evidence (9); For detemir: Class C, Level 3 evidence (10)]. - to reduce the risk of nocturnal hypoglycemia [For glargine: Class B, Level 2 evidence (10); For detemir: Class D, evidence-based consensus]. All individuals with type 1 diabetes should be evaluated about the risk of hypoglycemia, be counseled about the risk and prevention of insulin-induced hypoglycemia, and risk factors for severe hypoglycemia should be identified and addressed (Class D, evidence-based consensus). In individuals with hypoglycemia unawareness, the following strategies should be implemented to attempt to regain hypoglycemia awareness: - Increased frequency of SMBG, including periodic assessment at night (Class D, evidence-based consensus). Less strict glycemic control for a while (higher glycemia and A1C levels are targeted) until the patient is recovered [Class C, Level 3 evidence (11,12)].

7 46 The Principles of Insulin Therapy Turk JEM 2010; 14: Suppl 40-6 REFERENCES 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329: Plank J, Siebenhofer A, Berghold A, et al. Systematic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus. Arch Intern Med 2005;165: Singh SR, Ahmad F, Lal A, et al. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 2009;180: Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev 2006;(2):CD Warren E, Weatherley-Jones E, Chilcott J, et al. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine. Health Technol Assess 2004;8: Wang F, Carabino JM, Vergara CM. Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther 2003;25: Dunn CJ, Plosker GL, Keating GM, et al. Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs 2003;63: Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs 2004;64: Mullins P, Sharplin P, Yki-Jarvinen H, et al. Negative binomial meta-regression analysis of combined glycosylated hemoglobin and hypoglycemia outcomes across eleven phase III and IV studies of insulin glargine compared with neutral protamine Hagedorn insulin in type 1 and type 2 diabetes mellitus. Clin Ther 2007;29: Goldman-Levine JD, Lee KW. Insulin detemir a new basal insulin analog. Ann Pharmacother 2005;39: Liu D, McManus RM, Ryan EA. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycaemic control. Clin Invest Med 1996;19: Lingenfelser T, Buettner U, Martin J, et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM. Diabetes Care 1995;18:321-5.