Diagnosis and Management of Pituitary Disorders - part 5 docx

Chapter 12 / Intensive Insulin Therapy in T2DM 185 insulin without significant hypoglycemia but at the expense of progressive weight gain (7). All these studies clearly demonstrate the efficacy of various insulin regimens and the adverse consequences of such therapy. PREMIXED INSULIN REGIMENS Combinations of rapid-acting insulin analogs and intermediate acting insulins are manufactured as premixed insulin formulations. Premixed regimens are not appropriate for patients with type 1 diabetes and for most thin, insulin sensitive patients with T2DM; however, they can be effective for obese insulin resistant patients with T2DM. One such insulin preparation is Humalog Mix 75/25, which is a fixed-ratio mixture of 25% rapid-acting insulin lispro and 75% novel protamine-based intermediate-acting insulin called neutral protamine lispro (NPL). NPL was developed to solve the problem of instability with prolonged storage that occurs with NPH combined with short acting insulin. Studies of the pharmacokinetic and pharmacodynamic profiles of NPL show they are comparable to those of NPH insulin (8). Humalog Mix 75/25 was compared to premixed human insulin 70/30 in patients with T2DM in a 6-mo randomized, open-label, 2-period crossover study (9). Twice-daily injections of Humalog Mix 75/25 resulted in improved postprandial glycemic control after the morning and evening meals, reduced rate of nocturnal hypoglycemia, similar overall glycemic control, and the added convenience of administration immediately before meals. Humalog Mix 50/50 is also now available for those patients whose post prandial glucose values are not adequate on the 75/25 and 70/30 combinations. Insulin aspart, another rapid-acting insulin analog, is available in a premixed formulation with a protamine- retarded insulin aspart called Novolog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart). A comparison study (10) of the pharmacokinetic and pharmacodynamic parameters of the Novolog Mix 70/30 and human insulin 70/30 in healthy patients showed that the faster onset and greater peak action of insulin aspart was preserved in the aspart mixture. Another study (11) compared premixed aspart mixture 70/30 with premixed human insulin 70/30 administered twice daily in a randomized 12-wk open-label trial in 294 patients with type 1 or T2DM. Treatment with twice- daily premixed aspart mixture 70/30 resulted in similar overall glycemic control; yet postprandial control improved without additional hypoglycemia and with injections immediately before meals compared with premixed human insulin 70/30 given 30 min before the meal. PREMIXED INSULIN TWICE DAILY INJECTIONS VERSUS BASAL INSULIN ALONE Premixed insulins have been compared to regimens consisting of basal insulins alone in several clinical trials (12–16). The titration scheme that may have relevance to clinical practice used in the study is shown in (Table 2). To begin therapy, 12 U Novolog Mix 70/30 were given to insulin-naïve patients. For insulin-users, those on < 30 U Table 2 Titration algorithm for Novolog Mix 70/30 used up to 3 times a day (17) Blood glucose measure Blood glucose measure Predinner (for OD and BID Novolog Mix 70/30) Prelunch (for TID Novolog Mix 70/30)* Prebreakfast (for BID Novolog Mix 70/30) mg/dL mmol/L Insulin dose mg/dL mmol/L Insulin dose adjustment (U) adjustment (U) <80 <4.4 −3 n/a n/a n/a 80–110 4.4–6.1 0 <100 4.4–6.1 –3 111–140 6.2–7.8 +3 100–140 6.2–7.8 0 141–180 7.83–10 +6 141–180 7.83–10 +3 >180 >10 +9 >180 >10 +6 *People using Novolog Mix 70/30 TID could also adjust breakfast and dinner doses, but it was not recommended that more than 1 dose be adjusted at a time. 186 Edelman were transferred to the identical unit dose of Novolog Mix 70/30; for those on 31–60 U, the Novolog Mix 70/30 dose was started at 70% of the previous insulin dose. The dose was titrated based on average plasma glucose values from 3 previous days. In two separate studies, both Novolog Mix70/30 or Humalog Mix 75/25 given twice daily in conjunction with metformin, allowed more patients to reach target glucose control, than glargine of basal insulin administered once-daily with metformin (12,13). More recently, a treat-to-target trial in 100 patients poorly controlled with oral agents with or without insulin utilized the stepwise addition of premixed insulin until glycemic targets were attained (14). Using only 1 injection of Novolog Mix 70/30 daily, a total of 41% of patients were able to reach the ADA target of HbA1c < 7.0% and 21% reached the AACE/IDF target of ≤6.5%. This increased to 70% and 52% of subjects when twice-daily injections were used (among those not achieving HbA 1c ≤6.5% with once-daily therapy), and 77% and 60% when the small number of patients requiring 3 times daily administration was accounted for. This was accomplished without increasing the frequency of major or minor hypoglycemic episodes over that reported for once- or twice-daily use. In a different 24-wk study, 364 insulin-naïve patients with a baseline A1c of 8.84% on both a sulfonylurea and metformin were either continued on oral agents, and given glargine once daily, or given human premixed insulin twice daily (before breakfast and dinner) with discontinuation of oral agents (15). After 6 mo, the glargine plus oral agents group had a significantly greater reduction in A1c (−1.64%) compared to the human premixed insulin alone without oral agents twice daily group (−1.30%), p < 0.0005. In addition the glargine group used less insulin, had fewer documented hypoglycemic reactions and less weight gain. As demonstrated in three studies, the comparison of basal insulin vs. premixed can result in very different outcomes and conclusions depending on protocol design. When oral agents are continued, glargine at bedtime did better in terms of glycemic control than premix twice a day without oral agents. The ultimate results of these comparison studies depend on the patient characteristics, use of analog mixtures, continuation of oral agents, and number of injections per day. BASAL BOLUS INSULIN REGIMENS Basal–bolus insulin strategies, which can be used in patients with either T1DM or T2DM incorporates the concept of providing continuous basal insulin levels in addition to brief increases in insulin at the time of meals via bolus doses (16). The goals of therapy should be tailored to each patient individually. Candidates for intensive management should be motivated, compliant, educable, and be without other medical conditions or physical limitations that preclude accurate and reliable home glucose monitoring (HGM), continuous glucose monitoring (CGM), or insulin administration. Caution is advised in elderly patients or those with hypoglycemic unawareness in whom the goals of therapy may need to be relaxed. High titers of insulin antibodies, especially in patients with a history of intermittent use of impure insulins of animal origin may also impede insulin therapy. It has been estimated that 50% of the day to day variation in glucose values is owing to intra-subject variation in absorption and time course of action. Consistency is important to reduce fluctuations in glucose values. The site of injection may alter insulin pharmacokinetics and absorption, especially if lipohypertrophy is present. The periumbilical area is the preferred site to inject insulin because of the rapid and consistent absorption kinetics observed at this location; however, rotating the injection site is usually advised. It is also advisable to inject in the same body location for a certain meal time (i.e., triceps fat pad for breakfast, abdomen for lunch, and upper thighs for dinner). Selecting Patients for Intensive Insulin Therapy Insulin-naive patients with T2DM who are unable to achieve or maintain glycemic goals on oral agents can advance therapy to basal insulin plus oral agents and then advance to basal-prandial therapy in a stepwise manner. Prandial insulin is added to the regimens of patients not achieving glycemic goals despite well-controlled FBG after 3 mo of basal insulin (19). Initially, prandial insulin therapy may only need to be provided with the largest meal of the day, or whichever meal produces the greatest postprandial glucose excursions from baseline. Chapter 12 / Intensive Insulin Therapy in T2DM 187 Certain patients with newly diagnosed T2DM may benefit from early initiation of basal-prandial insulin therapy, including those with glucose toxicity or LADA. LADA is caused by immune-mediated destruction of the insulin- producing pancreatic -cells, similar to type 1 diabetes, but typically is diagnosed in patients aged 30–60 yr (the diagnosis is confirmed by blood tests for the presence of glutamic acid decarboxylase antibodies). Patients with LADA generally do not respond adequately to oral agents, and will require insulin therapy at an earlier stage than other patients with T2DM (17,18). Newly diagnosed patients with A1C >10.0% require more than a 3.0% reduction in A1C to achieve target glucose levels recommended by the ADA (19). Because reductions in A1C of this magnitude generally will not be achieved with oral agents alone, especially in the face of glucose toxicity, such patients who are symptomatic should be started on insulin immediately. Once insulin has successfully reversed glucose toxicity, many of these newly diagnosed patients can then be controlled on oral agents alone (20). BASIC CONCEPTS OF BASAL BOLUS STRATEGIES An individualized regimen may incorporate insulins of varying onset of action, peak, and duration (Table 3). The use of premeal regular insulin with bedtime NPH as the basal insulin has been a common strategy for intensive insulin therapy in the United States over the past decade. Because regular insulin should be administered 30 to 45 min before meals, a short term risk of hypoglycemia exists if the meal is delayed, and there is a risk of delayed hypoglycemia because of the overlap of pharmacodynamics of regular and NPH insulin. As a result, use of regular insulin may be complicated by high postprandial glucose levels and delayed hypoglycemia. An alternative strategy is the mealtime administration of rapid acting insulin analogs in combination with long-acting basal insulin, such as glargine or detemir (21–23). Regimens that use multiple doses of intermediate acting insulin such as NPH (usually only 2) can be associated with unpredictable nocturnal hypoglycemia and day-to-day instability of blood glucose patterns, in part because of intra-patient variability in the peak action profile of NPH. NPH, which is commonly given twice daily exhibits its peak action ∼4 to 8 h after administration, has also been used in combination with rapid-acting insulin analogs, Because of its time to peak action, NPH should ideally be given every6hor4times per day to be effective as a true basal insulin. NPH given 4 times a day would be difficult to implement and is not needed with the availability of long-acting insulin analogs. Improved mealtime glucose control with the rapid-acting analogs has exposed the gaps in basal insulin coverage provided by therapy with the traditional intermediate insulin preparations. Taking a long-acting basal insulin analog (e.g., glargine or detemir) with a relatively constant and flat pharmacokinetic profile once or twice a day will result in a more physiologic pattern of basal insulin replacement. Insulin glargine has been available in the United States since 2000 and in combination with a rapid-acting insulin analog has demonstrated effective glycemic control and a lower incidence of nocturnal hypoglycemia than other insulin preparations currently used for basal insulin supplementation (28,30,31). In a 22-wk randomized trial, 395 people with T2DM were randomized to a regimen using insulin aspart +insulin detemir, the newest basal insulin to become available, versus regular human insulin + NPH (24). Basal insulins were given once or twice daily, in accordance with prior treatment, and oral agents were discontinued. Treatment Table 3 Comparison of human and analogue insulins ∗ Insulin preparations Onset of action Peak Duration of action Lispro Aspart Glulisine 5−15 minutes 45−90 mins 3−5 hours Human Regular 30−60 minutes 2−4 hours 6−8 hours Human NPH 2−3 hours 6−8 hours 10−18 hours Detemir 1−2 hours ∼12−16 hours; relatively flat Up to 24 hours Glargine 1−2 hours Peakless ∼24 hours Ref (7) ∗ The time course of action of any insulin may vary in different individuals depending on the degree of obesity, site of injection and ambient glucose level at the time of injection. 188 Edelman with insulin detemir + aspart produced equivalent glycemic control to a similar regimen using NPH + regular insulin (HbA1c 7.46 versus 7.52%, respectively), but with less weight gain (0.52 versus 1.13 kg, p = 0.038) and less within-person variability in HGM (SD 21.6 versus 27.7 mg/dL, p < 0.001). Safety profiles were similar between the 2 treatments. PRACTICAL RECOMMENDATIONS FOR INITIATION OF BASAL PRANDIAL INSULIN Initiation of basal insulin is normally an important first clinical maneuver in patients failing oral agents. Some patients with T2DM may have enough endogenous basal insulin secretion to allow for improved glycemic control with prandial insulin alone. This phenomenon was seen with an inhaled insulin study that will be discussed below. Nonetheless, initiation of basal insulin is normally key to a successful intensive insulin regimen (25). The options for initiating basal insulin include: 1) insulin glargine given once daily, 2) insulin detemir once or twice daily, or 3) NPH given 2–4 times daily depending on HGM results. Patients should not experience hyper or hypoglycemia while fasting if the basal insulin dose is adjusted properly. A typical starting dose is 10 units of basal insulin, however most obese patients with T2DM will need approximately 40–60 units per day. Frequent follow-up to review HGM data is required to make the proper adjustments. If A1C goals are not achieved after a period of 3–6 mo of treatment with basal insulin plus oral agents, patients should be instructed to monitor glucose preprandially and/or 1–2 h after each meal on a rotating basis to identify the main meal that is contributing to hyperglycemia. Once identified, 5–10 U or 0.1 units/100Kg body weight of rapid-acting insulin should be administered before this meal. Adjustment of the dose is made on HGM results within 1 to 2 h after the meal or simply the blood glucose results before the next meal, or bedtime. If A1C goals are still not reached after 3–6 mo of basal insulin, oral agents, and 1 prandial insulin injection at the main meal, prandial insulin can be added before other meals based on home glucose monitoring as described above. Rapid-acting insulin doses should continue to be titrated according to home glucose monitoring data (either post prandial values or the glucose value before the subsequent meal). The amount of increase in the dose will depend on the total daily insulin dose (basal and prandial) in addition to the glucose levels. If the total daily insulin dose is less than 50 units then increase in the prandial dose should be in increments of 3 to 5 units at a time (< 10%). For patients on large daily doses of insulin changes of 5 to 10 units (40%) may be more appropriate. As the patient’s blood glucose levels approach goal, the changes in insulin doses should be more modest. Caution should also be taken in the elderly and in patients with hypoglycemia unawareness. Continuous glucose monitoring can help determine the correct dose safely. IMPLICATIONS OF BASAL-PRANDIAL REGIMENS FOR EXISTING ORAL AGENTS As a general rule the oral agent regimen should be continued until the addition of insulin achieves glycemic control goals. As glycemic control is established (A1C < 7.0%), the oral agents should be evaluated (reduced dose or discontinue) in patients on basal-prandial insulin therapy. Doses of sulfonylurea should be discontinued or reduced by ≥50% as necessary, especially if hypoglycemia occurs. If subsequent monitoring clearly shows prompt loss of control, the original dose of oral agent should be resumed or upward titration of the insulin. For patients receiving metformin, thiazolidinediones, and/or DPP4 inhibitors, the decision to continue and/or adjust doses may be left to the discretion of the physician. Typically, if significant glycemic benefit with the oral agent was achieved before starting insulin therapy it may be beneficial to continue the drug. EXTERNAL INSULIN PUMP THERAPY External insulin pump therapy or continuous subcutaneous insulin infusion (CSII) has been used traditionally in patients with type 1 diabetes. However, insulin pump therapy is extremely valuable in patients with T2DM who require insulin but who have not achieved glycemic control with subcutaneous injections or who are seeking a more flexible lifestyle (26). As seen in T1DM, insulin pump therapy allows for increased flexibility in meal timing and amounts, increased flexibility in the timing and intensity of exercise, improved glucose control while reducing the daily variability of blood glucose values and incidence of hypoglycemia. Although not documented well in clinical trials, many experts believe that because of the more physiologic delivery of insulin, glucose Chapter 12 / Intensive Insulin Therapy in T2DM 189 control is achieved with less insulin than that needed in a subcutaneous insulin regimen. This may be caused by a reduction in glucose toxicity and improvement of insulin resistance and beta-cell secretory function as a result of improved glycemic control with pump therapy. Weight gain may be lessened if the patient requires less insulin than was used before insulin pump therapy. In addition, with the reduction of hypoglycemic events, there is less overeating to compensate for excessive insulin. Because pumps deliver constant infusions of regular or fast-acting insulin, there is no peaking or waning of activity of injected intermediate- and long-acting insulins, which do not provide as constant a basal rate owing to variable absorption and pharmacokinetics. Insulin pump therapy may allow for more reliable insulin absorption and pharmacokinetic profile, resulting in improved reproducibility in insulin availability and reduced fluctuations in glycemic control (27). Presently, there is a paucity of clinical trials using insulin pumps in T2DM, but pump therapy is a viable option in insulin-requiring patients with T2DM who are unable to achieve adequate glycemic control with multiple- injection regimens. Although some studies demonstrate metabolic benefits of pump therapy in T2DM, all are limited by a relatively short period of evaluation and a small number of heterogeneous subjects. Interpretation of these studies is further confounded by the random assignment of subjects to dissimilar conventional insulin regimens, making comparison between studies difficult. Garvey et al (28) studied the effect of intensive insulin therapy on insulin secretion and insulin action before and after 3 wk of CSII therapy in 14 patients with T2DM (age 50 +/−3 yr, duration of diabetes 7.8 +/− 2.1 yr, and 119% ideal body weight). In 3 wk of therapy, the mean fasting plasma blood glucose and HbA1c values fell 46% and 38%, respectively. The mean daily insulin dose was 110 units/d, and there was a 74% increase in the insulin-stimulated glucose disposal rate, and a 45% reduction in hepatic glucose output to mean levels similar to those of normal subjects. In addition, there were significant improvements in both endogenous insulin and C-peptide secretion. This study demonstrates that pump therapy is feasible and effective at improving metabolic control and reversing glucose toxicity in these poorly controlled subjects with T2DM. In another recent study (29), 132 CSII naive type 2 diabetic patients were randomized to the pump or multiple daily injections (MDI). This study showed that pump therapy provided efficacy and safety equivalent to MDI therapy. Lower pre and post meal blood glucose values were shown by the CSII group at most time points (values were only significant 90 min after breakfast; 167 +/−47.5 mg/dL versus 192 +/− 65.0 mg/dL for CSII and MDI, respectively; p = 0.019). In summary, insulin pump therapy has not been fully evaluated in patients with T2DM. From published studies, however, it is apparent that CSII therapy can safely improve glycemic control while limiting hypoglycemia. CSII may be particularly useful in treating patients with T2DM who do not respond satisfactorily to more conventional insulin treatment strategies. INHALED INSULIN Insulin therapy is often delayed or suboptimally implemented in patients with T2DM. Although several factors contribute to poor implementation of insulin therapy, the inconvenience and complications, such as weight gain and poor patient acceptability, of a daily regimen of multiple injections, and psychological resistance may all play a role. These problems are being addressed by the ongoing development of alternate insulin delivery systems, including the inhaled and intranasal routes, as well as molecular modifications that may allow oral therapy. The first alternate insulin delivery system, inhaled human insulin powder (Exubera) (30–34), did become available, but was removed from the US market because of poor sales and reduced demand for the product. SUMMARY AND RECOMMENDATIONS Type 2 diabetes is a common disorder often accompanied by numerous metabolic abnormalities, leading to increased rates of cardiovascular morbidity and mortality. Improved glycemia will delay or prevent the development of microvascular disease and reduce many or all of the acute and subacute complications that worsen the quality of daily life. In selected patients, intensive insulin therapy can be a successful adjunct to diet and exercise for control of hyperglycemia (Table 5). This is best achieved in a multidisciplinary setting using complementary therapeutic modalities that include a combination of diet, exercise, and pharmacologic therapy. 190 Edelman Table 5 Levels of evidence for insulin therapy in type 2 diabetes Recommendation Level of evidence Combination therapy (oral agents during the day in addition to a basal insulin) is an effective way to improve glucose control and minimize weight gain 1A Split mixed or premixed insulin given 2 to 3 times a day can effectively get patients with type 2 diabetes safely to goal (A1c<7%) 1B Basal bolus or mutiple daily injection regimens in type 2 diabetes is an effective way to achieve glycemic goals. 1C+ Patients with type 2 diabetes may only need 1 injection of a fast acting insulin with their largest meal in addition to a basal insulin instead of before all meals 1C+ Patients with type 2 diabetes can be treated effectively with CSII (continuous subcutaneous insulin infusion) pumps 1C Emphasis should be placed on diet and exercise initially, and throughout the course of management as well, because even modest success with these therapies will enhance the glycemic response to both oral antidiabetic agents and insulin. With the development of newer insulin analogues, inhaled insulin, and pramlintide, increasing flexibility is available to tailor insulin regimens for successful use in individual patients. REFERENCES 1. American Diabetes Association. Clinical Practice Recommendations 2007 Diabetes Care. 30(1), 2007. 2. Colwell JA. Controlling T2DM: are the benefits worth the cost? JAMA (2006). 3. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR. Antibodies to glutamic acid decarboxy – lase reveal latent autoimmune diabetes mellitus in adults with a non-insulin dependent onset of disease. Diabetes 1993;42:359. 4. American Diabetes Association. Diabetes Dictionary. 2004. Available at http://www.diabetes.org/diabetes dictionary.jsp. Accessed on October 4, 2003. 5. Yu A, Wu PS, Edelman SV. The natural history of non-insulin dependent diabetes mellitus in a Filipino migrant population. Presented at the 3 rd International Diabetes Federation, Western Pacific Regional Congress: Hong Kong; September 25–28, 1996. 6. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS. Intensive conventional insulin therapy for type 2 diabetics. Metabolic effects duringa6mooutpatient trial. Diabetes Care 1993;161(1):21–31. 7. Kuddlacek S, Schernthaner G. The effect of insulin treatment on HbA1c, body weight and lipids in type 2 diabetic patients with secondary failure to sulfonylureas. A five-year follow-up study. Horm Metab Res 1992;24:478. 8. Roach P, Woodworth JR. Clinical Pharmacokinetics and pharmacodynamics of insulin lispro mixtures. Clini Pharmacokinet 2002;41(13):1043–1057. 9. Roach P, Yu L, Arora V for the Humalog Mix25 Study Group. Improved postprandial glycemic control during treatment with Humalog Mix25, a novel protamine-based insulin lispro formulation. Diabetes Care 1999;22:1258–1261. 10. Jacobsen LV, Sogaard B, Ris A. Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble andprotamine-retarded insulin aspart. Eur J Clin Pharmacol 2000;56(5):399–403. 11. Boehm BO, Home PD, Brehend C, Kamp NM, Lindholm A. Premixed insulin aspart 30 versus premixed human insulin 30/70 twice daily: a random mixed trial in type 1 and type 2 diabetic patients. Diabet Med 2002;19:393–399. 12. Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH; Lispro Mixture-Glargine Study Group. Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomiized, open label, crossover study in patients with T2DM beginning insulin therapy. Clin Ther 2004;26:2034–2044. 13. Raskin P, Allen E, Hollander P, Lewin A, Gabbay, RA, Hu P, Bode B, Garber A; INITIATE Study Group. Initiating insulin therapy in T2DM: a comparison of biphasic and basal insulin analogs. Diabetes Care 2005;28:260–265. 14. Garber AJ, Wahlen J, Wahl T, Bressler P, Braceras R, Allen E, Jain R. Attainment of glycemic goals in T2DM with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (The 1-2-3 Study. Diabetes Obes Metab 2006;8:58–66. 15. Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA, Yki-Jarvinen H. Initiation of Insulin in patients with Type 2 diabetes failing oral therapy. Diabetes Car. 2005;28:254–259. 16. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and T2DM mellitus scientific review. JAMA 2003;289:2254–2264. 17. Naik RG, Palmer JP. Latent autoimmune diabetes in adults (LADA). Rev Endocr Metab Disord 2003;4:223–241. 18. Pozzilli P, Di Mario U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 2001;24:1460–1467. 19. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2005;28 Suppl 1:S4–S36. 20. American Association of Clinical Endocrinologists. The American Association of Clinical Endocrinologists Medical Guidelines for the Management of Diabetes Mellitus: The AACE System of Intensive Diabetes Self-Management – 2002 Update. Endocr Prac 2002;8 Suppl 1:40–82. Chapter 12 / Intensive Insulin Therapy in T2DM 191 21. Yki-Jarvinen H, Dressler A, Ziemen M for the HOE 901/3002 Study Group. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in T2DM. Diabetes Care 2000;23:1130–1136. 22. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T, et al. Time-action profile of the long-acting insulin analog insulin glargine (HOE 901) in comparison with those off NPH insulin and placebo. Diabetes Care 2000;23:644–649. 23. Rosenstock J, Park G, Ziimmerman J; US insulin glargine (HOE 901) Type I Diabetes Investigator Group. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 ddiabetes on multiple daily insulin regimens. Diabetes Care 2000;23:1137–1142. 24. Raslova K, Bogoev M, Raz I, Leth G, Gall MA, Hancu N. Insulin detemir and insulin aspart: a promising basal-bolus regimen for T2DM. Diabetes Res Clin Pract 2004;66:193–201 25. Riddle MC, Rosenstock J, Gerich J, the Insulin Glargine Study Investigators. The Treat to Target Trial: randomized addidtion of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003;26:3080–3086 26. Plodkowski RA, Edelman SV. The State of Insulin Pump Therapy-2002. Current Opinion in Endo and Diabetes. Vol 9:4 2002. 27. Plodkowski, RA, Edelman, SV, Physiologic Insulin Replacement with Continuous Subcutaneous Insulin Infusion: Insulin Pump Therapy. Clinical Diabetes 2006; 429–441. 28. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG. The effect of insulin treatment on insulin secretion and insulin action in T2DM mellitus. Diabetes 1985;34:222. 29. Raskin P, Boode BW, Marks JB, Hirsch IB, Weinstein RL, McGill JB, Peterson GE, Mudaliar SR, Reinhardt RR. Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in T2DM: a randomized, parallel-group, 24-week study. Diabetes Care 2003;26(9):2598–2603. 30. EXUBERA (Package insert). New York, NY, Pfizer, Inc. 31. Rave K, Bott S, Heinemann L, et al. Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin. Diabetes Care. 2005;28:1077–1062. 32. Hollander PA, Blonde L, Rowe R, et al. Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes. Results of a 6-month, randomized, comparative trial. Diabetes Care. 2004;27:2356–2356. 33. Dreyer M, for the Exubera Phase 3 Study Group. Efficacy and 2-year pulmonary safety data of inhaled insulin as adjunctive therapy with metformin or glibenclamide in type 2 diabetes patients poorly controlled with oral monotherapy. Diabetologia. 2004; 47(suppl 1): A44. 34. Fineberg SE, Kawabata T, Finco-Kent D, et al. Antibody responses to inhaled insulin in patients with type 1 and type 2 diabetes. J Clin Endocrinol Metabol. 2005;90:3287–3294. 13 Hypoglycemia in Type 2 Diabetes Philip E. Cryer CONTENTS Hypoglycemia in Diabetes: The Clinical Problem Frequency of Hypoglycemia Physiology and Pathophysiology of Glucose Counterregulation Risk Factors for Hypoglycemia Prevention of Hypoglycemia: Risk Factor Reduction Treatment of Hypoglycemia Perspective Acknowledgments References Summary Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes. It can be caused by sulfonylureas or other insulin secretagogues, and perhaps by metformin, as well as by insulin. Hypoglycemia is less frequent overall in type 2 diabetes (T2DM), compared with type 1 diabetes (T1DM). However, it becomes a progressively more frequent problem, ultimately approaching that in T1DM, in advanced (i.e., insulin deficient) T2DM because of compromised glucose counterregulation – the syndromes of defective glucose counterregulation and hypoglycemia unawareness, the components of hypoglycemia-associated autonomic failure – analogous to that which develops early in the course of T1DM. Clearly, prevention of hypoglycemia is preferable to its treatment. By practicing hypoglycemia risk reduction – addressing the issue, applying the principles of aggressive glycemic therapy and considering both the conventional risk factors and those indicative of compromised glucose counterregulation – the therapeutic goal is to reduce mean glycemia as much as can be accomplished safely in a given patient at a given stage of T2DM. Particularly in view of the growing array of glucose-lowering drugs that can be used to optimize therapy, hypoglycemia should not be used as an excuse for poor glycemic control. Nonetheless, better methods, such as those that would provide plasma glucose regulated insulin secretion or replacement, are needed for people with T2DM, as well as those with T1DM, if euglycemia is to be maintained over a lifetime of diabetes. Key Words: Hypoglycemia; barrier to glycemic control; therapy with sulfonylureas; therapy with metformin; therapy with insulin; insulin analogues; glucagon; epinephrine; defective glucose counterregulation; hypoglycemia unawareness; hypoglycemia-associated autonomic; failure. HYPOGLYCEMIA IN DIABETES: THE CLINICAL PROBLEM Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (1–3). It causes recurrent morbidity in most people with type 1 diabetes (T1DM) and many with type 2 diabetes (T2DM), and is sometimes fatal. The barrier of hypoglycemia—its reality and its possibility—precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the vascular benefits of glycemic control (4–6). Importantly, episodes of hypoglycemia, even asymptomatic episodes, impair physiological and behavioral defenses against subsequent hypoglycemia by causing hypoglycemia-associated autonomic failure (the clinical syndromes of defective glucose counterregulation and hypoglycemia unawareness) and thus a vicious cycle of recurrent hypoglycemia (1–3). From: Contemporary Endocrinology: Type 2 Diabetes Mellitus: An Evidence-Based Approach to Practical Management Edited by: M. N. Feinglos and M. A. Bethel © Humana Press, Totowa, NJ 193 194 Cryer Table 1 American Diabetes Association Workgroup on Hypoglycemia recommended classification of hypoglycemia in people with diabetes (8) Severe Hypoglycemia. An episode requiring the assistance of another person to raise the plasma glucose concentration resulting in resolution of symptoms, with or without a measured low plasma glucose concentration. Documented Symptomatic Hypoglycemia. Symptoms consistent with hypoglycemia with a measured plasma glucose concen- tration < 70 mg/dL (3.9 mmol/L). Asymptomatic Hypoglycemia. A measured plasma glucose concentration < 70 mg/dL (3.9 mmol/L) in the absence of symptoms. Probable Symptomatic Hypoglycemia. Typical symptoms of hypoglycemia without a measured plasma glucose concentration. Relative Hypoglycemia. Typical symptoms of hypoglycemia with a measured plasma glucose concentration >70 mg/dL (3.9 mmol/L) but approaching that level. (Such episodes occur in people with poorly controlled diabetes.) Episodes of iatrogenic hypoglycemia cause both physical and psychological morbidity. The physical morbidity ranges from unpleasant neurogenic symptoms (e.g., sweating, hunger, anxiety, palpitations, and tremor) and neuroglycopenic manifestations (e.g. behavioral changes and cognitive impairment) to expressions of severe neuroglycopenia such as seizure and coma. Transient focal neurological deficits sometimes occur. Although seemingly complete neurological recovery is the rule, severe, prolonged hypoglycemia can result in permanent neurological damage, and even death (7). At the very least, an episode of hypoglycemia is a nuisance and a distraction. It can be embarrassing and lead to social ostracism. The additional psychological morbidity includes fear of hypoglycemia, guilt about that rational fear and high levels of anxiety that can be an impediment to glycemic control. The performance of critical tasks, such as driving, is measurably impaired, as is judgement. Because the glycemic thresholds for the manifestations of hypoglycemia are dynamic—they shift to higher than normal plasma glucose concentrations in poorly controlled diabetes and to lower than normal plasma glucose concentrations in well controlled diabetes, as discussed later—it is not possible to specify a plasma glucose concentration that defines hypoglycemia in people with diabetes. The diagnosis is made most convincingly by documentation of Whipple’s Triad: symptoms consistent with hypoglycemia, a low plasma glucose concentration, and relief of those symptoms after the plasma glucose concentration is raised to (or above) normal. Nonetheless, the American Diabetes Association Workgroup on Hypoglycemia (8) recommended that people with diabetes should become concerned, and consider defensive actions, at a plasma glucose concentration < 70 mg/dL (3.9 mmol/L). That plasma glucose level approximates the lower limit of the postabsorptive plasma glucose concen- tration range and the glycemic threshold for activation of glucose counterregulatory (plasma glucose-raising) systems, as well as the upper level at which an antecedent low plasma glucose concentration results in reduced glucose counterregulatory responses to subsequent hypoglycemia, in nondiabetic individuals. The Workgroup also recommended a classification of hypoglycemia in people with diabetes (Table 1). On this background of the clinical problem of hypoglycemia in diabetes, the incidence and pathophysiology of, and risk factors for, hypoglycemia in T2DM and clinical approaches to its prevention and treatment are discussed in this chapter. The premises are that iatrogenic hypoglycemia becomes progressively more limiting to glycemic control as patients approach the insulin deficient end of the spectrum of T2DM, that the pathophysiology of glucose counterregulation becomes similar to that in T1DM as patients progress across that spectrum, and that it is possible to both improve glycemic control and reduce the risk of hypoglycemia even in advanced, insulin deficient T2DM, just as it is in T1DM (1–3). FREQUENCY OF HYPOGLYCEMIA During aggressive glycemic therapy, the average patient with T1DM suffers plasma glucose concentrations <50 mg/dL (2.8 mmol/L) approx 10% of the time, symptomatic hypoglycemia about twice a week and severe, at least temporarily disabling, hypoglycemia about once a year (1). Valid estimates of the frequencies of these hypoglycemias (i.e., those based on controlled studies designed to include treatment to near euglycemia) during aggressive glycemic therapy of T2DM are limited (1). Ascertainment of hypoglycemia in T2DM is a Chapter 13 / Hypoglycemia in Type 2 Diabetes 195 Table 2 Cumulative prevalence of hypoglycemia (percent of patients affected) in T2DM over 6 yr in the United Kingdom Prospective Diabetes Study (9) Therapy* n HbA 1C (%) % with Any Hypoglycemia Major** Diet 379 8 3 015 Sulfonylurea 922 7145 33 Insulin 689 7176 112∗∗∗ Diet 297 822804 Metformin 251 7417624 * Taking assigned medication. ** Requiring medical assistance or admission to hospital. *** Compared with severe hypoglycemia (that requiring the assistance of another individual) in 65% of T1DM over 6.5 yr in the Diabetes Control and Complications Trial. major challenge. Event rates for asymptomatic hypoglycemia are virtually unknown and those for symptomatic hypoglycemia are undoubtedly minimum estimates. Those for severe hypoglycemia, a memorable event albeit reflecting only a small fraction of the hypoglycemic experience, are most reliable. Overall, however, hypoglycemia is less frequent in T2DM than it is in T1DM. That likely reflects intact defenses against falling plasma glucose concentrations early in the course of the disease, but compromised defenses later. Iatrogenic hypoglycemia occurs during treatment with a sulfonylurea or insulin, or perhaps with metformin, even in patients with T2DM treated with these drugs from the time of diagnosis. For example, although adjudicated hypoglycemia event rates in the UKPDS have not been published, self-reported data from the United Kingdom Prospective Diabetes Study (UKPDS) (9) indicate that, compared with diet alone, therapy with metformin, sulfonylurea or insulin was associated with a 6-fold, 22-fold and 75-fold increased risk, respectively, of the proportion of patients suffering major hypoglycemia over the first 6 yr of diagnosed T2DM (Table 2). Iatrogenic hypoglycemia becomes a progressively more frequent clinical problem as patients approach the insulin deficient end of the spectrum of T2DM. Insulin secretion decreases progressively (9) and hypoglycemia becomes more limiting to glycemic control over time (10). Indeed, in one series, the frequency of severe hypoglycemia was similar in T2DM and T1DM matched for duration of insulin therapy (11). Population-based data indicate that the incidence of hypoglycemia in insulin treated T2DM approaches that in T1DM. For example, data from Tayside, Scotland indicate that the event rates for any hypoglycemia and for severe hypoglycemia in insulin treated T2DM were 38% and 30%, respectively, of those in T1DM (12). Similarly, in insulin treated T2DM the event rates for hypoglycemia requiring emergency treatment in hospital regions of known total and diabetic populations have been reported to be 40% (13) or even 100% (14) of those in T1DM. The fact that hypoglycemia becomes a progressively more frequent clinical problem as patients approach the insulin deficient end of the spectrum of T2DM (9–14) is explicable on the basis of the pathophysiology of glucose counterregulation in the insulin deficient state. PHYSIOLOGY AND PATHOPHYSIOLOGY OF GLUCOSE COUNTERREGULATION The critical components of the physiology of glucose counterregulation (15)—the redundant, hierarchical mechanisms that normally prevent or rapidly correct hypoglycemia—are: 1) A decrease in pancreatic -cell insulin secretion that occurs as plasma glucose concentrations decline within the physiological range and favors increased endogenous hepatic (and renal) glucose production and decreased glucose utilization by insulin sensitive tissues such as muscle. 2) An increase in pancreatic -cell glucagon secretion, which occurs as plasma glucose concentrations fall just below the physiological range and stimulates hepatic glucose production. 3) An increase in adrenomedullary epinephrine secretion, which also occurs as plasma glucose concentrations fall just below the physiological range and which both stimulates hepatic (and renal) glucose production and limits glucose utilization by insulin sensitive tissues. Although demonstrably involved, epinephrine is not normally critical; however, it becomes critical when glucagon is deficient. [...]... Jee 20 05 (196) HR 1 .59 (1. 45 1.74) Prostate Bonovas 2004a (209) Chan 20 05 (210) Coker 2004a (211) Gonzalez-Perez 2005a (212) Rodriguez 2005a (213) Tavani 2002 (214) Jee 20 05 (196) Davey-Smith 1992 (1 95) RR 0.91 (0.86–0.96) OR 0. 95 (0. 95 1.02) adjusted OR 0.64 (0. 45 0.91) OR 0.72 (0 .5 9-0 .87); Treated DM OR 0.63 (0 .5 0-0 .80); Untreated DM OR 1.01 (0.73–1.40) RR 0.67 99 (0.60–0. 75) OR 1.02 (0. 75 1.40)... Mortality in 35/ 124 patients (28%) with DM vs 146 /50 4 (29%) without DM ( p = NS) (Continued ) 212 Dungan et al Table 5 (Continued ) Outcomes related to presence of diabetes Necrotizing fasciitis Pessa 19 85 ( 150 ) Gozal 1986 ( 151 ) Korkut 2003 ( 154 ) Yeniyol 2004 ( 155 ) Foot ulcers Currie 1998 ( 158 ) Mortality for DM 5/ 8 (62 .5% ), no DM 6/ 25 (24%) Mortality 2 /5 (40%) for DMvs 0/8 without DM Mortality 9/ 25 (36%)... (1.1–1 .5) OR 4.0 (2.3–7.7) 18 deaths (17%) with DM vs 40 deaths (8%) without DM ( p = 0.002) OR 1.66 (0 .54 5. 07) OR 1.0 (0.69–1. 45) 5 yr survival in HBV-related HCC 73% without DM vs 41% with DM ( p = 0.0 15) ; in HCV-related HCC 73% without DM vs 42% with DM ( p = 0.616) Persistent hepatitis 62% of 39 without DM vs 39% of 39 with DM ( p = 0.012) OR of cirrhosis 5. 2 d (2.0–13 .5) Length of stay 5. 2 d for... Diverse causes of hypoglycemia-associated autonomic failure in diabetes N Engl J Med 2004; 350 :2272–2279 3 Cryer PE Mechanisms of hypoglycemia-associated autonomic failure and its component syndromes in diabetes Diabetes 20 05; 54 : 359 2–3601 4 The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications... 20 05 (196) RR 2.29 (0.72–7. 25) HR 1.16 (1.04–1.28) IR 4 .5 (2.8–6.2) for FBG > 5. 8 mmol/L vs FBG < 5. 3 mmol/L RR 0.62 (0.09–4.47) RR 1.43 (1.10–1.87) OR for A1c > 5. 78 was 1 .57 (0.94–2.60, p = 0.02) RR 1.4 (1.1–1.8) HR 1.28 (1.06–1 .55 ) Pancreatic cancer Davey-Smith 1992 (1 95) Gullo 1994 (200) Jee 20 05 (196) Gapstur 2000 (201) Huxley 20 05 (202) Stolzenberg-Solomon 20 05 (203) RR 5. 27 (1.90–14.60) OR 3.04... controls for all-cause and infection-related mortality (age-adjusted RR 1.9, 95% CI 1 .5 2.3 and RR 2.4, 95% CI 1.2–4.7 for women respectively and RR 1.7, 95% CI 1.4–2.1 and RR 1.7, 95% CI 0.8–4.7 for men respectively) In addition, a retrospective Ontario cohort of 51 3,749 patients with diabetes found an increased relative risk for infectious disease hospitalization (RR1.21, 99% CI 1.20–1.22) (96) In particular,... with DM 5/ 13 patients (38 .5% ) with DM 20/26 patients (76.9%) with DM 18/ 25 patients (72%) with DM 25/ 45 patients (55 .6%) with DM T1DM: adjusted OR 1 .59 (1.12–2.24); T2DM: adjusted OR 1.33 (1. 15 1 .54 ) RR 1.81 (1.76–1.86) OR 7.6 (6.84–8.92) 9/132 patients (6.8%) with DM vs 1/383 (2.6%) without DM ( p = 0.003) OR 2.94 (1 .58 5. 48) RR 4.93 ( (3.8 5. 06) 11/29 patients (37.9%) had DM 4/17 patients (23 .5% ) had... (1.42–2.06) RR 2. 15 (1.22–3.80) RR 1.82 (1.66–1.89) HR 2.13 (1.04–4. 35) Endometrial cancer Anderson 2001 (204) Furberg 2003 (206) RR 1.43 (0.98–2.1) RR 2.41 (1.08 5. 37) Bladder cancer Davey-Smith 1992 (1 95) Tripathi 2002 (207) Jee 20 05 (196) RR 1.13 (0.84–1 .52 ) RR 2.46 (1.32–4 .59 ) HR 1. 45 (0.96–2.19) Breast cancer Michels 2003 (208) HR 1.17 (1.01–1. 35) Esophagus Davey-Smith 1992 (1 95) Jee 20 05 (196) RR 4.32... patients (38%) had DM 10/ 253 patients (4.0%) had DM RR 1 .50 (1.46–1 .54 ) Muller 20 05 (98) Romano 2001 (148) Necrotizing fasciitis Cellulitis Foot ulcers Osteomyelitis Discitis Septic Arthritis Bacterial Meningitis Pessa 19 85 ( 150 ) Gozal 1986 ( 151 ) Nisbet 2002 ( 153 ) Yeniyol 2004 ( 155 ) Korkut 2003 ( 154 ) Muller 20 05 (98) Shah 2003 (96) Currie 1998 ( 158 ) Leibovici 1996 (93) Walters 1992 ( 157 ) Shah 2003 (96) Friedman... 2003 (224) OR for DM 5. 5 (3 .5 8.7) Stenstrom 1984 (222) DM resolved in 89 .5% (51 /57 ) GIR decreased in patients with/without DM ( p < 0. 05) , DM resolved in 3 /5 patients DM resolved in 28/29 patients (96.6%) without previous diagnosis FBG > 126 mg/dL present in 24% of patients not previously suspected of DM Acromegaly Holdaway 1999 (2 25) DM 18 vs 2.8% of control Kasayama 2000 (226) HOMA-IS lower in patients . T2DM in a 6-mo randomized, open-label, 2-period crossover study (9). Twice-daily injections of Humalog Mix 75/ 25 resulted in improved postprandial glycemic control after the morning and evening. fixed-ratio mixture of 25% rapid-acting insulin lispro and 75% novel protamine-based intermediate-acting insulin called neutral protamine lispro (NPL). NPL was developed to solve the problem of. < 7.0% and 21% reached the AACE/IDF target of ≤6 .5% . This increased to 70% and 52 % of subjects when twice-daily injections were used (among those not achieving HbA 1c ≤6 .5% with once-daily therapy),