Editor’s Note: A correction to this article was published in the July 2013 issue of The Journal of the American Osteopathic Association (2013;113[7]:507). The correction has been incorporated in this online version of the article, Insulin Therapy for Challenging which was posted July 2013. An explanation of the change Patient Cases is available at http://www.jaoa.org/content/113/7/507.2.full. Jay H. Shubrook Jr, DO

From the Ohio University Heritage College of Osteopathic Medicine in Athens.

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 Shubrook receives research support from Eli Lilly and Company and sanofi-aventis US.

Address correspondence to Jay H. Shubrook Jr, DO, Ohio University Heritage College of Osteopathic Medicine, Grosvenor Hall, Initiating and advancing insulin therapy in patients with type 2 Athens, OH 45701-2979. diabetes mellitus can be challenging. However, with the avail- E-mail: [email protected] ability of insulin analogs with more physiologic profiles, and with the initiation of simple insulin regimens (eg, the use of basal insulin administered once daily), an opportunity is created to empower patients to self-titrate their insulin. Self-titration can reduce the burden on the physician as well as improve glycemic control in patients. More options for intensifying insulin now exist, including gradually adding prandial insulin (referred to as a basal “plus” strategy) or using premixed insulin analogs for patients with relatively consistent lifestyles and habits. More-concentrated forms of insulin, such as U-500 insulin, may be helpful for patients requiring very large doses of insulin. The key is to match the insulin regimen to the patient; engage in dialogue to understand the patient’s lifestyle, concerns, and skill sets; and develop, through a shared decision-making process, appropriate individualized treatment recommenda- tions. The present review article focuses on the use of insulin replacement therapy in challenging patient cases.

J Am Osteopath Assoc. 2013;113(4 suppl 2):S17-S28 [Published correction appears in J Am Osteopath Assoc. 2013;113(7):507.]

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S17 pproximately 26 million cal inertia exists with respect to initiating livery device used.13,14 For most patients

people in the United States appropriate insulin therapy in patients whose HbA1c levels are not at goal, the Ahave diabetes, and the vast with T2DM.10 The present article will ex- simplest first step is to start insulin ther- majority have type 2 diabetes mellitus plore some challenging cases for which apy with a single injection of a long-act- (T2DM).1 Even with the establishment the use of insulin is indicated, initiated, ing basal insulin analog.9 Basal insulin of treatment goals and the development and adjusted, albeit not always with im- suppresses hepatic glucose production of considerable advancements in dia- mediate patient acceptance. overnight and between meals. It con- betes treatment,2 inadequate metabolic stitutes approximately 50% of the daily control is pervasive.3-5 The proportion insulin needs of an individual.9 Once- of patients with glycated hemoglobin General Principles daily use of a basal insulin analog (insu- 9 (HbA1c) levels that are at goal is still well Since 2012, treatment algorithms for lin glargine or insulin detemir) offers the below the diabetes indicators discussed the management of patients with T2DM advantages of simple dosing and ease in the Healthy People 2020 initiative.6 have followed the approach to pa- of titration (ie, patients can learn to man- Available data show that many patients tient-centered care established by the age their T2DM with limited training).15-18 with T2DM still have poor glycemic Committee on Quality of Health Care This treatment is highly effective in im- control along with comorbid conditions in America: “providing care that is re- proving glycemic control in patients who that may complicate treatment deci- spectful of and responsive to individual no longer respond to combination oral sions. These conditions include a high patient preferences, needs, and values antidiabetic therapy.13 The goal of basal prevalence of hypertension, heart fail- and ensuring that patient values guide insulin analog therapy is to improve fast- ure, stroke, and nephropathy, as well all clinical decisions.”11 Diabetes man- ing blood glucose levels. Typical starting as other comorbidities associated with agement includes the setting of individu- doses are 10 to 20 U of insulin glargine 7 T2DM. When glycemic control is not alized glucose targets to achieve HbA1c or insulin detemir given once daily (or, optimized, diabetes imposes burden- levels as close to normal as possible in as an alternative, 0.2 U/kg).9 Neutral some care requirements, increased patients who are most likely to benefit protamine Hagedorn (NPH) insulin can health care costs, and a high risk of from good glycemic control (ie, those be a more economical option, but physi- disabling complications.1 These situa- without clinical evidence of macrovas- cians should be aware that NPH insulin tions are especially evident in socioeco- cular complications) while also minimiz- is more of an intermediate-acting insulin nomically disadvantaged and minority ing the possible risks of hypoglycemia. It and that it therefore must be dosed 2 to populations, who are already at higher also includes relaxing targets in patients 3 times per day to serve as a basal in- risk for diabetes. Achieving reductions with limited life expectancy, in patients sulin. Physicians should also be aware

in HbA1c levels through a combination with existing diabetes complications or that NPH insulin is associated with a of clinical management and effective longer duration of disease, and in those greater risk of hypoglycemia, especially self-management has demonstrated a for whom there is greater concern about nocturnal hypoglycemia, than are basal reduced risk of microvascular complica- the development of hypoglycemia.10,12 insulin analogs.19 tions.8 More personalized approaches Oral antidiabetic agents are usually to therapy are needed.8 continued when insulin is started, un- Despite the well-documented ben- Initiation of Insulin Therapy less there are specific contraindications efits of both timely glycemic control and When prescribing insulin therapy, the or substantial risks of hypoglycemia (in consensus guidelines that encourage astute osteopathic physician imple- some cases, the dose of sulfonylureas the therapeutic use of insulin earlier in ments the most appropriate form on the may be decreased or discontinued).9 the course of T2DM,9 considerable clini- basis of the insulin type, dose, and de- This continuance of therapy helps pa-

S18 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 tients avoid the loss of further glycemic is not currently approved by the US ment are paramount. The body may re- control during the transition to insulin. Food and Drug Administration for use spond to extremely low nocturnal blood The insulin dose should be titrated on with insulin therapy. glucose levels by rebounding with high the basis of a fasting blood glucose tar- blood glucose levels in the morning (re- get. The American Diabetes Association ferred to as the Somogyi effect). This recommends a goal of less than 130 mg/ Proactively Addressing rebound could be incorrectly identified dL.20 A patient should expect an approxi- Hypoglycemia as fasting hyperglycemia. Both the pa- mately 0.5% decrease in the HbA1c level Hypoglycemia has always been the tient and the physician should routinely for each insulin dose increment of 0.1 U/ rate-limiting step in achieving perfect review blood glucose patterns. Patients kg per day. Basal insulins can be self- glycemic control for patients with T2DM. with type 1 diabetes mellitus, as well titrated up to either a target fasting blood Hypoglycemia can be dangerous, and as those with T2DM of long duration, glucose level or an approximate dose assessing patients for this condition is may be at risk of hypoglycemia. With of 0.5 U/kg per day. At higher doses, critically important. For patients, a fear increasing age, the potential reaction the improvement in the decrease in the of hypoglycemia can often have a con- time between awareness and onset of

HbA1c level is less substantial, and the siderable negative impact on diabetes symptoms is decreased, contributing risk of hypoglycemia increases.21 If, after management, metabolic control, and to an increased risk for asymptomatic

23 sufficient time, the HbA1c level still has subsequent health outcomes. Not hypoglycemia and greater susceptibility not reached goal with the use of 0.5 U of performing this assessment may result to cognitive impairment.25,26 Recurrent, basal insulin per kilogram per day, then in patients taking such actions as en- unrecognized hypoglycemia can occur attention should be focused on meal- gaging in “defensive” eating or omitting even in patients with T2DM who have time or prandial glucose excursions. If insulin doses to preclude hypoglycemia, well-controlled glycemia.27 Asymptom- excursions are present, consider adding thus thwarting the best efforts of the atic hypoglycemia and nocturnal hy- an agent to target postprandial hyper- physician to help patients achieve gly- poglycemia can interfere with the abil- glycemia, which is the likely cause of cemic control. This behavior becomes ity of patients to recognize subsequent persistent hyperglycemia. This can be particularly dangerous if the physician hypoglycemia, and they can also limit confirmed by having the patient check is titrating insulin regimens. patients’ ability to take appropriate ac- his or her glucose level 2 hours after the Failure to address even mild hypo- tion, thereby exacerbating the situation. meal.22 A number of options exist for the glycemia and glycemic control early in This outcome, known as hypoglycemic treatment of prandial hyperglycemia, in- the course of T2DM may compromise unawareness, is a marker of a high risk cluding prandial insulin (eg, a fast-acting the success of treatment in the long of severe hypoglycemia. insulin or rapid-acting insulin analog, term.24 Fear of hypoglycemia certainly Furthermore, high glucose variabil- such as insulin lispro, insulin aspart, or affects the willingness of the patient to ity (blood glucose excursions occurring insulin glulisine) or an incretin-based accept insulin therapy, so it is vital to throughout the day) may be a predictor therapy (eg, a dipeptidyl peptidase-4 choose regimens carefully and to ad- of diabetic complications, independent 28 [DPP-4] inhibitor [such as sitagliptin, dress this topic with patients. Some of HbA1c levels, in patients with T2DM. saxagliptin, or linagliptin] or a glucagon- hypoglycemia may occur in associa- As a result, because patients fear like peptide-1 [GLP-1] receptor agonist tion with insulin therapy, even when the hypoglycemia, they may be reluctant to [such as exenatide (administered twice most skilled physicians and knowledge- follow or adjust their insulin regimens per day), liraglutide (administered once able patients are involved in its use. when needed. This lack of action may per day), or exenatide (administered Thus, identifying hypoglycemia and result in chronic hyperglycemia, oxida- weekly)]). Exenatide extended release providing prompt, appropriate treat- tive stress, and the risk of long-term

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S19 complications.29 Better daily control of currently taking 1000 mg of metformin for the basal insulin, insulin glargine, blood glucose excursions, especially twice daily and 10 mg of glipizide twice indicates that it may be given either in

in the postprandial period, may re- daily. Her current HbA1c level is 10.8%. the morning or evening, insulin detemir duce glucose variability in patients with Edith checks her fasting blood glucose indications are for administration in the T2DM30 and may also reduce the risk of level every morning. She has a history evening only. In clinical practice, both complications. of OA and hypertension and has under- insulin analogs can be given at any time gone percutaneous transluminal coro- of day. If nocturnal hypoglycemia is the nary angioplasty. She reports wanting major concern, a basal insulin analog Intensifying Therapy to be more active. can be administered in the morning; this For patients who require intensification may be an off-label use, but it will allow of insulin therapy,31 strategies may in- Assessment the physician and the patient to become clude sequentially adding prandial in- Edith has uncontrolled T2DM and is comfortable with the dosing and titra- sulin doses and then switching to pre- likely to have comorbidities. Her renal tion of the insulin. In setting a treatment mixed insulin (which provides basal function should be checked. (Older pa- goal for Edith, it is noted that her current

and prandial insulin in a single injection, tients and those with elevated HbA1c HbA1c level is 10.8%. Insulin is very ef- albeit in a fixed-dose ratio) or full basal- levels are at greater risk for evidence of fective at lowering blood glucose levels, bolus dosing (which involves multiple renal impairment,35 which may influence with its dose limited only by hypoglyce- daily injections of insulin).9,21,32 Patients the approach to antihyperglycemic ther- mia. However, that is a strong caveat who have severe insulin resistance (eg, apy.36) Edith’s serum creatinine level is to consider, especially in an older pa- those who require more than 200 U of 1.2 mg/dL; however, her glomerular fil- tient. Increased age and impaired renal insulin)33 may benefit from receiving tration rate is 65 mL/min/1.73 m2. function are considered risk factors for concentrated insulin formulations (eg, hypoglycemia.37 500 U/mL, as opposed to 100 U/mL for Considerations and most insulins).33 Providing very large Precautions Related to Considerations for doses of less concentrated insulin may Antihyperglycemic Agents Diabetes of Long Duration result in difficulties with reliable insulin Metformin should be avoided if Edith’s The diabetes guidelines from the US absorption because of simple volume serum creatinine level is 1.4 mg/dL or Department of Veterans Affairs and the problems. higher (a serum creatinine level of ⩾1.5 US Department of Defense (VA/DoD) mg/dL is the cutoff for men). Because of were updated in 2010. As with other the risk of hypoglycemia, sulfonylureas guidelines, the VA/DoD guidelines do Case Study: Edith should be used cautiously in patients not distinguish treatment goals by age Edith, a 74-year-old African American with renal impairment. If a sulfonylurea group. However, they do provide some woman (weight, 100 kg), presents with is used, glipizide is preferred because guidance that may be applicable to this substantial osteoarthritis (OA) of the hip of its route of excretion. If insulin is cho- case study: “for the patient with longer that requires total hip replacement. Her sen—which is likely because Edith’s duration diabetes (more than 10 years) surgeon has reported that he will not blood glucose level needs to be low- or with comorbid conditions and who operate until Edith’s diabetes is better ered expeditiously before her opera- requires a combination medication regi- controlled. Edith has T2DM of 10 years’ tion—more modest dosing and the use men including insulin should have an duration. Although her T2DM initially of insulin analogs are warranted to mini- A1C target of <8%.”38(p46) If following had been controlled through lifestyle mize the risks of nocturnal hypoglyce- these guidelines, physicians may set changes and metformin therapy, she is mia. Whereas prescribing information one goal for the preoperative period and

S20 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 another goal for the postoperative pe- Table 1. riod, depending on how successful the Physician-Directed or Patient-Driven Treat-to-Target Titration Algorithms operation is and when more time might for Basal Insulin Analogs be available to titrate insulin therapy. Mean of Self- Change in Insulin Dose, U/d Monitored FPG Physician Patient Self-Titration of Insulin Study Values,a mg/dL General Directed Managed by Patients Riddle et al39 ⩾180 +8 NA NA Patients can safely and effectively self- 140-180 +6 NA NA titrate basal insulin by using one of 120-140 +4 NA NA several physician-directed or patient- 100-120 +2 NA NA driven treat-to-target titration algorithms Davies et al40 ⩾180 NA +6 to +8 +2 (Table 1).39-41 Prescribing information 140-179 NA +4 +2 suggests a starting dose of 10 U of a 120-139 NA +2 +2 basal insulin analog. This dose may 100-119 NA 0 to +2 0 to +2 frustrate patients with T2DM, who may Meneghini et al41 >110 +3 NA NA be insulin resistant and overweight. 80-110 0 NA NA For patients with T2DM, it may make <80 −3 NA NA more sense to refer to the guidelines a Means were calculated from data obtained on 2 successive days for Riddle et al39 and from data obtained of the American Diabetes Association, on 3 successive days for Davies et al40 and Meneghini et al.41 which recommend starting basal insulin Abbreviations: FPG, fasting plasma glucose; NA, not applicable. therapy at a dose of 0.2 U/kg.9 Self-titra- tion empowers patients to be involved in their therapy, allows for more rapid any signs or symptoms of hypoglyce- men consists of 1000 mg of metformin adjustments of insulin than do visits to mia. Her blood glucose data logs show twice daily and 10 mg of glipizide twice the physician’s office, and reduces the improvements not only in her fasting daily; she also takes 62 U of basal insu- burden on the physician. The insulin glucose levels but also in her postpran- lin analog once daily. dose should be titrated on the basis of dial glucose levels (Table 2). Evidence of documented hypoglyce- the fasting blood glucose level noted In this case study, Edith under- mia exists, as do signs of increased glu- before breakfast. The target is a fast- goes the operation and rehabilitation cose variability in the aforementioned ing blood glucose level below 130 mg/ and then resumes walking. When she patterns. The basal insulin analogs have dL.20 Continuation of oral antidiabetic returns to the physician’s office, her stable profiles, and patients who are re- drugs is typical unless there is a spe- HbA1c level is 6.4%. Edith now checks ceiving stable doses should have stable cific contraindication. These drugs can her glucose levels only in the morning glucose profiles. Edith, however, is ex- be reduced or eliminated once glucose and whenever she feels like her blood periencing a lot of glucose variability in control is improving, but it is always bet- glucose levels are low (Table 3), which her morning blood glucose level. Her ter to add to therapy when the patient sometimes occurs when she is “out and blood glucose levels may be decreasing has hyperglycemia. about.” She carries food with her, “just during the night and then rebounding Edith starts receiving 20 U of a basal in case.” If Edith experiences “low blood with hyperglycemia in the morning (the insulin analog in the morning. She is al- sugar,” she sometimes decides to skip Somogyi effect). Edith’s lifestyle is now lowed to self-titrate but is advised to call her insulin dose the next day. Her cur- limited by hypoglycemia; she is experi- the physician’s office if she experiences rent antihyperglycemic medication regi- encing symptoms, eating defensively,

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S21 skipping insulin doses, and possibly ex- most occurrences of hypoglycemia in cemia than are younger patients with periencing hypoglycemia without being people without diabetes or in individu- T2DM (Figure 1).25,26 aware of it. Table 442 summarizes the als with T2DM of limited duration. If the signs and symptoms of hypoglycemia, blood glucose levels continue to drop Medication Adjustment whereas Table 542 shows the physi- after suppression of insulin and secre- Concerns about hypoglycemia are dis- ologic responses to hypoglycemia. At tion of glucagon, then release of epi- cussed with Edith, and it is agreed that Edith’s age, and with her lifestyle-limit- nephrine, cortisol, and growth hormone the glipizide dose will be reduced to ing symptoms, the most important step will follow. At even lower blood glucose 10 mg given once daily, and the basal is to address her hypoglycemia. levels, defensive eating is observed as insulin analog dose is reduced to 52 It is very important to educate pa- a response. U. She is asked to send in her blood tients about the signs and symptoms Patients with type 1 diabetes mel- glucose readings 2 weeks after mak- of hypoglycemia. The body has mul- litus are missing the 2 aforementioned ing this medication adjustment. At that tiple defenses with which to prevent lines of defense, which is why they are time, her morning blood glucose level is hypoglycemia, but age and a history more prone to hypoglycemia than are more stable, and the hypoglycemia has of hypoglycemia can affect the body’s patients with T2DM. However, by the stopped. Edith says that she notices hypoglycemic threshold for symptoms time patients with T2DM require insu- that she needs to eat snacks a lot less and when it can respond. The first line lin, they are physiologically similar to often. of defense is suppression of insulin pro- patients with type 1 diabetes mellitus. Six months later, Edith’s fasting blood duction; the second is increased gluca- These patients with T2DM of longer glucose levels are at goal (Table 6),

gon secretion. These 2 steps prevent duration are at greater risk for hypogly- but her HbA1c level is elevated, suggest-

Men aged 23 (2) y (n=7) Men aged 65 (3) y (n=7) 72 72 Hypoglycemic awareness

63 63 Hypoglycemic Greater reaction time awareness for corrective action Less reaction time 54 54 for corrective action Onset of cognitive dysfunction 45 Onset of 45 cognitive dysfunction Blood Glucose Concentration, mg/dL Blood Glucose Concentration, mg/dL 36 36

Figure 1. Thresholds for symptomatic hypoglycemia vary with age. With increasing age, the potential reaction time between awareness and onset of symptoms is decreased, contributing to an increased risk for asymptomatic hypoglycemia and a greater susceptibility to cognitive impairment. Age designations are presented as mean [standard deviation] years. Data are for nondiabetic patients with no family history of diabetes.25,26 Reprinted with permission from the American Diabetes Association, from Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care. 2005;28(12):2948-2961 and from Matyka K et al. Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men. Diabetes Care. 1997;20(2):135-141; permission conveyed through Copyright Clearance Center, Inc.

S22 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 Table 2. short-acting and long-acting insulins. Glucose Diaries: Edith’s Preoperative Blood Glucose Levels People who have erratic daily sched- With Addition of Basal Analog Insulin ules and mealtimes or people who skip Blood Glucose Levels, mg/dL meals would not be good candidates for Week Mon Tue Wed Thu Fri Sat Sun premixed insulin regimens. Regarding premixed insulin, it is also important to 1 differentiate between the human and Morning 240 242 210 160 188 160 164 the analog formulations available. The Evening 240 286 200 268 200 168 240 pharmacokinetics are remarkably differ- 2 ent because the short-acting insulin in Morning 148 140 140 128 120 122 114 the human formulation is regular insu- Evening ... 154 ... 158 ... 148 ... lin, which has a very different pattern of action than the rapid-acting analog insu- lins (insulin aspart and insulin lispro) in ing that postprandial hyperglycemia or switch to a premixed insulin analog the analog formulations. may be the cause. Increasing the sul- by dividing the total basal dose in half Given Edith’s history, a single dose fonylurea dose will not correct the situ- and administering it twice daily before of prandial insulin is added before her ation and may even increase the risk of breakfast and dinner.32,44 Ideally, the pa- largest meal; she is asked to check pre- hypoglycemia. It is time to consider in- tient should have a regular, stable, daily prandial and postprandial glucose lev- tensifying the insulin therapy. treatment schedule to minimize the risk els at dinner (her biggest meal) and to of hypoglycemia resulting from these check her morning glucose levels less Prandial Correction Insulin fixed-dose products. Concern sur- often. We reduce her basal analog in- Several options are available for in- rounds the low levels of blood glucose sulin dose and discuss her sending in troducing prandial correction insulin, noted at 3 to 5 hours after injection, monthly readings to help with titration including adding a single injection of when there is overlap in the action of the of her therapy. With her age and need prandial insulin to the largest meal or the meal with the highest postmeal glucose level (a basal “plus” strategy), Basal providing basal-bolus insulin (in multiple daily injections), or using premixed insu- lin (which provides basal and prandial insulin in a single injection). The basal Basal “Plus” (plus a shot of mealtime insulin) “plus” strategy can be used to transition to the use of basal-bolus insulin (Fig-

ure 2). When the patient’s HbA1c level is not at goal after 1 injection of basal insu-

lin analog, options include adding a rap- Basal-bolus id-acting insulin analog before meals. If this is done, then the physician should subtract 10% of the basal dose and Figure 2. add that amount to the largest meal,43 Strategy for switching from basal to basal-bolus insulin.

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S23 for insulin at mealtime, it appears that Table 3. Glucose Diaries: Edith’s Postoperative Blood Glucose Levelsa Edith is no longer responding to the sul-

fonylurea, so it will be removed as part Blood Glucose Levels, mg/dL of her titration. One month later, she is Week Mon Tue Wed Thu Fri Sat Sun taking 46 U of basal insulin and 6 U of a 1 rapid-acting insulin analog at dinner. We Morning 110 180 80 106 162 78 102 then stop the glipizide and increase her Evening 64 146 ... 56 144 ...... insulin dose at mealtime to 12 U. After 220 ...... 182 ...... another month, we reduce her basal in- 2 sulin because she has further increased Morning 126 140 148 70 110 102 56 her activity level. With increased activ- Evening 66 112 120 72 116 120 ... ity, and with less snacking caused by 204 ...... 84 128 146 ... defensive eating, Edith has lost 10 lbs ...... 188 ...... and is feeling good about her progress

a Edith checks her glucose levels in the morning and whenever she feels that her glucose levels are low. (Table 7). Edith is taking metformin (1000 mg twice daily), a basal insulin analog (40 U) in the morning, and a Table 4. rapid-acting insulin analog (12 U) be- Signs and Symptoms of Hypoglycemia42 fore dinner. Edith is so pleased with her

Adrenergic Cholinergic Neuroglycopenic results that she refers her son, William.

Palpitations Sweating Confusion Anxiety Hunger Decreased senses Tremulousness Paresthesias Behavior changes Case Study: William William is a 52-year-old man who works Irritability Lethargy as an accountant. He has had diabetes Seizures mellitus for 15 years, and his current Coma

HbA1c level is 9.6%. William takes 80 U of basal insulin analog twice daily. He

Table 5. also takes 10 U of rapid-acting insulin 42 Physiologic Response to Hypoglycemia at meals, when he remembers to do so; he takes it, on average, twice daily. His Glucose Level, mg/dL Response Result blood glucose levels are not low. William

80-85 Suppression of insulin Primary defense—stops also has hypertension, dyslipidemia, secretion most hypoglycemia and obstructive sleep apnea (OSA). 65-70 Increased glucagon secretion Primary counter-regulatory response The Challenge of 55-65 Increase in cortisol and Slower system: minor role the “Diabetes Belt” growth hormone Localized predominantly in the south- 50-55 Hunger Increase in exogenous glucose ern states and Appalachia, the “Dia- <50 Neuroglycopenic signs Compromises further betes Belt” is an area of the United and symptoms responses States where the incidence of diabe-

S24 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 tes is 11.7%, compared with the 8.7% incidence in the rest of the country (Figure 3).45 Nearly one-third of the in- creased risk of diabetes among individ- uals in the Diabetes Belt is associated with a sedentary lifestyle and obesity.46 There also are more African Americans with diabetes in the Diabetes Belt than in other areas of the United States. Wil- liam shares some of the characteristics of individuals from the Diabetes Belt (Figure 4).46 He also has OSA, which is Prevalence of Population another common comorbidity of T2DM. With Diagnosed Diabetes Primary care providers tend to underdi- Diabetes belt: 11.7% agnose OSA in patients with T2DM,47 so Rest of the United States: 8.5% William’s OSA is something to consider.

Figure 3. Poor Glycemic Control in the The “Diabetes Belt,” which consists of the southern Face of High Insulin Doses United States and Appalachian regions. Reprinted from the Centers for Disease Control and Prevention website.45 Physicians should always remember to confirm treatment adherence in pa- tients who experience poor glycemic control while ostensibly receiving very Diabetes belt high doses of insulin therapy. Inspection of injection sites and review of injection Rest of the United States technique are also important, because 30 injection-related problems have been known to affect glycemic control. Many patients will develop changes in the 20 subcutaneous tissue, including lipohy- pertrophy or lipoatrophy. This scarring 10 or dimpling of the skin will also affect Prevalence, % insulin absorption. Check to make sure that insulin is not expired or denatured. 0 In William’s case, he had many vials of African American Obesity Sedentary “used” insulin in his house; many vials Lifestyle were not dated when he started to use Figure 4. them, and some had clearly expired. In Characteristics of individuals in the Diabetes Belt.46 addition, it should be noted that large doses of insulin may produce a depot effect (albeit less so with analog insulin)

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S25 52 Table 6. receptor, or obesity. U-500 insulin is Glucose Diaries: Edith’s Blood Glucose Levels also very helpful for people who need 6 Months After the Operationa more than 300 U of insulin per day and Blood Glucose Levels, mg/dL still have uncontrolled hyperglycemia. Time Mon Tue Wed Thu Fri Sat Sun U-500 is a human regular insulin, but Morning 120 130 125 135 120 120 125 its time-action profile is not the same as Random 180 160 ... 280 160 240 ... that of the usual U-100 formulation. It has the same peak as U-100 regular in- 220 ...... 220 ...... sulin, but its duration is more like that of a Edith’s glycated hemoglobin level is 8.5%. She checks her glucose levels NPH insulin (approximately 12 h). Given in the morning and whenever she feels that her glucose levels are low. these characteristics, U-500 works as both basal and prandial (bolus) insulin, so patients who use it not only take less insulin by volume, but they also typically Table 7. Glucose Diaries: Edith’s Blood Glucose Levels need only one type of insulin. The use of 12 Months After the Operationa U-500 insulin has also been associated Blood Glucose Levels, mg/dL with increased patient satisfaction and 34 Time Mon Tue Wed Thu Fri Sat Sun cost savings. U-500 insulin is 5 times as potent Morning 120 ... 125 ... 120 ... 105 as U-100 insulin. When converting Postprandial ... 135 ... 140 ... 160 ... U-100 insulin dosing to U-500 dosing,

a Edith’s glycated hemoglobin level is 6.7%. She checks her glucose levels intermittently. if the total daily insulin dose is less than 200 U, first divide by 5 and then split to twice-daily dosing (with 60% of the and may be associated with unpredict- that clinicians should be aware of is the total daily dose given before the morn- able absorption.48 It is more likely that use of U-500 insulin (Humulin R U-500; ing meal and 40% given before the William was not actually absorbing the Eli Lilly and Company, Indianapolis, evening meal). If the total daily dose is full dose of insulin that he was injecting. Indiana), which substantially reduces more than 200 U, first divide by 5 and the volume of insulin to be injected.49 then use thrice-daily dosing (at break- U-500 Insulin Obese patients with uncontrolled T2DM fast, lunch, and bedtime). In William’s Some patients with T2DM are pro- who are severely insulin resistant can case, he takes a total of 180 U per day; foundly insulin resistant and require achieve satisfactory glycemic control because 180 U÷5=36 U, William can very large doses of insulin for glycemic with the use of U-500 regular insu- take 22 U before breakfast and 14 U be- control. Large volumes of subcutane- lin administered either by subcutane- fore dinner. This allows William to obtain ous conventional U-100 insulin can ous injection or via insulin pump.33,50,51 insulin coverage with only 2 injections. cause discomfort at the injection site, Candidates for U-500 insulin include This dosing provides a less physiologic resulting in poor patient adherence to patients who have immune-mediated profile than what William was previously insulin therapy. Furthermore, the depot insulin resistance, lipoatrophic diabetes, taking, but he shows increased adher- effect may change insulin absorption as antibodies against the insulin recep- ence with this treatment and improves mentioned above. A therapeutic option tor, genetic abnormalities of the insulin his glycemic control.

S26 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 References 12. Skyler JS, Bergenstal R, Bonow RO, et al. Conclusion Intensive glycemic control and the prevention Insulin remains our most effective agent 1. Centers for Disease Control and Prevention. of cardiovascular events: implications of the National Diabetes Fact Sheet: National ACCORD, ADVANCE, and VA diabetes trials: for lowering blood glucose levels. Insu- Estimates and General Information on a position statement of the American Diabetes lin formulations continue to be devel- Diabetes and Prediabetes in the United States, Association and a scientific statement of the 2011. Atlanta, GA: US Dept of Health and American College of Cardiology Foundation and oped and refined, and they will likely Human Services, Centers for Disease Control the American Heart Association. Diabetes Care. continue to be essential in the manage- and Prevention; 2011. http://www.cdc.gov 2009;32(1):187-192. /diabetes/pubs/pdf/ndfs_2011.pdf. ment of T2DM. Physicians should feel Accessed February 14, 2013. 13. Rolla AR. Starting insulin strategies for patients with an inadequate response to oral therapy. comfortable initiating insulin therapy at 2. American Diabetes Association. Standards of Diabetes Obes Metab. 2009;11(suppl 5):6-9. medical care in diabetes—2013. Diabetes Care. any stage of T2DM, and they should 2013;36(suppl 1):S11-S66. 14. Lavernia F. What options are available be able to teach patients to self-titrate when considering starting insulin: premix 3. Dodd AH, Colby MS, Boye KS, Fahlman C, Kim or basal? Diabetes Technol Ther. their insulin. Insulin therapy should be S, Briefel RR. Treatment approach and HbA1c 2011;13(suppl 1):S85-S92. control among US adults with type 2 diabetes: intensified in a patient-centric fashion, NHANES 1999-2004. Curr Med Res Opin. 15. Davies M, Storms F, Shutler S, Bianchi-Biscay using the method that best fits each pa- 2009;25(7):1605-1613. M, Gomis R; for the ATLANTUS Study Group. Improvement of glycemic control in subjects with tient’s profile, including adding prandial 4. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. poorly controlled type 2 diabetes: comparison of Is glycemic control improving in U.S. adults? two treatment algorithms using insulin glargine. insulin, using full basal-bolus therapy, Diabetes Care. 2008;31(1):81-86. Diabetes Care. 2005;28(6):1282-1288. switching to premixed insulin therapy, 5. Miech RA, Kim J, McConnell C, Hamman RF. 16. Meneghini L, Koenen C, Weng W, Selam JL. or using more-concentrated insulin for- A growing disparity in diabetes-related mortality The usage of a simplified self-titration dosing U.S. trends, 1989-2005. Am J Prev Med. guideline (303 Algorithm) for insulin detemir in mulations. It is beneficial for patients to 2009;36(2):126-132. patients with type 2 diabetes—results of the randomized, controlled PREDICTIVE 303 study. titrate insulin themselves, using param- 6. HealthyPeople 2020 summary of objectives: Diabetes Obes Metab. 2007;9(6):902-913. eters that let them know what dose or diabetes. US Dept of Health and Human Services website. http://www.healthypeople 17. Selam JL, Koenen C, Weng W, Meneghini L. events signal the need to stop titration. .gov/2020/topicsobjectives2020/pdfs Improving glycemic control with insulin detemir /Diabetes.pdf. Updated October 20, 2012. Glucose variability and hypoglycemia using the 303 Algorithm in insulin naïve patients Accessed February 18, 2013. with type 2 diabetes: a subgroup analysis of the are unexpected and warrant a call to the US PREDICTIVE 303 study. Curr Med Res Opin. 7. Shaya FT, Yan X, Lin PJ, et al. US trends in 2008;24(1):11-20. physician. By increasing patient levels glycemic control, treatment, and comorbidity burden in patients with diabetes. J Clin of comfort with regard to insulin therapy, 18. Blonde L, Merilainen M, Karwe V, Raskin Hypertens (Greenwich). 2010;12(10):826-832. P; for the TITRATE Study Group. Patient- directed titration for achieving glycaemic goals improved rates of glycemic control can 8. Fradkin JE. Confronting the urgent challenge using a once-daily basal insulin analogue: an of diabetes: an overview. Health Aff (Millwood). be achieved. assessment of two different fasting plasma 2012;31(1):12-19. glucose targets—the TITRATE study. Diabetes 9. Inzucchi SE, Bergenstal RM, Buse JB, Obes Metab. 2009;11(6):623-631. et al. Management of hyperglycemia in type 2 19. Hirsch IB. Insulin analogues. N Engl J Med. diabetes: a patient-centered approach. Position 2005;352(2):174-183. statement of the American Diabetes Association (ADA) and the European Association for the 20. American Diabetes Association. Standards of Study of Diabetes (EASD). Diabetes Care. medical care in diabetes—2012. Diabetes Care. 2012;35(6):1364-1379. 2012;35(suppl 1):S11-S66.

10. Handelsman Y, Mechanick JI, Blonde L, 21. Monnier L, Colette C. Addition of rapid-acting et al; for the AACE Task Force for Developing insulin to basal insulin therapy in type 2 diabetes: Diabetes Comprehensive Care Plan. American indications and modalities. Diabetes Metab. Association of Clinical Endocrinologists Medical 2006;32(1):7-13. Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. 22. Monnier L, Lapinski H, Colette C. Contributions Endocr Pract. 2011;17(suppl 2):1-53. of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia 11. Committee on Quality of Health Care in America, of type 2 diabetic patients: variations with Institute of Medicine. Crossing the Quality increasing levels of HbA(1c). Diabetes Care. Chasm: A New Health System for the 21st 2003;26(3):881-885. Century. Washington, DC: National Academy Press; 2001:40.

A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 S27 23. Wild D, von Maltzahn R, Brohan E, Christensen 35. Bash LD, Selvin E, Steffes M, Coresh J, 45. Centers for Disease Control and Prevention. T, Clauson P, Gonder-Frederick L. A critical Astor BC. Poor glycemic control in diabetes Behavioral Risk Factor Surveillance System review of the literature on fear of hypoglycemia and the risk of incident chronic kidney Survey Data. Atlanta, GA: US Dept of in diabetes: implications for diabetes disease even in the absence of albuminuria Health and Human Services, Centers for management and patient education. and retinopathy: Atherosclerosis Risk in Disease Control and Prevention; 2009. Patient Educ Couns. 2007;68(1):10-15. Communities (ARIC) Study. Arch Intern Med. http://apps.nccd.cdc.gov/brfsslistasp?cat 2008;168(22):2440-2447. =DB&yr=2009&qkey=1363&state=All. 24. Barnett AH. Avoiding hypoglycaemia while Accessed February 22, 2013. achieving good glycaemic control in type 2 36. Fonseca VA. Incretin-based therapies in diabetes through optimal use of oral agent complex patients: practical implications and 46. Barker LE, Kirtland KA, Gregg EW, Geiss therapy. Curr Med Res Opin. opportunities for maximizing clinical outcomes: LS, Thompson TJ. Geographic distribution of 2010;26(6):1333-1342. a discussion with Dr. Vivian A. Fonseca. diagnosed diabetes in the U.S.: a diabetes belt. Am J Med. Jan 2011;124(1 suppl):S54-S61. Am J Prev Med. 2011;40(4):434-439. 25. Zammitt NN, Frier BM. Hypoglycemia in type 2 diabetes: pathophysiology, frequency, 37. Farrokhi F, Klindukhova O, Chandra P, et al. 47. Heffner JE, Rozenfeld Y, Kai M, Stephens EA, and effects of different treatment modalities. Risk factors for inpatient hypoglycemia during Brown LK. Prevalence of diagnosed sleep apnea Diabetes Care. 2005;28(12):2948-2961. subcutaneous insulin therapy in non-critically among patients with type 2 diabetes in primary ill patients with type 2 diabetes. J Diabetes Sci care. Chest. 2012;141(6):1414-1421. 26. Matyka K, Evans M, Lomas J, Cranston I, Technol. 2012;6(5):1022-1029. Macdonald I, Amiel SA. Altered hierarchy 48. Tibaldi JM. Evolution of insulin development: of protective responses against severe 38. United States Department of Veterans Affairs. focus on key parameters. Adv Ther. hypoglycemia in normal aging in healthy men. VA/DoD Clincal Practice Guideline for the 2012;29(7):590-619. Diabetes Care. 1997;20(2):135-141. Management of Diabetes Mellitus. Washington, 49. Crasto W, Jarvis J, Hackett E, et al. DC: US Department of Veterans Affairs; 2010. 27. Weber KK, Lohmann T, Busch K, Insulin U-500 in severe insulin resistance http://www.healthquality.va.gov/diabetes Donati-Hirsch I, Riel R. High frequency of in type 2 diabetes mellitus. _mellitus.asp. Accessed February 14, 2013. unrecognized hypoglycaemias in patients with Postgrad Med J. 2009;85(1002):219-222. Type 2 diabetes is discovered by continuous 39. Riddle MC, Rosenstock J, Gerich J. 50. Lane WS, Cochran EK, Jackson JA, et al. glucose monitoring. Exp Clin Endocrinol The treat-to-target trial: randomized addition High-dose insulin therapy: is it time for U-500 Diabetes. 2007;115(8):491-494. of glargine or human NPH insulin to oral therapy insulin? Endocr Pract. 2009;15(1):71-79. of type 2 diabetic patients. Diabetes Care. 28. Nalysnyk L, Hernandez-Medina M, 2003;26(11):3080-3086. 51. Lane WS. Use of U-500 regular insulin by Krishnarajah G. Glycaemic variability and continuous subcutaneous insulin infusion in complications in patients with diabetes mellitus: 40. Davies M, Lavalle-Gonzalez F, Storms F, patients with type 2 diabetes and severe insulin evidence from a systematic review of the Gomis R. Initiation of insulin glargine therapy resistance. Endocr Pract. 2006;12(3):251-256. literature. Diabetes Obes Metab. in type 2 diabetes subjects suboptimally 2010;12(4):288-298. controlled on oral antidiabetic agents: results 52. Ballani P, Tran MT, Navar MD, Davidson MB. from the AT.LANTUS trial. Diabetes Obes Clinical experience with U-500 regular insulin 29. Unger J, Parkin C. Recognition, prevention, Metab. 2008;10(5):387-399. in obese, markedly insulin-resistant and proactive management of hypoglycemia type 2 diabetic patients. Diabetes Care. in patients with type 1 diabetes mellitus. 41. Meneghini L, Koenen C, Weng W, Selam JL. 2006;29(11):2504-2505. Postgrad Med. 2011;123(4):71-80. The usage of a simplified self-titration dosing guideline (303 Algorithm) for insulin detemir in © 2013 American Osteopathic Association 30. Hirsch IB, Yuan H, Campaigne BN, Tan MH. patients with type 2 diabetes—results of the Impact of prandial plus basal vs basal insulin randomized, controlled PREDICTIVE 303 study. on glycemic variability in type 2 diabetic patients. Diabetes Obes Metab. 2007;9(6):902-913. Endocr Pract. 2009;15(4):343-348. 42. Cryer PE, Davis SN, Shamoon H. Hypoglycemia 31. Garber AJ. Insulin intensification strategies in diabetes. Diabetes Care. 2003;26(6):1902- in type 2 diabetes: when one injection is 1912. no longer sufficient.Diabetes Obes Metab. 2009;11(suppl 5):14-18. 43. Monnier L, Colette C. Addition of rapid-acting insulin to basal insulin therapy in type 2 diabetes: 32. Raccah D, Bretzel RG, Owens D, Riddle M. indications and modalities. Diabetes Metab. When basal insulin therapy in type 2 diabetes 2006;32(1):7-13. mellitus is not enough—what next? Diabetes Metab Res Rev. 2007;23(4):257-264. 44. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 33. Davidson MB, Navar MD, Echeverry D, diabetes: a consensus algorithm for the initiation Duran P. U-500 regular insulin: clinical and adjustment of therapy: a consensus experience and pharmacokinetics in obese, statement of the American Diabetes Association severely insulin-resistant type 2 diabetic and the European Association for the Study of patients. Diabetes Care. 2010;33(2):281-283. Diabetes. Diabetes Care. 2009;32(1):193-203. 34. Reutrakul S, Wroblewski K, Brown RL. Clinical use of U-500 regular insulin: review and meta-analysis. J Diabetes Sci Technol. 2012;6(2):412-420.

S28 A Supplement to The Journal of the American Osteopathic Association April 2013 | Vol 113 | No. 4 | Supplement 2 The Future of Insulin Therapy for Patients With Type 2 Diabetes 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 type 2 diabetes 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 incretin-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 glucagon 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- insulin analog 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 liver 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 glycated hemoglobin (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 metformin. 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 hypoglycemia without pro- a new job that has required his attention enter the muscle. His problematic glu- viding much benefit. Sulfonylureas 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 liraglutide and short-acting with insulin therapy.28,29,35 patients who are receiving basal in- exenatide, 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, Sitagliptin 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, Saxagliptin 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 Insulins 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. Insulin degludec, 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 ↓ Amylin 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 nausea 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 pharmacokinetics and rious condition, such as pancreatitis. 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, insulin lispro) 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 sulfonylurea 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% insulin aspart 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 insulin glargine, 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

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