Insulin therapy in type 2 diabetes

Insulin therapy in type 2 diabetes

Trent Davis, MD, Steven V. Edelman, MD*

3350 La Jolla Village Drive 111G, San Diego, CA 92161, USA

Diabetes mellitus affects approximately 18 million people in the United States, which is approximately 6% of the overall population, and over 800,000 new cases are diagnosed annually [1]. Diabetes may actually be more endemic than these figures indicate because there are no symptoms in the early stages of the disease, and potentially one undiagnosed individual exists for every one that is identified[2]. Of the total diabetic population, 85% to 90% of individuals have type 2 diabetes whereas 10% to 15% have type 1 diabetes[3].

Type 2 diabetes leads to a tremendous amount of death and disability and uses a large portion of the health care dollar[4]. Although diabetes is associated with multiple disorders with distinct pathologic mechanisms, insulin resistance is the common denominator and is associated with several comorbidities, including obesity, hypertension, and vascular disease. The natural history of the disease is often complicated by various microvascular and macrovascular sequelae that can lead to blindness, end-stage renal disease, lower-extremity amputation, and atherosclerosis resulting in heart attack or stroke [3,5]. Although most of the human suffering is caused by end-stage microvascular disease, 80% of diabetics die of macrovascular cardiovascular disease. There is now clear evidence from the United Kingdom Prospective Diabetes Study (UKPDS) and the Kumamoto study that improved glycemic control through intensive diabetes management delays the onset and significantly retards the progression of microvascular complications in patients with type 2 diabetes mellitus[6,7]. The results from the UKPDS are reassuring in that, although intensive treatment with insulin was associated with increased weight gain and hypoglycemia, there is no evidence of any harmful effect of insulin on cardiovascular outcomes, which has been a controversial issue. An epidemiologic analysis of the UKPDS

* Corresponding author.

E-mail address:svedelman@vapop.ucsd.edu(S.V. Edelman).

0025-7125/04/$ - see front matter2004 Elsevier Inc. All rights reserved. doi:10.1016/j.mcna.2004.04.005

data shows a continuous association between the risk of cardiovascular complications and glycemia, such that for every percentage point of decrease in HbA1c(eg, from 9% to 8%), there is a 25% reduction in diabetes-related

deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction[6].

To achieve glycemic goals in patients with type 2 diabetes, we now have multiple pharmacologic agents with different mechanisms of action, in-cluding sulfonylureas, meglitinides, metformin, a-glucosidase inhibitors, thiazolidinediones, and insulin. It must be emphasized, however, that unlike patients with type 1 diabetes, who have no significant insulin secretion and hence require insulin therapy from the onset of their disease, a prominent feature in the early stages of the disease for patients with type 2 diabetes is insulin resistance with hyperinsulinemia. Therefore, improving insulin sensitivity be means of caloric restriction, exercise, and weight management early in the disease process will benefit type 2 diabetics. When these measures fail, glycemic goals can often be achieved with oral agents used alone or in combination with each other. When patients are diagnosed late in the natural history, however, there is progressive loss of pancreatic beta-cell function and endogenous insulin secretion, making diurnal glycemic control difficult. At this late stage, most patients require exogenous insulin therapy to achieve optimal glucose control. The American Diabetes Association (ADA) now recommends that the glycemic objective for patients with type 2 diabetes to normalize glycemia and glycosylated hemoglobin concentrations should be similar to that for type 1 diabetes.

Pathogenesis and natural history of type 2 diabetes

Of the Americans diagnosed with type 2 diabetes, 80% to 90% are obese, and the remainder are lean [8]. The genesis of hyperglycemia in type 2 diabetes involves a triad of abnormalities: excessive hepatic glucose pro-duction, impaired pancreatic insulin secretion, and peripheral resistance to insulin action, occurring principally in liver and muscle tissue [9]. The severity of these abnormalities and their contribution to the degree of hyperglycemia can vary considerably, causing heterogeneity in the metabolic expression of the diabetic state. Such differences are best exemplified by the lean and obese varieties of type 2 diabetes, which have the same underlying pathophysiologic basis but differ in the extent to which each abnormality contributes to the development of the hyperglycemic state. Of these ab-normalities, peripheral insulin resistance to insulin action and impaired pancreatic beta-cell secretion are early and primary abnormalities, whereas increased hepatic glucose production is a late and secondary manifestation. Early in their disease, patients with type 2 diabetes compensate for increased insulin resistance at the tissue level by increasing pancreatic beta-cell insulin secretion[10]. When this compensation is no longer adequate to overcome

the insulin resistance, blood glucose levels begin to rise. Over the course of the disease, endogenous insulin levels slowly begin to decrease and, ultimately, many patients with type 2 diabetes are unable to achieve optimal glycemic control with oral agents[11].

In subjects with type 2 diabetes who are lean, impaired insulin secretion is the predominant defect, and insulin resistance tends to be less severe than in the obese variety [12]. On the other hand, insulin resistance and hyper-insulinemia are the classical abnormalities of obese persons with type 2 diabetes [12]. In type 2 diabetes, insulin secretion is often excessive compared with the nondiabetic situation but is still insufficient to overcome the insulin resistance that is present. It is important to understand and appreciate these fundamental differences when considering insulin therapy in type 2 diabetes. Based on this knowledge, lean type 2 diabetic subjects usually fail oral agents faster and will require considerably less insulin to control their hyperglycemia than their obese counterparts. In contrast, large doses of exogenous insulin are the rule in the obese form of this disorder when euglycemia is desired[13].

The need for large amounts of exogenous insulin in obese type 2 diabetes also raises the question of the most appropriate methods of insulin delivery. Under normal circumstances, insulin is secreted from the pancreas into the portal vein, going directly to the liver in which a large first-pass extraction of portal insulin occurs [14]. When insulin is injected subcutaneously, absorption occurs directly into the peripheral circulation, without the initial effects of hepatic extraction. Therefore, the tissues are exposed to greater levels of insulin than if insulin was provided by the portal route. Because the primary target of exogenous insulin is the liver, type 2 diabetes may be uniquely suited to delivery of insulin through the portal vein. Such a situation occurs when insulin is delivered intraperitoneally, and the majority of insulin is absorbed into the portal circulation[15]. Intraperitoneal insulin delivery systems will not be discussed in this section, however, this method holds considerable promise in type 2 diabetes because of the more physiologic delivery of insulin and because of selective and effective inhibition of hepatic glucose output, with less peripheral insulinemia than occurs with subcutaneous insulin injections[16].

Intensive insulin therapy

Successful insulin management requires an educated and motivated patient, as well as the participation of a multidisciplinary health care team. Intensive insulin therapy requires a substantial input of physician and support staff time, which has a significant economic impact on the health care system [17]. Although long-term data on costs are not yet available, projections suggest that substantial savings from the high costs of end-stage disease could be achieved by following ADA guidelines [18].

Furthermore, as discussed later, we now have the opportunity to use combinations of insulin and a variety of oral antidiabetic agents with differing mechanisms of action. The use of these potent combinations permit us to safely and effectively lower blood glucose levels and to achieve ADA target glycemic levels with relatively low risk for hypogly-cemia or weight gain.

In addition to the natural history of type 2 diabetes, there is heterogeneity in the pathophysiology of type 2 diabetes mellitus that may influence when patients require insulin. Some patients who have been diagnosed with type 2 diabetes may actually have a condition more closely related to insulin-dependent or type 1 diabetes, with severe insulinopenia. Many of these pa-tients have been shown to have islet cell antibody positivity or antibodies to glutamic acid decarboxylase, with a decreased C-peptide response to glucagon stimulation and a propensity for primary oral medication failure [19]. These individuals are now labeled with the conditionlatent autoimmune diabetes in adults[20]. There are also wide geographic and racial differences that may influence the need for insulin therapy. For example, Asian patients with type 2 diabetes tend to be thinner, are diagnosed with diabetes at an earlier age, fail oral hypoglycemic agents much sooner, and are more sensitive to insulin therapy than the classic centrally obese patient in the United States and some parts of Europe[21].

The goals of therapy should be tailored to individual patients. Candidates for intensive management should be motivated, compliant, and educable, and be without other medical conditions and physical limitations that preclude accurate and reliable home glucose monitoring (HGM) and insulin administration; caution is advised in patients who are aged or have hypo-glycemic unawareness. Other limitations to achieving normoglycemia may include high titers of insulin antibodies, especially in patients with a history of intermittent use of insulin of animal origin. The site of insulin injection also may change the pharmacokinetics, and absorption can be highly variable, especially if lipohypertrophy is present. The periumbilical area has been shown to be one of the most desirable areas to inject insulin because of the rapid and consistent absorption kinetics observed at this location; however, rotating the injection site is usually advised[22]. It is also advisable to inject in the same body location for a certain meal time (ie, triceps fat pad for breakfast, abdomen for lunch, and upper thighs for dinner)[23].

In summary, before starting insulin therapy, the patient should be well educated in the techniques of HGM, proper insulin administration, and self-adjustment of the insulin dose, if appropriate, as well as knowledgeable about dietary and exercise strategies, including carbohydrate counting. The patient and family members also need to be informed about hypoglycemia prevention, recognition, and treatment. Initial and ongoing education by a diabetes management team, including a certified diabetes educator, is crucial for long-term success and safety.

Insulin treatment strategies

Combination therapy

Combination therapy usually refers to the use of daytime oral antidia-betic agents together with a single injection of intermediate or long-acting insulin at bedtime. Several studies [24–36] have looked at the safety and efficacy of combination therapy. For many of the reasons mentioned earlier, the analysis of studies to evaluate the efficacy and safety of combination therapy is difficult. Several review articles using meta-analysis conclude that combination therapy results in only modest improvements in glucose con-trol and contribute to increased medical costs of diabetes management compared with insulin therapy alone. These earlier studies, however, were conducted when sulfonylureas were the only available type of oral agent. Because of heterogeneity in type 2 diabetes together with variability in the design and clinical situations of previous studies, however, the use of meta-analysis may be inappropriate for making generalized statements regarding this form of therapy [27,37]. Based on several recent reports, the use of combination therapy has been quite successful in selected patients, especially with the newer oral agents used alone or together with insulin [26– 29,35,36,38–41].

For a number of practical reasons, combination therapy may be beneficial. The patient does not need to learn how to mix different types of insulin, and patient compliance and acceptance are better with a single injection than with multiple injections of insulin. Combination therapy also requires a lower total dose of exogenous insulin than regimens of two or three injections per day. Combination therapy also contributes to less weight gain and peripheral hyperinsulinemia. Last, combination therapy is ideally suited to suppress excessive hepatic glucose production overnight.

The rationale for combination therapy with insulin and sulfonylureas is based on the assumption that, if evening insulin lowers the fasting glucose concentration to normal, then daytime oral agents will be more effective in controlling postprandial hyperglycemia and maintaining euglycemia throughout the day. Metabolic profiles of patients who have type 2 diabetes have demonstrated that fasting blood glucose contributes significantly to daytime hyperglycemia[42]. In addition, the fasting blood glucose concen-tration is highly correlated with the degree of hepatic glucose production during the early morning hours [13]. Hepatic glucose output is directly decreased by insulin[43]and indirectly inhibited by the ability of insulin to reduce adipose tissue lipolysis, with lower concentrations of free fatty acids and gluconeogenesis [41]. Also, the peak of bedtime intermediate-acting insulin coincides with the onset of the dawn phenomenon (early morning resistance to insulin caused by diurnal variations in growth hormone and possibly in levels of norepinephrine), which usually occurs between 3 and 7 AM. Bedtime insulin also increases the morning serum insulin

concentration and may assist in reducing the post-breakfast glucose rise in addition to the fasting value.

Combination of insulin and sulfonylurea agents

In one of the first large studies demonstrating the efficacy of insulin/ sulfonylurea combination therapy, Yki-Jarvinen et al [38] compared com-bination therapy with regimens of two and four insulin injections per day in patients with type 2 diabetes. These patients were on submaximal doses of glyburide (12.5 mg/d), glipizide (20 mg/d), and metformin (1.4 g/d), with fasting blood glucose concentrations at approximately 225 mg/dL and mean fasting serum C-peptide values of 0.66 nmol/L. After 3 months, all treatment groups had similar reductions in mean diurnal glucose con-centrations and glycosylated hemoglobin levels (1.6%–1.9%) compared with the control group, who were taking oral agents alone. The group treated with a combination of oral agents and bedtime neutral protamine Hagedorn (NPH) insulin, however, had the least weight gain (1.20.5 kg) of any group and a 50% to 65% lower increment in mean diurnal serum-free insulin concentrations. There was no evidence of severe hypoglycemia with combination therapy, and patient acceptance was excellent.

Several other recent publications [26,28,29,31,34,40] also support the additional efficacy and safety of combination therapy in patients who are inadequately controlled by oral hypoglycemic agents alone. A recent study conducted by Riddle and Schneider[36]demonstrates the efficacy and safety of a combination consisting of 70% NPH insulin and 30% regular insulin (70/30) insulin at dinnertime and sulfonylurea therapy. In this study, 145 type 2 diabetics with uncontrolled hyperglycemia (fasting plasma glucose level [FPG] 180–300 mg/dL), on maximum sulfonylurea therapy (glimepir-ide, 8 mg orally, twice daily) were randomized to placebo plus insulin or glimepiride plus insulin for 6 months. The dose of 70/30 insulin at dinnertime was titrated to keep fasting fingerstick capillary blood glucose to less than 120 mg/dL. At 24 weeks, HbA1clevels decreased significantly

and similarly in both groups (9.9%–7.6%). The combination therapy group, however, needed nearly 35% less insulin than the insulin-only group (49 versus 78 units) and achieved glycemic control faster, with fewer dropouts (3% versus 15%,P\0.01). Surprisingly, weight gain was similar (4.0 kg) in both groups.

Insulin and metformin

Weight gain is a constant occurrence in most clinical trials in which insulin or sulfonylureas, or both agents, are used to treat type 2 diabetes. Although it was attenuated with combination therapy with sulfonylureas in the study by Yki-Jarvinen[38], weight gain remains a problem because it can exacerbate insulin resistance and hyperinsulinemia. The use of metformin in

this situation may prove advantageous because its use is associated with reduced weight gain.

The safety and efficacy of metformin in combination with insulin has been demonstrated in a recent multicenter study by Yki-Jarvinen et al[35]. In this placebo-controlled study, 96 type 2 diabetics who were poorly controlled with oral sulfonylurea therapy (mean glycosylated hemoglobin value 9.9%0.2%; mean fasting plasma glucose level 2145 mg/dL) were randomized to 1 year of treatment with bedtime intermediate-acting insulin plus either glyburide (10.5 mg), metformin (2 g), glyburide and metformin, or a second injection of intermediate-acting insulin in the morning. Patients were taught to adjust the bedtime insulin dose on the basis of fasting glucose measurements. At 1 year, body weight remained unchanged in patients receiving bedtime insulin plus metformin (mean change 0.9 1.2 kg) but increased by 3.90.7 kg, 3.61.2 kg, and 4.61.0 kg, respectively, in patients receiving bedtime insulin plus glyburide, bedtime insulin plus both oral drugs, and bedtime and morning insulin. In addition, the greatest decrease in the glycosylated hemoglobin value was observed in the bedtime insulin and metformin group (from 9.70.4% to 7.20.2%, a difference of 2.5 0.4 percentage points) at 1 year (P 0.001 compared with baseline andP 0.05 compared with other groups). This group also had significantly fewer symptomatic and biochemical cases of hypoglycemia (P0.05) than the other groups. The authors conclude that combination therapy with bedtime insulin plus metformin not only prevents weight gain but also seems superior to other bedtime insulin regimens, with respect to improvements in glycemic control and frequency of hypoglycemia.

In a more recent study [44] of approximately 390 type 2 diabetics, the combination of insulin and metformin led to a significant improvement in glycemic control that was greater than with insulin alone. The mean daily glucose level decreased from 14134 to 13731 mg/dL in the insulin-only group (mean decrease0.16; 95% confidence interval [CI];10–4 mg/dL) and from 14140 to 14031 mg/dL in the metformin group (P= 0.006 versus placebo; mean decrease 1.04; 95% CI; 27 to 9 mg/dL). The mean daily glucose level decreased by 13 mg/dL more in the metformin group compared with the placebo groupFig 1.

Insulin and thiazolidinediones

The glitazones are potent insulin sensitizers and are, therefore, well suited for use in insulin-resistant patients with type 2 diabetes. In several early studies, troglitazone was documented to not only improve glycemic control but also to reduce exogenous insulin requirements in obese patients with type 2 diabetes [45,46]; however, troglitazone was withdrawn from the US market as a result of an increased risk of severe idiosyncratic liver damage. Presently there are two glitazones available, rosiglitazone and pioglitazone, for clinical use in the US, and several more are in development.

In one 16-week study, Rubin et al[47]demonstrated that the daily addition of 15 and 30 mg of pioglitazone to the regimen of patients receiving a median dose of 61 units of insulin resulted in mean FPG reductions of 36 and 49 mg/ dL and HbA1creductions of 0.7% and 1.0%, respectively, compared with

placebo. The insulin-sparing properties of rosiglitazone were shown in a 6-month study conducted by Raskin et al [48]. They demonstrated that the addition of 2 and 4 mg orally twice daily of rosiglitazone improved HbA1c

Fig. 1. (A) Blood glucose levels measured at home. (B) Change in blood glucose levels measured at home. Data are means with SD error bars. For each time point indicated, the first and the second bars show values at baseline and the third and the fourth show values at 16 weeks. Blood glucose levels in the metformin group compared with the placebo group are all significantly lower at 16 weeks (P0.05). The change in glucose values is also significantly greater in the metformin than in the placebo group at all times during the day (P0.05). (From

Wulffele MG, Kooy K, Lehert P. Bets D Ogterop JC, Van Der Burg BB, Donker AJM, Stehouwer CDA. Combination of insulin and metformin in the treatment of type 2 diabetes. Diabetes Care 2002;25(12):2133–40; with permission.)

levels by 0.6% and 1.2%, respectively, compared with placebo, in 312 patients with type 2 diabetes who were uncontrolled on approximately 70 units of insulin daily (baseline HbA1c9%). Moreover, insulin requirements

were also reduced by approximately 5 and 10 units, respectively, in the two groups treated with rosiglitazone, in keeping with the insulin sensitizing effects of the glitazones. In summary, both rosiglitazone and pioglitazone improve glucose control in poorly controlled, insulin-treated patients with type 2 diabetes mellitus. There have been no reports of insulin added to subjects treated with glitazones alone.

Insulin anda-glucosidase inhibitors

The addition of acarbose to insulin therapy may be an option in patients who have pronounced postprandial hyperglycemia. The first long-term controlled study to demonstrate a beneficial effect of acarbose in patients on insulin therapy was reported by Chiasson et al[49]. Of the total number of patients in this study, 91 were receiving insulin and had glycosylated hemoglobin values greater than 7%. Postprandial plasma glucose levels at 90 minutes were significantly reduced to 282 mg/dL with the addition of acarbose, compared with 331 mg/dL seen with insulin alone. Glycosylated hemoglobin values decreased by 0.4% in the acarbose group, but, as ex-pected, no significant decreases in fasting plasma glucose levels were seen. Acarbose may be initiated in patients on insulin treatment by starting with a low dose of 25 mg with breakfast and titrating up by 25 mg weekly to 50 to 100 mg three times daily with meals (100 mg three times daily for patients60 kg body weight), depending on gastrointestinal tolerance and efficacy.

Insulin glargine and oral agents

The long-acting analog insulin glargine was studied in comparison with NPH insulin in 756 patients with type 2 diabetes in an open-label, 24-week, multicenter study [50]. In this study, patients who were inadequately controlled on oral agents including sulfonylurea, metformin, and glitazones were randomized to receive either bedtime insulin glargine or NPH insulin, and the doses were adjusted to obtain a target fasting glucose level of less than 100 mg/dL (5.6 mmol/L). At the conclusion of the trial, the median daily dose of insulin was approximately 0.45 IU/kg of body weight in both groups. The two forms of insulin produced a similar improvement in HbA1c

(6.96 versus 6.97%) and similar reductions in fasting glucose levels (117 versus 120 mg/dL); however, the incidence of mild nocturnal hypoglycemia was significantly lower among patients treated with insulin glargine than in the group treated with NPH insulin (P\0.001)[50]. There was a reduction of approximately 45% of nocturnal hypoglycemia with glargine compared

with NPH[50]. Treatment with NPH or glargine in addition to oral therapy in type 2 diabetic patients resulted in a decrease of fasting glucose in both groups, reaching a plateau by 12 weeks. HbA1c declined at a predictably

slower rate, stabilizing after 18 weeks (Fig. 2)[50].

Fig. 2. (A) FPG and (B) HbA1cduring the study. Values in both figures are means; error bars

indicate SE. (FromRiddle MC, Rosenstock J, Gerich J. 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(11):3080–6; with permission.)

Selection of patients most likely to succeed on combination treatment

The most common type of patient in whom combination therapy will succeed is the one who is failing oral treatment without significant glucose toxicity and has some evidence of responsiveness to oral agents. Patients have a higher likelihood of success using combination therapy if they are obese, have had overt diabetes for less than 10 to 15 years, are diagnosed with type 2 diabetes after the age of 35, do not have fasting blood glucose values consistently over 250 to 300 mg/dL, and have evidence of endogenous insulin secretory ability. Although standard measurement conditions and C-peptide concentrations have not been established for this clinical situation, a fasting C-peptide concentration (0.2 nmol/L) or glucagon-stimulated level (0.40 nmol/L) indicates some degree of endogenous insulin secretory ability[51,52]. Patients with type 2 diabetes diagnosed before the age of 35 more often have atypical forms of diabetes. Patients who have had diabetes for more than 10 to 15 years tend to have a greater chance of beta-cell exhaustion and, thus, tend to be less responsive to oral hypoglycemic agents and combination therapy. Thin patients are more likely to be hypoinsuli-nemic and often respond inadequately to oral agents, which lead to combination therapy failure. In addition, markedly elevated fasting glucose concentration is often associated with a concomitant decrease in endoge-nous insulin secretory ability, which renders oral agents ineffective. The actual number of patients who might respond favorably to combination therapy is unknown but is estimated to be between 20% and 40%.

Initiating combination therapy

Calculation of the initial bedtime dose of intermediate-acting insulin can be based on clinical judgment or various formulas based on the fasting blood glucose concentration or body weight. For example, the average fasting blood glucose (mg/dL) can be divided by 18 or body weight (kg) can be divided by 10 to calculate the initial dose of NPH or insulin glargine to be started at bedtime[43]. Also, 5 to 10 units of insulin can be safely started for thin patients, and 10 to 15 units can be started for obese patients at bedtime, as an initial estimated dose. In either case, the dose is increased in increments of 2 to 5 units every 3 to 4 days until the morning fasting blood glucose concentration is consistently in the range of 70 to 120 mg/dL[53].

The best time to give the evening injection of intermediate-acting insulin is between 10 PM and midnight. Insulin glargine has been shown to be effective when taken either in the morning or evening. Many reliable pa-tients can make their own adjustments using HGM.

Based on the results of HGM, combination therapy can be altered to reduce hyperglycemia at identified times during the day. For example, a common situation seen with daytime oral agents and bedtime intermediate-acting insulin therapy is an improvement in the fasting, lunch, and pre-dinner blood sugar values, although the post-pre-dinner blood glucose

concentration remains excessively high (200 mg/dL). In this clinical situation, an injection of premixed insulin (70/30 or 75/25 mix) can be given before dinner instead of a bedtime dose of intermediate- or long-acting insulin. This regimen will often improve the post-dinner blood glucose values because the premixed insulin contains rapid-acting analogs yet allows overnight glucose control secondary to the intermediate-acting component. With this regimen, however, one must be more cautious about early morning hypoglycemia because the intermediate-acting insulin given before dinner will exert its peak effect earlier. In the experience of these authors, this has not been a major clinical problem in obese patients with type 2 diabetes compared with those with type 1 diabetes mellitus. Normally the dose of bedtime intermediate- or long-acting insulin can be converted to the dose of premixed insulin, dose per dose, and adjustments can be made through HGM.

Dose adjustment

Once the fasting blood glucose concentrations are consistently in a desir-able range, the pre-lunch, pre-dinner, and bedtime blood sugar values must be monitored to determine if the oral hypoglycemic agents are maintaining daylong glycemia. It is recommended that after the addition of evening insulin patients continue to take the maximal dose of the oral sulfonylurea agent. If the daytime blood glucose concentrations become excessively low, the dose of oral medication must be reduced. The morning dose of sul-fonylurea should be reduced or discontinued first. This situation is common because glucose toxicity may be reduced because of improved glucose control, leading to enhanced sensitivity to both oral agents and insulin. If the pre-lunch and pre-dinner blood glucose concentrations remain exces-sively high on combination therapy, it is likely that the oral agents are not contributing significantly to glycemic control throughout the day. In this situation, a more conventional or intensive regimen of two injections per day is indicated.

Multiple-injection regimens

One of the most common insulin regimens used in type 2 diabetes mellitus is the split-mixed regimen consisting of a pre-breakfast and pre-dinner dose of intermediate- and fast-acting insulin. This split-mixed regimen of two injections per day is often inadequate for patients with type 1 or lean patients with type 2 diabetes and can result in persistent early morning hypoglycemia and fasting hyperglycemia. Such problems do not appear to occur as frequently in obese type 2 diabetes. This is likely caused by pathophysiologic differences, particularly in endogenous insulin secretory ability, insulin resistance, and counter-regulatory mechanisms in type 1 and type 2 diabetes.

In a landmark trial with type 2 diabetes by Henry et al[54], daylong gly-cemia and glycosylated hemoglobin were essentially normalized by 6 months of intensive treatment with a split-mixed insulin regimen. In this study, 14 typical obese patients with type 2 diabetes mellitus (age 59 2 years; duration of diabetes 7 2 years; body mass index 31 2 kg/m2; fasting blood glucose concentration 283 13 mg/dL) failing therapy with oral antidiabetic agents were intensively managed with breakfast and pre-dinner NPH and regular insulin over a 6-month period. The insulin dose was adjusted based on HGM results of four injections per day. Glycemic control was rapidly achieved within 1 month and was maintained for the duration of the study.

The average total insulin dose needed to maintain glycemic control approached 100 units per day, with approximately 50% of the total dose required before breakfast and 50% before dinner. The ratio of NPH to regular insulin was approximately 75%:25%. There was a very low incidence of mild hypoglycemic reactions, which decreased as the study progressed, and no reactions were severe or required assistance. In addition, patient compliance and sense of well being were excellent. Near-normalization of the glycosylated hemoglobin, however, led to some adverse effects in these patients. The mean serum insulin concentration obtained during 24-hour metabolic profile studies increased from 308 80 pmol/L at baseline to 510 102 pmol/L (P 0.05) at completion of the 6-month study. The exacerbation of hyperinsulinemia by exogenous insulin therapy was strongly correlated with weight gain throughout the study. Despite biweekly visits with the study dietitian and instructions to reduce the daily caloric intake, a mean weight gain of approximately 9 kg or 18.8 pounds occurred. Interestingly, the total daily insulin dose was 86þ13 units at 1 month and 100þ24 units at 6 months, despite minimal additional improvement in glycemic control during that period. Most of the improvement in glycemic control was caused by the suppression of basal hepatic glucose production (from 628þ44 to 350þ17lmol/m2/min,P0.001), with a more modest but significant improvement in peripheral glucose uptake (from 1418þ156 to 1657þ128lmol/m2/min,P0.05), as determined by the glucose clamp technique.

This study emphasizes a number of important aspects of intensive glucose control with insulin in obese subjects with type 2 diabetes. First, the average daily dose of insulin needed to control such patients approximates 1 unit per kilogram of body weight. Second, the total daily insulin requirement can be split equally between the pre-breakfast and pre-dinner injections. Third, the split-mixed regimen in patients with type 2 diabetes is usually devoid of the common problems seen with this regimen in type 1 diabetes, particularly early morning hypoglycemia and fasting (pre-prandial) hyperglycemia. Fourth, both severe and mild hypoglycemic events are much less fre-quent in patients with type 2 compared with patients with type 1 diabetes undergoing intensive insulin therapy. And finally, weight gain with

peripheral hyperinsulinemia occurs, which may contribute to metabolic and vascular complications.

A similar but larger 3-month clinical trial [38] compared a split-mixed combination with a multiple-injection regimen consisting of pre-meal regular and bedtime NPH insulin injections. Both the split-mixed and multiple-injection regimen treatment groups achieved equivalent and near-normal glycosylated hemoglobin values. These therapies, however, were associated with weight gain of 0.80.05 and 2.90.05 kg, a 39% and 36% increase in mean diurnal serum-free insulin levels, and a total daily insulin dose of 43 and 45 units, respectively. The authors demonstrated that the change in body weight was negatively correlated with the change in glycosylated hemoglobin values and positively correlated with the mean diurnal serum-free insulin values. The differences between these two studies with regard to total insulin requirements, mean insulin concentrations, and weight gain are primarily the result of differences in patient characteristics. Patients in the latter study were leaner (body mass index 29 versus 31 kg/ m2), had lower baseline fasting blood glucose values (225 versus 283 mg/dL) and reduced baseline mean diurnal serum-free insulin values (138 versus 308 pmol), and were previously treated with submaximal doses of sulfonylureas, compared with the patients in the former study. In addition, the latter study was conducted over a shorter period of time (3 months versus 6 months). Another long-term (5-year) clinical trial using a split-mixed regimen of two injections per day in 102 nonobese type 2 diabetic patients demonstrated that excellent glycemic control could be achieved with intensive split-dose insulin without significant hypoglycemia but at the expense of progressive weight gain[55]. All these studies clearly demonstrate the efficacy of various insulin regimens and the adverse consequences of such therapy.

Premixed insulin approach: rapid-acting insulin analogs

Rapid-acting insulin analogs are also available as manufactured, pre-mixed insulin formulations. One such insulin preparation is Humalog Mix 75/25, which is a fixed-ratio mixture of 25% rapid-acting insulin lispro and 75% novel protamine-based intermediate-acting insulin called neutral protamine lispro (NPL). NPL was developed to solve the problem of instability with prolonged storage that occurs with NPH combined with insulin. Studies of the pharmacokinetic and pharmacodynamic profiles of NPL show they are comparable to those of NPH insulin[56].

Humalog Mix 75/25 was studied in comparison to premixed human insulin 70/30 in 89 patients with type 2 diabetes in a 6-month randomized, open-label, two-period crossover study[57]. All patients had been previously treated with mixed insulin therapies, including short- or rapid-acting and an intermediate- or long-acting insulin, twice daily for at least 30 days before enrollment. During a 2 to 4 week lead-in period, patients were treated with

human insulin 70/30. The patients were randomized to receive one of two treatment sequences: therapy twice per day with Humalog Mix 75/25 in-jected before morning and evening meals for 3 months, after which they were crossed over to receive human insulin 70/30 using the same dosing frequency for an additional 3 months, or the alternate treatment sequence. Patients performed self-monitoring blood glucose (SMBG) at scheduled intervals during the study period (preprandial, 2-h postprandial, and occasional 3 AM readings) and recorded this information along with any hypoglycemic episodes in a study diary. Mean insulin doses were similar or identical between treatments. Blood glucose values after the morning meal were significantly lower during treatment with Humalog Mix 75/25 (Humalog Mix 75/25 8.95 2.17 versus human insulin 70/30 10.00

2.28 mmol/L, P= 0.017). Treatment with Humalog Mix 75/25 produced similar significant blood glucose results 2 hours after the evening meal as well (Humalog Mix 75/25 9.282.15 versus human insulin 70/30 10.27

2.76 mmol/L,P= 0.014). Blood glucose results at other time points, HbA1c

levels, daytime hypoglycemia, and nocturnal hypoglycemia were not sig-nificantly different between treatments. Compared with human insulin 70/ 30, twice-daily injections of Humalog Mix 75/25 in patients with type 2 diabetes resulted in improved postprandial glycemic control after the morning and evening meals, similar overall glycemic control, and the added convenience of administration immediately before meals.

Insulin aspart, another rapid-acting insulin analog, is available in a premixed formulation with a protamine-retarded insulin aspart called Novolog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart). A comparison study [58] of the pharmacokinetic and pharmacodynamic parameters of the Novolog Mix 70/30 and human insulin 70/30 in healthy patients showed that the faster onset and greater peak action of insulin aspart was preserved in the aspart mixture.

Another study [59] compared premixed aspart mixture 70/30 with premixed human insulin 70/30 administered twice daily in a randomized 12-week open-label trial in 294 patients with type 1 and type 2 diabetes. Patients were instructed to inject the human insulin 70/30 30 minutes before morning and evening meals and the premixed aspart mixture 10 minutes before morning and evening meals. SMBG levels and hypoglycemia incidence were recorded in diaries. Patients required a small increase in the total daily aspart mixture dose compared with human insulin 70/30 (mean difference at 12 weeks [95% CI 0.01; 0.05]), P 0.01; 0.03 U/kg. There was no significant difference in HbA1cbetween groups, yet the mean

blood glucose values after treatment with the aspart mixture showed statistically significant treatment differences after breakfast, before lunch, after dinner, and at bedtime. Blood glucose values were approximately 1.0 mmol/L lower compared with the human insulin 70/30 group at each time point (P0.05). The incidence of hypoglycemia was not found to be different between the two groups, and weight gain was not significant during

the study period with either type of insulin. Treatment with twice-daily premixed aspart mixture 70/30 resulted in similar overall glycemic control; yet postprandial control improved without additional hypoglycemia and with injections immediately before meals compared with premixed human insulin 70/30 given 30 minutes before the meal.

In a more recent study that focused on changes in lipid levels, Schwartz et al[60] compared insulin 70/30 mix taken twice per day plus metformin versus triple oral therapy (secretagogues, metformin, and thiazolidine-diones) and clearly demonstrated that insulin plus metformin are superior in lowering total cholesterol and triglycerides levels. The baseline values for total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides indicated no differences between the triple OHA and insulin/ metformin groups. By the end of the study (week 24) significant decreases in total cholesterol and triglycerides were evident in the insulin plus metformin group (P= 0.038 and 0.033, respectively, compared with the triple oral therapy group). Subjects in the triple oral therapy group showed a small increase in cholesterol and less of a decrease in triglyceride levels[60]. For glucose control, both groups had similar FPG values at the beginning of the study. After 24 weeks of treatment, the changes from baseline mean FPG values were55 and65 mg/dL for the triple oral therapy and insulin plus metformin, respectively[60]. Baseline HbA1cvalues were 9.62 1.25% for

subjects in the triple oral therapy and 9.65 1.62% in the insulin group. HbA1cvalues at weeks 2 and 6 demonstrated the efficacy of both treatments;

however, insulin plus metformin treatment achieved improvements in HbA1c values at weeks 2 and 6 (9.03 1.35% and 8.11 1.20%,

respectively) that were significantly greater than the response to triple oral therapy (P= 0.001 and 0.001, respectively). At weeks 12 and 24, no statistically significant difference in HbA1c between the two groups were

observed (final values at week 24 were 7.591.4% for triple oral therapy and 7.59 1.25% for insulin plus metformin [P= 0.772]) (Fig. 3)[60].

Along with SMBG, the use of rapid-acting premixed insulin analogs is convenient and can be beneficial in reducing postprandial hyperglycemia and in helping patients achieve glycemic control without the increased incidence of hypoglycemia. In addition, protocols are currently underway to assess the efficacy of using rapid-acting premixed insulin analogs three times per day before breakfast lunch and dinner, based on HGM data. This regimen is more related to a basal bolus strategy discussed below.

Basal–bolus strategy

The basal–bolus insulin strategy, which can be used in patients with either type 1 or type 2 diabetes, incorporates the concept of providing continuous basal insulin levels throughout the day and night with brief increases in insulin levels at the time of meal ingestion by bolus doses.

The use of pre-meal regular insulin with bedtime NPH as the basal insulin has been a common strategy for intensive insulin therapy in the United States, but because regular insulin should be administered 20 to 40 minutes before meals, a risk of hypoglycemia exists if the meal is delayed. If regular Fig. 3. (A) Mean FPG values at screening and weeks 12 and 24 by treatment group. No statistically significant changes were observed between the triple oral therapy (•) and insulin plus metformin (). (B) Mean SEM changes for the total cholesterol, HDL, LDL, and triglycerides at week 24. * Statistically significant (P0.05) reduction in total cholesterol and triglyceride levels in the insulin plus metformin group compared with the triple oral therapy group. HDL, high-density lipoprotein; LDL, low-density lipoprotein; OHA, XXX. (From

Schwartz S, Sievers R, Strange P Lyness W, Hollander P. Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis. Diabetes Care 2003;26(8):2598–603; with permission.)

insulin is given just before a meal, high postprandial glucose levels and delayed hypoglycemia may result. A strategy that provides for some flexibility in the mealtime administration of insulin with the use of rapid-acting insulin analogs, lispro or aspart, administered immediately before meals, and long-acting insulin, such as glargine, ultralente, lente, or NPH as the basal insulin. These regimens that use multiple doses of intermediate-acting insulin such as NPH can be associated with unpredictable nocturnal hypoglycemia and day-to-day instability of blood glucose patterns in part because of intrapatient variability of the effect of subcutaneous injected insulin and the patient’s peak action profile[61]. NPH, which exhibits peak action 5 to 7 hours after administration, has also been used in combination with rapid-acting insulin analogs, commonly given at least twice daily, although the disadvantages of NPH used in this manner are similar to those associated with Ultralente [62]. Because of its time to peak action, NPH should be given every 6 hours or 4 times per day to be effective as a basal insulin, in many patients[63].

Improved mealtime glucose control with the rapid-acting analogs has exposed the gaps in basal insulin coverage provided by therapy with the traditional intermediate- and long-acting insulin preparations. Taking a basal insulin analog with a relatively constant and flat pharmacokinetic profile such as insulin glargine once per day will result in a more physiologic pattern of basal insulin replacement. Insulin glargine in combination with a rapid-acting insulin analog has demonstrated effective glycemic control and a lower incidence of nocturnal hypoglycemia[64]than other insulin preparations currently used for basal insulin supplementation [64–68].

Patients on multiple-injection basal–bolus regiments should use carbo-hydrate counting to estimate their pre-meal bolus dose of a rapid-acting analog. In addition, a correction factor should be determined by HGM before and after rapid-acting insulin boluses. For example, a typical insulin-resistant subject with type 2 diabetes may need 1 unit of lispro or aspart for every 8 g of carbohydrate compared with a 1:15 ratio for a lean insulin-sensitive person with type 1 diabetes. A typical correction factor would be 1 unit of lispro or aspart to bring down the blood glucose value to 25 mg/dL compared with a person with type 1 diabetes whose cor-rection factor is 1 unit of lispro or aspart to bring down the blood glucose value to 50 mg/dL. The carbohydrate to insulin ratio and correction factor may be different depending on the time of the day and degree of hyperglycemia.

The availability of mealtime and basal insulin analogs, combination therapy with oral agents, and the use of insulin regimens comprising basal and mealtime (bolus) insulin components that better simulate normal insulin secretion represent important advances in insulin therapy. All of these approaches can have a significant impact on treatment outcomes.

External insulin pump therapy

External insulin pump therapy or continuous subcutaneous insulin infusion (CSII) has been traditionally used mainly in people with type 1 diabetes. However, insulin pump therapy is extremely valuable in patients with type 2 diabetes who require insulin but who have not achieved glycemic control with subcutaneous injections or who are seeking for a more flexible lifestyle. All of the benefits that are enjoyed by patients with type 1 diabetes are shared with people with type 2 diabetes. Many experts believe that because of the more physiologic delivery of insulin, glucose control is achieved with less insulin than was needed with the subcutaneous insulin regimen. This may be caused by a reduction in glucose toxicity and im-provement of insulin resistance and beta-cell secretory function as a result of improved glycemic control with pump therapy. Weight gain is less of an issue because the patient is using less insulin than was used before insulin pump therapy. In addition, with the reduction of hypoglycemic events there is less overeating to compensate for excessive insulin. Last, it is possible that pump therapy may result in less strain placed on the pancreatic beta-cells of patients with type 2 diabetes, and this may help with overall glycemic control because a functioning beta-cell can also autoregulate against hyper-and hypoglycemia, as seen in non-diabetic individuals.

Many older patients with the diagnosis of ‘‘insulin-requiring type 2 diabetes’’ have acute, true, late-onset type 1 diabetes. The literature documents large groups of patients with insulin-requiring type 2 diabetes who were tested for anti-glutamic acid decarboxylase antibodies with a positivity rate of approximately 5% to 8%. These individuals are thinner at the time of diagnosis, generally do not respond well to oral agents, and require insulin, although they do not present in severe diabetic ketoacidosis. These patients generally should be put on an intensive insulin injection regimen, and insulin pump therapy should be considered.

Insulin pump therapy allows for increased flexibility in meal timing and amounts, increased flexibility in the time and intensity of exercise, improved glucose control while traveling across time zones or with variable working schedules, and quality of life in terms of self-reliance and control.

Because pumps use only regular and fast-acting insulin, there is no peaking of injected intermediate- and long-acting insulins, which do not provide as constant a basal rate caused by variable absorption and pharmacokinetics. Insulin glargine is an exception in that it serves as excellent basal insulin. Variable insulin absorption and pharmacokinetics are probably responsible for up to 50% to 60% of the day-to-day fluctuation in blood glucose values in individuals using multiple-injection regimens with various insulin types. Insulin pump therapy allows for more regular insulin absorption and pharmacokinetic profile, resulting in im-proved reproducibility in insulin availability and reduced fluctuations in glycemic control[62].

Presently, there is a paucity of clinical trials using insulin pumps in type 2 diabetes, but pump therapy is a viable option in insulin-requiring patients with type 2 diabetes who are unable to achieve adequate glycemic control with multiple-injection regimens. Although some studies demonstrate metabolic benefits of pump therapy in type 2 diabetes, all are limited by a relatively short period of evaluation and a small number of heterogeneous subjects. Interpretation of these studies is further confounded by the random assignment of subjects to dissimilar conventional insulin regimens, making comparison between studies difficult.

Garvey et al[69]studied the effect of intensive insulin therapy on insulin secretion and insulin action before and after 3 weeks of CSII therapy in 14 patients with type 2 diabetes (age 503 years, duration of diabetes 7.8

2.1 years, and 119% ideal body weight). In 3 weeks of therapy, the mean fasting plasma blood glucose and glycosylated hemoglobin values fell 46% and 38%, respectively. The mean daily insulin dose stabilized at approxi-mately 110 units/d, and there was a 74% increase in the insulin-stimulated glucose disposal rate and a 45% reduction in hepatic glucose output to mean levels similar to those of normal subjects. In addition, there were significant improvements in both endogenous insulin and C-peptide secretion. This study demonstrated that pump therapy was feasible and ef-fective at improving metabolic control and reversing glucose toxicity in these poorly controlled subjects with type 2 diabetes.

Jennings et al[70]randomized 20 type 2 diabetic subjects (median age 61 years, duration of diabetes 6 years, and percentage of ideal body weight 120%) to either CSII or twice-daily injections of regular and NPH insulin for 4 months. Glycemic control improved in both groups, although there was a 30% reduction in the glycosylated hemoglobin in the CSII-treated group and only a 17% reduction in the twice-daily injection-treated group. There were no significant differences between the two groups in median daily insulin requirement (0.58 versus 0.65 units/kg), weight gained (4.5 versus 4.2 kg), prevalence of mild hypoglycemic reactions, or patient acceptance. In addition, in the CSII group 58% of the total daily insulin requirement was given as a basal infusion, with the remainder as pre-meal bolus injections using insulin algorithms. This ratio of basal to bolus insulin requirements are similar to the rates commonly used in type 1 diabetes, but there are characteristics of pump therapy that are very different in type 2 diabetes.

In a more recent study, Pouwels et al[71]prospectively studied 8 patients with poorly controlled (HbA1c 12.0 1.7%) type 2 diabetes with high

insulin requirements (1.920.66 U/kg/d). The subjects where aggressively treated with intravenous (IV) insulin for approximately 1 month followed by 12 months of CSII therapy. Insulin sensitivity and secretion were measured before and after the IV insulin treatment phase.

Euglycemia was achieved after 12 days of IV therapy, and the insulin requirements eventually reduced from 1.70.09 to 1.10.06 U/kg/d (P

uptake increased from 12.75.7 to 22.48.8lmol/kg/min (P0.0005), and in 1 month of intensive therapy, the HbA1cdropped to 8.9%1.2% with no

significant change in the patients’ body weight. After 6 and 12 months of CSII therapy, the mean HbA1cvalues were 7.10.6% and 8.31.4%, respectively

(P0.001 versus pretreatment values for all time points)[71].

In another recent study [72], 132 CSII naıı¨ve type 2 diabetics were randomized to the pump or multiple daily injections (MDI). This study showed that pump therapy provided efficacy and safety equivalent to MDI therapy. Lower 8-point blood glucose values were shown by the CSII group at most time points (values were only significant 90 min after breakfast; 167

47.5 mg/dL versus 192 65.0 mg/dL for CSII and MDI, respectively;

P= 0.019) (Fig. 4).

In summary, insulin pump therapy has not been fully evaluated in patients with type 2 diabetes. From published studies, however, it is apparent that CSII therapy can safely improve glycemic control while limiting hypoglycemia. CSII may be particularly useful in treating patients with type 2 diabetes who do not respond satisfactorily to more conventional insulin treatment strategies.

Alternative insulin delivery systems

Inhaled insulin is currently under development by several pharmaceutical companies for use in people with type 1 and type 2 diabetes. The insulin is

Fig. 4. Baseline and end-of-study 8-point blood glucose profiles (meanSEM) for the intent-to-treat population.Dashed linesrepresent baseline profiles;solid linesrepresent end-of-study profiles;•, means for CSII;n, means for MDI therapy. Number of patients at each time point: CSII, 56–63; MDI, 54–59. *P, 0.02.BB, before breakfast;B90, 90 minutes after breakfast;

BL, before lunch;L90, 90 minutes after lunch;BD, before dinner;D90, 90 minutes after dinner;

BE, at bedtime. (From Raskin P, Bode BW, Marks JB, Hirsh IB, Weinstein RL, McGill JB, Peterson GE, Mudaliar SR, Reinhardt RR. Continuous subcutaneous insulin infusion and multiple daily injection are equally effective in type 2 diabetes: a randomized, parallel-group, 24-week study. Diabetes Care 2003;26(9):2598–603; with permission.)

contained in a pellet and is vaporized in an inhaler, which aerosolizes the liquid insulin. Inhaled insulin can also be delivered to the pulmonary microvasculature as a dry powder system and inhaled through a mouthpiece. It provides the obvious incentive for diabetic patients to use insulin without the need for injections.

Cefalu et al[73]conducted a randomized, open-label, 3-month study with 26 patients (16 men, 10 women; average age, 51.1 years) with type 2 diabetes (average duration of diabetes, 11.2 years). Patients received inhaled insulin before each meal plus a bedtime injection of ultralente insulin, performed HGM, and adjusted their insulin dose weekly. The target level for preprandial plasma glucose was 100 to 160 mg/dL. At the end of 3 months, inhaled insulin treatment significantly improved glycemic control compared with baseline, and mean HbA1clevels decreased by 0.07%. Hypoglycemic

events were mild, and patients showed no significant weight gain or change in pulmonary function compared with baseline. Thus in this study, pul-monary delivery of insulin in type 2 diabetic patients who require insulin improved glycemic control was well tolerated and demonstrated no short-term adverse pulmonary effects[74].

A new Aerodose insulin inhaler proved to be comparable to sub-cutaneous injections through overlapping dose-response curves, with con-sistent relative bioavailability and relative biopotency. The inhaler delivered a pharmacologically predictable insulin dose to type 2 diabetics, similar to that with subcutaneous insulin injections[75]. The Aerodose inhaler used regular insulin (Humulin R), U-500, whereas Humulin R, U-100 was used for subcutaneous injections. Serum insulin levels before exogenous insulin administrations were similar between inhaled and subcutaneously inject insulin (t, baseline,P= 0.12). At the end of dosing (t, 0 min), serum insulin levels were significantly higher for inhalation treatments than for sub-cutaneously injected treatments, indicating rapid, systemic insulin absorp-tion following inhalaabsorp-tion. The area under the curve (AUC)0-8h and

maximum serum insulin concentration demonstrated a clear dose-response relationship for the three doses of inhaled insulin and the three doses of subcutaneously injected insulin (Fig. 5)[75].

Insulin can also be taken orally by capsules, enterocoated with a soybean trypsin inhibitor that prevents insulin degradation. This approach has clinical potential, but large clinical trials have not been carried out. Chemically modified human insulin, called hexyl insulin, using proprietary conjugation technology to improve its stability and oral absorption has shown promise. Preliminary results reported that in healthy human volunteers, hexyl insulin caused dose-dependent glucose lowering, was safe, and was well tolerated. In a small clinical study, oral insulin illustrates the similarities and differences among hexyl insulin monoconjugate (HIM)2 oral insulin, subcutaneous insulin, and placebo. All three curves are indistin-guishable from each other during the first hour postdose. The placebo curve then separates from the other two curves, displaying a significantly higher

peak excursion. The HIM2 and subcutaneous insulin curves remain nearly indistinguishable for at least another hour. During the fourth hour postdose, the HIM2 curve clearly separates from the subcutaneous insulin curve, becoming nearly identical to the placebo curve, as the glucose excursion values in all three groups decline toward baseline. Peripheral plasma insulin revealed an initial peak in peripheral plasma insulin concentrations following administration of HIM2; however, this initial insulin peak was caused by one patient who had a rapid peak of insulin. The median insulin Cmax values, following administration of HIM2 and

sub-cutaneous regular insulin, were nearly identical (Fig. 6)[76].

Amylin analog: a novel injectable peptide that compliments the action of insulin

Destruction and dysfunction of pancreatic beta-cells, resulting in absolute and relative insulin deficiency, represent key abnormalities in the pathogenesis of type 1 and type 2 diabetes, respectively[77]. Following the Fig. 5. Glucose infusion rate (GIR) registered following administration of inhaled insulin (¤, 80 units;n,160 units;•, 240 units) and subcutaneous injection (}, 8 units;, 16 units;, 24 units) in patients with type 2 diabetes. GIRs have been averaged over 30-minute periods. Data points are meansSE (n = 16) at each time point for low, medium, and high doses for inhaled and injected insulin. (FromKim D, Mudaliar S, Chinnapongse S, Chu N, Boies SM, Davis T, Perera AD, Fishman RS, Shapiro DA, Henry R. Dose-response relationships of inhaled insulin delivered via the Aerodose insulin inhaler and subcutaneously injected insulin in patients with type 2 diabetes. Diabetes Care 2003;26(10):2842–7; with permission.)

discovery of amylin in 1987, a second beta-cell 37-amino acid hormone that is co-secreted with insulin in response to nutrient stimuli, it was realized that diabetes represents a state of bi-hormonal beta-cell deficiency and that a lack of amylin action may contribute to abnormal glucose homeostasis. Experimental studies show that amylin acts as a neuroendocrine hormone that complements the effects of insulin in postprandial glucose regulation through several centrally mediated effects. These include a suppression of postprandial glucagon secretion and a vagus mediated regulation of gastric emptying, thereby helping to control the inflow of endogenous and exogenous glucose, respectively. In animal studies, amylin also reduces food intake and body weight, consistent with an early satiety effect[78].

Insulin is the major hormonal regulator of glucose disposal. Preclinical and clinical studies indicate that amylin complements the effects of insulin by regulating the rate of glucose inflow to the bloodstream, suppressing glucagons secretion and inducing satiety.

Pramlintide is a soluble, nonaggregating, injectable, synthetic analog of human amylin currently under development for the treatment of type 1 and insulin-using type 2 diabetes. Long-term clinical studies have consistently demonstrated that prandial subcutaneous. injections of pramlintide, in addition to the current insulin regimen, reduce HbA1cand body weight in

type 1 and type 2 diabetic patients, without an increase in insulin use or in the incidence of severe hypoglycemia[79].

Treatment with 120lg twice per day of pramlintide in subjects with type 2 diabetes led to a sustained reduction from baseline in HbA1c(0.68 and

0.62% at weeks 26 and 52, respectively) that was significantly greater than that in the placebo group (P\0.05) (Fig. 7)[80]. The greater reduction of HbA1cobserved with pramlintide was not accompanied by an increase in

body weight. Instead, patients in both pramlintide treatment groups experienced a sustained reduction in body weight that was significantly different from placebo at week 26 (both P 0.05) [80]. In the group of subjects who took 120 lg twice daily, the reduction in body weight was sustained to week 52 (P0.05 versus placebo).

The most commonly observed side effects were gastrointestinal-related, mainly mild nausea, which typically occurred on initiation of treatment and

Fig. 6. 0.5 mg/kg and 1.0 mg/kg HIM2 dose groups; pooled data. (A) Mean plasma glucose excursion versus time profiles and (B) mean plasma insulin concentration versus time profiles. At time 0, patients received 0.5 or 1.0 mg/kg oral HIM2, 8 units subcutaneous regular insulin or oral placebo. At 30 min, patients began ingesting the standardized meal (Boost Plus). Patients ingested the entire meal over a 10-minute period. Postprandial plasma glucose excursions and insulin concentrations were determined from blood samples collected a the time points indicated. Data are expressed as meansSE (n = 12 patients). , oral HIM2 (0.5) and 1.0 mg/kg dose groups combined); , 8 units of subcutaneous regular insulin; , oral placebo. (FromKipnes M, Dandona P, Tripathy D, Still JG, Kosutic G. Control of postprandial plasma glucose by an oral insulin product (hexyl-insulin monoconjugate 2 [HIM2]) in patients with type 2 diabetes. Diabetes Care 2003;26(2):421–6; with permission.)

resolved within days or weeks. Amylin replacement with pramlintide as an adjunct to insulin therapy is a novel physiological approach toward improved long-term glycemic and weight control in patients with type 1 and type 2 diabetes.

Summary

Type 2 diabetes is a common disorder often accompanied by numerous metabolic abnormalities leading to elevated rates of cardiovascular morbid-ity and mortalmorbid-ity. Improved glycemia will delay or prevent the development of microvascular disease and reduce many or all of the acute and subacute complications that worsen the quality of daily life. Exogenous insulin is Fig. 7. Change from baseline in mean HbA1c(A) and weight (B) (intent-to-treat population).

*P0.05 for treatment arm versus placebo., placebo;n, 90lg twice daily;•, 120lg. (From

Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 2003;26(3):784–90; with permission.)

usually the last line of treatment used to normalize glycosylated hemoglobin in patients with type 2 diabetes who have failed other therapeutic modalities. Not all patients are candidates for aggressive insulin management; therefore, the goals of therapy should be tailored to the individual. Candidates for intensive management should be motivated, compliant, educable, and without other medical conditions and physical limitations that would preclude accurate and reliable HGM and insulin administration.

In selected patients, combination therapy with insulin and oral antidia-betic medications can be an effective method for normalizing glycemia without the need for rigorous insulin regimens. The most common clinical situation in which combination therapy can be successful occurs in patients who are failing daytime oral agents therapy and still show some evidence of responsiveness to the medications. Bedtime intermediate- and long acting-insulin are administered and progressively increased until the fasting blood glucose concentration is normalized. Additional benefits of combination therapy include ease of administration, excellent patient compliance and safety, and lower exogenous insulin requirements with less peripheral hyperinsulinemia and weight gain. If combination therapy is not successful, a split-mixed regimen of an intermediate- and a fast-acting insulin equally divided between the pre-breakfast and pre-dinner periods can be effective especially in obese patients.

For patients who do not achieve glucose control on combination or split-mixed regimens, an intensive basal bolus multiple-injection regimen is indicated. Continuous subcutaneous insulin infusion pumps can be partic-ularly useful in treating patients with type 2 diabetes mellitus who do not respond satisfactorily to more conventional treatment strategies. The use of fast-acting insulin analogs should be used in the majority of insulin-requiring diabetics because of its more physiologic pharmacokinesis. Inhaled insulin and the amylin analog pramlintide also hold promise to intensively control glycemia in patients with insulin-requiring type 2 diabetes.

The glycemic objectives for patients with type 2 diabetes should be similar to those for patients with type 1 diabetes, namely, to normalize glycemia and glycosylated hemoglobin without causing undue weight gain or hypoglyce-mia or adversely affecting the quality of daily life. This is best achieved in a multidisciplinary setting using complementary therapeutic modalities that include a combination of diet, exercise, and pharmacologic therapy. Emphasis should be placed on diet and exercise initially, and throughout the course of management as well, since even modest success with these therapies will enhance the glycemic response to both oral antidiabetic agents and insulin.

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