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Practical Strategies to Improve Treatment of Type 2 Diabetes

Another Downloadable Article from the Diabetes Educational Services Site

This white paper is authored by our faculty member, Evelyne Fleury Milfort, and published in the Journal of American Association of Nurse Practitioners (JAANP), June 2008.

It addresses practical strategies to improve treatment of type 2 diabetes. The purpose of this review is to document the need for, barriers to,and available treatment options for patients with type 2 diabetes, with a focus on modern insulins and delivery systems.

Diabetes Educational Services Beverly Dyck Thomassian 45 Old Chico Way Chico, CA 95928

530 893-8635

[email protected]

http://www.diabetesed.net/ PRACTICE Practical strategies to improve treatment of type 2 diabetes Evelyne Fleury-Milfort, MSN, C-RNP, BC-ADM, CDE (Nurse Practitioner and Instructor in Clinical Medicine)

Division of Endocrinology and Diabetes, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California

Keywords Abstract Diabetes; insulin; analogs; tight glycemic control. Purpose: The purpose of this review was to document the need for, barriers to, and available treatment options for patients with type 2 diabetes, with a focus on Correspondence modern insulins and delivery systems. Evelyne Fleury-Milfort, MSN, C-RNP, BC-ADM, Data sources: Extensive review of the scientific literature was carried out, CDE, Division of Endocrinology and Diabetes, concentrating on data supporting the need for tight glycemic control, and Department of Medicine, Keck School of efficacy and safety data on oral antidiabetes agents, insulins (particularly insulin Medicine, University of Southern California, analog therapies), incretins, and insulin delivery devices. 1520 San Pablo Street, Suite 1000, Los Angeles, CA 90033. Conclusions: Nurse practitioners and other clinicians need to be aware of the Tel: 323-442-5662; Fax: 323-442-6180; urgent need to help patients optimize glycemic control using therapies that can E-mail: fl[email protected] bring blood glucose levels within the target range throughout the day. Choice of

therapy must take into account anticipated hemoglobin A1c decrease, tolera- Received: February 2007; bility, effect on comorbid conditions, and cost. As diabetes progresses, insulin is accepted: July 2007 the only hypoglycemic agent with unlimited potential to lower blood glucose; earlier initiation of insulin therapy can help many patients achieve glucose doi:10.1111/j.1745-7599.2008.00323.x targets more rapidly and provide symptomatic relief. Modern insulins and related therapies in conjunction with innovative delivery devices, appropriate counseling, and patient education can help overcome many barriers to insulin therapy. Implications for practice: The incidence of type 2 diabetes is increasing at an alarming rate. More aggressive treatment, based on the pathophysiology of the disease, is necessary and should include greater attention to control both fasting and postmeal glucose excursions, as well as earlier introduction of insulin therapy that is both effective and acceptable to patients. The educated use of oral antidiabetes agents, modern insulin analogs, incretin agents, and innova- tive delivery devices can help many patients achieve blood glucose targets in a scientifically logical manner that takes into account a patient’s lifestyle needs.

toward treating patients to target, based on our under- Introduction standing of the pathophysiology of the disease. It is well known that the number of individuals with type 2 Failure to normalize blood glucose in our patients may diabetes is increasing rapidly, and disease onset is occur- be partially because of patient factors such as misconcep- ring at progressively earlier ages (Alberti et al., 2004; Wild, tions about diabetes, myths regarding insulin therapy, and Roglic, Green, Sicree, & King, 2004). This situation is inadequate understanding of the consequences of poor a serious challenge, considering the possible burden that control. We must also recognize that healthcare profes- diabetes-related complications can impose on the health- sionals’ comfort level with using the strategies available care system. As clinicians, if we want to prevent the and concerns over possible hypoglycemia have prevented inevitable consequences of poor glycemic control in this a more proactive and aggressive approach to achieving growing population, we must concentrate our efforts target blood sugar. This article discusses how new tools and

Journal of the American Academy of Nurse Practitioners 20 (2008) 295–304 ª 2008 The Author(s) 295 Journal compilation ª 2008 American Academy of Nurse Practitioners Treatment of type 2 diabetes E. Fleury-Milfort treatment regimens, if applied in a timely and appropriate Stratton et al., 2000). In addition, in the United Kingdom fashion based on the current understanding of the path- Prospective Diabetes Study (UKPDS), the risk of myocar- ophysiology of the disease, can help many more patients dial infarction, stroke, and heart failure was decreased by achieve optimal levels of glycemic control. 14%, 12%, and 16% per 1% reduction in hemoglobin A1c, respectively, and by as much as 43% for peripheral vascular disease (Stratton et al., 2000; Figure 1). Based The typical case on these results, professional organizations such as the The spectrum of patients with type 2 diabetes presenting American Diabetes Association (ADA) and the American to nurse practitioners or physician assistants for help with Association of Clinical Endocrinologists (AACE) have pub- their diabetes management is quite variable, and thus, case lished clinical standards and protocols to guide healthcare management must be individualized. Nevertheless, for professionals in optimizing diabetes management. How- purposes of discussing treatment regimens, let us consider ever, the sad reality is that most individuals with diabetes the case of John, a 48-year-old male with type 2 diabetes are not reaching the current population targets proposed of 5 years’ duration, hypertension, hyperlipidemia, and by these organizations (<7.0% proposed by the ADA a body mass index of 32 kg/m2. He came to the office with [2006] and 6.5% by the AACE [Lebovitz et al., 2006]), complaints of feeling poorly and pain in his lower extrem- which research suggests are too conservative. Even appar- ities. He is on maximum dosage of sulfonylurea + metfor- ently small improvements in glycemic control can have min, with a fasting plasma glucose of 284 mg/dL and great clinical impact: each 0.5% reduction in hemoglobin hemoglobin A1c of 9.6% at his first visit. He had a blood A1c is associated with an 11.5% decrease in risk of com- glucose monitor that he was using occasionally, but he lost plications of diabetes. The opposite is also dramatic. In one it 6 months ago. epidemiologic study, any increase in hemoglobin A1c above 5% was associated with increased risk for cardio- vascular disease and all-cause mortality (Khaw et al., The need for tight glycemic control 2004). Our goal should be to normalize, not just lower, We all know that diabetes is a serious disease, and the blood sugar. In fact, the most recent ADA clinical practice consequences of persistently elevated blood glucose recommendations advise that individuals strive for hemo- include stroke, retinopathy leading to blindness, kidney globin A1c < 6.0%, provided hypoglycemia can be avoided disease, erectile dysfunction, neuropathy, peripheral vas- (ADA). cular disease, and diabetic foot disease, as well as mortality However, close attention to hemoglobin A1c alone is from cardiovascular causes (Stratton et al., 2000). The insufficient to ensure optimal glycemic control. Hemoglo- good news is that, as shown in Figure 1, efforts toward bin A1c represents average blood glucose during the pre- better control pay off. Numerous studies have demon- vious 3 months (approximately) but cannot indicate the strated the importance of blood sugar control in the pre- quality of control on a daily basis. Therefore, it is possible vention of these complications (DCCT Research Group, for a patient to have hemoglobin A1c approaching targets, 1993; Shichiri, Kishikawa, Ohkubo, & Wake, 2000; yet still have intermittent but frequent postprandial glucose

Figure 1 Improvements in glycemic control significantly reduced complications of type 2 diabetes (UKPDS). Note. Data from Stratton et al. (2000). *p < .0001.

296 E. Fleury-Milfort Treatment of type 2 diabetes

Figure 2 Postmeal glucose increases years before fasting blood glucose in patients with type 2 diabetes. Note. ª 2003 Kendall and Bergenstal. excursions (i.e., after meals) that expose them to all the changes (TLC) and work with him and his family to help unwanted effects of hyperglycemia. As shown in Figure 2, enhance their knowledge and skills in this area. However, postmeal glucose is likely to be raised for several years before we have to be mindful that, although TLC may decrease there are detectable elevations in fasting blood glucose. In hemoglobin A1c by 1%–2%, follow-through tends to fail a study of more than 1100 patients newly diagnosed with after 1 year. Consequently, the latest consensus paper type 2 diabetes, poor mealtime blood glucose (measured 1 h suggests starting newly diagnosed patients on TLC and after a patient’s normal breakfast), but not fasting blood metformin concurrently (Nathan et al., 2006). Metformin glucose, was a significant risk factor for mortality during the may decrease hemoglobin A1c by up to 1.5%, has a positive 11-year follow-up (p < .05). These findings take on addi- effect on lipids, is weight neutral, or may lead to mild tional importance when considering that most people spend weight loss in some patients. Although it can have gas- about 50% of the time in the postmeal state (Monnier, trointestinal (GI) side effects, metformin is generally well 2000). Furthermore, the relative contribution of mealtime tolerated by most patients without severe complications glucose to overall hemoglobin A1c levels increases as overall when clinical indications are followed and is inexpensive. glycemic control improves (Monnier, Lapinski, & Colette, Now, let us look at John’s pharmaceutical management. 2003; Figure 3). In the case of our typical patient presented According to the recent consensus algorithm for the man- here (hemoglobin A1c: 8.0%–9.0%), mealtime glucose con- agement of type 2 diabetes, decision making should be tributes about half of total hemoglobin A1c. guided by several factors: the expected hemoglobin A1c lowering, tolerability, effect on comorbidity, and cost (Nathan et al., 2006). For John, adding a thiazolidinedione Treatment options (TZD) to existing metformin and sulfonylurea therapy to Several options are possible for treating John, who has create a triple-therapy regimen would not be the most not reached targets on dual oral therapy. First, we will need efficient strategy. Based on the expected hemoglobin A1c to check how well John is applying therapeutic lifestyle decrease of 0.5%–1.4%, this is most likely to be effective in

Figure 3 Mealtime glucose makes its greatest contribution to hemoglobin A1c in patients who have the best overall control. Note. Data from Monnier et al. (2003).

297 Treatment of type 2 diabetes E. Fleury-Milfort

those patients whose hemoglobin A1c is no more than insulin because of beta-cell dysfunction and uncontrolled about 8.0% (Riddle, 2005). It should be noted that TZDs production of glucose by the liver because of alpha- and have the advantage of improving blood lipids (Nathan beta-cell dysfunction. Its effect on weight is neutral. The et al., 2006). Undesirable consequences of TZD treatment sitagliptin phosphate effect in hemoglobin A1c lowering include weight gain and fluid retention. These agents are appears to be related to the degree of hemoglobin A1c also relatively costly, and in addition, liver function needs elevation at baseline. In a pooled analysis of two mono- to be monitored. At this time, in the treatment of patients therapy studies, a prespecified subgroup analysis showed like John, adding a glinide would be inappropriate as this that when patients were grouped by baseline hemoglobin treatment strategy would not yield more insulin secretory A1c into those with mildly elevated hemoglobin A1c levels capacity. An alpha-glucosidase inhibitor would also be (<8%, n = 411), those with moderately elevated hemo- unwise as it would have little or no effect on his fasting globin A1c levels (>8% to <9%, n = 239), and those with blood sugar, and this class of drug only has a modest effect the highest elevated hemoglobin A1c levels (>9%, n = 119), on the hemoglobin A1c. mean differences in hemoglobin A1c from placebo after 18 Addition of an incretin is an increasingly popular option. weeks were 20.6%, 20.7%, and 21.4%, respectively (p < This class of compounds mimics or enhances actions of .001; Sitagliptin prescribing information). Stuffy or runny natural GI hormones that help regulate metabolism and nose and sore throat, upper respiratory infection, and eating behavior. Exenatide (Byetta; Amylin Pharmaceut- headache are the most common side effects reported with icals Inc., San Diego, CA) is a glucagon-like peptide-1 sitagliptin phosphate. This medication would not be a receptor agonist that has been approved for patients with good choice for John because the expected hemoglobin type 2 diabetes who are unable to achieve glycemic control A1c decrease would not be sufficient to reach target, using other oral antidiabetic drugs (OADs; metformin ± especially if his sulfonylureas had to be removed. sulfonylureas ± TZD). For John, this could have the pos- Like TZDs, this drug has only a modest hemoglobin A1c- sible added benefit of weight loss. Exenatide works by lowering effect and is costly. slowing gastric emptying and decreasing the sensation of Another, more appropriate, option is to initiate insulin hunger. It also enhances existing nutrient-stimulated therapy. Unfortunately, many patients with type 2 diabe- insulin secretion and suppresses glucagon levels, leading tes, as well as their healthcare providers, may feel that to reduced hepatic glucose production. In a 30-week, insulin is a treatment to be avoided (Peyrot et al., 2005). randomized, placebo-controlled trial in 733 people with This attitude fails to recognize that type 2 diabetes is type 2 diabetes who were unable to achieve glycemic a disease with progressive decline in beta-cell secretion control with metformin + sulfonylurea therapy, 34% of that, for most patients, will eventually require insulin subjects taking exenatide 10 lg daily (plus OADs) and 27% supplementation and later replacement (UKPDS, 1998; of those taking exenatide 5 lg daily (plus OADs) reached Wright et al., 2002). hemoglobin A1c  7.0%, compared with only 9.0% of those continuing on metformin + sulfonylureas (p < .0001; Planning for insulin therapy Kendall et al., 2005). Each group on exenatide also lost a mean of 1.6 ± 0.2 kg from baseline. Of course, the efficacy Despite the availability of five different classes of OADs, of such a regimen depends on the level of baseline glycemic insulin remains the only medication that can theoretically control and the extent of endogenous insulin secretion. bring any patient to target if appropriate dosage is used, The recent consensus statement indicates that the ex- limited only by potential for hypoglycemia and with the pected decrease in hemoglobin A1c with exenatide would advantage of a positive effect on lipids. Unfortunately, be 0.5%–1.0% (Nathan et al., 2006). GI side effects are also insulin remains underused in type 2 diabetes, and when the main potential problem, and like insulin, exenatide it is used, it is often delayed and/or not titrated sufficiently must be given by injection. (Riddle, Rosenstock, Gerich, & Insulin Glargine 4002 Sitagliptin phosphate, a dipeptidyl peptidase-4 (DPP-4) Study Investigators, 2003). Failure to realize the potential inhibitor recently approved by the Food and Drug Admin- of insulin therapy for achieving tight control can be attrib- istration as monotherapy and as add-on therapy to either uted to a variety of barriers, all of which can potentially be metformin or TZDs, is not approved with sulfonylureas, as overcome (Table 1). the risk of hypoglycemia is unknown. Like exenatide, but The most common patient barriers are fear of beginning through a different mechanism, sitagliptin phosphate an injection regimen, including the implications of insulin enhances the incretin system to help regulate glucose by therapy concerning progression; time; cost; and compli- affecting the beta- and alpha-cells in the pancreas. cations. Many clinicians tend to use scare tactics as a way Through DPP-4 inhibition, sitagliptin phosphate works to bring patients to follow treatment recommendations. only when blood sugar is elevated to address diminished In my own experience, much of the fear of insulin can be

298 E. Fleury-Milfort Treatment of type 2 diabetes

Table 1 Overcoming barriers to insulin therapy in type 2 diabetes mitigated if patients are introduced early in their diabetes Response or strategy for education to the likely need for insulin at some stage. By Barrier overcoming barrier discussing with them the progressive nature of type 2 diabetes, patients can come to regard insulin supplemen- Physical barriers l Provide assistance with injection tation and eventual replacement as a normal and expected l Select a regimen minimizing the number of injections development. I usually tell them that insulin is a hormone l Select a less complex regimen that will eventually need to be replaced. This is also the l Use a modern delivery device instead of time to emphasize the importance of blood glucose control syringe and the role of lifestyle modifications in postponing this Fear of needles l Reassure that many patients have this fear process. l or injections Show the patient an injection device—pa- For patients like John, we must keep in mind that tients often think that they will need to use optimal control does not need to occur all at once; as long long needles l Highlight that the injection is into fat, not as the desired target is kept in mind, intensification can a vein take place gradually. The important point is to keep l Get first injection out of the way as soon as patients progressing at a rate that is achievable, comfort- possible able, and safe for them. Potential complications of insulin l Discuss use of specific devices to address therapy must be thoroughly explained and kept in per- this fear spective. For example, it is important to communicate that l If patient has severe needle phobia, consider there may be some initial weight gain, or some swelling use of injection aids or referral to secondary psychological care from osmotic shift, and that the blurred vision that can Fear of injecting l Suggest regimen involving fewer injections, occur when insulin is initiated—especially after severe in public decreasing likelihood of need to inject in hyperglycemia—is not the same as the retinopathy that public arises as a long-term complication of poor control. It may l Suggest coping strategies be important for some patients that insulin therapy may l Discuss discretion of using a modern injec- actually be less costly than triple oral therapy (Schwartz tion device et al., 2003). Are they becoming l Discuss as part of initial education and rein- more ill/feelings force over time that type 2 diabetes is a pro- The result of these barriers and beliefs is that many of failure gressive disease; hence, treatment has to people with type 2 diabetes, including those using insulin, change as the disease progresses continue to live with suboptimal glycemic control. Data l This is an expected part of the disease pro- from the 1999–2002 National Health and Nutrition Exam- cess: insulin is a hormone that will have to be ination Survey (NHANES) survey indicate that only half supplemented and later replaced (49.8%) of the U.S. adults with diabetes had hemoglobin l Use of insulin will help achieve control and A < 7% and nearly one third (29.7%) had values 8.0% minimize the risk of complications 1c Concerns over l Reassure the patient that hypoglycemia is (Resnick, Foster, Bardsley, & Ratner, 2006). Only about hypoglycemia relatively rare 27% of the sample reported using insulin. Clinicians must l Educate the patient on how to prevent and remember that in the treatment of type 2 diabetes com- recognize symptoms pared to type 1 diabetes, larger dosages of insulin may be l Make sure the patient and partner/family required to help overcome insulin resistance. (if applicable) know how to deal with it Cost l Insulin therapy may be less expensive than triple oral therapy New insulin analogs Concerns over l Encourage healthy food intake and moderate weight gain exercise Ideally, insulin therapy should reproduce normal insu- l Explain that initial weight gain may be asso- lin secretion during fasting and after meals. Unfortunately, ciated with improved control but does not conventional insulins and traditional therapy regimens fail necessarily continue indefinitely to accomplish this. The result has been either poor control l Combine insulin with metformin or increased risk of hypoglycemia, neither of which is l Consider using an insulin formulation less desirable. Although neutral protamine Hagedorn (NPH) associated with weight gaina insulin may still have a place in the management of certain Note. Adapted from MERIT educational website (UK). patients who do not want to take too many injections and a From Haak et al. (2005) and Raslova et al. (2006). need lunchtime coverage, insulin analogs represent an important advance in technology as they overcome, at least partially, some of the major limitations of conven- tional insulins and better approximate physiological

299 Treatment of type 2 diabetes E. Fleury-Milfort insulin secretion. Insulin analogs are available in basal, events, confirmed events 72 mg/dL, and confirmed rapid-acting, and premixed formulations (Table 2). The events 56 mg/dL, respectively (Riddle et al.). Clinical rapid-acting insulin analogs all have a more rapid onset of studies indicate that of the two basal analogs, insulin action and reach peak concentration much faster than detemir appears to have the least within-patient variability regular human insulin (Becker, Frick, Burger, Potgieter, in insulin action (Heise et al., 2004; Klein et al., 2007). & Scholtz, 2005; Homko, Deluzio, Jimenez, Kolaczynski, & Another feature to be aware of, which may be of particular Boden, 2003). The main advantage conferred by this importance for overweight patients, is that insulin detemir change is that patients can inject at the start of a meal has consistently been associated with lesser weight gain or 10–20 min afterward, depending on the insulin, instead than NPH in type 2 diabetic patients (Haak et al., 2005; of the 30 min prior to meals recommended for regular Hermansen et al., 2006; Meneghini, Rosenberg, Koenen, human insulin or premixed human insulin. This feature Merilainen, & Lu¨ ddeke, 2007; Raslova et al., 2004). allows more flexibility in meals and also lets patients better match insulin dose to the actual carbohydrate intake. Choosing an insulin regimen Postmeal dosing is also possible for the premixed analog biphasic insulin aspart 30 (BIAsp 30, 215 to +15 min; There are many different treatment regimens available NovoMix product insert); lispro 75/25 is only approved for for type 2 diabetes, but those involving insulin can be premeal dosing (215 to 0 min; Lispro 75/25 product insert). divided into three general types: The two basal analog insulins have a longer duration of 1. Basal insulin + OADs action and a relatively flat time action profile without 2. Split-mixed or premixed insulin once or twice daily ± a pronounced peak and less variability in their absorption OADs compared to NPH (Haak, Tiengo, Draeger, Suntum, & 3. Basal–bolus regimen. Waldhausl, 2005; Lepore et al., 2000; Raslova et al., Each regimen has advantages and disadvantages 2004; Riddle et al., 2003). This feature should make them (Table 3), and the selection of a regimen needs to be more predictable in their glucose-lowering action, com- tailored to the needs and abilities of individual patients, pared to NPH, and likely contributes to the lower incidence who should be involved in the process at every stage. of hypoglycemia in type 2 diabetes (Hermansen et al., Supplementation with basal insulin regimens, usually 2006; Raslova et al., 2004; Riddle et al.; Rosenstock used in conjunction with OADs such as metformin, sulfo- et al., 2001; Yki-Jarvinen, Dressler, Ziemen, & HOE nylureas, or TZDs, offer the advantage of requiring only 901/300s Study Group, 2000). In one recently published one daily injection usually given at bedtime, and slowly treat-to-target study, the incidence of all hypoglycemia in titrating the dose upward, based on fasting blood sugar. subjects treated with insulin detemir was reduced by 47% This is a popular starting regimen because of its simplicity. and nocturnal hypoglycemia by 55%, compared with NPH This regimen allows patients like John to improve glycemic (Hermansen et al., 2006). In another treat-to-target trial control while becoming used to managing insulin self- comparing insulin glargine to NPH, hypoglycemia was injection and the blood glucose monitoring that should reduced by 21%, 29%, and 41%, for all symptomatic accompany it. One drawback of basal insulin regimens is

Table 2 Commercially available insulin analogs and their advantages over conventional human insulin formulations

Type Generic name Brand (manufacturer) Improvement over conventional insulin

Rapid acting Insulin aspart NovoLog (Novo Nordisk) Higher peak concentration, faster time to onset, and Insulin lispro Humalog (Eli Lilly) can administer closer to meals. Insulin glulisine Apidra (Sanofi-Aventis) Basal Insulin detemir Levemir (Novo Nordisk) More predictable glucose-lowering effect, flatter profile Insulin glargine Lantus (Sanofi-Aventis) without a pronounced peak, prolonged action, and less hypoglycemia. Each can be used once daily. Premixed BIAsp 30a NovoLog Mix 70/30 (Novo Nordisk) Higher peak concentration, faster time to onset, and Biphasic insulin lispro Humalog MixTM75/25 (Eli Lilly) can administer closer to meals. mix 25 (lispro 75/25)b Biphasic insulin lispro Humalog Mix 50/50 (Eli Lilly) mix 50 (lispro 50/50)c aContains 30% insulin aspart and 70% protaminated insulin aspart. bContains 25% insulin lispro and 75% protaminated insulin lispro. cContains 50% insulin lispro and 50% protaminated insulin lispro.

300 E. Fleury-Milfort Treatment of type 2 diabetes

Table 3 Advantages and disadvantages of three common insulin regimens

Insulin regimen Advantages Disadvantages

Basal insulin with OADs l A simple starting regimen for insulin-naı¨ve patients, l Does not provide insulin specifically for postmeal requires only one injection per day glucose control and assumes that patient can l Particularly useful when patient’s blood glucose is produce sufficient insulin to cover mealtime high overnight and in the morning requirements l Convenient for patients who require a third party to l Dosing during the day is inflexible, so patients need administer their insulin to keep to stricter and more predictable diet l With stable control, can test two to three times l Temporary and likely to require a change in regimen weekly, but with OADs need daily testing Premixed insulin, with l Targets mealtime glucose as well as fasting glucose l May not cover lunchtime glucose excursions (if only or without OADs l Can be initiated as one injection per day to used once or twice daily) familiarize patient with injecting l Requires regular scheduled meals, consistent l Second or third daily injections of same insulin in carbohydrate intake, and physical activity level same device can be added if necessary to optimize l Does not allow for incremental adjustment of control individual components within the premix l Can use this regimen long term l Should test at least twice daily Basal–bolus multi-injection l Most physiological insulin replacement regimen l Requires most skills regimen (other than insulin pump) Frequent monitoring of glucose l Opportunity to achieve very tight glycemic control Adjusting dose l Can use this regimen long term Four or more daily injections using two different l Improved lifestyle flexibility insulins Carbohydrate estimation Problem-solving skills Higher learning curve Skillful clinician

Note. Adapted from the MERIT educational website. OADs, oral antidiabetic drugs. that they do not provide mealtime glucose control, so they algorithm or guidelines to help adjustment toward glyce- work best in patients who have sufficient endogenous mic targets. A variant of this option for patients who are glucose production remaining to take care of mealtime unable or unwilling to mix insulin is the use of a twice- insulin requirements. Because of the slow progressive daily premixed analog. Several studies using either lispro decline in insulin secretion, eventually most patients on 75/25 or BIAsp 30 twice daily have demonstrated that a basal-only regimen will require mealtime insulin. One more patients can reach target glucose on such a regimen option for these patients is to use a once-daily injection of than on a once-daily regimen of insulin glargine. In the premixed insulin regimen, usually with dinner. The pri- INITIATE treat-to-target trial, 66% of patients using BIAsp mary advantage of this approach is that patients can stay 30 twice daily with metformin (±TZD) reached hemoglo- on the same regimen for a longer period, as both meal- bin A1c < 7.0% compared to 40% of those using glargine time and fasting glucose are addressed (Malone, Bai, once daily + metformin (Raskin et al., 2005). By compar- Campaigne, Reviriego, & Augendre-Ferrante, 2005; ison, in the two trials using lispro 75/25 + metformin Malone et al., 2004; Raskin et al., 2005). (other OADs discontinued), the proportion reaching

As insulin deficiency progresses, patients will require hemoglobin A1c  7.0% was 30% vs. 12% for lispro coverage of more than one meal with prandial insulins. In 75/25 (Malone et al., 2005) and 42% vs. 18% (Malone this phase, the secretagogue, such as sulfonylurea, is no et al., 2004) for insulin glargine. longer needed; however, insulin sensitizers such as met- The most efficient and physiological way to replace formin or TZDs can be continued to decrease insulin insulin is the basal–bolus regimen, also referred to as resistance. Several insulin replacement regimens can be multiple daily injections, in which patients take long- initiated, such as split-mixed dosing with NPH and rapid- acting insulin to cover their basal needs and cover their acting insulin. This option can be considered if patients are carbohydrate intake with boluses of rapid-acting insulin. unwilling or unable to take more than two daily injections Supplemental dosages are added to cover blood sugars and have stable activity levels and consistent intake of outside target range. This option is good for patients carbohydrates. In this regimen, the dosage of rapid-acting interested in tighter control, in need of flexibility, willing insulin can be constant or the patient can be given a dosage and having the ability to test their blood sugar three to four

301 Treatment of type 2 diabetes E. Fleury-Milfort times a day, and able to use the results to determine their Table 4 Simplified regimen for basal insulin analogs and premixed insulin insulin dosage. It requires more skill on the part of both the analogs patient and the clinician. Glargine or detemir BIAsp 30 or lispro For patients who need replacement therapy, who are once daily 75/25 twice dailya unwilling or unable to use the above-mentioned basal– Blood glucose (mg/dL) bolus regimen, and who have a stable physical activity and Blood glucose Insulin dose prebreakfast or Insulin dose carbohydrate intake, one regimen that I have been suc- (mg/dL) adjustment (U) predinner valueb adjustment (U) cessfully using for several years is three times daily (TID) >250 +4 to +8 >250 +2 to +4 premixed insulin. A recent clinical study (1-2-3 Trial) has 140–250 +2 to +4 140–250 +1 to +2 shown that it is possible to use BIAsp 30 safely once, twice, 70–139 0 70–139 0 or up to three time a day to achieve glucose targets (Garber <70 21to22 <70 21to22 et al., 2006). After 16 weeks of once-daily use, 21% of the Note. Simplified regimens drawn from data from International Diabetes patients achieved hemoglobin A1c  6.5% and 41% Center and Pearson and Powers (2006); Table 3 for basal insulins and reached a hemoglobin A1c < 7%; these proportions Table 4 for premixed insulins. increased to 52% and 70% of patients, respectively, when aNote that BIAsp 30 can also be used once daily and titrated up to TID those who moved to twice-daily use were included. A administration if needed (Garber et al., 2006). b small number of patients increased to TID, bringing the Predinner doses adjusted on the basis of fasting (prebreakfast blood proportions reaching these targets to 65% and 77%. More glucose) and prebreakfast doses adjusted on the basis of predinner blood glucose values. importantly, using BIAsp 30 TID was not associated with any increased risk of hypoglycemia: the frequency of ance coverage. Studies have shown that most patients rate minor events was 15.4, 22.4, and 12.0 events/patient/ these new devices more highly than vial and syringe in year, for once-, twice-, and thrice-daily dosing. In certain terms of lifestyle flexibility, quality of life, and overall circumstances, for example, where the patient likes to preference (Bohannon; Graff & McClanahan, 1998; snack on carbohydrates but does not like to take additional Korytkowski, Niskanen, & Asakura, 2005). injections, a TID regimen would be possible using human A range of devices are available, most of which have premixed insulin. However, its extended duration of a very discreet appearance resembling a pen: for some action would increase the risk of hypoglycemia if a snack patients, these devices are less associated with ‘‘drugs.’’ The is missed. two basic types are prefilled disposable devices and reus- Patients can be brought to target using either aggressive able devices, which require the insertion and changing of or conservative titration algorithms with any of these a cartridge filled with insulin. It is important to remember regimens. It should be kept in mind that the treat-to-target that devices are often insulin specific; thus, selection may regimens derived from clinical trials represent an aggres- dictate the choice of insulin, or vice versa. A prefilled sive approach because of the time constraints of a trial and disposable device might be best for a patient with a busy may need to be modified for use in general practice. Simple lifestyle who needs to keep a pen in the office, car, travel and advanced dosing regimens for basal and premixed kit, or sports bag, for example. A prefilled device may be insulin analogs are presented in Table 4. These should a better choice for patients with limited manual dexterity be used only as guides and modified to accommodate (FlexPen [Novo Nordisk A/S, Bagsvaerd, Denmark], Solo- the needs, wants, and abilities of individual patients. Star [Sanofi-Aventis, Bridgewater, NJ], and Lilly Prefilled Pen [Eli Lilly, Indianapolis, IN]). Other devices, such as Innolet (Novo Nordisk) are designed to accommodate Insulin delivery devices patients with poor vision. All these devices use small- Some of the patient barriers to initiation of insulin gauge needles and offer features such as single-unit doses therapy have been fear of needles, difficulty managing and an audible click for dose confirmation. Two reviews of with the syringe and vial system, and association of syrin- clinical studies conclude that pens provide accurate insulin ges with drug addiction. During the past 10 years, a variety delivery, enhance quality of life, and are preferred over of advanced pen-type delivery devices have been devel- vial and syringe (Robertson, Glazer, & Campbell, 2000). oped to make self-injection easier, less painful, more Another insulin delivery device for patients on replace- accurate, and more convenient than ever before. ment therapy is continuous subcutaneous insulin infusion Although widely used in Europe, they have been slower using an insulin pump. These battery-operated devices can to gain acceptance in the United States (Bohannon, 1999). be preprogrammed to deliver continuous microdoses of The appearance and many of the features of these new rapid-acting insulin by pulses termed ‘‘basal rate.’’ Boluses devices may also be helpful in aiding patients who are of larger amounts of insulin are taken by the patient as reluctant to use insulin, the only limitation being insur- needed to cover the carbohydrate in meals or snacks and to

302 E. Fleury-Milfort Treatment of type 2 diabetes counteract hyperglycemia. Although they are used more dosing with biphasic insulin aspart 70/30 (The 1-2-3 study). Diabetes, Obesity & often for patients with type 1 diabetes, these devices pro- Metabolism, 8, 58–66. Graff, M. R., & McClanahan, M. A. (1998). Assessment by patients with diabetes vide a more physiological delivery of insulin and can be an mellitus of two insulin pen delivery systems versus a vial and syringe. Clinical option for some patients with type 2 diabetes on insulin Therapeutics, 20, 486–496. replacement therapy who need more flexibility and Haak, T., Tiengo, A., Draeger, E., Suntum, M., & Waldhausl, W. (2005). Lower greater delivery choices. Several of these devices are avail- within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes, able with various insulin delivery features. Obesity & Metabolism, 7, 56–64. Inhaled insulin was briefly available (Exubera; Pfizer Inc., Heise, T., Nosek, L., Ronn, B. B., Endahl, L., Heinemann, L., Kapitza, C., et al. (2004). New York, NY) to patients but has been withdrawn from the Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes, 53, 1614–1620. marketplace. Clinical trials are ongoing with other inhaled Hermansen, K., Davies, M., Derezinski, T., Martinez Ravn, G., Clauson, P., & Home, insulins. P. (2006). A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care, 29, 1269–1274. Conclusions and summary Homko, C., Deluzio, A., Jimenez, C., Kolaczynski, J. W., & Boden, G. (2003). Comparison of insulin aspart and lispro: Pharmacokinetic and metabolic effects. Nurse practitioners and other clinicians need to be Diabetes Care, 26, 2027–2031. aware of the urgent need for helping more patients to Kendall, D. M., & Bergenstal, R. M. (2003). The natural history of type 2 diabetes over optimize their glycemic control, which can only be time. Minneapolis, MN: International Diabetes Center. Kendall, D. M., Riddle, M. C., Rosenstock, J., Zhuang, D., Kim, D. D., Fineman, M. S., accomplished by normalizing blood glucose throughout et al. (2005). Effects of exenatide (exendin-4) on glycemic control over 30 weeks in the day. Treatment should be based on the pathophysi- patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes ology of the disease and needs to consider factors such as Care, 28, 1083–1091. Khaw, K. T., Wareham, N., Bingham, S., Luben, R., Welch, A., & Day, N. (2004). expected hemoglobin A1c decrease, patient tolerance, Association of hemoglobin A1C with cardiovascular disease and mortality in effect on comorbidity such as lipid levels, and cost. As adults: The European prospective investigation into cancer in Norfolk. Annals of beta-cell secretion declines, insulin is the most effective Internal Medicine, 141, 413–420. hypoglycemic agent that given in appropriate dosage, can Klein, O., Lynge, J., Endahl, L., Damholt, B., Nosek, L., & Heise, T. (2007). Albumin- allow any patient to reach desired glycemic targets. Appro- bound basal insulin analogues (insulin detemir and NN344): Comparable time- action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes, priate counseling and patient education, coupled with use Obesity & Metabolism, 9, 290–299. of insulin analogs, delivery devices, and treatment regi- Korytkowski, M., Niskanen, L., & Asakura, T. (2005). FlexPen: Addressing issues of mens, can help overcome many of the traditional barriers confidence and convenience in insulin delivery. Clinical Therapeutics, 27(Suppl. B), S89–S100. to insulin therapy. Lebovitz, H. E., Austin, M. M., Blonde, L., Davidson, J. A., Del Prato, S., Gavin, J. R., III, et al. & ACE/AACE Diabetes Recommendations Implementation Writing Committee. (2006). ACE/AACE consensus conference on the implementation of Acknowledgments outpatient management of diabetes mellitus: Consensus conference recommendations. Endocrine Practice, 12(Suppl. 1), 6–12. Development of this manuscript was supported by Novo Lepore, M., Pampanelli, S., Fanelli, C., Porcellati, F., Bartocci, L., Di Vincenzo, A., Nordisk. Medical writing assistance was provided by et al. (2000). 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