Pharmacy Drug Class Review

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1 April 25, 2009 Pharmacy Drug Class Review Insulin in Type II DM 2009 Disclaimer: Specific agents may have variations Focus On Dosing, When to Initiate, Fate of Oral Agents, etc. 1. Where do the American Academy of Clinical Endocrinology (AACE) and the American Diabetes Association (ADA) place insulin therapy for Type 2 Diabetes Mellitus (T2DM)? 2. Why insulin should, or should not, be used in patients with T2DM? 3. Who should use insulin and when should insulin be initiated in T2DM? a. Does initiating insulin therapy EARLY have any additional benefit? Or detriment? 4. Which insulin products should be used? a. What role does controlling post-prandial glucose play in diabetic therapy? b. Comparison of various insulin preparations. c. How should insulin be dosed? d. Efficacy of once-daily vs. twice-daily dosing of basal insulins? 5. How long should ORAL anti-diabetic agents be used when initiating insulin therapy? 6. When should an insulin pump be utilized? Who is an ideal candidate for an insulin pump? 7. What is a continuous glucose monitoring system (CGMS)? a. Is there any evidence regarding the benefits of using continuous glucose monitoring systems? 8. Is there any data to support that lowering A1C (i.e., through intensive insulin therapy) reduces MACROvascular outcomes in T2DM? 9. Which measure has a greater influence when A1C is slightly elevated (>7 9%)? Fasting blood glucose (FBG) or post-prandial blood glucose (PPG)? a. Conversely, which measure has a greater influence when A1C is very elevated (>10%)? FBG or PPG? Highlights: The Quick-Read Information Comparative and Descriptive Charts Start on p.2 1. Which of the following has NOT shown reduction in MACROvascular outcomes in Type II DM? a. [Alpha-glucosidase inhibitor]; b. [Metformin]; c. [Insulin]; 2. Which of the following insulin formulations can be stored at room temp for up to 42 days (the in-use product)? a. [Lantus] b. [Levemir] c. [Novolog] d. [Humalog] 3. What is benefit of the very long acting insulin analogues (glargine or detemir) vs. NPH? a. [greater efficacy] b. [less hypoglycemia] 4. What is the benefit of the very short acting insulin analogues (lispo, glulisine, aspart) vs. Regular? a. [greater efficacy] b. [less hypoglycemia] 5. True or False, Type II DM patients are much more likely to suffer from severe hypoglycemic episodes than Type I s? a. [True] b. [False] Most type 2 diabetics will eventually require insulin as beta cell function declines over time (insulin resistance can increase as well). Insulin is highly efficacious and lacks a maximum dose (though total number of units delivered at one time to one site is an issue). o However, when hyperinsulinemia is present significant detrimental effects may result In T2DM (FBG > 250 mg/dl OR A1C > 8.5 9%), insulin considered as 1 st line therapy (w/metformin whenever possible). 2, 3 Insulin should also be considered for patients failing monotherapy with metformin or failing combination oral therapy. 4 Starting insulin as very early initial therapy may provide additional benefits to patients (temporary restoration of 1 st phase insulin response or incretin effect), although more studies are needed to confirm this. 5-8 PPG hyperglycemia may play a role in endothelial dysfunction. Additional research is still needed. 9 Using basal insulin in combination with rapid-acting insulin (basal-bolus) is generally considered the ideal regimen as it enhances both 4, 9-12 fasting and post-prandial glycemic control and provides most flexible dosing adjustments. Patients requiring insulin therapy generally prefer minimizing the number of injections. Combining oral therapy w/ a once-daily to twice daily insulin regimen can help minimize # of injections. Patients not achieving PPG control should be initiated on meal-time insulin. 4 Patients requiring multiple daily injections of insulin OR very large TDDs of insulin may be good candidates for an insulin pump. 13 CGMS may benefit patients who are NOT able to detect the signs and symptoms of hypoglycemia. 1

2 Table 1 Basal-Only Insulin Once- or Twice-daily Premixed Insulin 1. A1C: 2. Medication: 3. Pattern: 4. Diet History: 5. Lifestyle: 6. Monitoring: Tips to tailor a patients insulin regimen: Rapid-acting/Intermediate acting (ie.novolog) 1. A1C: 2. Medication: 3. Pattern: 4. Diet History: 5. Lifestyle: 6. Monitoring: Regular/NPH (ie.novolin) 1. A1C: 2. Medication: 3. Pattern: 4. Diet History: 5. Lifestyle: 6. Monitoring: 1. > % 2. Oral medications adequately control postprandial glucose (PPG) excursions 3. High fasting glucose (FBG) with minimal glucose rise during the day 4. Small, regular meals (large meals will result in PPG excursions) 5. Reluctance to do MDI, requires oral agents 6. Fasting 1. > 7.5% 2. Oral agent failure (max tolerated dosages, contraindications or cost issues) 3. Any FBG; glucose rises during the day 4. Large suppers/small lunches 5. Consistent daily routine, reluctance to do MDI 6. Fasting and pre-supper (if insulin is administered twice daily) 1. > 7.5% 2. Oral agent failure (max tolerated dosages, contraindications or cost issues) 3. Any FBG; glucose rises during the day 4. Isocaloric meals or larger lunches 5. Consistent daily routine, reluctance to do MDI 6. Fasting and pre-supper (if insulin is administered twice daily) Basal-Bolus Insulin (MDI) 1. A1C: 2. Pattern: 3. Diet History: 4. Lifestyle: 5. Monitoring: 1. > 7.5 % 2. Regimen can be matched to any pattern to achieve glycemic control 3. Regimen can be matched to any diet to achieve glycemic control 4. Erratic schedule, motivated to achieve tight glycemic control 5. Frequent blood glucose monitoring (minimum before meals and bedtime) Adapted from Hirsch IB, Bergenstal RM, Parkin CG, Wright Jr E, Buse JB. A real-world approach to insulin therapy in primary care practice. Clinical Diabetes. 2005;23(2):

3 Fig.1. Road map to assist clinicians in achieving glycemic goals (established by the American College of Endocrinology and the American Association of Clinical Endocrinologists) in treatment-naïve patients with type 2 diabetes. Modified from Endocr Pract. 2007;13: Initial A1C% >10 Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2) Abbreviations in Road Maps: AACE = American Association of Clinical Endocrinologists; A1C = hemoglobin A1c; ACE = American College of Endocrinology; AGI = α-glucosidase inhibitor; DPP-4 = dipeptidyl peptidase-4; FDA = US Food and Drug Administration; FPG = fasting plasma glucose; HDL = high-density lipoprotein; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; MNT = medical nutrition therapy; OGTT = oral glucose tolerance test; PPG = postprandial glucose; Rx = treatment; SU = sulfonylurea; TZD = thiazolidinedione Lifestyle Modification * Available as exenatide ** Available as pramlintide 1 Indicated for patients not at goal despite SU and/or metformin or TZD therapy; incretin mimetic is not indicated for insulin-using patients 2 For selected patients presenting with an A1C of >10%, certain oral agent combinations may be effective 3 Insulin sensitizer (metformin preferred) may be combined with initial insulin therapy 4 Preferred first agent in most patients 5 Analog preparations preferred 6 Appropriate for most patients Achieve ACE Glycemic Goals (FPG, PPG, and A1C) Assess FPG and PPG Target: PPG and FPG Target: FPG and PPG Target: FPG and PPG Insulin Therapy 2,3 Initial Therapy Preferred: Metformin 4 TZD 10,11,12 AGI DPP-4 Inhibitor Intervention Combine Therapies 6,7 Metformin Glinides AGI TZD 12 SU DPP-4 Inhibitor + met Colesevelam + met, SU or insulin Combine Therapies to Address FPG and PPG 7 Metformin TZD 10,11,12 SU Glinides DPP-4 Inhibitor Basal insulin analog 9 Combine Therapies to Address FPG and PPG 7 Metformin TZD 12 SU Glinides Basal insulin analog 9 Basal insulin analog 9 or NPH + prandial insulin 5,8 Premixed insulin preparations or more agents may be required 8 Rapid-acting insulin analog (available as lispro, aspart and glulisine) or regular insulin 9 Available as glargine and detemir 10 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated In their entirety, the available data on the risk of myocardial infarction are inconclusive. 11 Cannot be used in NYHA CHF Class 3 or 4 12 According to the FDA, rosiglitazone not recommended with insulin Alternatives Glinides SU (low dose) Prandial insulin 5,8 Alternatives Prandial insulin 5,8 Premixed insulin preparations 5 Basal insulin analog 9 Prandial insulin 5,8 Premixed insulin preparations 5 NPH Other approved combinations Prandial insulin 5,8 Premixed insulin preparations 5 NPH Other approved combinations ACE Glycemic Goals 6.5% A1C < 110 mg/dl FPG < 110 mg/dl Preprandial < 140 mg/dl 2-hr PPG Revision April 2008 Continuous Titration of Rx (2-3 months) to maximal effective dose to meet ACE Glycemic Goals to maximal effective dose to meet ACE Glycemic Goals to maximal effective dose to meet ACE Glycemic Goals to maximal effective dose to meet ACE Glycemic Goals to maximal effective dose to meet ACE Glycemic Goals ACE/AACE Diabetes Road Map Task Force If 6.5% A1C Goal Not Achieved Intensify Lifestyle Modification Intensify or combine Rx including incretin mimetic* 1 Intensify Lifestyle Modification Intensify or combine Rx, including incretin mimetic with SU, TZD, and/or metformin Intensify Lifestyle Modification Intensify or combine Rx, including prandial insulin 5,8, incretin mimetic 1, or amylin analog ** (with prandial insulin 5,8 ) Intensify Lifestyle Modification Initiate or intensify insulin therapy or add incretin mimetic 1 Intensify Lifestyle Modification Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE; Daniel Einhorn, MD, FACP, FACE; George Grunberger, MD, FACP, FACE; Yehuda Handelsman, MD, FACP, FACE; Richard Hellman, MD, FACP, FACE; Harold Lebovitz, MD, FACE; Philip Levy, MD, FACE; Victor L. Roberts, MD, MBA, FACP, FACE AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

4 Fig.2. Road map to assist clinicians in achieving glycemic goals (established by the American College of Endocrinology and the American Association of Clinical Endocrinologists) in treated patients with type 2 diabetes not at hemoglobin A1c goal. Modified from Endocr Pract. 2007;13: <6.5% >8.5 Road Map to Achieve Glycemic Goals: Treated Patients (Type 2) Abbreviations in Road Maps: AACE = American Association of Clinical Endocrinologists; A1C = hemoglobin A1c; ACE = American College of Endocrinology; AGI = α-glucosidase inhibitor; DPP-4 = dipeptidyl peptidase-4; FDA = US Food and Drug Administration; FPG = fasting plasma glucose; HDL = high-density lipoprotein; IFG = impaired fasting glucose; IGT = impaired glucose tolerance; MNT = medical nutrition therapy; OGTT = oral glucose tolerance test; PPG = postprandial glucose; Rx = treatment; SU = sulfonylurea; TZD = thiazolidinedione Current A1C% Current Therapy Intervention Continue Lifestyle Modification Monotherapy or Combination Therapy Monotherapy: Glinides, SU, AGI, metformin, TZD, DPP-4, premixed insulin preparations, prandial 2 or basal insulin 3 Combination Therapy: Glinides, SU, DPP-4, AGI, metformin, TZD, colesevelam, incretin mimetic*, premixed insulin preparations, prandial 2 or basal insulin 3 Monotherapy or Combination Therapy * Available as exenatide ** Available as pramlintide 1 Analog preparations preferred 2 Prandial insulin (rapid-acting insulin analogs available as lispro, aspart, glulisine or regular insulin) can be added to any therapeutic intervention at any time to address persistent postprandial hyperglycemia 3 Available as glargine and detemir 4 A recent meta-analysis suggests a possible link of rosiglitazone to cardiovascular events; other studies do not confirm or exclude this risk. The FDA has stated In their entirety, the available data on the risk of myocardial infarction are inconclusive.. 5 Cannot be used in NYHA CHF Class 3 or 4 6 According to the FDA, rosiglitazone not recommended with insulin Continue current therapy if all ACE glycemic goals are met Adjust therapy as needed to meet ACE FPG and PPG goals Intensify Lifestyle Modification Initiate Combination Therapy Metformin + SU or Glinide Incretin mimetic + metformin Metformin + TZD 4,5 or AGI and/or TZD TZD + SU Basal 3 or premixed insulin DPP-4 + Metformin ± SU preparations 1 DPP-4 + TZD Amylin analog** with prandial insulin 2 Colesevelam + met, SU or insulin Incretin mimetic* + metformin and/or SU Other approved combinations including approved oral agents with insulin 6 Intensify Lifestyle Modification Maximize Combination Therapy Maximize Insulin Therapy If elevated FPG, add or increase basal insulin 3 If elevated PPG, add or increase prandial insulin 2 If elevated FPG and PPG, add or intensify basal 3 + prandial 2 or premixed insulin therapy 1 Combine with approved oral agents 6 Amylin analog** with prandial insulin 2 Add incretin mimetic to patients on SU, TZD, and/or metformin Intensify Lifestyle Modification Initiate Insulin Therapy (Basal-Bolus) Basal 3 + prandial insulin 2 Premixed insulin preparations 1 Combine with approved oral agents 6 ACE Glycemic Goals 6.5% A1C < 110 mg/dl FPG < 110 mg/dl Preprandial < 140 mg/dl 2-hr PPG Revision April 2008 Continuous Titration of Rx (2-3 months) to maintain ACE Glycemic Goals to meet ACE Glycemic Goals to meet ACE Glycemic Goals to meet ACE Glycemic Goals ACE/AACE Diabetes Road Map Task Force Paul S. Jellinger, MD, MACE, Co-Chair Jaime A. Davidson, MD, FACE, Co-Chair Lawrence Blonde, MD, FACP, FACE; Daniel Einhorn, MD, FACP, FACE; George Grunberger, MD, FACP, FACE; Yehuda Handelsman, MD, FACP, FACE; Richard Hellman, MD, FACP, FACE; Harold Lebovitz, MD, FACE; Philip Levy, MD, FACE; Victor L. Roberts, MD, MBA, FACP, FACE AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced or distributed in any form without the express permission of AACE.

5 Table 2 Insulin formulations Brand name t ½ Onset Peak duration Stability (in-use product at room temp) Short or Rapid acting Intermediate Long acting Pre-Mixes Regular Humulin-R, Novolin-R min 1 5 hours 6 10 hours Huma 28 days Novo 30 days Lispro Humalog 1 hr min 30 min 2.5 hours hours 28 days Aspart Novolog 1.5 hr min 1 3 hours 3 5 hours 28 days Glulisine Apidra 0.7 hr min hours 3 5 hours 28 days NPH Humulin-N, Novolin-N Detemir Levemir hours Relatively flat Dose-dependent, 12 hours for 0.2 u/kg, 20 hours for 0.4 u/kg up to 24 hours - 30 min 2 hours 6 14 hours hours Huma 28 days Novo 30 days 42 days Glargine Lantus hours NONE 24 hours 28 days 70% aspart, Novolog Mix min Mean 2.4 hours hours, max 28 days 30% aspart 70/30 Range 1 4 hours up to 24 hrs protamine 75% lispro, 25% lispro protamine 70% NPH, 30% regular Humalog Mix 75/25 Humulin 70/30, Novolin 70/30 - Faster than humulin 70/30 Mean 2.6 hours Range 1.5 to 6.5 hours min Mean 4.4 hours Range hours Up to 24 hours hours, max up to hours 28 days Huma 28 days Novo 30 days 50% NPH, Humulin 50/ min Mean 3.3 hours hours, max 28 days 50% regular Range hrs up to hours No generic insulin products are yet available. Every insulin is now available as pre-filled pens. Novolog s pens are called Flexpens and Lilly s pens are called Solostar or just pens. The Opticlick device that utilizes prefilled cartriges for Lantus and Apidra is being phased out (replaced by Solostar pens). Other cartridge devices are still available, but are NOT recommended over the newer prefilled disposable pens. Administration points: Insulin suspensions should be gently shaken before each injection. Pens and cartridges of insulin suspensions should be rolled and tipped back and forth times to re-suspend the insulin. Insulin mixtures or dilutions should NOT be used in external pumps. Note: Most pens will advise that they should be primed before each dose. This is a good safety measure and included in the drug information packaged with each products. However, several studies have indicated that this process does not improve efficacy and some suggest this process is a waste. Nevertheless, at the very least, the patient should be instructed to prime each pen (recall dispensed as a box of 5 pens) the very first time it is used to ensure it is working properly. Priming beyond this may be up to physician and/or patient considerations. 5

6 Points of Interest 1. Where do the American Academy of Clinical Endocrinology (AACE) and the American Diabetes Association (ADA) place insulin therapy for Type 2 Diabetes Mellitus (T2DM)? Back to Top AACE: The AACE has created Road Map to Achieve Glycemic Goals for patients with T2DM that are naïve to therapy, already treated as well as to prevent T2DM. They break up recommendations based upon the patient s initial A1C and ALL recommendations start with lifestyle modifications. Naïve to ANY antidiabetic agents (Type II): The AACE does NOT include insulin as a preferred INITIAL therapy unless the initial A1C is 8% or higher. o They state, Consider insulin therapy in patients with HbA1c levels greater than 8% and symptomatic hyperglycemia and in patients with elevated FBG levels OR exaggerated PPG excursions regardless of HbA1c levels When the A1C is greater than 10%, the AACE indicates that insulin should be the first choice. At this point, oral sensitizing agents (metformin or TZD) should be considered for initial therapy only as adjunct to insulin therapy. The AACE actually places insulin therapy as an alternative INITIAL therapy for ALL levels of initial A1C. Treated Patients (Type II) As expected the AACE s Road Map for treated patients indicates combination therapy if patient does not achieve goal (their goal is <6.5%). Combinations include insulin with oral sensitizing agents (they caution but don t rule out combination specifically of insulin with rosiglitazone). If patient is already on combination therapy, recommendations include maximizing combination and/or insulin therapy. They specify that if: o Fasting blood glucose (FBG) is elevated add or increase basal insulin o Post prandial blood glucose (PPG) is elevated add or increase prandial insulin o Both FBG and PPG are elevated add or intensify both basal and prandial insulins. If treated patient has A1C greater than 8.5% basal + bolus insulin dosing strategy is specifically recommended. ADA: In 2006 the American Diabetes Association (ADA), in collaboration with European Association of Cardiology (ESC) / European Association for the Study of Diabetes (EASD) updated their algorithm for treatment of hyperglycemia in Type II DM. In January 2009, they again updated their guidelines and recommendations in light of the ACCORD, ADVANCE, and VADT trials. The 2009 update attempts to take a more personalized approach to achieving A1C goals. Their personalizing approach in A1C goals is based on patient factors such as duration of diabetes, comorbidities, history of hypoglycemia, etc. They have begun to include estimated average glucose (eag) values alongside A1C values. They feature lower goals to reduce microvascular complications for those who can tolerate intense therapy and higher goals for patients with a history of severe hypoglycemia, limited life expectancy, advanced micro or macrovascular complications, extensive comorbid complications, and those with longstanding diabetes resistant to intense therapy. Step 1 is still lifestyle intervention plus metformin When glycemia is high (A1C > 8.5%), classes with greater and more rapid glucose-lowering, or potentially earlier initiation of combination therapy are recommended. o They note that those with shorter duration of diabetes (new onset) tend to respond to less intensive therapy, compared with those having longer duration of diabetes When glyecemia is low (A1C < 7.5%), medications with lesser potential to lower glycemia and/or slower onset of action may be considered. Insulin is placed at STEP 2 in the new algorithm o When A1C > 8.5%, long or intermediate acting insulin plus metformin (and lifestyle changes) preferred. See Figure 2 below under section 3 a of this review [Jump to] 6

7 Note: By most effective, these organizations are indicating the reduction of A1C, not necessarily the most improved outcome data. Studies published since this algorithm have brought viewing simply A1C reduction, without including HOW the reduction is achieved, into question. Such studies include; UKPDS 10 year follow up, ACCORD, ADVANCE and VADT. These will be discussed in greater detail below. It is important to distinguish between Type I and II DM when viewing outcome data. Acarbose (alpha glucosidase inhibitor) and metformin are the ONLY two drugs thus far to demonstrate positive data with respect to MACROvascular outcome data in T2DM. Pioglitazone has demonstrated positive data in the PROactive trial in regards to death, myocardial infarction, and stroke, as secondary end-points with marginal significance. However, adding to confusion, in this trial the composite primary CVD outcome showed no significant improvement. Typically, composite end-points make it easier to show benefit. Note that despite this, acarbose is entirely absent from the ADA s preferred algorithm! [Back to quick-read info] 2. Why insulin should, or should not be used in patients with T2DM? Back to Top Studies have shown that most diabetic patients, despite having adequate glycemic control initially with diet and/or oral antidiabetic medications, will be UNABLE to sustain glycemic control over time due to a continual decline in β-cell function (and possibly other factors). Table 3 Literature Highlight: Turner et al. Glycemic Control with Diet, Sulfonylurea, Metformin, or Insulin in Patients with Type II Diabetes United Kingdom Prospective Diabetes Study (UKPDS). JAMA A prospective, observational study conducted between 1977 and 1997 in diabetes clinics in the United Kingdom to evaluate how often the following treatments achieved target glycemic levels. Newly diagnosed patients were randomized to diet, insulin, metformin, or sulfonylurea and were followed over a 9-year period. Results: See Table 3 for the proportion of patients sustaining FBG and HbA1c goals after 9 years. Note: statistical significance is unknown (P-values or confidence intervals were not reported). Turner et al. JAMA Study Groups Percentage of Patients Able to Sustain Goal FBG (<140 mg/dl) (%) Percentage of Patients Able to Sustain Goal HbA1c (<7%) (%) Diet 8 9 Insulin Sulfonylurea Metformin* *Obese patients only Conclusions: Monotherapy with a sulfonylurea, metformin, or insulin does NOT allow the majority of patients to achieve tight glycemic control over the long-term (here just 9 years). o Insulin therapy was more effective at achieving FBG and HbA1c targets than sulfonylurea or metformin (again, can t necessarily relate this to MACROvascular outcome data). o Most patients will require insulin to achieve glycemic goals, despite using combination oral agents. Note: Metformin was only used in obese patients in this study, limiting the comparison somewhat. Metformin has been shown to be beneficial in most patients, not just those that are obese. In addition, obese patients may have other significant factors affecting the efficacy of a drug regimen perhaps more so than just any given diabetic patient (diet, exercise, insulin resistance, compliance, dosing, co-morbid conditions, etc). 3. Who should use insulin and when should insulin be initiated in T2DM? Back to Top 7

8 Figure 1 - ADA 2009 Algorithm a. Does initiating insulin therapy EARLY in T2DM have any additional benefit? Or detriment? Back to Top Using intensive short-term insulin treatment as INITIAL therapy may help achieve normal glycemic levels in newly diagnosed patients. 5-8 This strategy may also improve insulin secretion and sensitivity, allowing patients to maintain long-term glycemic control with diet and exercise alone. Is it possible this strategy restarts/restores the incretin effect or first phase insulin response? FPIR = the incremental insulin response in the first 10 min after the IV glucose bolus (26% of response in 1 hour) T2DM patients lose FPIR, evident when FBG>115 mg/dl Literature Highlight: Ryan et al. Short-Term Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetes. Diabetes Care Randomized, open-label study in 16 newly diagnosed type 2 diabetics. Patients were treated with a 2-3 week course of intense insulin therapy involving pre-meal regular insulin and bedtime NPH insulin. Results: FBG significantly decreased after the 2-3 week treatment period (P < 0.01). The drop in FBG was maintained at the 1-year follow-up point; 7 patients maintained glycemic control with diet alone, 8 patients required the initiation of an oral agent, and 1 patient required insulin therapy. Conclusion: Response to early insulin therapy is a major predictor of study outcome, as the patients who did not require therapy with insulin or oral agents at the end of the study were better responders to initial insulin therapy. Limitations: Lack of a control group and small sample size. Further studies are required to determine the generalizability of these findings as well as the impact of longer duration of intense insulin therapy. 8

9 Several other studies showed similar results. 5-7 However, it should be noted that two of these studies used continuous subcutaneous insulin infusions (CSII) for two weeks instead of multiple daily insulin injections. 6 Contrast the above with the following An emerging model for management of T2DM (Glucose Supply and Insulin Demand ) highlights some significant pathophysiologic consequences to hyperglycemia, insulin (or secretagogue) use and resulting hyperinsulinemia and intracellular hyperglycemia. Figure 2 S. Monte, Pharm.D., J. Schentag, Pharm.D. CPL Associates. Another emerging factor that may impact the model for management of T2DM is the impact of insulin resistance on the vascular endothelium. One group hypothesizes that the unexplained CV risk in T2DM (despite significant A1C lowering) is explained by the basic molecular defects responsible for the insulin resistance. Thus, a group has shown that individuals with IGT and T2DM have a severe impairment in the ability of insulin to activate the PI-3 kinase pathway (metabolic pathway). This leads to impaired glucose transport in muscle and the resultant hyperglycemia causes increased insulin secretion by the pancreatic beta-cells. The increased plasma insulin causes excessive stimulation of the MAP kinase pathway (mitogenic pathway). Activation of the MAP kinase pathway leads to increased growth and proliferation of vascular smooth muscle cells, increased collagen formation, and the release of other growth and chemotactic factos that play a central role in the development of atherosclerosis (Ralph DeFronzo 22003). 4. Which insulin products should be used? Back to Top a. What role does controlling post-prandial glucose play in diabetic therapy? 9

10 Using intensive short-term insulin treatment as initial therapy may help achieve normal glycemic levels in newly diagnosed patients. 5-8 This strategy may also improve insulin secretion and sensitivity, allowing patients to maintain long-term glycemic control with diet and exercise alone. Ryan et al. 8 (Diabetes Care 2004): Short-Term Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetes Randomized, open-label study in 16 newly diagnosed type 2 diabetics. Patients were treated with a 2-3 week course of intense insulin therapy involving pre-meal regular insulin and bedtime NPH insulin. Results: FBG significantly decreased after the 2-3 week treatment period (P < 0.01). The drop in FBG was maintained at the 1-year follow-up point; 7 patients maintained glycemic control with diet alone, 8 patients required the initiation of an oral agent, and 1 patient required insulin therapy. Conclusion: Response to early insulin therapy is a major predictor of study outcome, as the patients who did not require therapy with insulin or oral agents at the end of the study were better responders to initial insulin therapy. Limitations: Lack of a control group and small sample size. Further studies are required to determine the generalizability of these findings as well as the impact of longer duration of intense insulin therapy. Several other studies showed similar results. 5-7 However, it should be noted that two of these studies used continuous subcutaneous insulin infusions (CSII) for two weeks instead of multiple daily insulin injections. 6 b. Comparison of various insulin preparations. Studies have shown that there is no difference in efficacy between the various insulin preparations. However, different insulin preparations vary as far as how they are used and titrated. Literature Highlight: Rosenstock et al. A randomized, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetologia Randomized, open-label, parallel-group, non-inferiority trial conducted to compare the clinical outcomes of insulin detemir to insulin glargine in 582 insulin-naïve patients over 52-weeks Patients had to be taking 1 or 2 oral agents (metformin, insulin secretagogues, or alphaglucosidase inhibitors) for at least 4 months. Excluded for taking TZDs or use of more than 2 oral agents within 6 months Results A1C decreased from a baseline value of 8.6% to 7.2% and 7.1% for insulin detemir and insulin glargine, respectively. When starting or adjusting insulin therapy, it is important to match the regimen to the patient s individual needs. Given the number of insulin analogs and formulations this should be possible. See the tables above for tips on matching the patient s characteristics and needs to a specific type of insulin preparation. [Dosing Tips/matching patients to formulations], [Kinetic comparisons of formulations] c. How should insulin be dosed? A couple excerpts highlighting dosing strategies, then the ADA algorithm: For intermediate acting insulins (AACE): Adjustments in prebreakfast dosages are based on presupper glucose levels Adjustments in presupper dosage adjustments are based on prebreakfast glucose levels Regarding Dose Titrations, ADA recommends: Check FBG usually daily and increase dose, typically by 2 units every 3 days until FBG are in target range Can increase dose in larger increments, e.g. by 4 units every 3 days, if FBG > 180 mg/dl 10

11 Figure 3 d. Efficacy of once-daily vs. twice-daily dosing of basal insulins. Glargine: Giving twice daily glargine does not allow for insulin dosage reductions. In a trial comparing once-daily to twicedaily glargine in patients with Type I Diabetes; although A1C concentrations were similar between the two groups, those in the split-dose group required 70% more insulin that those treated with once-daily glargine. Literature Highlight: Albright E, Desmond R, Bell D. Diabetes Care. 2004; 27(2): Split-dose glargine required 44 +/- 26 units Once-daily glargine required 26 +/- units 5. How long should ORAL anti-diabetic agents be used when initiating insulin therapy? Back to Top 11

12 In general, there is no consensus regarding how long oral anti-diabetic drugs should be continued when initiating insulin therapy (with exception of secretagogues sulfonylureas and glinides). Various evidence supports retaining insulin sensitizers as long as possible (until limiting adverse reactions or risks occur) TZDs edema, CHF risk Metformin renal function (SCr 1.5 men, 1.4 women or ClCr <60 ml/min) It makes logical sense to simplify a patient s regimen as soon as, and as much as possible, i.e., maximize insulin and minimize non-sensitizing oral antidiabetic drugs. Sulfonynlureas (and glinides): Per ADA 2009 update: Sulfonylurea agents should be STOPPED when insulin is started because they are NOT considered to be synergistic 3a. In other words, not exactly insulin-sparing, as their mechanism of action is stimulating insulin secretion Thus, consider it better to use more predictable insulin injection to increase effective insulin dose as opposed to less predictable type II DM pancreatic insulin secretion (both will be subject to insulin resistance) Note: Per AACE; Although optimal dosing of sulfonylureas varies by agent, the glucose-lowering effect usually plateaus at approximately one half of the maximum recommended dose. Consider the ADOPT trial, in which success rates and durability of first-line monotherapy with glibenclamide (aka - glyburide in US), metformin and rosiglitazone were evaluated in a randomized fashion in a large cohort with early type 2 DM over a mean follow-up of 4 years. Medscape Figure 3 below shows glyburide least durable over time of the tested agents. This makes sense physiologically as well, since pancreatic beta-cells would be expected to decline in function (thus less able and less available to be stimulated to secrete insulin). 6. When should an insulin pump be utilized? Who is an ideal candidate for an insulin pump? Back to Top Per AACE, Insulin pump therapy is an effective alternative to multiple insulin injections in patients with diabetes mellitus Results from studies have demonstrated that pump therapy can improve overall glucose control, reduce hypoglycemia, reduce hypoglycemia unawareness, reduce morning hyperglycemia due to the dawn phenomenon, and increase lifestyle flexibility Children and adolescents have been successfully treated with insulin pump therapy The efficacy and safety of continuous subcutaneous insulin infusion with an insulin pump are comparable to multiple daily injection insulin therapy for patients with T2DM Patients with T2DM can be taught as outpatients to use continuous subcutaneous insulin infusion and prefer this treatment modality over injections Patients requiring large total daily doses (TDD) of insulin are good candidates for insulin pumps. Continuous subcutaneous insulin infusion (CSII) pumps have demonstrated a reduction in TDD for required adequate control. 12

13 This CSII strategy appears to overcome some of the insulin resistance present in T2DM Using CSII vs. multiple subq injections may limit excessive dosing and hyperinsulinemia, and in theory be less likely to induce oxidative stress as a result of more consistent control. 7. What is a continuous glucose monitoring system (CGMS)? Back to Top a. Is there any evidence regarding the benefits of using continuous glucose monitoring systems? The efficacy of CGMS in diabetic patients still remains uncertain. The greatest use for CGMS is in patients who are unable to detect the signs and symptoms of severe hypoglycemia. Garg et al. 37 (Diabetes Care 2006): Improvement in Glycemic Excursions with Transcutaneous, Real- Time Continuous Glucose Sensor: A Randomized Controlled Trial 91 patients diagnosed with type 1 or types 2 diabetes requiring insulin therapy were randomized into two groups. One group used CGMS and the other was a control group. Patients wore CGMS for three consecutive 72 hour periods. Results: The CGMS group spent 21% less time in hypoglycemia, 23% less time in hyperglycemia, and 26% more time in the target range ( mg/dl) compared to the control group. Nocturnal hypoglycemia was also reduced by 38% in the CGMS group. Tanenberg et al. 38 (Mayo Clinic Proceedings 2004): Use of the Continuous Glucose Monitoring System to Guide Therapy in Patients with Insulin-Treated Diabetes: A Randomized Controlled Trial Randomized, controlled, parallel-group study in 128 patients with insulin treated diabetes and inadequate metabolic control. Patients were randomized to either CGMS or Self Measured Blood Glucose (SMBG) groups. Patients in the CGMS group wore the monitors twice (weeks 1 and 3) for 3 consecutive days during the 12-week study. Results: Mean HbA1c levels for the CGMS group decreased from 9.1 ± 1.1 to 8.3 ± 0.9% (P < 0.01) and mean HbA1c levels for the SMBG group decreased from 9.0 ± 1.0 to 8.3 ± 0.9% (P < 0.01). There was no significant difference in the mean HbA1c change between the two groups (P = 0.70). However, the CGMS group had significantly shorter duration of hypoglycemia when compared to SMBG group (P = 0.009). Take-Home Point: CGMS is appropriate for long standing diabetic patients with hypoglycemic unawareness or who have severe recurrent hypoglycemia. 8. Is there any data to support that lowering A1C (i.e., through intensive insulin therapy) reduces MACROvascular outcomes? Back to Top No, In fact a number of recent trials suggest potential detriment to macrovascular outcomes in light of intensive vs. normal diabetes management (intensive generally means a greater use of insulin). Recent trial analysis (UKPDS 10 year follow up, ACCORD, ADVANCE, VADT): Trial Subjects (mean age) UKPDS 3867 (54 yrs) ACCORD 10,251 (62.2 yrs) Patient type Description T2DM new onset T2DM avg duration of DM was 10 years, median baseline A1C 10 yr follow up of standard vs. intensive treatment. 3.5 yr follow up of standard vs. intensive treatment Note: stopped early due to increase CV risk in intensive A1C Intense vs. standard Results 7.0% vs. 7.9% Intensive blood glucose control decreases the risk of microvascular, but NOT macrovascular complications MI (16.5 vs. 14.2%) Fatal MI (4.4 vs. 7.59%) Stroke (4.8 vs. 5.4%) Fatal Stroke (1.3 vs. 1.6%) 6.4% vs. 7.5% No significant effects of the type of control on major macrovascular events: Non-fatal MI (4.6 vs. 3.6%) Nonfatal stroke (1.2 vs. 1.3%) CV-related death (1.8 vs. 2.6%) 13

14 ADVANCE 11,140 (66.0 yrs) VADT 1,791 (60.4 yrs) 8.1% treatment group. T2DM 5 yr follow up of Avg duration standard vs. of DM was 8 intensive treatment years, avg baseline A1C was 7.5% T2DM Avg duration of DM was 11.5 years, avg baseline A1C was 9.4% 5.6 yr follow up of standard vs. intensive treatment 6.5% vs. 7.3% No significant effects of the type of control on major macrovascular events: Non-fatal MI (2.8 vs. 2.7%) Nonfatal stroke (3.8 vs. 3.8%) CV-related death (5.2 vs. 4.5%) 6.9% vs. 8.4% No significant effects of the type of control on major macrovascular events: Non-fatal MI (8.7 vs. 7.2%) Nonfatal stroke (4.0 vs. 3.2%) CV-related death (3.2 vs. 4.3%) Due to time constraints comments and further details on the significance of these very significant trials in Type II DM (T2DM) patients will be discussed in a later drug class review. However, the introduction to emerging models of diabetes management (above in section 3 a) was included to suggest a possible explanation for the surprising results of each of these trials, as well as initiate our thinking into HOW we get to goal, not just getting to goal. 9. Which measure has a greater influence when A1C is slightly elevated (>7 9%)? Fasting blood glucose (FBG) or post-prandial blood glucose (PPG)? Back to Top a. Conversely, which measure has a greater influence when A1C is very elevated (>10%)? FBG or PPG? Per AACE, As demonstrated by Monnier and colleagues, the relative contribution of fasting glucose levels to overall glycemia is approximately 70% in patients with HbA1c levels greater than 10.2%. The contribution of fasting glucose to overall glycemia decreases to approximately 30% when HbA1c levels are less than 7.3%. (Thus, majority of effect is related to PPG when A1C < 7.3%) The contributions of fasting and postprandial glucose levels are approximately equal when HbA1c levels are between 7.3% and 8.4% Points for Discussion: If PPG accounts for the majority of effect when A1C levels are less than 7.3% (accounting for ~70% of the A1C value), why do we use FBG as our gold standard for DM diagnosis? How many patients are we missing that could have been caught earlier in their disease course if diagnosis included a PPG component? Would knowledge that at lower A1C s the PPG was the greater issue contribute to our selection of appropriate pharmacologic therapy, given that certain drugs/insulins target PPG, FBG or both? For example, a newly diagnosed type II diabetic has an A1C of 7.2%, is a sulfonylurea (which targets FBG primarily) the best initial choice? Should we begin to focus not only on the glucose numbers achieved, but HOW these numbers are achieved as well? Note: Per AACE, Glucose abnormalities are first demonstrated by postprandial hyperglycemia, which is caused by the loss of first-phase insulin secretion and reduced suppression of hepatic glucose output after meals due to insulin deficiency and glucagon excess. When hepatic glucose output exceeds glucose use, fasting hyperglycemia results. Misc Excerpts: Raz et al. 19 (Diabetes Care 2009): The Effects of Prandial Versus Fasting Glycemia on Cardiovascular Outcomes in Type 2 Diabetes: The HEART2D Trial 14

15 Randomized, controlled trial to compare the effects of prandial versus fasting glycemic control on risk for cardiovascular outcomes in patients with type 2 diabetes after acute myocardial infarction (AMI). Patients (n=1,115) with an AMI within the past 21 days were randomized to prandial insulin (premeal insulin lispro) or a basal insulin (twice daily insulin NPH or once daily glargine). Results: No difference in cardiovascular events between the prandial (n = 174, 31.4%) and the basal groups (n = 181, 32.4%) (hazard ratio = 0.98, 95% CI ) (See Figure 3). Mean HbA1c did not differ significantly between the two groups (P = 0.4); both groups did not achieve the goal HbA1c of < 7%. Post-prandial blood glucose was slightly better in the prandial group (P < 0.001), but still did not achieve the target level of < 7.5 mmol/l. Basal group showed lower mean FBG (P < 0.001) compared to the prandial group. Note: Study was stopped early due to a lack of efficacy. Despite these results, there is strong evidence that post-prandial plasma glucose levels can 20, 21 independently predict cardiovascular events. 15

16 Wrong answer try again or read on. [Back to quick-read info and quiz question] Insulin analogues with longer, nonspeaking profiles decrease the risk of hypoglycemia modestly compared with NPH, and analogues with very short durations of action reduce the risk of hypoglycemia compared with regular insulin 1a,2a. Severe hypoglycemia episodes (defined as requiring help from another person to treat) occurred at a rate of between 1 and 3 per 100 patient-years in a trial involving Type II DM patients compared with 61 per 100 patient-years in a trial involving Type I DM patients 3a. Some Key references: IHA Provider formulary. user: partners, pass: partners Individual product information sheets for each drug were also utilized. Links to each provided in first chart. 1. Nathan D, Buse J, Davidson M, Heine R, Holman R, Sherwin R. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29(8): Defronzo R. Pharmacologic therapy for type 2 diabetes mellitus. Annals of Internal Medicine. 1999;131(4): Mayfield J, White R. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. American Family Physician. 2004;70(3): Hirsch IB, Bergenstal RM, Parkin CG, Wright Jr E, Buse JB. A real-world approach to insulin therapy in primary care practice. Clinical Diabetes. 2005;23(2): Garvey W, Olefsky J, Griffin J, Hamman R, Kolterman O. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34(3): Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin therapy. Diabetes Care. 1997;20(9): Li Y, Xu W, Liao Z, Yao B, Chen X, Huang Z. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients is associated with improvement of beta-cell function. Diabetes Care. 2004;27(11): Ryan E, Imes S, Wallace C. Short-term intensive insulin therapy in newly diagnosed type 2 diabetes. Diabetes Care. 2004;27(5): Ceriello A, Cavarape A, Martinelli L, Da Ros R, Marra G, Quagliaro G. The post-prandial state in type 2 diabetes and endothelial dysfunction: effects of insulin aspart. Diabetic Medicine. 2004;21(2): Jacobsen L, Sogaard B, Riis A. Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart. European Journal of Clinical Pharmacology. 2000;56(5): Roach P, Trautmann M, Anderson J. The Mix 25 Study Group: improved postprandial glycemia during treatment with an intermediate-acting Mixture, Mix 25 (Abstract). Diabetologia. 1998;41(1):A Roach P, Trautmann M, Arora V. The Mix 50 Study Group: improved postprandial blood glucose control and reduced nocturnal hypoglycemia during treatment with two novel insulin lispro-protamine formulations, Insulin Lispro Mix 25 and Insulin Lispro Mix 50. Clinical Therapeutics. 1999;21: Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes Care. 2003;26(4): Turner R, Cull C, Frighi V, Holman R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type II diabetes: progressive requirement for multiple therapies. UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281(2): Poulsen M, Henriksen J, Hother-Nielsen O, Beck-Nielsen H. The combined effect of triple therapy with rosiglitazone, metformin and insulin aspart in type 2 diabetic patients. Diabetes Care. 2003;26(12): Strowig S, Aviles-Santa M, Raskin P. Improved glycemic control without weight gain using triple therapy in type 2 diabetes. Diabetes Care. 2004;27(7): Yki-Jarvinen H, Ryysy L, Nikkila K. Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. Annals of Internal Medicine. 1999;130(5): Schwartz S, Sievers R, Strange P. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis. Diabetes Care. 2003;26(8): Raz I, Wilson P, Krzysztof S, Kowalska I, Bozikov V, Gitt A. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: The HEART2D Trial. Diabetes Care. 2009;32(3): Megis J, Nathan D, D'Angostino R. Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care. 2002;25: Koivisto V, Tuominen J, Ebeling P. Lispro Mix25 insulin as premeal therapy in type 2 diabetic patients. Diabetes Care. 1999;22(3): Malone J, Bai S, Campaigne B, Reviriego J, Augendre-Ferrantet B. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycemic control in patients with type 2 diabetes. Diabetic Medicine. 2005;22(4): Rosenstock J, Davies M, Home P, Larsen J, Koenan 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): Rosenstock J, Schwartz S, Clark C, Park G, Donley D, Edwards M. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24(4): Raskin P, Allen E, Hollander P, Lewin A, Gabbay R, Hu P. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28(2): Roach P, Koledova E, Metcalfe S, Hultman C, Milicevic Z. Glycemic control with humalog Mix25 in type 2 diabetes inadequately controlled with glyburide. Clinical Therapeutics. 2001;23(10):

17 27. Fritsche A, Schweitzer M, Haring H. Glimepride combined with morning insulin glargine, bedtime neutral protamine hagedron insulin, or bedtime insulin glargine in patients with type 2 diabetes.. Annals of Internal Medicine. 2003;138(12): Bretzel R, Nuber U, Landgraf W, Owens D, Bradley C, Linn T. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. The Lancet. 2008;371(371): Cusi K, Cunningham G, Comstock J. Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM. Diabetes Care. 1995;18(6): Philis-Tsimikas A, Charpentier G, Clauson P, Ravn G, Roberts V, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clinical Therapeutics. 2006;28(10): Hermansen K, Davies M, Derezinski T, 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 M, 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): Phillip M, Battelino T, Rodriguez H, Danne T, Kaufman F. Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2007;30(6): Mukhopadhyay A, Farrell T, Fraser R, Ola B. Continuous subcutaneous insulin infusion vs. intensive conventional insulin therapy in pregnant diabetic women: a systematic review and meta-analysis of randomized controlled trials. American Journal of Obstetrics & Gynecology. 2007;197(5): Blackett P. Insulin pump treatment for recurrent ketoacidosis in adolescence. Diabetes Care. 1995;18( ). 36. Farkas-Hirsch R, Hirsch I. Continuous subcutaneous insulin infusion: a review of the past and its implementation for the future. Diabetes Spectrum. 1994;7: Garg S, Zisser H, Schwartz SB, T, Kaplan R, Ellis SJ, L. Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care. 2006;29(1): Tanenberg R, Bode B, Lane W, Levetan C, Mestman J, Harmel A. Use of the continuous glucose monitoring system to guide therapy in patients with insulin-treated diabetes: a randomized controlled trial. Mayo Clinic Proceedings. 2004;79(12): a Zammit NN, Frier BM: Hypoglycemia in type 2 diabetes. Diabetes Care. 28: , a Miller CD, Phillips LS, Ziemer DC, et al. Hypoglycemia in patients with type 2 diabetes mellitus. Arch Int Med. 161: , a Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care ;1: