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Home , Saxagliptin, Sitagliptin

The Future of Therapy for Patients With Type 2 Mellitus Joseph M. Tibaldi, MD

From the Albert Einstein College of Medicine in Flushing, New York.

This article is based on a continuing medical education symposium held on October 10, 2012, during the American Osteopathic Association’s 2012 annual Osteopathic Medical Conference & Exposition in San Diego, California. This article was developed with assistance from Global Directions in Medicine. The author has approved the article and all of its content.

Financial Disclosures: Dr Tibaldi is on the speakers’ bureaus for Daiichi Sankyo Company, Merck & Co, Inc, and Novo Nordisk Inc. He is also a consultant for Novo Nordisk Inc.

Address correspondence to Joseph M. Tibaldi, MD, Insulin therapy has been the mainstay of therapy for patients Queens Diabetes and Endocrinology Associates, with mellitus for the past 90 years. This trend 59-45 161st St, is likely to continue as new formulations are developed to more Flushing, NY 11365-1414. closely mimic physiologic insulin secretion and to provide E-mail: [email protected] patients who have diabetes with more convenient options for integrating this therapy into their lifestyle. The present article reviews how the role of insulin continues to evolve, from its earlier use in the treatment paradigm (even at first diagnosis) to its role in combination therapy with -based thera- pies, as well as new formulations that provide more-convenient forms of insulin replacement therapy.

J Am Osteopath Assoc. 2013;113(4 suppl 2):S29-S39

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S29 he number of patients with type cated and patient-friendly agents.2 The patients with T2DM, the normal post- 2 diabetes mellitus (T2DM) far present review article discusses ini- prandial suppression of secre- Texceeds the number of endo- tiation of insulin replacement therapy at tion is inadequate, leading to increased crinologists and diabetes specialists the time of diagnosis, basal insulin ther- hepatic glucose output that worsens available to treat them. The majority apy used in combination with incretin hyperglycemia. In turn, chronic hyper- of patients are treated in primary care therapy, and second-generation basal glycemia leads to glucose toxicity that environments, and by virtue of the com- therapy, using a case paradoxically results in reduced syn- mon comorbidities that “travel” with study to demonstrate clinical applica- thesis and secretion of insulin.6 Native diabetes, including hypertension, dys- tion. Other means of enhancing delivery glucagon-like peptide-1 (GLP-1) is an lipidemia, and obesity or overweight, of insulin to patients are also discussed. incretin hormone secreted by the gut comprehensive and holistic approaches that normally slows gastric emptying, to care are required. Osteopathic physi- acts on the pancreas to stimulate glu- cians are likely to encounter more and Pathophysiologic cose-dependent insulin secretion, and more such patients in their practices. As Profile of T2DM Drives suppresses the release of glucagon.7 a result of improvements in health care Treatment Choices Incretin deficits or incretin resistance and increases in longevity, patients are Insulin is instrumental in managing T2DM, may result in the abnormal regulation more likely to require insulin therapy at which is a complex, multihormonal, and of insulin and glucagon secretion that some point during the progression of progressive chronic disease.3 Our ap- characterizes T2DM.8 Like insulin, GLP-1 T2DM. With advances in insulin therapy proach to the treatment of patients with and glucagon are important targets of still occurring, it is well worth keeping T2DM requires an understanding of the pharmacologic treatment strategies for up to date on trends in the use of this pathophysiologic profile of this condition improving glycemic control.9 powerful glucose-lowering agent. to determine when and how to use the Patients with T2DM are insulin resis- many pharmacologic agents available. tant, have relatively low insulin produc- Type 2 diabetes mellitus results from Use of Insulin Therapy tion, or have both characteristics. Most the abnormal secretion or abnormal Early in the T2DM patients with T2DM eventually require actions of key hormones that regulate Treatment Paradigm insulin if other medications fail to control glucose production by the and glu- Insulin remains integral to the treatment their blood glucose levels adequately.1 cose uptake in the peripheral muscle of patients with diabetes.10 For patients Insulin replacement therapy lets pa- and adipose tissue. In patients with with T1DM, insulin therapy is essential tients know that a key component of established T2DM, insulin secretion is and lifesaving. For patients with T2DM, their natural glucose-regulating system reduced because of progressive loss use of insulin therapy was formerly is being restored. When insulin replace- of pancreatic β-cell function.4 Plasma relegated to use during later stages of ment therapy was introduced more than glucose levels increase as insulin the disease. This approach is being 90 years ago,2 it was a lifesaving option deficiency and insulin resistance reduce reexamined as more recent treatment for patients with type 1 diabetes mellitus normal insulin activity, leading to dimin- paradigms encourage earlier use of in- (T1DM), even though the formulations ished stimulation of peripheral glucose sulin treatment algorithms for patients used were relatively crude. During past uptake and decreased inhibition of he- with T2DM.11 On the basis of guidelines decades, major advances in our abil- patic glucose production.5 from the American Association of Clini- ity to synthesize more reproducible and Glucagon normally helps maintain cal Endocrinologists, insulin therapy physiologic formulations have enabled fasting plasma glucose levels by stim- clearly is recommended for patients the production of much more sophisti- ulating hepatic glucose production. In with severe hyperglycemia and for pa-

S30 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 tients receiving oral antidiabetic drugs 420 who have (HbA1c) levels greater than 9%.12 360 Before insulin therapy Of particular interest are data as- 270 sessing the use of insulin as a first-line Immediately after insulin therapy treatment option for T2DM, often in pa- 180 tients who initially have very high levels 1 year after insulin therapy Glucose, mg/dL of glucose toxicity. This treatment op- 90 tion was reviewed by Rolla13 in 2009, and additional data have since been 0 published. Several studies14-16 have 0 30 60 90 120 150 180 shown prolonged remission of T2DM Time, min in patients receiving intensive insulin therapy for 2 weeks. A 2- to 3-week 600 course of intensive insulin therapy can lay the foundation for prolonged good 500 glycemic control in patients with newly 400 diagnosed T2DM who have elevated fasting glucose levels. Figure 1 shows 300 1 year after insulin therapy an example of the effects of short-term intensive insulin therapy on glucose and Insulin, pmol/L 200 Immediately after insulin therapy insulin levels.14 Before insulin therapy In a more recent study, the use of 100 low-dose insulin therapy (given as pre- mixed insulin in one study) for patients 0 with newly diagnosed T2DM led to evi- 0 30 60 90 120 150 180 dence of β-cell recovery, as document- Time, min ed by plasma insulin and C-peptide lev- els.17 It appears that reversing glucose toxicity may result in a rapid improve- Figure 1. ment in β-cell function, which then al- Glucose and insulin levels before insulin therapy, immediately after insulin therapy, and 1 year after insulin therapy, lows the β cell to start to function and demonstrating the effects of short-term intensive insulin therapy to secrete adequate amounts of insulin in patients with newly diagnosed type 2 diabetes mellitus.14 Reprinted with permission from the American Diabetes for clinically significant periods of up to Association, from Ryan EA, Imes S, Wallace C. Short-term 14-16 1 year. This series of events is also intensive insulin therapy in newly diagnosed type 2 diabetes known as a “second-wind” phenomenon mellitus. Diabetes Care. 2004;27(5):1028-1032; permission conveyed through Copyright Clearance Center, Inc. for the β cell.13 After symptom relief oc- curs and glucose levels are normalized in such patients, oral agents often can be added to therapy, and it may be pos- sible to withdraw insulin.

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S31 Other recent data show that β-cell thinking that he might have diabetes. Harry, 2-Year Follow-Up function can be preserved for at least After talking with the owner, Harry real- Harry’s diabetes treatment regimen 3.5 years with the use of early and in- ized that he had unquenchable thirst. now includes basal insulin as well as tensive T2DM therapy involving admin- He promptly made an appointment to . During the 2 years since istration of either insulin plus metfor- see his primary care physician, even Harry was first seen in the physician’s min or triple oral therapy after an initial though he had been negligent in doing office, he has been self-titrating his bas- 3-month period of insulin-based treat- so for the past year. al insulin and has generally been able

18 ment. These data support the premise The findings from Harry’s visit to to keep his HbA1c level at less than 7%. that insulin should not be relegated to his physician were notable. He had a However, despite engaging in exercise use as a last-line therapy but, rather, weight loss of 15 lbs, a nonfasting glu- on a relatively consistent basis, he has

could be used earlier in the disease cose level of 430 mg/dL, an HbA1c level gained 11 lbs. For the past 6 months,

paradigm, when some β-cell function of 12%, and trace levels of ketone bod- however, his HbA1c level has been remains intact. Insulin therapy can be ies in his urine sample. Insulin replace- 8.3%, in spite of fasting blood glucose discontinued in patients who have early ment therapy was recommended as levels between 90 and 115 mg/dL. disease, and it can be restarted when initial treatment. Harry’s goal is to once again attain an

necessary or continued in conjunction In Harry’s case, insulin therapy was HbA1c level of less than 7%. with other oral agents or GLP-1 recep- clearly indicated. He had T2DM, clini- Many patients who receive basal tor agonists. cally significant hyperglycemia, and insulin therapy will ultimately require signs of catabolism (weight loss), and treatment intensification. Notably, the

no oral agent or other noninsulin agent HbA1c level reflects not only fasting Case Study would begin to bring him close to his blood glucose levels but also postpran- 19 Harry goal HbA1c level. Pathophysiologic find- dial glucose levels. Adding a sulfonyl- Harry is a 52-year-old man who, for the ings revealed that his liver was secret- urea to insulin-based therapy increases past 6 months, has been struggling with ing excess glucose that was unable to the risk of without pro- a new job that has required his attention enter the muscle. His problematic glu- viding much benefit. during most of his waking hours. His cose levels occurred in part because also lower fasting glucose levels much past medical history includes hyperten- Harry has diminished insulin levels. more than postprandial glucose levels, sion, for which he takes a diuretic, and However, it also occurred because Har- so they may not be the best treatment mixed hyperlipidemia managed with a ry has a GLP-1 deficit, and because, option for Harry. At this point, the clini- modest dose of a statin. with that deficit, he was producing too cal decision traditionally is to switch to Harry has been fastidious in taking much glucagon. a premixed insulin or move toward a his medications, but his job keeps him It is gratifying to treat a patient like basal-bolus regimen (which is often at his desk most of the time. His only Harry, who arrives at the office feeling done by sequentially adding prandial exercise is walking to the local fast food poorly but who, after approximately 3 to insulin before meals as needed and as restaurant where he buys most of his 6 months, is in much better health and tolerated).11,20-22 This clinical decision meals. The owner of the restaurant can have blood glucose levels that are is certainly a well-validated and effec- noted that Harry was returning more close to normal. Chronic hyperglycemia tive treatment strategy, but there are frequently and buying more juice and leads to reduced insulin secretion drawbacks for some patients—namely, soda. The owner’s wife had diabetes, (Figure 2).6 By reversing glucotoxicity, an increased risk of hypoglycemia, so the owner gently questioned Harry it is possible for the body to resume weight gain, and number of complica- about his thirst levels and weight loss, insulin secretory capacity. tions for patients in terms of the number

S32 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 Chronic hyperglycemia

Oxidative stress (ROS) ↑ Glucose Pancreatic β cell

↓ Glucokinase activity

↓ PDX-1 activity

↓ Insulin biosynthesis ↓↓ Insulin secretion

Figure 2. The mechanism of insulin secretion reduction caused by glucose toxic effects. The binding capacity of PDX-1 decreases as a result of oxidative stress caused by hyperglycemia, while insulin biosynthesis and secretion also decrease. Reprinted from Kawahito et al.6 Abbreviations: PDX-1, pancreatic duodenal homeobox-1; ROS, reactive oxidative species.

of injections needed and the complex- efficacy in lowering glucose levels.24-27 lower postprandial glucose levels, with ity of titrating both basal and prandial The benefit of using these approaches a low associated risk of hypoglycemia insulin doses.23 is that incretin-based therapies work and without weight gain (an advan- in a glucose-dependent manner (ie, tage over prandial insulin analogs).28-33 only in the presence of hyperglycemia). However, basal insulin doses may need Basal Insulin Therapy They also are weight neutral (dipepti- to be adjusted downward or sulfonyl- in Combination With dyl peptidase-4 [DPP-4] inhibitors) or ureas may need to be discontinued.34 Incretin-Based Therapy are associated with weight loss (GLP-1 Table 1 provides a summary of some Another approach used to augment receptor agonists). of the available published literature on insulin therapy is to add incretin-based Currently, DPP-4 inhibitors, as well DPP-4 inhibitors used in combination agents to the treatment regimens of as both and short-acting with insulin therapy.28,29,35 patients who are receiving basal in- , are approved for use with The use of GLP-1 agonists in com- sulin therapy but who are no longer long-acting basal insulin analogs in pa- bination with insulin therapy for post- achieving treatment goals. Although tients with T2DM who are not achiev- prandial glucose control also may these approaches are similar, they ing their goals for glycemic control. In- result in some weight loss.33 Some have important differences (Figure 3).9 cretin-based therapies primarily target clinicians prefer to start with a GLP-1 Glucagon-like peptide-1 receptor ago- postprandial hyperglycemia (although agonist or an incretin-based therapy nists provide supraphysiologic levels of longer-acting GLP-1 agonists also af- early in the treatment paradigm, before the incretin hormone and have greater fect fasting plasma glucose levels) and initiating insulin.36,37

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S33 Table 1. Outcomes of Select Studies of Dipeptidyl Peptidase-4 Inhibitors in Combination With Insulin Over 24 Weeks Duration

Source Agent Comparison Patients Outcome

Hong et al, Add-on to insulin vs Patients with T2DM (n=140); Compared with a 25% increase 28 2012 an insulin dose increase baseline HbA1c level, 9.2% in the insulin dose, adding sitagliptin to an insulin-based regimen was more effective

at lowering HbA1c levels and was associated with less hypoglycemia and weight gain Barnett et al, Insulin alone or insulin Patients with T2DM (n=455); Addition of saxagliptin improved 35 2012 plus metformin, addition baseline HbA1c level, glycemic control and was of saxagliptin vs placebo 7.5% to 11% generally well tolerated Vilsboll et al, Sitagliptin Add-on to basal or Patients with T2DM (n=451); Addition of sitagliptin improved 29 2010 premixed insulin vs baseline HbA1c level, glycemic control and was placebo 7.5% to 11% generally well tolerated

Abbreviations: HbA1c, glycated hemoglobin; T2DM, type 2 diabetes mellitus.

Table 2. Case Study Revisited Comparison of Onset, Peak, and Duration of Longer-Acting Basal Harry Follow-Up Harry was presented with options to Basal Insulin Onset Peak Duration help him return to his goal HbA1c level of Neutral protamine 1-2 h 4-8 h 8-12 h 7%. A DPP-4 inhibitor would be a sim- Hagedorn ple treatment option but would not al- Glargine 30-60 min Relatively peakless 16-24 h low him to attain this goal. A successful Detemir 30-60 min Relatively peakless 16-24 h treatment option that could achieve this Degludec 30-90 min Peakless >24 h goal is the addition of prandial insulin injections at mealtimes. Source: Reprinted from Nasrallah SN, Reynolds LR. , the new generation basal insulin or just another basal insulin? Clin Med Insights Endocrinol Diabetes. 2012;5:31-37.38 Copyright 2012, Harry was also concerned about with permission from Libertas Academica Ltd. losing weight, so it was decided to use GLP-1 receptor agonists. Because Har- ry was traveling a great deal and eat- ing at irregular times (usually at a res- taurant), he wanted a simple treatment plan that involved the least number of injections and a medication that did not require strict dosing in relation to meals. Therefore, once-daily liraglutide was se- lected. Liraglutide is administered once daily, without regard to mealtime, but it

S34 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 Brain

Muscle

Liver ↑ Glucose Adipose tissue

↓ Insulin ↓ Native GLP-1 (β cells) ↓ Insulin cells) (β

↑ Glucagon ↓ Pancreas (α cells) (β cells)

Figure 3. Different approaches to enhancing the effects of the naturally occurring incretin hormone—pharmacologic replacement or minimizing degradation.9 Abbreviation: GLP-1, glucagon-like peptide 1.

should be administered at approximate- GLP-1 receptor agonists, the need for using the insulin pen. At that visit, ly the same time each day, if possible. lower doses of insulin has been ob- mild had occurred; however, Short-acting exenatide is administered served. There also is the possibility it abated 3 weeks later. Harry had a twice daily before meals. It should be that patients may transiently eat less if weight loss of 5 lbs, and he noted that noted that the once-weekly formulation nausea is problematic, which may in- his fasting blood glucose level was still of exenatide is not currently approved crease the possibility of insulin-related between 80 and 120 mg/dL. by the US Food and Drug Administra- hypoglycemia developing. Furthermore, The next follow-up visit occurred af- tion (FDA) for use with insulin. by means of mechanisms independent ter Harry had been receiving the new The physician discussed the possi- of adverse gastrointestinal effects, pa- medication for 12 weeks. At that time, bility of nausea occurring in association tients treated with GLP-1 receptor ago- he had lost an additional 4 lbs, and his with initiation of GLP-1 receptor agonist nists experience greater satiety than HbA1c level was 6.8%. therapy. The nausea tends to be mild placebo-treated patients, and their food to moderate and of a transient nature. intake may decrease. Harry was told that if severe nausea or Harry already knew how to use an What Else Is New? abdominal pain were to occur, he would insulin pen delivery device, so he was Ultra-Long-Acting Basal need to call the physician’s office right told to start with a dose of 0.6 mg of Insulin in Development away, because the presence of these insulin given subcutaneously daily. Current research efforts are focusing symptoms might be a sign of a more se- One week later, Harry increased the on improving the and rious condition, such as . insulin dose to 1.2 mg given subcuta- pharmacodynamics of long-acting insu- Harry’s basal insulin dose was re- neously daily. lin analogs to make them even less vari- duced by 20%, from 40 U to 33 U, at A follow-up appointment was sched- able and longer acting (ie, make them night. When basal insulin is used with uled for 6 weeks after Harry started truly once-daily insulin analogs). These

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S35 Table 3. Published Trials of Ultra-Long-Acting Insulins

Insulin Patient Insulin Source Agent Characteristics Comparator Design Outcomes Rosenstock LY2605541 T1DM; basal-bolus Glargine 8-wk randomized, Greater improvements in glycemic et al, 201356 (pegylated therapy phase 2, open-label, control, increased total hypoglycemia, ) 2×2 crossover study reduced nocturnal hypoglycemia, reduced weight, and lowered insulin doses at mealtime

Bergenstal LY2605541 T2DM (HbA1c level Glargine 12-wk, randomized, Comparable glucose control; total et al, 201257 (pegylated ⩽10.5%); metformin open-label, phase 2 hypoglycemia rates, reduced intraday insulin lispro) and/or study variability, and lower nocturnal hypo- with glargine or NPH glycemia, as well as weight loss, insulin once daily relative to glargine

Birkeland Degludec T1DM; mean HbA1c Glargine 16-wk randomized, Comparable glucose control at et al, 201143 level 8.4% phase 2 controlled trial similar doses, with reduced rates of hypoglycemia Heise et al, Degludec/ T2DM; background Glargine 16-wk, open-label trial Comparable glucose control at 201145 aspart metformin therapy similar doses, similar low rates of hypoglycemia, and better glucose control after dinner Zinman et al, Degludec T2DM; background Glargine 1-year treat-to-target, Comparable glucose control, 201250 therapy for OAD; open-label, randomized much lower rates of nocturnal

baseline HbA1c level trial hypoglycemia 7% to 10% Heller et al, Degludec T1DM; basal-bolus Glargine 1-year treat-to-target, Comparable glucose control and 201246 insulin therapy; open-label, randomized much lower rates of nocturnal

HbA1c level ⩽10% trial hypoglycemia Garber et al, Degludec T2DM; basal-bolus Glargine 1-year treat-to-target, Comparable glucose control and 44 2012 insulin; HbA1c level, open-label, randomized much lower rates of overall and 7% to 10% trial nocturnal hypoglycemia

Niskanen Degludec/ T2DM; HbA1c level Biphasic 16-wk, open-label, Comparable glucose control and et al, 201258 aspart (twice 7% to 11% randomized, lower rates of hypoglycemia daily) and an twice daily treat-to-target trial alternative formulation

Abbreviations: HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drugs; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

longer-acting insulin analogs will be analogs at a consistent time each day, reduced risk of hypoglycemia and more more forgiving of the busy schedules of on the basis of their duration of action. convenience for the patient.39,40 patients, because they have little to no Table 2 provides a comparison of the Advances have been made in the impact on glucose levels if there is some pharmacodynamics of longer-acting clinical development of both insulin variation in the time of administration. insulin analogs.38 The goal of ongoing degludec (administered alone or in Optimal glycemic benefits are achieved research is to come close to achieving combination with insulin aspart) and with the injection of current basal insulin glycemic control while benefitting from a pegylated insulin lispro. Insulin de-

S36 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 gludec has been submitted to the FDA tively. Low rates of hypoglycemia were Technosphere insulin (MannKind Cor- for review. This ultra-long-acting basal noted with both regimens. This trial49 poration, Valencia, California), another insulin has a flat and stable glucose- showed that insulin degludec can be inhaled insulin, was compared with sub- lowering effect,41 and it is associated administered at varying times without cutaneous regular human insulin in a with a much lower risk of nocturnal resulting in either a loss of glycemic randomized, open-label study of their hypoglycemia than , as control or the development of hypogly- efficacy and safety in covering prandial has been demonstrated in studies of cemia to accommodate changes in a insulin needs.54,55 Technosphere insulin patients with T1DM and T2DM.42-47 The patient’s daily schedule. substantially improved postprandial glu- pharmacodynamic variability of insulin Another new agent, pegylated in- cose levels and had a more favorable degludec is much lower than that of in- sulin lispro, is currently moving into pharmacodynamic profile than subcuta- sulin glargine.41,48 Insulin degludec has phase 3 of clinical development. This neous regular human insulin. The Tech- received an approvable status from an agent appears to be associated with nosphere insulin system is currently FDA regulatory panel and has been ap- less variability, less nocturnal hypogly- undergoing phase 3 trials. proved for use in Europe. cemia, perhaps slightly more overall All of these efforts illustrate the diffi- Because insulin degludec has a sta- hypoglycemia (which may be related to culty of working with complex proteins, ble and prolonged time-action profile, some dosing and titration issues), and such as hormones, and highlight the coupled with low within-subject variabil- some interesting effects on weight. To successes that have been achieved ity, it allows for more-flexible once-daily my knowledge, few data on this com- with current and emerging formula- dosing. Insulin degludec has a flat and pound have been published in the peer- tions as they continue through the stable glucose-lowering effect that is not reviewed literature to date. approval process. affected by dose.48 This concept was A summary of available data from tested in patients with T2DM participat- clinical trials is shown in Table 3.43-46,50 Oral Insulin ing in a 26-week randomized trial49 in Overall, these exciting developments The physiologic barriers of the gastro- which insulin degludec (administered may be used by physicians to improve intestinal tract pose a major challenge in variable dosing intervals in a flexible glycemic control and to increase pa- for the optimal delivery of any hormone, regimen) was compared with insulin tient acceptance of and adherence to including insulin. Oral insulin would pro- glargine (administered at the same time insulin therapy. vide a convenient method of adminis- each day). Both insulins were added tration, potentially leading to improved to an existing regimen of oral glucose- Inhaled Insulin glycemic control for patients with poor lowering therapy, as in the case study Inhaled insulin has been under devel- adherence to subcutaneous insulin described here, and study patients opment for many years, but a product regimens.2 were titrated to achieve fasting plasma that actually reached market (Exubera, glucose levels of less than 90 mg/dL. an insulin human [recombinant DNA The once-daily regimen of insulin de- origin] inhalation powder; Pfizer, New Conclusion gludec involved a compulsory, rotating York, New York) was eventually with- Development of insulin replacement morning-and-evening schedule of dos- drawn because of poor market up- therapy is ongoing. Physicians need to ing that created 8- to 40-hour dosing take,51 perhaps because of the complex understand the central role of insulin in 52 intervals. From a baseline HbA1c level requirements for its administration. the pathophysiologic profile of diabetes, of 8.4%, HbA1c values were reduced by Other inhaled insulin agents that have how it can be used early or late in the 1.28% and 1.26% with the use of insulin been investigated have been found disease process, and how it comple- degludec and insulin glargine, respec- to produce nocturnal hypoglycemia.53 ments other agents. As more insulin

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S37 products become available, an under- 12. Rodbard HW, Jellinger PS, Davidson JA, 23. Holman RR, Farmer AJ, Davies MJ, et al; et al. Statement by an American Association for the 4-T Study Group. Three-year efficacy standing of the relative characteristics, of Clinical Endocrinologists/American College of complex insulin regimens in type 2 diabetes. benefits, and potential of these agents of Endocrinology consensus panel on type 2 N Engl J Med. 2009;361(18):1736-1747. diabetes mellitus: an algorithm for glycemic 24. Pratley RE, Nauck M, Bailey T, et al; for the in helping us to improve glycemic con- control. Endocr Pract. 2009;15(6):540-559. 1860-LIRA-DDP-4 Study Group. Liraglutide trol in patients currently coping with 13. Rolla AR. 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