Insulin Analog Therapy: Improving the Match with Physiologic Insulin Secretion

CLINICAL PRACTICE

Insulin Analog Therapy: Improving the Match With Physiologic Insulin Secretion

Jeffrey S. Freeman, DO

Context: Among the growing population of individuals with ype 2 diabetes mellitus is becoming a pandemic in the type 2 diabetes mellitus, many patients are failing to meet Tdeveloped world. According to 2007 data,1 23.6 million glycemic targets and are therefore at increased risk of com- people in the United States are estimated to have diabetes, plications. with type 2 diabetes mellitus accounting for up to 95% of all diagnoses. The diseases’s prevalence in US children and ado- Data Overview: Rapid-acting insulin analogs (ie, aspart, lescents is also increasing, as illustrated by the fact that 30% lispro, glulisine) have a pharmacokinetic profile that mirrors of all patients aged between 10 and 19 years with newly endogenous insulin more closely than regular human insulin. diagnosed diabetes have type 2 diabetes mellitus.2 According These insulin analogs can also be given closer to mealtimes and to 2002-2003 data, 15,000 individuals younger than 20 years are less likely to cause hypoglycemia. Long-acting insulin are newly diagnosed as having type 1 diabetes mellitus annu- analogs (ie, detemir, glargine) have relatively flat time-action ally, and 3700 are newly diagnosed as having type 2 dia- profiles and last up to 24 hours, thus simulating endogenous betes mellitus.1 basal insulin more precisely than neutral protamine Hagedorn Current guidelines3-6 from the American Diabetes Asso- insulin and producing less nocturnal hypoglycemia. The sim- ciation (ADA) and other organizations stress the impor- plicity and efficacy of insulin analogs should help facilitate a tance of intensive treatment to achieve glycated hemoglobin patient’s transition to insulin therapy. Current guidelines (HbA ) levels less than 7% (lower than 6% in individuals advocate starting insulin therapy in patients who have not 1c who don’t have hypoglycemic episodes) because patients achieved glycemic targets or those with glycated hemoglobin with inadequately controlled diabetes are at increased risk greater than 8.5% and adjusting doses as necessary. Two case of micro- and macrovascular complications. Several land- studies illustrate the benefits of insulin analog therapy. mark studies7-10 have shown that good glycemic control can Conclusions: Insulin analogs offer many benefits over human limit complications, highlighting the importance of more insulins, including improved physiologic profile, greater con- physiologic insulin profiles in achieving this goal after other venience, reduced risk of hypoglycemia, and, in some therapies have proven to be insufficient. instances, less weight gain. Combined, these elements may The UK Prospective Diabetes Study8,11 showed that each increase a patient’s adherence to treatment, potentially 1% reduction in mean HbA1c was associated with a 21% risk increasing the level of glycemic control and improving the reduction for any diabetes-related end point, the lowest risk prognosis in patients with type 2 diabetes mellitus. being in those with HbA1c values in the normal range. Early J Am Osteopath Assoc. 2009;109:26-36 intervention with insulin therapy may help improve out- comes12-15—a viewpoint reflected in current US treatment guidelines.3-6 This rationale is based on the progressive decline in ␤-cell secretion, which limits the efficacy of insulin secretagogues and insulin sensitizers. Novo Nordisk funded writing and editing assistance, which was provided by Of particular concern, 43% of patients with type 1 or Jackie Mayne, MSc, and Emma Campbell, PhD, of Bioscript Stirling Ltd. This 16 financial assistance was not part of an educational grant. Editing and med- type 2 diabetes mellitus fail to achieve HbA1c targets. In ical accuracy review of the manuscript were done by Novo Nordisk. fact, recent survey data showed that 89% of adults with dia- In addition, Dr Freeman discloses that he serves on the speakers bureaus betes in New York City did not know their HbA1c levels, of GlaxoSmithKlein, Novartis Pharmaceuticals Corporation, Novo Nordisk U, and sanofi-aventis US, and that he has received grants and research support prompting the New York Board of Health to introduce from AstraZeneca Pharmaceuticals LP and Bristol-Myers Squibb Company. mandatory electronic reporting.17 These test results will be Address correspondence to Jeffrey S. Freeman, DO, Professor of Internal used to create a statewide registry so that the diabetes epi- Medicine, Division of Endocrinology and Metabolism, Philadelphia College of Osteopathic Medicine, 4190 City Ave, Suite 324, Philadelphia, PA 19131-1633. demic can be better monitored and patients who need more E-mail: [email protected] support can be identified.17 Control of fasting plasma glucose (FPG) and postpran- Submitted January 23, 2008; revision received June 9, 2008; accepted June 12, 2008. dial glucose (PPG) levels is essential to reduce the risk of complications.3,5,7,8 For example, elevated 2-hour PPG values

26 • JAOA • Vol 109 • No 1 • January 2009 Freeman • Clinical Practice CLINICAL PRACTICE have been associated with increased cardiovascular risk independent of FPG.3 The Diabetes Epidemi- Breakfast Lunch Dinner ology: Collaborative Analysis of Diagnostic Criteria in Europe study18 demonstrated that patients with 50 higher than recommended levels of fasting and 2- hour plasma glucose levels require more intensive treatment because they are at higher risk of prema- 25 ture death than patients with abnormal FPG alone. The ideal goal of insulin therapy is to mimic the pattern of physiologic insulin secretion to control Plasma Insulin, mU/L both FPG and PPG—in other words, combine a long- 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 acting basal component that suppresses endoge- Clock Time, h nous hepatic glucose production to control FPG and a shorter-acting component to address PPG.12,13 Such Figure 1. Physiologic insulin secretion of a healthy pancreas. Source: regimens should help optimize glycemic control to mini- This figure was published in Current Paediatrics, Vol 16, Thompson R, 19 mize the risk of diabetes-related complications. In addi- Christie D, Hindmarsh PC, The role for insulin analogs in diabetes tion, patients can be taught to self-monitor blood glucose care, pages 117-122, Copyright Elsevier 2006.20 Reproduced with per- and adjust their therapy—crucial steps in insulin therapy— mission. on the basis of fasting and postprandial readings. Patients should keep a blood glucose diary and work with the physician and office staff to set up a monitoring schedule that has levels in the majority of patients, even when given in combi- minimal impact on patient lifestyle. nation, making exogenous insulin necessary. Although joint Newer insulin analogs mimic the profile of endogenous guidelines from the ADA and European Association for the insulin more closely than recombinant human formulations Study of Diabetes13 and the American College of Endocrinology and are therefore a step closer to this ideal. The present and American Association of Clinical Endocrinologists24 rec- review discusses how insulin analogs can contribute to the ognize this problem with oral antidiabetic medications, they effective management of type 2 diabetes mellitus and provide somewhat different algorithms for initiating phar- describes the limitations of other medications once ␤-cell macotherapy. Four dosing algorithms are described later in dysfunction reaches a critical threshold. Case studies are also greater detail. provided to further illustrate the benefits of insulin analogs. Human insulin analogs, which may improve glycemic control, have been modified by altering the amino acid The Match: Injected vs Secreted Insulin sequence. For example, this change can take place by trans- In a person with a healthy pancreas, basal insulin is continuously posing two amino acids, replacing one amino acid with released at low levels in response to hepatic glucose output, another, or adding a fatty-acid side chain to a specific amino while prandial (bolus) insulin is released intermittently in acid.20 As a result of these genetic modifications, human insulin response to elevated glucose levels following a meal (Figure 1).20 analogs have enabled insulin therapy to more closely mimic Within seconds of food ingestion, there is an initial release of normal physiologic insulin secretion, as shown in Figure 2.25,26 insulin, which peaks in 1 to 2 minutes and lasts about 10 min- A comparison of the time courses of various human insulins utes.21,22 This first phase is responsible for suppressing hepatic and insulin analogs is shown in Table 1.27,28 glucose output, limiting PPG elevations, and stimulating phase Basal insulin is commonly administered to patients starting 2 insulin release of newly manufactured insulin. This second insulin therapy. Detemir and glargine, the two long-acting phase lasts 1 to 2 hours until normoglycemia is restored.20,21 insulin analogs available in the United States, have relatively However, in patients with type 2 diabetes mellitus, phase 1 flat time-action profiles and more closely mirror the physiologic insulin secretion is markedly decreased or absent. As the disease action of basal insulin than NPH insulin, which peaks at 6 to progresses, phase 2 insulin release is also reduced, often by 14 hours. As the therapeutic effect of detemir and glargine more than 50%.21,23 can last for up to 24 hours,29,30 the recommended dose is once Patients with type 2 diabetes mellitus can be treated ini- or twice daily for insulin detemir29 and once daily for insulin tially with oral medications that increase insulin secretion glargine30. However, the duration of action of detemir increases throughout the day (secretagogues or incretins), enhance with doses. insulin action (sensitizers), or reversibly inhibit carbohydrate In two large observational studies31,32 of patients with breakdown (␣-glucosidase inhibitors). However, the latter type 2 diabetes mellitus, once daily dosing was used in the agents are used infrequently in the United States because of low majority of cases (77% to 79%). Clinical data33-38 suggest that efficacy and adverse gastrointestinal effects. Also, oral agents long-acting analogs control glucose levels as effectively as may slowly lose durability and therefore fail to control glucose NPH but with less nocturnal hypoglycemia and intrasubject

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betic agents such as secretagogues provide insufficient prandial insulin. Patients with unpredictable Insulin Type eating habits should be encouraged to use basal-bolus Endogenous (ie, nondiabetic) therapy. Rapid-acting (eg, aspart, lispro) Analog premixes Short-acting (ie, regular) Initiating Insulin Analog Therapy Intermediate-acting (eg, NPH) Some evidence13,43 suggests that early introduction of Long-acting (ie, glargine, detemir) insulin can help lower insulin resistance, reverse glucose toxicity, and preserve ␤-cell function for longer than is possible with oral medications alone. It could also help reduce the incidence of cardiovascular complications,

Relative Insulin Effects as insulin has been shown to reduce the level of pro - inflammatory cytokines, a group of substances involved in obesity-linked insulin resistance and impli- 0 2 4 6 8 101214161820 cated in the occurrence of atherosclerosis.44-46 These Time, h findings have been supported by results from the Diabetes Control and Complications Trial/Epidemio- Figure 2. Pharmacokinetic profiles of human insulins compared with logy of Diabetes Interventions and Complications insulin analogs and endogenous insulin. Abbreviation: NPH, neutral study47 in patients with type 1 diabetes mellitus. As that study47 protamine Hagedorn. Sources: Data for graph were extracted from suggests, intensive, early intervention before complications US Pharmacist.26 Data for the endogenous curve were adapted from manifest produces the best outcomes. Edelman SV and Morello CM.25

Table 1 Pharmacokinetic Profiles of Insulin Analogs variability and a more predictable time-action profile. Also, and Human Insulins detemir and glargine have been shown to cause less weight gain than NPH. In fact, this difference was shown to be sta- Onset of Action, tistically significant in clinical trials.34-36,39,40 Insulin min Peak, h Duration, h Compared with regular human insulin, rapid-acting Analog analogs (ie, aspart, lispro, glulisine) have a time-action profile ▫ Long-acting that is more similar to endogenous postprandial insulin – detemir 48-120 NA Ͻ24 release.41 They can be injected within 15 minutes of a meal, – glargine 66 NA Ͻ24 unlike regular human insulin, which must be administered 30 ▫ Rapid-acting to 45 minutes before a meal. Rapid-acting analogs also provide – aspart 10-20 1-3 3-5 better control of postprandial glucose excursions. A combi- – lispro 15-30 0.5-2.5 3-6.5 nation of rapid-acting insulin with each meal and basal insulin – glulisine 10-15 1-1.5 3-5 (ie, basal-bolus therapy) is required by most patients with ▫ Premixed type 1 diabetes mellitus as well as those with type 2 diabetes – 70% aspart protamine mellitus that cannot be controlled with other insulin regimens. suspension/30% aspart 10-20 1-4 (2.4)* Ͻ24 An alternative to these multiple daily injections is an insulin – 75% lispro protamine pump, which continually infuses a rapid-acting insulin to suspension/25% lispro 10-30 1-6.5 (2.6)* Ͻ24 supply basal needs and delivers bolus doses at mealtimes, as Human selected by the patient.42 ▫ Intermediate-acting Premixed insulin analogs contain a rapid-acting analog for – NPH 60-120 6-14 16-Ͼ24 prandial coverage and a protaminated analog for basal needs. ▫ Short-acting Currently, biphasic insulin aspart 70/30 (70% insulin aspart – regular 30-60 1-5 6-10 protamine suspension, 30% insulin aspart injection), insulin ▫ Premixed lispro 75/25 (75% insulin lispro protamine suspension, 25% – 70% NPH/30% regular 30-60 1.5-16 (4.4)* 18-24 insulin lispro injection), and insulin lispro 50/50 (50% insulin lispro protamine suspension, 50% insulin lispro injection) are * Data reported as range (mean). available in the United States. Premixed insulins eliminate Abbreviations: NA, not applicable (ie, no pronounced peak); NPH, neutral self-mixing and minimize the number of injections. These for- protamine Hagedorn. mulations are also used to initiate insulin therapy, particu- Sources: Mooradian AD et al27 and Allen J.28 larly in patients with regular eating habits, after oral antidia-

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Traditionally, insulin is introduced to patients only after combinations of two or even three oral antidiabetic medications Table 2 have failed to provide adequate glycemic control. In fact, only Effect of Hypoglycemic Agents 11% of patients with type 2 diabetes who are taking medica- on Glycated Hemoglobin (HbA1c) Levels tion are given insulin therapy,48 which reflects the general in Patients With Diabetes Mellitus trend of using insulin as a last resort in managing type 2 diabetes mellitus.49 Drug Therapy HbA1c Reduction, % However, the established superior efficacy of insulin over Monotherapy oral agents in reducing HbA levels,3 augmented by the ben- 1c ▫ Biguanides (ie, metformin) 1.1-3.0 eficial profile of the new insulin analogs versus human insulins, ▫ Sulfonylureas 0.9-2.5 may be changing this view.13,33,50 Furthermore, trials such as ▫ Thiazolidinediones 1.5-1.6 the Glycemia Optimization Treatment study51 are addressing ▫ ␣-glucosidase inhibitors 0.6-1.3 the concern that causes many physicians to delay or inade- ▫ Dipeptidyl-peptidase 4 inhibitors 0.8 quately dose insulin—namely, that tight glycemic control can Noninsulin Injections lead to hypoglycemia. This particular trial51 involves 4823 ▫ Pramlintide 0.43-0.56 insulin-naïve patients with type 2 diabetes mellitus and was ini- ▫ Exenatide 0.8-0.9 tiated to ascertain the optimum dose of insulin glargine (in com- Combination Therapy bination with oral agents) to achieve glycemic targets without ▫ Sulfonylurea + metformin 1.7 increasing the risk of severe hypoglycemia. ▫ Sulfonylurea + rosiglitazone 1.4 While the capacity of insulin to reduce HbA is unlim- 1c ▫ Sulfonylurea + pioglitazone 1.2 ited, it is restricted by the potential for hypoglycemia. Most ▫ Sulfonylurea + acarbose 1.3 noninsulin diabetes medications have limited efficacy, whether ▫ Repaglinide + metformin 1.4 alone or in combination (Table 2).24 However, key trials33,52,53 have ▫ Pioglitazone + metformin 0.7 shown that because of their simplicity and efficacy, insulin ▫ Rosiglitazone + metformin 0.8 analogs may help facilitate the transition between oral agents and ▫ Dipeptidyl-peptidase 4 inhibitor + metformin 0.7 insulin therapy more successfully than human insulins. ▫ Dipeptidyl-peptidase 4 inhibitor + pioglitazone 0.7 While current treatment guidelines differ, they all recommend that insulin therapy be instituted earlier than usual Source: Copyright 2007 by the American Association of Clinical 3-6 in patients not achieving HbA1c targets. The ADA and Euro- Endocrinologists as featured in Endocrine Practice. 2007;13(suppl):1-68.24 pean Association for the Study of Diabetes3,6 adopted a step- Reproduced with permission. wise approach: (1) start with metformin and lifestyle modifi- cation; (2) add either basal insulin, a sulfonylurea, or a thiazolidinedione if HbA1c is still higher than 7%; and (3) add glucosidase inhibitor; a DPP-4 inhibitor plus metformin or a thi- or intensify insulin therapy if targets remain unmet. The guide- azolidinedione) is recommended, while prandial, basal, or lines3,6 also recommend early initiation of insulin for individ- premixed insulin are offered as alternatives. For patients with uals presenting with weight loss, more severe symptoms, FPG an HbA1c level between 8% and 10%, basal, prandial, pre- levels greater than 250 mg/dL, or random glucose levels con- mixed, or NPH insulin can be combined with oral agents to sistently higher than 300 mg/dL. achieve appropriate FPG and PPG levels, though glinides and While pramlintide and exenatide have been approved DPP-4 inhibitors are not suitable for HbA1c levels between for use in the United States as adjunctive therapy, they are 9% to 10%. Finally, for those with HbA1c levels greater than not included in the ADA treatment algorithm6 because of 10%, a basal-bolus or premixed insulin regimen is required.4 their relatively low glucose-lowering effectiveness, limited If glycemic goals are not met after 2 to 3 months of therapy, a clinical data, and relative expense. However, they are acknowl- more intensive regimen should be initiated. For example, exe- edged as appropriate choices for “selected patients.”6 natide or pramlintide may be added, though pramlintide The American College of Endocrinology and American should only be used as an adjunct to prandial insulin.4,54 Association of Clinical Endocrinologists6 recommend various For patients already receiving pharmacologic treatment, treatment options depending on HbA1c levels at diagnosis. the therapeutic options for combination therapy are appro- For treatment-naïve patients with an HbA1c level between 6% priate, though exenatide and pramlintide may be introduced and 7%, monotherapy with metformin, a thiazolidinedione, a at an earlier stage in this patient group. Insulin should be ␣ dipeptidyl-peptidase 4 (DPP-4) inhibitor, or an -glucosidase added if the HbA1c levels of patients on maximum combina- inhibitor is preferred, while prandial insulin, a glinide, or a sul- tion therapy (ie, multiple oral agents or oral agents plus exe- fonylurea are alternative options. For those with an HbA1c natide) are between 6.5% and 8.5%. Also, basal-bolus insulin level between 7% and 8%, a combination of oral agents (eg, a should be considered for patients with HbA1c levels greater sulfonylurea plus metformin, a thiazolidinedione, or an ␣- than 8.5%.4,54

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Although the timing of patient introduction to insulin fonylurea. At 1 year, the proportions of patients with HbA1c varies, if HbA1c levels continue to exceed stated targets, insulin values at 6.5% or lower were 17%, 23.9%, and 8.1%, respec- should be introduced. While there is no best way to initiate tively. The final 2 years of the trial will investigate the more insulin therapy in patients with type 2 diabetes mellitus, a complex insulin regimens required as the disease progresses. long-acting basal insulin such as detemir or glargine, either at bedtime or in the morning, combined with oral antidiabetic Benefits of Insulin Analog Therapy therapy is a common starting regimen.5,6,55 Whether insulin is given as a basal, basal-bolus, or premixed Unfortunately, if insulin treatment is initiated late in the regimen or is used in a continuous subcutaneous insulin infu- disease process, patients with type 2 diabetes may have little sion pump, insulin analogs offer several advantages over con- ␤-cell function left, making once-daily injection of basal insulin ventional human formulations. insufficient to achieve glycemic targets.56 At this point, agents that stimulate insulin release—such as sulfonylureas, exe- Time-Action Profile natide, or DPP-4 inhibitors—should be discontinued and pran- A basal-bolus regimen with long- and rapid-acting insulin dial insulin should added to the basal insulin, thus providing analogs more closely mimics physiologic insulin secretion the physiologic basal-bolus regimen. Adjunctive treatment while providing glycemic control that is at least as effective as with pramlintide has been shown to improve postprandial regular human insulin and NPH (Figure 4).14,25,33-35,37,52,60,61 and overall glycemic control when given with prandial insulin.57 Convenience After basal insulin alone has become insufficient, prandial Unlike short-acting and premixed human insulins, rapid- insulin is typically initiated with one injection at the largest meal acting analogs and premixed analog formulations can be of the day and additional injections as necessary to achieve injected immediately before or just after a meal. This option glycemic control.55 Patients may prefer to use premixed analog gives patients more flexibility, which is particularly welcome formulations, which combine rapid- and long-acting insulins for those with irregular lifestyles, such as individuals with in one preparation. However, strict adherence to mealtimes and variable work hours. Long-acting analogs are slowly absorbed exercise schedules is necessary to maintain glycemic control.55 and distributed, with relatively flat and predictable time-action A summary of the key insulin options is given in Figure 3 with profiles that last up to 24 hours.62 As a result, they usually an indication of patient profiles.14,58 need to be given only once daily, which can be at bedtime for The first phase of the Treating to Target in Type 2 Diabetes minimum disruption. study59 suggests that most patients are likely to need more In patients who had not achieved glycemic control on than one type of insulin. This study59 investigated the rela- one or two oral hypoglycemic agents, treat-to-target trials33,35 tive benefits of adding a premixed insulin analog twice daily, demonstrated that initiating basal insulin therapy with either a rapid-acting analog three times daily, or a basal insulin insulin glargine or insulin detemir—rather than NPH—is a analog once or twice daily to patients with suboptimal glycemic simple and standardized way to achieve glycemic control control on maximally tolerated doses of metformin and a sul- with a substantially reduced risk of hypoglycemia. In gen-

Patient Profile

Patient 1 Patient 2 Patient 3 Patient 4 ▫ Continuing use of ▫ Erratic schedule ▫ Consistent daily routine ▫ Erratic schedule oral agents ▫ Optimum glycemic ▫ Reluctant to administer ▫ Highly motivated ▫ Overweight control needed because multiple injections to learn technique ▫ Insulin resistant of complications ▫ Optimal control not vital ▫ Motivated to acheive (eg, elderly with no glycemic control complications) ▫ Reluctant to administer multiple injections

Recommended Insulin Regimen Basal only Basal-bolus Premixed (once, twice, Continuous or three times daily) subcutaneous insulin infusion

Figure 3. Recommended insulin regimen according to patient’s profile. Patients should meet all characteristics listed in the profile before following the recommended insulin regimen. Sources: Hirsch IB et al14 and Gallichan M et al.58

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infusion to multiple daily injection regimens. Rapid-acting A insulin analogs are currently considered the insulins of choice Regular for insulin pumps.72,73 NPH at bedtime Hypoglycemia Human insulins have variable peaks in activity and unpredictable action durations, which can make patients vulner- BL S HS B able to episodes of hypoglycemia.62 Long-acting insulin analogs were specifically developed to address these problems and have less within-subject variability and a lower incidence of Rapid acting hypoglycemia than NPH (Figure 5).5,6,33,35,37,74-81 This is par- B Basal at bedtime ticularly true of insulin detemir, which has a statistically sig-

Plasma Insulin, mU/L nificant lower variation coefficient than insulin glargine and NPH: 27% versus 46% and 59%, respectively (PϽ.001 for both comparisons).82 BL S HS B Hypoglycemia can occur if regular human insulin is administered more than 30 minutes before eating. By con- trast, rapid-acting insulin analogs decrease the potential for Time hypoglycemic episodes. Although severe hypoglycemia is uncommon in patients with type 2 diabetes mellitus,8 fear of Figure 4. Comparison of human (A) and analog (B) basal-bolus insulin hypoglycemia is a major concern for patients receiving insulin regimens. The shaded areas depict normal insulin secretion, thus therapy and can be a barrier to the practice of strict glycemic showing the relationship of each insulin therapy to normal physiologic control.75 Educating patients about the time-action profiles of conditions. Abbreviations: B, breakfast; HS, bedtime; L, lunch; NPH, different insulin preparations and prevention of hypoglycemia neutral protamine Hagedorn; S, supper. Source: Edelman SV, Morello increases patients’ confidence in their treatment and makes CM. Strategies for insulin therapy in type 2 diabetes. South Med J. them more willing to accept dose adjustments.49 2005;98:363-371.25 Copyright Southern Medical Association. Modified with permission of Lippincott Williams & Wilkins. Weight Gain Clinical trials suggest that long-acting analogs cause less weight gain than NPH insulin.34-36,38-40,83 This difference may be asso- eral, basal insulin is initiated at 10 IU/day in insulin-naïve ciated with a decreased need for additional snacks because patients and is increased according to mean FPG or PPG levels patients are less worried about the risk of hypoglycemia.34 from self-monitored blood glucose readings, as described in Addressing the problem of weight gain should help reduce the several key trials (Table 3).33,63-66 potential for obesity-related complications and improve patient For patients who have regular eating patterns, the use of self-esteem. premixed analog formulations can reduce the number of injections needed per day. Such patients have the advantages of Implications for Patient Adherence both rapid- and long-acting insulin analogs with respect to It is generally accepted that restoring normal or near-normal prandial dosing but need fewer injections than basal-bolus glucose homeostasis can substantially reduce the risk of dia- regimens. In the 1-2-3 study,67 the percentages of patients who betes-related complications. Therefore, the more physiologic Ͻ achieved target HbA1c levels ( 7%) with once, twice, or three- time-action profiles and convenient dosing of insulin analogs times daily biphasic insulin aspart were 41%, 70%, and 77%, may help improve the long-term prognosis for patients with 12 respectively, while the percentages of patients achieving HbA1c type 2 diabetes. However, the advantages identified in clin- levels of 6.5% or lower were 21%, 52%, and 60%, respectively. ical trials need to be documented in clinical practice. The dosing algorithm was based on titration increments of 3 Two studies31,84 in a “real-world” setting have shown units. that long-acting insulin analogs provide good glycemic control All insulin analogs are available with pen delivery devices, with low levels of hypoglycemia. The Predictable Results and either prefilled or cartridge. Not only do these devices make Experience in Diabetes through Intensification and Control administration more discreet and comfortable, but they also to Target trial31 was a 3-month observational study in which help improve patient compliance and, consequently, glycemic patients were transferred from NPH plus oral agents, insulin control.68-71 Administration is also more accurate with pen glargine plus oral agents, or oral agents only to detemir plus devices than with a conventional syringe and vial, so patients oral agents. Once started on detemir, changes in insulin dose are less likely to administer the wrong dose. or oral agents during the study period were made as needed Some patients prefer continuous subcutaneous insulin by the patient’s physician. All three detemir groups had sta-

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Case Study 1 Table 3 A 54-year-old male dockworker Dosing Algorithms for Initiation of Basal Insulin Therapy with a history of hypertension was in Patients With Type 2 Diabetes Mellitus diagnosed as having type 2 dia- Starting Dose, Increase Mean FPG or PPG Change in Insulin, betes mellitus 12 years ago. He had Insulin IU/day Interval Values,* mg/dL IU/day† no history of retinopathy or peripheral neuropathy. His current med- Glargine ▫ Riddle MC et al33 10 Weekly 100-120 ϩ2 ications included metformin, 120-140 ϩ4 500 mg twice daily, and morning 140-180 ϩ6 doses of glipizide, 20 mg, and у180 ϩ8 lisinopril, 10 mg. ▫ Davies M et al64 10 Weekly у100-Ͻ120 ϩ0-2 On physical examination, his у120-Ͻ140 ϩ2 weight was 216 lbs; body mass у140-Ͻ180 ϩ4 index, 32; and blood pressure, у180 ϩ6-8 130/82 mm Hg. Cardiac and res- Detemir piratory examinations were normal, ▫ 63 Ͻ Ϫ ‡ Selam JL et al NA Every 3 days 80 3 and there was no evidence of 80-110 0‡ reduced peripheral pain sense or Ͼ110 ϩ3‡ ▫ Philis-Tsimikas A et al66 10 At least once р108 0 peripheral edema. His most recent every 4 weeks 109-126 ϩ2 HbA1c value was 9.4%, and his 127-144 ϩ2 urine microalbumin/creatinine 145-162 ϩ4 ratio was 38 ␮g/mg creatinine. 163-180 ϩ6 The patient typically ate very Ͼ180 ϩ8 little breakfast and lunch and had a Ͻ § Ϫ 56 4 large, mixed meal dinner after 8 PM. 56-72§ Ϫ2 He regularly checked his blood glucose levels before breakfast and at * The titration regimen used by Riddle MC et al33 was based on mean fasting plasma glucose (FPG) values of the bedtime (11 PM), and he reported previous 2 days. Davies M et al.64 also used mean FPG values, but they were based on measurements of the previous 3 days. The titration regimen set by Philis-Tsimikas A et al66 was based on mean postprandial glucose that his most recent glucose levels (PPG) values for the previous 3 days. were 156 mg/dL (before breakfast) † A “ϩ“ denotes an increase in insulin dose; a “Ϫ“ denotes a decrease in insulin dose. ‡ According to the 3-0-3 algorithm used in the PREDICTIVE study,65 insulin is increased or decreased by 3 units or and 246 mg/dL (3 hours after left unchanged depending on the patient’s mean FPG values from three measurements. dinner). The patient’s postprandial § Mean plasma glucose values were based on three consecutive measurements. If one or more of the three plasma glucos measurements were within the range of less than 56 mg/dL or between 56 to 72 mg/dL for no obvious dinner hyperglycemia was of reason, the insulin dose was decreased by the amounts shown in the next column of this table. greatest concern. Although the

Abbreviation: NA, not available. patient reported attempting lifestyle changes, he continued this food consumption pattern. Ͻ tistically significant reductions in HbA1c from baseline (P .001), To improve glycemic control, three treatment options no major hypoglycemic events, and a combined average weight were available: loss of 0.9 kg.31 In the Glycemic Optimization With Algorithms and Labs ▫ addition of another insulin sensitizer at Point of Care trial,84 which was based in a predominantly pri- ▫ addition of a DPP-4 inhibitor and discontinuation of glipizide mary care setting, insulin glargine plus oral antidiabetic agents ▫ initiation of basal-bolus insulin or premixed insulin analog produced statistically significant HbA1c reductions over formulation 24 weeks (PϽ.001) with low rates of hypoglycemia. The benefits of insulin analogs can help patients over- Because the patient did not want to initiate a basal-bolus pro- come their reluctance to start insulin therapy. Convenient gram, premixed insulin aspart 70/30 administered at dinner dosing and reduced risk of hypoglycemia, combined with the was determined to be the preferred option. This therapy option variety of delivery systems available, help patients adhere to would provide his dinner insulin requirements and improve their prescribed regimens and so reap the benefits of good his overnight glycemic control without the risk of fasting hypoglycemic control. The two case studies presented below rep- glycemia. (Insulin lispro 75/25 would also have been an resent examples of typical patients and circumstances sur- appropriate option.) rounding poor glycemic control. Further, they illustrate insulin Premixed insulin analog aspart 70/30 was initiated at titration and the benefits of insulin analog therapy. 10 units with dinner and titrated up to 20 units. The patient

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Figure 5. Total number of hypoglycemic events in patients on 400 Insulin detemir insulin detemir and aspart insulin therapy (n=237) compared NPH with those on neutral protamine Hagedorn (NPH) and regular human insulin therapy (n=238).35 Source: Copyright 350 2006 American Diabetes Association. From Diabetes Care, Vol 29, 2006; 1269-1274.35 Reprinted with permission from the 300 American Diabetes Association.

250 to manage glucose levels. A few years later, he was placed on glyburide but was later taken off glyburide 200 and switched to glimepiride (4 mg per day). How- ever, his blood glucose levels continued to rise. Met- formin was added as a cotherapy with a slow titration 150 up to 2 g per day. Despite using these oral agents, his HbA1c was 8.6%. Hypoglycemic Events, No. 100 To better control HbA1c levels, insulin detemir was added to the patient’s regimen at a starting dose of 50 10 units at bedtime followed by self-titration based on his FPG level—an average of the previous 3 days. He 0 was instructed to titrate detemir as follows: 0 2 4 8 12 16 20 24 Study Interval, weeks If FPG is less than 80 mg/dL, reduce insulin by 3 IU. If FPG is 80-110 mg/dL, continue current dose. If FPG is greater than 110 mg/dL, increase insulin by remained on his oral antidiabetic medication. 3IU. As a result of this regimen, the postprandial dinner and FPG levels were reduced and, 3 months later, his HbA1c level This treatment algorithm was similar to that used in the US had fallen to 8.0%. Although this value was above the target PREDICTIVE 303 trial.65 level, continued titration should continue to decrease and The patient noted that FPG levels declined to the 120 improve the patient’s glycemic control. mg/dL range. Glimepiride was stopped and metformin main- tained at the dosage of 2 g per day. His HbA1c value was Case Study 2 reduced to 6.65%. In an effort to control mealtime glucose A 48-year-old man was diagnosed as having type 2 diabetes levels, he began insulin aspart with carbohydrate counting mellitus 18 years ago. He had a history of hypertension, hyper- and bolus coverage. His HbA1c declined to 5.7% with no evi- lipidemia, proteinuria, and diabetic peripheral neuropathy, dence of hypoglycemia. and he had suffered a recent thrombotic stroke. His medications included carvedilol, 3 mg twice a day; Discussion ezetimibe, 10 mg daily; furosemide, 40 mg daily; gabapentin, Groundbreaking studies7-10 have proven that maintaining 100 mg daily; glimepiride, 4 mg daily; hydrochlorothiazide, HbA1c levels less than or equal to 7%, in accordance with pro- 12.5 mg daily; lorsartan potassium, 100 mg daily; and sim- fessional guidelines,3-6 can limit the progression of complica- vastatin, 40 mg daily. tions in type 2 diabetes mellitus. In order to achieve optimum On physical examination his blood pressure was glycemic control, insulin analogs have proven to mimic phys- 110/74 mm Hg; pulse rate, 76 beats per minute; and respira- iologic insulin secretion better than other therapy options. For tions, 18 breaths per minute. Cardiac examination revealed example, compared with short-acting human insulins, rapid- an audible S4. Pulmonary and abdominal examinations were acting insulin analogs have a time-action profile closer to that normal. He had an FPG of 263 mg/dL and an HbA1c level of of endogenous insulin and can be given immediately before or 8.6%. Kidney function tests revealed a 24-hour urine protein after meals. level of 2.8 g, blood urea nitrogen of 37 mg/dL, and serum cre- Long-acting insulin analogs are relatively peakless, pro- atinine of 1.5 mg/dL. Subsequent laboratory tests revealed viding insulin for up to 24 hours in a way similar to endoge- total cholesterol to be 114 mg/dL; low-density lipoprotein nous basal insulin. In addition, premixed insulin analog for- cholesterol, 52 mg/dL; high-density lipoprotein cholesterol, mulations have proven effective in reducing both FPG and 32 mg/dL; and triglycerides, 216 mg/dL. PPG in patients inadequately controlled on oral agents, as The patient reported that when he was first diagnosed demonstrated in both the 1-2-3 study67 and the INITIATE as having type 2 diabetes mellitus, he used diet and exercise study.85 In the 1-2-3 study,67 the majority of patients were con-

Freeman • Clinical Practice JAOA • Vol 109 • No 1 • January 2009 • 33 CLINICAL PRACTICE trolled on two injections of biphasic insulin aspart 70/30 per mittee. ACE/AACE consensus conference on the implementation of outpatient management of diabetes mellitus: consensus conference recommendations day, an important consideration for patients reluctant to start [review]. Endocr Pract. 2006;12(suppl 1):6-12. basal-bolus insulin, such as the patient in the first case study. 6. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Premixed insulins are a very attractive option for the ini- Management of hyperglycemia in type 2 diabetes: a consensus algorithm for tial introduction of insulin therapy in type 2 diabetes mel- the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study litus: they reduce the injection load, making insulin treat- of Diabetes [published correction appears in Diabetes Care. 2006;49:2816-2818]. ment easier to accept; provide prandial coverage from the Diabetes Care. 2006;29:1963-1972. Available at: http://care.diabetesjournals beginning; avoid the possibility of mixing errors; and have .org/cgi/content/full/29/8/1963. Accessed December 9, 2008. proven more effective than basal insulin plus oral agents in 7. The Diabetes Control and Complications Trial Research Group. The effect 85-87 of intensive treatment of diabetes on the development and progression of lowering HbA1c. However, premixed insulins are less long-term complications in insulin-dependent diabetes mellitus. N Engl J suitable as the disease progresses because of the substantially Med. 1993;329:977-986. increased incidence of weight gain and hypoglycemia com- 8. The United Kingdom Prospective Diabetes Study Group. Intensive blood- pared with basal analog therapy.85,86 glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes [published The longer patients have type 2 diabetes mellitus, the correction appears in Lancet. 1999;354:602]. Lancet. 1998;352:837-853. more vulnerable they become to low blood glucose levels as 9. Writing team for the Diabetes Control and Complications Trial/Epidemiology a result of failure of endogenous counter-regulatory mecha- of Diabetes Interventions and Complications Research Group. Effect of inten- nisms that help protect against hypoglycemia.74 The body sive therapy on the microvascular complications of type 1 diabetes mellitus. normally produces various hormones in response to hypo- JAMA. 2002;2887:2563-2569. 10. Shichiri M, Kishikawa H, Ohkubo Y, Wake N. Long-term results of the glycemia, including glucagon, epinephrine, cortisol, and growth Kumamoto Study on optimal diabetes control in type 2 diabetic patients. Dia- hormone. The primary effect of these hormones is to suppress betes Care. 2000;23(suppl 2):B21-B29. insulin release and stimulate glucagon- and epinephrine-medi- 11. Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, et al. ated glucose production. Epinephrine is also key to the initi- Association of glycaemia with macrovascular and microvascular complica- 74 tions of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. ation of glucose-sparing lipolysis. In patients with type 2 2000;321:405-412. Available at: http://www.pubmedcentral.nih.gov/article diabetes mellitus, the glucagon response is virtually absent.88 render.fcgi?tool=pubmed&pubmedid=10938048. Accessed December 9, 2008. Given that insulin analogs are associated with a lower 12. Brunton SA, Davis SN, Renda SM. Early intervention to achieve optimal out- incidence of hypoglycemia and a higher level of convenience comes in type 2 diabetes: a case presentation. Clin Cornerstone. 2006;8(suppl than human insulins, patient adherence is more likely. 2):S6-S18. 13. Palumbo PJ. The case for insulin treatment early in type 2 diabetes. Cleve Clin J Med. 2004;71:385-386,392-392,394. Conclusion 14. Hirsch IB, Bergenstal RM, Parkin CG, Wright E Jr, Buse JB. A real-world The goals of insulin therapy are to achieve glycemic control and approach to insulin therapy in primary care practice. Clin Diabetes. 2005;23:78- to minimize the risks of hypoglycemia and weight gain. 86. Available at: http://clinical.diabetesjournals.org/cgi/content/full/23/2/78. Regardless of the insulin regimen given, insulin analogs should Accessed December 9, 2008. 15. LeRoith D, Levetan CS, Hirsch IB, Riddle MC. Type 2 diabetes: the role of help improve glycemic control and the health outlook for basal insulin therapy. J Fam Pract. 2004;53:215-222. patients with type 2 diabetes mellitus. 16. Ford ES, Li C, Little RR, Mokdad AH. Trends in A1C concentrations among US adults with diagnosed diabetes from 1999 to 2004. Diabetes Care. Acknowledgments 2008;31:102-104. Available at: http://care.diabetesjournals.org I thank Jackie Mayne, MSc, Medical Writer, and Emma Campbell, /cgi/content/full/31/1/102. Accessed January 6, 2009. 17. Steinbrook R. Facing the diabetes epidemic—mandatory reporting of PhD, Medical Editor, at Bioscript Stirling Ltd for their editorial glycosylated hemoglobin values in New York City. N Engl J Med. 2006;354:545- support. 548. 18. Balkau B. The DECODE study. 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Campbell RK, White JR Jr. Insulin therapy in type 2 diabetes. J Am Pharm Diabetes Care. 2008;31(suppl 1):S12-S54. Available at: http://care.diabetes Assoc (Wash). 2002;42:602-611. journals.org/cgi/content/full/31/Supplement_1/S12. Accessed January 6, 2009. 22. Davis S, Granner D. Insulin, oral hypoglycemic agents, and the pharma- 4. Jellinger PS, Davidson JA, Blonde L, Einhorn D, Grunberger G, Handelsman cology of the endocrine pancreas. In: Hardman JG, Limbird LE, Molinoff PB, Y, et al; ACE/AACE Diabetes Road Map Task Force. Road maps to achieve Ruddon RW, Gilman AG, eds. Goodman and Gilman’s: The Pharmacologic Basis glycemic control in type 2 diabetes mellitus: ACE/AACE Diabetes Road Map of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:1487-1518. Task Force. Endocr Pract. 2007;3:260-268. Available at: www.aace.com/meetings 23. Bonadonna RC, Stumvoll M, Fritsche A, Muggeo M, Häring H, Bonora E, /consensus/odimplementation/roadmap.pdf. Accessed December 9, 2008. et al. 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34 • JAOA • Vol 109 • No 1 • January 2009 Freeman • Clinical Practice CLINICAL PRACTICE http://diabetes.diabetesjournals.org/cgi/content/full/52/2/470. Accessed 40. Siegmund T, Weber S, Blankenfeld H, Oeffner A, Schumm-Draeger PM. December 9, 2008. Comparison of insulin glargine versus NPH in people with type 2 diabetes mel- 24. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American litus under outpatient-clinic conditions for 18 months using a basal-bolus Association of Clinical Endocrinologists medical guidelines for clinical practice regimen with a rapid-acting insulin analogue as mealtime insulin. Exp Clin for the management of diabetes mellitus. Endocr Pract. 2007;13(suppl 1):1- Endocrinol Diabetes. 2007;115:349-353. 68. 41. White JR, Campbell R, Hirsch IB. Novel insulins and strict glycemic control. 25. Edelman SV, Morello CM. Strategies for insulin therapy in type 2 dia- Analogues approximate normal insulin secretory response [published cor- betes [review]. 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Meneghini LF, Rosenberg KH, Koenen C, Merilainen MJ, Lüddeke HJ. able at: http://edrv.endojournals.org/cgi/content/full/24/3/278. Accessed Insulin detemir improves glycaemic control with less hypoglycaemia and no December 10, 2008. weight gain in patients with type 2 diabetes who were insulin naïve or 46. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine treated with NPH or insulin glargine: clinical practice experience from a receptors in inflammation [review]. N Engl J Med. 2006;354:610-621. German subgroup of the PREDICTIVE study. Diabetes Obes Metab. 2007;9:418- 427. 47. Genuth S. Insights from the diabetes control and complications trial/epidemiology of diabetes interventions and complications study on the 32. Dornhorst A, Lüddeke HJ, Sreenan S, Koenen C, Hansen JB, Tsur A, Land- use of intensive glycemic treatment to reduce the risk of complications in type 1 stedt-Hallin L. Safety and efficacy of insulin detemir in clinical practice: 14-week diabetes [review]. Endocr Pract. 2006;12(suppl 1):34-41. follow-up data from type 1 and type 2 diabetes patients in the PREDICTIVE European cohort. Int J Clin Pract. 2007;61:523-528. 48. Koro CE, Bowlin SJ, Bourgeois N, Fedder DO. Glycemic control from 1988 to 2000 among US adults diagnosed with type 2 diabetes: a preliminary 33. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investiga- report. Diabetes Care. 2004;27:17-20. Available at: http://care.diabetesjournals tors. The treat-to-target trial: randomized addition of glargine or human .org/cgi/content/full/27/1/17. Accessed December 10, 2008. NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086. Available at: http://care.diabetesjournals.org/cgi 49. Meece J. Dispelling myths and removing barriers about insulin in type 2 /content/full/26/11/3080. Accessed December 10, 2008. diabetes [review]. Diabetes Educ. 2006;32(suppl 1):9S-18S. 34. Raslová K, Bogoev M, Raz I, Leth G, Gall MA, Hâncu N. 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(continued) quality of life, and cost-effectiveness [review]. Diabetes Metab Res Rev. 2004;20:178-188. insulin therapy. Clin Diabetes. 2002;20:137-144. Available at: http://clinical .diabetesjournals.org/cgi/content/full/20/3/137. Accessed December 10, 2008. 74. Briscoe VJ, Davis SN. Hypoglycemia in type 1 and type 2 diabetes: physi- ology, pathophysiology, and management [review]. Clin Diabetes. 2006;24:115- 58. Gallichan M, O’Brien S, Dromgoole B, Nute B, Preston F, Tipson M. Starting 121. Available at: http://clinical.diabetesjournals.org/cgi/content/full/24/3/115. insulin treatment in adults with type 2 diabetes: RCN guidance for nurses. Accessed December 10, 2008. London, UK: Royal College of Nursing; 2004. Available at: http://www.rcn.org .uk/__data/assets/pdf_file/0009/78606/002254.pdf. Accessed December 10, 75. Cryer PE, Childs BP. Negotiating the barrier of hypoglycemia in diabetes. 2008. Diabetes Spectrum. 2002;15:20-27. 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36 • JAOA • Vol 109 • No 1 • January 2009 Freeman • Clinical Practice