familiar, have inherent limitations in their ability to help patients reach recommended glycemic targets and comply

Transcription

1 New Therapeutic Options for Treating Type-2 Diabetes: A Review of Insulin Analogs and Premixed Insulin Analogs Charles Choe, MD and Steve Edelman, MD Financial support: Dr. Edelman is a consultant and speaker for Novo, Lilly and Sanofi Aventis, and has received grant support. Development of this manuscript was supported by Novo Nordisk. Medical writing assistance was provided by Dr. Gary Patronek. There is a growing consensus that blood glucose control, and postprandial control in particular, must become more aggressive if we are to stem the growing tide of diabetesrelated complications and mortality. For most patients, this means that insulin therapy must begin earlier and that insulin must be titrated sufficiently to achieve tighter glycemic targets. The limitations of traditional treatment regimens, delivery devices and conventional insulin formulations, in conjunction with patient factors, have prevented the majority of people with type-2 diabetes from realizing the potential benefits of insulin therapy and achieving recommended glycemic targets. Fortunately, modern insulin analog formulations, new treatment regimens, and advanced delivery devices are now available. This review will discuss features of these new tools, and compare the benefits of using premixed insulin versus a basal-only approach to initiating insulin therapy. Once physicians become familiar with these tools and incorporate them into daily practice, they will be able to better tailor diabetes self-management programs to the needs of individual patients. The result will be that more patients should be able to reach recommended glycemic targets with greater convenience and safety than has previously been available. Key words: diabetes a therapy From the Veterans Affairs Medical Center, University of California San Diego, San Diego, CA (Choe, assistant clinical professor of medicine; Edelman, professor of medicine). Send correspondence and reprnt requests for J NatI Med Assoc. 2007;99: to: Dr. Steve Edelman, University of California San Diego, Veterans Affairs Medical Center, 3350 La Jolla Village Drive (11 1G), San Diego, CA 92161; phone: (858) ext. 7361; fax: (858) ; svedelman@vapop.ucsd.edu INTRODUCTION E very physician in primary care practice is no doubt aware that the incidence of type-2 diabetes is increasing and that the disease is extracting a greater toll on health and quality of life each year. 1,2 Many physicians may be frustrated by a variety of patient- and treatment-related factors that seem to foil their best attempts at helping patients improve diabetes self-management. Some of this frustration may be due to reliance on treatment regimens and insulins that, while being familiar, have inherent limitations in their ability to help patients reach recommended glycemic targets and comply with therapy. During the last decade, a host of new tools, treatment regimens and advanced delivery devices have become available. These therapeutic advances warrant rethinking some of our ideas about treatments for type-2 diabetes. This article will highlight some of these developments and put new thinking about the treatment oftype-2 diabetes in context. THE NEED FOR IMPROVED GLYCEMIC CONTROL Type-2 diabetes is a progressive disease, involving defects in beta-cell function and insulin sensitivity, for which most patients will eventually require insulin therapy. Type-2 diabetes begins largely as a disorder of poor postprandial glucose control, since the earliest pathophysiological defect is deficient early-phase insulin secretion.3 In comparison, detectable deficits in fasting glucose control do not appear until years later. By time of diagnosis, patients may have lost up to 50% of insulin secretory ability. Therefore, therapy must be adjusted over time to control both fasting and postprandial glucose excursions. A consequence of this silent, early progression is that blood glucose levels are likely to be elevated for many years, primarily due to excessive postprandial excursions, before diagnosis and intervention occurs. This elevation in postprandial glucose further exacerbates risk and may be a better predictor of all-cause mortality and cardiovascular disease than fasting blood glucose.4'5 There is grow- JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL

2 ing awareness that levels of hemoglobin (Hb)A1c traditionally considered to be in the subdiabetic range can still have serious adverse effects. In one population-based cohort study of 4,662 men and 5,570 women, years old, recruited from private practice registers in Norfolk, United Kingdom, the relationship between HbAic and all-cause mortality was continuous and statistically significant, in persons with and without diabetes.6 In fact, in an earlier report from that cohort, men with diagnosed diabetes contributed only 18% of the excess mortality for all causes related to HbAic >5%; the remainder of the excess deaths could be attributed to men with HbAic 5.0_6.9%.7 This highlights the limitations of relying solely on HbA1c as the gold standard for assessing adequacy of glycemic control. Because HbAic is a measure of average glycation of proteins over the preceding 2-3 months, a seemingly good HbAic can mask substantial postmeal excursions in blood glucose occurring on a daily basis. Given that most people eat.3 meals during an average 12-hour daytime period, it is likely that a significant portion of overall glucose exposure occurs in the postprandial state.8'9 Therefore, optimal control must focus on maintaining a normal blood glucose throughout the entire day, including after meals, and not just during periods of fasting. LIMITATIONS OF PREVAILING APPROACHES TO TREATMENT Prevailing treatment approaches common in primary care practice involve progressive steps, beginning with diet and exercise, followed by the addition of one oral antidiabetic drug (OAD) and eventual escalation to maximal tolerable dose, then addition of a second or third OAD, and, finally, insulin-initially usually in combination with OAD(s). For some patients, treatment may progress to basal-bolus therapy, which involves administering a long-acting basal insulin once or twice daily and a different faster-acting insulin as a bolus for meals. The advantage of this stepwise escalation of treatment is its apparent simplicity. However, this is a reactive approach, in which treatment typically lags behind the progression of disease and which needlessly exposes patients to damaging levels of hyperglycemia. There is ample evidence to support this criticism. For example, in one population-based study of >7,000 patients in the Kaiser Permanente Northwest Region, initiating therapy for type-2 diabetes, the last HbA,c recorded before initiating, switching or supplementing pharmacotherapy ranged from 8.6% in patients not on pharmacotherapy to 9.6% for those on combination therapy. 10 Thus, the average patient accumulated nearly five HbA1c-years of excess glycemic burden (HbA,c >8%) from diagnosis until starting insulin. Given what is known about the glucose-lowering potential of available OADs and the popularity of stepwise treatment, suboptimal glycemic control should not be surprising. Depending on the agent chosen, OAD monotherapy can reduce HbAic by at most 1-2%, 1,12 and no single OAD can address both insulin secretory deficits and insulin resistance, each of which contributes to the pathogenesis of type-2 diabetes. Therefore, OAD monotherapy is likely destined to fail if instituted in patients with HbAjc >9%; many patients have HbA1c levels much higher than 9.0% at the time of evaluation. The inadequacy of current approaches to diabetes therapy is further illustrated by data from National Health and Nutrition Examination Survey (NHANES), a cross-sectional nationally representative survey ofthe U.S. population.2 In NHANES , only half (49.8%) of U.S. adults with diabetes age.18 years had HbA,c <7%. Nearly one-third (29.7%) had values.8.0%.13 This represents negligible improvement from NHANES III (44.6% of adults with type-2 diabetes.20 years had HbAic <7.0%).14 NEW IDEAS ABOUT TREATMENT Healthcare providers are facing a challenging situation. The task of helping a growing population ofpeople with type-2 diabetes to reach glycemic targets is becoming more difficult even as our concept of "safe" levels of hyperglycemia continues to be revised downward. Given the trend for type-2 diabetes to develop at progressively younger ages,"5 the burden of diabetes complica- Table 1. Commercially available Insulin analogs Type Generic Name Brand and Manufacturer Rapid Acting Insulin aspart NovoLogg, Novo Nordisk Insulin lispro Humalog, Lilly Insulin glulisine Apidrall, Sanofi-Aventis Basal Insulin detemir Levemir s, Novo Nordisk Insulin glargine Lantus, Sanofi-Aventis Premixed Biphasic insulin aspart 70/30 (BlAsp 30) NovoLog Mix 70/30, Novo Nordisk Biphasic insulin lispro mix 75/25 (Mix 75/25) Humalog Mix75/25TM, Lilly Biphasic insulin lispro mix 50/50 (Mix 50/50) Humalog Mix 50/50Tm, Lilly 358 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL 2007

3 tions will escalate out of control unless we adjust our treatment approach using new tools and the most up-todate regimens. To remedy this situation, there is a growing consensus that diabetes treatment must be more aggressive than occurs with most current treatment approaches. 11,12,16-18 This includes beginning pharmacotherapy using OADs in combination rather than as monotherapy,19 using oral agents in conjunction with incretin mimetics,'8 earlier initiation of insulin therapy,' 117'20 greater attention to postprandial glucose control particularly for those patients with HbAic <7.3%5 12_and more aggressive titration of insulin. Indeed, the concept of addressing multiple pathophysiological defects (e.g., insulin secretory deficiency and insulin resistance) in type-2 diabetes has been aided by the development of single-tablet fixed-dose combination therapy, such as sulfonylurea/metformin and metformin/thiazolidinedione tablets.22 This new treatment paradigm is evident in the most recent American Association of Clinical Endocrinologists (AACE) roadmap guidelines. They indicate that patients naive to therapy with HbA1c >10 should begin with either basal-bolus therapy or premixed insulin; stepwise treatment with OADs is not recommended.23 Basal-bolus therapy or premixed insulins are also recommended for treated patients with HbAic remaining above 8.5%. The role of emerging therapies, such as amylin analogs (pramlintide), GLP-1 receptor agonists (exenatide and liraglutide) and DPP IV inhibitors (vildagliptin and sitagliptin) is evolving. The advantage of these agents is that they address deficits in prandial glucose control not adequately managed by other oral therapies and, with the exception of DPP IV inhibitors, they have beneficial effects on weight. The use of these agents looks promising, though the long-term risks and benefits of these agents will need to be established. As more experience is gained with these novel therapies, how they are best used in the treatment of type-2 diabetes can be determined. NEW THERAPEUTIC OPTIONS FOR TYPE-2 DIABETES THE ROLE OF INSULIN Insulin remains the single medication that can theoretically bring any patient to target, limited only by potential for hypoglycemia and patient willingness to initiate and comply with therapy. Nevertheless, patients and physicians alike may be reluctant to initiate insulin. This "psychological insulin resistance" can be attributed to needle phobia, fear of hypoglycemia, concern about lifestyle restrictions or weight gain, and belief that insulin represents a personal failure or (unexpected) disease progression.' 2425 Acceptance of insulin therapy can be a problem even among presumably highly motivated patients. In one survey of 708 patients with type-2 diabetes attending a diabetes conference, more than onequarter indicated an unwillingness to take insulin if prescribed.25 Unfortunately, overcoming barriers to initiating insulin therapy is only one part of the problem faced by clinicians. Once prescribed, adherence to an insulin regimen is also likely to be low in one metaanalysis as low as 62-64%.26 Despite the historical challenges of insulin therapy, during the past years, treatment modalities have advanced considerably and have likely outpaced popular perceptions of their risks and benefits. New insulin analogs, advanced delivery devices, finer coated needles and more effective therapeutic regimens made possible by these new tools have revolutionized insulin therapy and can help overcome many ofthese traditional barriers. These tools, used in conjunction with effective diabetes education, can reduce perception of pain and associated anxiety, improve convenience and remove many of the lifestyle restrictions formerly associated with insulin therapy. They are the key to better outcomes for patients. A more complex challenge is to educate patients about how other aspects of "psychological insulin resistance," particularly fear of hypoglycemia, may be due to past clinical experience with conventional insulins [e.g., regular human insulin and neutral protamine Hagedom (NPH)] but which does not reflect the reality of current insulin therapy, nor the significant improvements made possible by analog insulins. Table 2. Weekly titration schedule for once-daily insulin glargine Insulin Dose Adjustment (Units) If mean of SMFPG from preceding 2 days: >180 mg/dl (10 mmol/l) mg/dl ( mmol/1) mg/dl ( mmol/1) mg/dl ( mmol/l) +2 If SMFPG during the preceding week: <72 mg/dl (<4.0 mmol/l) 0 If any severe hypoglycemia or SMFPG during preceding week: <56 mg/dl (<3.1 mmol/1) SMFPG: Self-measured fasting plasma glucose; Copyright 2003 American Diabetes Association; From Diabetes Care. 2003;26: Reprinted with permission from The American Diabetes Association JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL

4 The goal of insulin therapy is to recreate the normal pattern of pancreatic insulin secretion consisting of a low constant (basal) secretion during the interprandial period, supplemented by bursts in close approximation to food ingestion at meals. Conventional insulins fail to replicate either of these conditions. At mealtime, absorption of regular human insulin is too slow, resulting in insufficient insulin to control prandial glucose. Correctly timing the prandial doses of regular human insulin to 30 minutes before meals is often difficult for the patient. Even with optimal administration, the prolonged action of regular human insulin during the postprandial period can also predispose to hypoglycemia. Basal insulins such as NPH have undesirable peaks during the interprandial period and tend to be quite variable in their absorption, both between patients and within the same individual, which results in an unpredictable glucose-lowering effect with a given dose. This puts the user at risk of hypoglycemia and limits the dose of insulin that can be titrated safely, which is a source of frustration for healthcare providers and patients alike. INSULIN ANALOGS IN TYPE-2 DIABETES Insulin analogs [rapid-acting (prandial), long-acting (basal) and premixed (basal and prandial in one preparation)] all correct the pharmacokinetic and pharmacodynamic drawbacks of their conventional counterparts to some degree, producing a more physiological insulin time-action profile. This translates into distinct clinical advantages for patients. These points will be discussed, with examples from clinical studies where appropriate. Currently, eight insulin analogs are commercially available in the United States (Table 1). The three premixed products (BIAsp 30, and Humalog Mix 75/25. or Mix 50/5O.) are single-peak insulins containing either 30%, 25% or 50% rapid-acting insulin for prandial coverage, plus 70%, 75% or 50% protamine suspension of the respective insulin analog for basal coverage. This is in contrast to premixed human insulin, which has two distinct peaks. All of the analogs may be injected using pen-type delivery devices. The three rapid-acting insulin analogs (glulisine, lispro, aspart) appear to have very similar action profiles, reaching higher peak levels and achieving that peak much closer to injection time, compared with regular human insulin.27'28 This allows them to be administered much closer to meals than regular human insulin (i.e., minutes for insulin lispro; minutes for insulin glulisine, and minutes for insulin aspart).2913' This allows patients to more closely match mealtime insulin dose with anticipated carbohydrate intake. The tangible clinical result of these features is improved convenience and better postprandial control. This convenience of postmeal dosing is retained for BIAsp 30 ( minutes), but Mix 75/25 is only approved for premeal dosing (-15-0 minutes).29 The two basal insulin analogs, insulin detemir and insulin glargine, each have important advantages over NPH, including a prolonged duration of action without a pronounced peak.32 This lack of a pronounced peak likely contributes to the lower incidence of nocturnal and overall hypoglycemia reported for these two insulins in patients with type-2 diabetes Both basal analogs also have lower within-subject variability in blood or plasma glucose measures compared to NPH, which may lead to more consistent blood glucose readings on a day-to-day basis. There have additionally been two head-to-head comparisons in which insulin detemir showed lower variability in self-measured blood glucose compared with insulin glargine in both type-2 (P<0.00 1)32 and type-1 diabetes (P<0.001).4 Another issue to consider with insulin therapy is its effects on weight. Insulin therapy, regardless of type, has Table 3. Insulin detemir titration algorithm (insulin was administered twice daily: before breakfast and in the evening) Criteria for Titration If If Insulin Dose Adjustment (Units) Responders Nonresponders average prebreakfast/predinner plasma glucose: > 1 80 mg/di (>IOmmol/l) mg/dl ( mmol/li mg/dl ( mmol/l) mg/dl ( mmol/l) mg/dl ( mmol/l) one prebreakfast plasma glucose: mg/dl ( mmol/l) -2-4 <56 mg/dl (<3.1 mmol/l) Plasma glucose categories are based on the average of three consecutive self-measurements immediately preceding each contact. Responders: people in whom the average plasma glucose value was reduced to a lower category following the previous adjustment. Nonresponders: people in whom the average plasma glucose value remained in the same category or increased following the last adjustment. Copyright 2006 American Diabetes Association. From Diabetes Care. 2006;29: Reprinted with permission from The American Diabetes Association 360 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL 2007

5 consistently been associated with weight gain. This is true for both insulin detemir and insulin glargine. However, in several studies, insulin detemir has been shown to be associated with less weight gain compared to NPH in patients with type-2 diabetes In one observational trial involving 1,321 insulin-naive type-2 patients, insulin detemir (used mainly in conjunction with previous OADs) reduced weight by 0.9 kg after three months' treatment.4' The overall effect of insulin glargine treatment on weight is less clear. In the majority of trials, there have been no differences in weight gain between patients with type-2 diabetes treated with insulin glargine versus NPH,33,34 although in one randomized trial, 259 patients allocated to insulin glargine once-daily did gain less weight than those treated with NPH.35 NEW DELIVERY DEVICES Second- and third-generation pen-type delivery devices are now available for the injection of analog insulins. Features of these pens that represent an improvement over conventional vial-and-syringe delivery include:42 * improved accuracy of insulin delivery; * single-unit dosing increments; * audible click to confirm dose; * large easy-to-read dial; * prefilled/disposable versions and reusable, cartridge-based options; * visual confirmation of dose delivery; * less stigma/more discreet due to pen-type appearance; * less pain upon injection due to finer-gauge needles; * simpler to use for specific populations, such as older adults. Patients generally rate pens more highly over vial and syringe with respect to convenience, flexibility, quality of life and overall preference.42-" These features could potentially lead to more confidence in. insulin injection and improved adherence among insulin users. Unfortunately, the low penetration of pen use in the United States (<5% of insulin users) is in marked contrast to that in some other countries, where most (70-90%) insulin is delivered by pen.42 Cost of the devices and perceived lack of reimbursement are important contributing factors, but this ignores the much greater cost ofpoor glycemic control. A new development is the recent availability of inhaled human insulin as an alternative prandial insulin. In type-2 diabetes, clinical trials have demonstrated efficacy and safety equivalent to regular human insulin in patients suboptimally controlled with diet and exercise,45 patients using a stable injectable insulin schedule46 and patients not controlled with OADs.4748 Patient satisfaction has also been reported as improved when compared with a subcutaneous insulin regimen,49 and in one trial this persisted at 12 months.50 Most of these studies were shortterm (12-week) trials, so questions remain about longterm efficacy and safety, particularly with respect to the effects of chronic pulmonary administration. Use of inhaled insulin also does not eliminate the need for basal insulin coverage by injection, nor is it known how inhaled human insulin will compare to rapid-acting insulin analogs delivered by subcutaneous injection. Therefore, its role in diabetes care remains to be determined. INITIATING AND INTENSIFYING THERAPY WITH INSULIN ANALOGS The benefits of new insulin analogs are only fully realized if matched to optimal treatment regimens. One way to minimize the potential dose-limiting side effects of insulin therapy is to use insulin in combination with OADs, such as metformin. Depending on the drug and trial, decreases in insulin dose from 21% to 74% have been reported when used in combination with OADs.5' Besides allowing a reduction in insulin dose, there may be additional benefits; for example, metformin has a significant weight-sparing effect in addition to reducing insulin requirements by about 32%.i Table 4. Insulin dose and glycemic control in three studies comparing twice-daily premixed analog insulin + mefformin with once-daily glargine + mefformin Premixed Insulin End-of-Trial Mean Mean HbA1c at Beginning Percent Reaching [Ref_ Insulin Dose (U/kg) and End of Trial HbAic Target Premix Glargine Premix Glargine Premix Glargine BlAsp 30 [56]* 0.82 ± ± ± 1.5% 9.8 ± 1.4% 66% < 7.0% 40% < 7.0% 6.91 ± 1.17% 7.41 ± 1.24% Mix 75/25 [55]t 0.42 ± ± ± 0.95% 8.48 ± 0.80% 30% < 7.0% 12% < 7.0% 7.5 ± 0.87% 8.1 ± 1.03% Mix 75/25 [54]* 0.62 ± ± ± 1.3% 8.7 ± 1.3% 42% < 7.0% 18% < 7.0% 7.4 ± 1.1% 7.8 ± 1.1% * Insulin natve; some subjects also used thiazolidinediones, t Inadequate control with prior insulin regimen neutral protamine Hagedorn once or twice daily with or without oral agents, or human insulin; $ Insulin natve JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL

6 BASAL INSULIN An advantage of insulin/oad combination therapy is that, for some patients, adding a single dose of basal insulin to OAD therapy may provide a more comfortable transition without risking loss of glycemic control and allow gradual titration to desired doses.20 Dosing is straightforward: for insulin-naive patients, the recommended starting dose for insulin glargine is 10 units once daily,30 and for insulin detemir is units/kg/day in the evening or 10 units once or twice daily.52 Doses should then be adjusted to patient response. Switching from other basal insulins can be done on a unit-to-unit basis for either insulin detemir or insulin glargine. The manufacturer for insulin glargine does recommend reducing the initial dose by approximately 20% in order to minimize the risk of hypoglycemia when converting patients previously using NPH twice daily, but the actual starting dose may be individualized to each patient based on his/her degree of control at the time of switching. The efficacy of such an approach was demonstrated in a randomized trial comparing insulin glargine to NPH insulin in 756 overweight men and women unable to reach glycemic targets on one or two OADs.33 Mean fasting plasma glucose after 24 weeks was nearly identical for the two insulins (1 17 vs. 120 mg/dl, for glargine and NPH, respectively), as was HbAic (6.96 vs. 6.97%). A target of HbAic <7.0% was reached by about 58% of patients in each treatment group. However, more patients attained this target without nocturnal hypoglycemia in the insulin glargine group (33.2 versus 26.7%, P<0.05). The titration regimen for once-daily glargine is shown in Table 2. It has been demonstrated that insulin detemir used in a basal + OAD regimen can be safely intensified to twice-daily administration. In a 24-week, parallelgroup, treat-to-target trial, 476 patients were randomized to twice-daily insulin detemir or NPH, in conjunction with OADs.36 A target of HbAlc <7.0% was reached by 70% of patients in each group, but more in the insulin detemir group achieved the target without hypoglycemia (26 vs. 16%, P=0.008). The titration algorithm used in this study is shown in Table 3. In a 52-week multinational treat-to-target trial, 582 insulin-nayve patients with type-2 diabetes were randomized to either insulin detemir (once or twice daily) or insulin glargine once daily, as per label.53 HbAic decreased by 1.45% in both groups, and 52% in each group achieved HbA1c <7.0%. Measures of hypoglycemia were similar in both groups, as was withinpatient fasting plasma glucose. Weight gain, however, was lower for those using insulin detemir (3.0 vs. 3.9 kg for completers at 52 weeks, P=0.0 12; and 2.7 vs. 3.5 kg, for all exposed patients, P=0.03). The success of such a regimen (basal-only insulin) hinges on a patient having sufficient endogenous insulin secretion to suppress hepatic glucose production and prevent excessive postprandial glucose excursions. As discussed earlier, for many patients, as the disease progresses, endogenous insulin production will become insufficient to control postprandial glucose excursions, and a rapid-acting insulin will be needed at meals. PREMIXED INSULIN An alternative strategy for initiating insulin therapy involves use of premixed insulin analogs. Besides the convenience of using a single product, premixed insulins have the additional advantage of providing mealtime coverage from the beginning-something not available with basal insulin. This feature can also extend the usefulness of this start-up insulin regimen. Several trials using BIAsp 30 or Mix 75/25 have demonstrated that a twice-daily regimen, in conjunction with metformin, can bring the majority of patients to target and provide improved glucose control, compared to use of basal insulin alone (administered as once-daily insulin glargine) plus metformin (Table 4) All within-trial, end-of-trial comparisons of premixed insulin versus insulin glargine were significantly different (P value <0.05). In the above three trials, there were low rates of hypoglycemia overall and no significant differences in Table 5. Titration algorithm for BlAsp 30 used in the study Blood Glucose Measure Blood Glucose Measure Predinner (for OD and BID BlAsp 30) Prebreakfast (for BID BlAsp 30) ---Prelunch (for TID BlAsp 30)* mg/dl mmol/i Insulin Dose Adjustment (U) mg/di mmol/i Insulin Dose Adjustment (U) <80 <4.4-3 n/a n/a n/a < >180 >10 +9 >180 >10 +6 * People using BlAsp 30 TID could also adjust breakfast and dinner doses, but it was not recommended that more than one dose be adjusted at a time. 364 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL 2007

7 rates of severe hypoglycemia with either BIAsp 30 or Mix 75/25 compared to glargine.56 Overall minor hypoglycemia (i.e., episodes of blood glucose <56 mg/dl that were self-treated) was reported more often with BIAsp 30 compared to insulin glargine (3.4 ± 6.6 vs. 0.7 ± 2.0 episodes/patient/year, P<0.05),56 and overall hypoglycemia was slightly more frequent with Mix 75/25 (0.68 ± 1.38 vs ± 1.24 episodes/patient/30 days, P=0.041) in insulin-naive patients.54 In patients previously treated with insulin, rates of overall hypoglycemia were no different for Mix 75/25 (0.61 ± 1.41 episodes/patient/30 days) versus insulin glargine (0.44 ± 1.07 episodes/patient/30 days), P= More recently, a treat-to-target trial (1-2-3 Study) involving 100 patients not reaching target on oral therapy (with or without concurrent use of a basal insulin) demonstrated the feasibility and flexibility of an incremental approach, adding BIAsp 30 once, twice or thrice daily to existing OAD therapy, until glycemic targets were attained.57 Using only one injection of BIAsp 30 daily, a total of 41% of patients were able to reach the ADA target of HbAic <7.0%, and 21% the AACE/International Diabetes Federation (IDF) target of <6.5%. This increased to 70% and 52% of subjects when used twice daily (among those not achieving HbA,c <6.5% with once-daily therapy). Ultimately, when the small number of patients requiring thrice-daily administration were accounted for, 77% and 60% of patients overall safely achieved these respective targets. This was accomplished without increasing the frequency of major or minor hypoglycemic episodes over that reported for once- or twice-daily use. This simple and flexible dosing, providing the option to intensify without changing products or devices, may be very attractive to patients. The titration scheme used in the Study is shown in Table 5. To begin therapy, 12 units BIAsp 30 were given to insulin-naive patients. For insulin-users, those on <30 units were transferred to the identical unit dose of BIAsp 30; for those on units, the BIAsp 30 dose was started at 70% of the previous insulin dose. The dose was titrated based on average fasting plasma glucose values from three previous days. BASAL-BOLUS REGIMENS For those patients desiring tighter control and who are capable of a more aggressive and complicated insulin regimen, or for those in whom other therapies fail and more aggressive mealtime control is needed, dual analog basal-bolus multi-injection therapy is a viable option. In one 22-week randomized trial, 395 people with type-2 diabetes were randomized to an allanalog regimen with insulin aspart + insulin detemir or regular human insulin + NPH.37 Basal insulins were given once or twice daily, in accordance with prior treatment, and OADs were discontinued. Treatment with insulin detemir + aspart produced equivalent glycemic control to a similar regimen using NPH + human insulin (HbA1c 7.46 vs. 7.52%, respectively) but with less weight gain (0.52 vs kg, P=0.038) and less withinperson variability in self-measured plasma glucose (SD 21.6 vs mg/dl, P<0.001).37 Safety profiles were similar between the two treatments. In another trial of 28 weeks duration, 518 people with type-2 diabetes previously using NPH insulin with or without mealtime insulin were randomized to either insulin glargine oncedaily (n=259) or NPH once or twice daily.35 Premeal insulin was continued based on prior usage (n=161, 62.2% with glargine and n=167, 64.4% for NPH). Both regimens produced similar mean change in baseline HbA1c (-0.41 ± 0.1% vs ± 0.1%, for the glargine and NPH groups, respectively. Subjects in the insulin glargine group gained less weight than those using NPH (0.4 vs. 1.4 kg, P<0.0007). Whether a premixed regimen versus a basal-bolus regimen is best depends on the characteristics of each individual patient, particularly the degree to which he/she is able and willing to adhere to a complex insulin regimen, as both regimens are effective in controlling blood sugars. In a randomized treat-to-target trial comparing twice-daily BIAsp 30 (n=178) to basal-bolus therapy with detemir + aspart (n=537),58 a total of 50% of patients treated with BIAsp 30 and 60% treated with detemir + aspart reached an HbAic <7.0% even though titration was not particularly aggressive and OADs were not used. These results indicated that for this patient population, BIAsp 30 (HbA1c decreased by 1.23%) was nearly as effective as a basal-bolus regimen (HbA,c decreased by 1.56%). Given that basal-bolus therapy can be more complex to teach and implement, in some patients, the more -convenient premixed insulin analog regimens may be an effective alternative in patients otherwise requiring multiple daily injections of basal and prandial insulin. CONCLUSIONS The development of insulin analogs and premixed insulin analogs, novel therapy regimens and treatment algorithms, and improved delivery devices provide an array ofnew tools that should be very helpful in overcoming traditional barriers to earlier initiation of insulin therapy. The improved action profiles, more predictable glucose-lowering effect and improved convenience now available with modern analog insulins should allow more patients to titrate their dose sufficiently to reach recommended targets without increasing the risk of hypoglycemia. The range of options now available provides new opportunities to tailor diabetes self-management programs to the needs of individual patients. Insulin treatment has never been safer or more convenient. Greater patient acceptance and improved overall control will be the result once physicians become familiar with these tools and incorporate them into daily practice. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL

8 REFERENCES 1. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for Diabetes Care. 2004;27: Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey Diabetes Care. 2006;29: del Prato S. Loss of eary insulin secretion leads to postprandial hyperglycaemia. Diabetologia. 2003;46(suppl 1 ):M2-M8. 4. DECODE Study Group, the European Diabetes Epidemiology Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intem Med. 2001;1 61: Leiter LA, Ceriello A, Davidson JA, et al. International Prandial Glucose Regulation Study Group. Postprandial glucose regulation: new data and new implications. Clin Ther. 2005;27(suppl B):S42-S Khaw KT, Wareham N, Bingham S, et al. Association of hemoglobin Al C with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intem Med. 2004;141 : Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ. 2001;322: Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(lc). Diabetes Care. 2003;26: Dungan KM, Buse JB, Largay J, et al. 1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care. 2006;29: Brown JB, Nichols GA, Perry A. The burden of treatment failure in type 2 diabetes. Diabetes Care. 2004;27: Bergenstal RM. Treatment models from the International Diabetes Center: advancing from oral agents to insulin therapy in type 2 diabetes. Endocr Pract. 2006;1 2(suppl 1): Riddle MC. Glycemic management of type 2 diabetes: an emerging strategy with oral agents, insulins, and combinations. Endocrinol Metab Clin N Am. 2005;34: Resnick HE, Foster GL, Bardsley J, et al. Achievement of American Diabetes Association clinical practice recommendations among U.S. adults with diabetes, : the National Health and Nutrition Examination Survey. Diabetes Care. 2006;29: Harris Ml, Eastman RC, Cowie CC, et al. Racial and ethnic differences in glycemic control of adults with type 2 diabetes. Diabetes Care. 1999;22: Alberti G, Zimmet P, Shaw J, et al. Consensus Workshop Group. Type 2 diabetes in the young: the evolving epidemic: the international diabetes federation consensus workshop. Diabetes Care. 2004;27: Gavin JR 111. How can we implement current therapies and interventions to achieve glycemic control? Endocr Pract. 2006;12 (Suppl. 1): Chan JL, Abrahamson MJ. Pharmacological management of type 2 diabetes mellitus: rationale for rational use of insulin. Mayo Clin Proc. 2003;78: Lebovitz HE, Austin MM, Blonde L, et al. ACE/AACE Diabetes Recommendations Implementation Writing Committee. ACE/AACE consensus conference on the implementation of outpatient management of diabetes mellitus: consensus conference recommendations. Endocr Pract. 2006;1 2 (Suppl. 1): Bell DS. The case for combination therapy as first-line treatment for the type 2 diabetic patient. Treat Endocrinol. 2006; 5: Riddle MC. Timely initiation of basal insulin. Am J Med. 2004; 1 16(3A):3S-9S. 21. Monnier L, Benichou M, ChArra-Ebrard 5, et al. An overview of the rationale for pharmacological strategies in type 2 diabetes: from the evidence to new perspectives. Diabetes Metab. 2005;31: Mooradian AD. Towards single-tablet therapy for type 2 diabetes mellitus. Rationale and recent developments. Treat Endocrinol. 2004;3: Davidson J, Jellinger P, Blonde L, et al. ACE/AACE Diabetes Road Map Task Force. Road map for the prevention and treatment of type 2 diabetes Accessed May 6, Jeavons D, Hungin AP, Cornford CS. Patients with poorly controlled diabetes in primary care: healthcare clinicians' beliefs and attitudes. Postgrad Med J. 2006;82: Polonsky WH, Fisher L, Guzman S, et al. Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem. Diabetes Care. 2005;28: Cramer JA. A systematic review of adherence with medications for diabetes. Diabetes Care. 2004;27: Becker RH, Frick AD, Burger F, et al. A comparison of the steady-state pharmacokinetics and pharmacodynamics of a novel rapid-acting insulin analog, insulin glulisine, and regular human insulin in healthy volunteers using the euglycemic clamp technique. Exp Clin Endocrinol Diabetes. 2005; 1 1 3: Homko C, Deluzio A, Jimenez C, et al. Comparison of insulin aspart and lispro: pharmacokinetic and metabolic effects. Diabetes Care. 2003;26: Product insert Product insert Product insert. humalog%20prescribing% Klein 0, Lynge J, Endahl L, et al. Insulin detemir and insulin glargine: similar time-action profiles in subjects with type 2 diabetes. Diabetes 2006;55 (Suppl. 1):A76 (Abstract 325-OR). 33. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26: Yki-Jarvinen H, Dressler A, Ziemen M; HOE 901/300s Study Group. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. HOE 901/3002 Study Group. Diabetes Care. 2000;23: Rosenstock J, Schwartz SL, Clark CM Jr, et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care. 2001;24: Hermansen K, Davies M, Derezinski T, et al., on behalf of the Levemir Treat-to-Target Study Group. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care. 2006; 29: Raslova K, Bogoev M, Raz 1, et al. Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. Diabetes Res Clin Pract. 2004;66: Erratum in: Diabetes Res Clin Pract. 2006;72: Haak T, Tiengo A, Draeger E, et al. Lower 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 Obes Metab. 2005;7: Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargire, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49: Heise 2004: Heise T, Nosek L, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53: Dornhorst A, Merilainen M, Ratzmann KP. Initiating insulin detemir improves glycemic control without weight gain in OAD-treated insulin nacfve patients with type 2 diabetes: Results from a German subgroup of the PREDICTIVE study. Diabetes. 2006;55(suppl 1 ):A1 10(abstract 462-P). 42. Bohannon NJ. Insulin delivery using pen devices. Simple-to-use tools may help young and old alike. Postgrad Med. 1999;106:57-58,61-64, Korytkowski M, Niskanen L, Asakura T. FlexPen: addressing issues of confidence and convenience in insulin delivery. Clin Ther. 2005:27(suppl B): S89-S Graff MR. McClanahan MA. Assessment by patients with diabetes melli- 366 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL 2007

9 tus of two insulin pen delivery systems versus a vial and syringe. Clin Ther ;20: DeFronzo RA, Bergenstal RM, Cefalu WT, et al. Exubera Phase Ill Study Group. Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise: a 12-week, randomized, comparative trial. Diabetes Care. 2005;28: Cefalu WT, Skyler JS, Kourides IA, et al. Inhaled Insulin Study Group. Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann Intern Med. 2001;134: Weiss SR, Cheng SL, Kourides IA, et al. Inhaled Insulin Phase 11 Study Group. Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial. Arch Intem Med. 2003;163: Rosenstock J, Zinman B, Murphy LJ, et al. Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2005;1 43: Cappeller JC, Cefalu WT, Rosenstock J, et al. Treatment satisfaction in type 2 diabetes: a comparison between an inhaled insulin regimen and a subcutaneous insulin regimen. Clin Ther. 2002;24: Rosenstock J, Cappelleri JC, Bolinder B, et al. Patient satisfaction and glycemic control after 1 year with inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes. Diabetes Care. 2004;27: Yki-Jarvinen H. Combination therapies with insulin in type 2 diabetes. Diabetes Care ;4: Product insert Rosenstock J, Davies M, Home PD, et al. Insulin detemir added to oral anti-diabetic drugs in type 2 diabetes provides glycemic control comparable to insulin glargine with less weight gain. Diabetes. 2006;55(suppl 1 ):A 132(abstract 555-P). 54. Malone JK, Kerr LF, Campaigne BN, et al. Lispro Mixture-Glargine Study Group. Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther. 2004;26: Malone JK, Bai S, Campaigne BN, et al. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with Type 2 diabetes. Diabet Med. 2005; 22: Raskin P, Allen E, Hollander P, et al. INITIATE Study Group. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28: Garber AJ, Wahlen J, Wahl T, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (the study). Diabetes Obes Metab. 2006;8: Leibl A, Prager R, Kaiser M, et al. Biphasic insulin aspart 30 (BlAsp 30), insulin detemir (IDet) and insulin aspart (lasp) allow patients with type 2 diabetes to reach Aic target: the PREFER study. Diabetes. 2006;55(suppl 1 ):A1 23(abstract 51 7-P). U We Welcome Your Comments The Journal of the National Medical Association welcomes your Letters to the Editor about articles that appear in the JNMA or issues relevant to minority healthcare. Address correspondence to EditorJNMA@nnmanet.org. ~~~~~~~~~~~~~~~~~~~~~~~~~~~ NMA National Medical 7 ll..~ l, lg 4!>'>'0Association ( 3tU t lee: 7 _ 2007 Annual Convention and Scientific Assembly f/%8t 69me,awmz 9 -. E. Maui, Hawaii * August 9-12, 2007 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION VOL. 99, NO. 4, APRIL