14 Clarifying the Role of Insulin in Type 2 Diabetes Management John R. White, Jr., PA-C, PharmD; Stephen N. Davis, MD, FRCP; Ramachandiran Cooppan, MD; Mayer B. Davidson, MD; Kathryn Mulcahy, RN, MSN, CDE; Gary A. Manko, MD; Donald Nelinson, PhD; and the Diabetes Consortium Medical Advisory Board D iabetes is a highly prevalent chronic disease. The Third National Health and Nutrition Examination Survey, conducted between 1988 and 1994, estimated the prevalence of diagnosed and undiagnosed diabetes in people aged 20 years and older at 15.6 million. 1 Of these people, ~9095% have type 2 diabetes, with a higher prevalence seen among Native Americans and Americans of African, Mexican, and Japanese descent. 2 The prevalence of diabetes rose from 4.9% in 1990 to 6.9% in 1999, primarily because of an increase in the prevalence of obesity. It has been postulated that, with the growing obesity problem, dia- betes will become an even more perva- sive threat. 3 Type 2 diabetes produces or is a con- tributor to considerable morbidity in the form of metabolic complications, vision disorders, neuropathy, kidney disease, peripheral vascular disease, ulcerations and amputations, heart disease, stroke, digestive diseases, infection, oral com- plications, and depression. The associat- ed mortality rate has been estimated at 5.5% annually. Moreover, the disease reduces life expectancy by 510 years. 1 Although there is no cure for dia- betes, two large controlled studies, the Diabetes Control and Complications Tri- al (DCCT) 4 and the U.K. Prospective Diabetes Study (UKPDS) 5 have pointed to the importance of intensive blood glu- cose control in reducing its associated morbidity. In fact, the UKPDS, the largest and longest trial ever conducted in patients with type 2 diabetes, found that for each 1% reduction in hemoglo- bin A 1c (A1C), there was a 21% decrease in any endpoint related to diabetes and in diabetes-related death, a 14% decrease in all-cause mortality and myocardial infarction, a 43% decrease in amputation or death from peripheral vascular dis- ease, and a 37% decreased risk for microvascular complications, each of which was statistically significant. 5 The Japanese Kumamoto study 6 also found that intensive glycemic control reduced the risk for retinopathy, nephropathy, and neuropathy in patients with type 2 dia- betes. Although sulfonylurea therapy has been the mainstay of treatment for type 2 diabetes for >40 years, the UKPDS reported that over a 6-year period, ~53% of patients who were randomized to receive treatment with sulfonylureas needed additional insulin therapy, rein- forcing the concept that hyperglycemia in type 2 diabetes is progressive. 7 Clini- cians should consider this when estab- lishing a therapeutic regimen for patients with type 2 diabetes. This article addresses the pathophys- iology of type 2 diabetes, goals of thera- py, misconceptions about insulin, restoration of natural insulin patterns, and ways to incorporate basal insulin into a strategy that promotes compliance. Pathophysiology of Type 2 Diabetes Type 2 diabetes is characterized by hyperglycemia caused by defects in insulin secretion (impaired -cell func- tion) and insulin action (insulin resist- ance by the liver and muscle tissue). 810 These defects occur early in the course of the disease and are often present before diagnosis. In a prospective study 11 of Pima Indi- ans, a group at high risk for developing diabetes, body composition, insulin action, insulin secretion, and endogenous glucose output were measured over sev- eral years in subjects whose glucose tol- erance went from normal to impaired to diabetic. A two-step hyperinsulinemic, euglycemic glucose clamp test assessed insulin action. During the transition from normal to impaired glucose tolerance, there was a 27% decrease in the acute insulin secretory response (AIR), the average incremental plasma insulin con- centration from the third to the fifth minute after the glucose bolus. Further- more, during the transition from impaired glucose tolerance to diabetes, there was an additional 57% decrease in AIR. Another controlled study in patients with type 2 diabetes who were either untreated or attempting to achieve con- trol using diet or oral hypoglycemic agents 9 found that basal and mean 24- hour glucose concentrations were signif- The prevalence of type 2 diabetes has been increasing rapidly and with it has been resultant morbidity and mor- tality. Strict glycemic control reduces the progression of diabetic microvas- cular disease; however, most patients treated with sulfonylureas require additional insulin therapy. This article addresses common clinician concerns about prescribing insulin early in type 2 diabetes. It presents strategies for incorporating basal insulin therapy with glargine (Lantus) into a regimen that promotes compliance. I N BRI EF F E A T U R E A R T I C L E 15 CLINICAL DIABETESVolume 21, Number 1, 2003 immune-mediated -cell destruction that is characteristic of type 1 diabetes. This disease, latent autoimmune diabetes of adulthood, is often treated in the same way as type 2 diabetes because it does not require insulin initially. 13 Therapeutic Objective The American Diabetes Association (ADA) recommends that patients with diabetes receive care from a medical team. Working with patients and their families, these teams develop self-man- agement and problem-solving plans that consider each patients cultural, social, physical, and medical needs. ADA sup- ports the findings of the DCCT and the UKPDS for intensive glycemic control; Table 2 lists its recommendations for nonpregnant people with diabetes. 14 Insulin: Misconceptions and Reality Contrary to some beliefs, there is no evidence that doses of insulin used in clinical practice exacerbate insulin resistance. It has long been recognized that the chronic hyperglycemia associ- ated with type 2 diabetes (glucose toxi- city) leads to impairment in insulin secretion and a possible defect in glyco- gen synthesis. 15 In a study of intensive insulin therapy in patients with type 2 icantly higher in the diabetic patients, pointing to potentially impaired insulin secretion. During the hyperglycemic clamp portion of this study, patients secreted ~70% less insulin than control subjects (Table 1). In nondiabetic indi- viduals, a biphasic insulin response begins upon glucose stimulation, starting with a rapid rise in insulin 13 minutes after the glucose level is raised (first phase), returning toward baseline 610 minutes after glucose stimulation, and rising gradually once again (second phase). 12 Among patients in this study, however, the first-phase response after meals (glycemic load) was either absent or greatly diminished. 9 As a result of bolus (mealtime) and basal (between- meal) defects in insulin activity in type 2 diabetes, bolus and basal glucose levels are increased, producing hyperglycemia. In the early stages of type 2 diabetes, blood glucose levels can often be con- trolled with changes in diet and physical activity along with sulfonylureas. Unfor- tunately, the -cell dysfunction that leads to impaired insulin secretion is progressive, and eventually patients will require a treatment strategy that includes insulin, either alone or with oral agents. 7 It should be noted that some patients who develop diabetes in adulthood have diabetes, 16 the use of insulin partially reversed the postbinding defect in peripheral insulin action, produced near-normal basal hepatic glucose out- put, and enhanced insulin secretion, thereby maintaining lower glucose val- ues. In addition, the mean daily insulin requirement fell by 23% after ~2 weeks of therapy, leveling off thereafter. The use of insulin has been associat- ed with weight gain, which in turn has been considered a major factor in insulin resistance. In the UKPDS, patients in intensive therapy gained more weight than those in conventional therapy groups; patients taking insulin gained ~4 kg compared to 2.6 kg for those on chlorpropamide (Diabinese) and 1.7 kg for those on glibenclamide (glyburide [Micronase]). 17 Yet patients in the inten- sive therapy groups also had fewer microvascular complications, suggesting that tight glycemic control may be more important in therapeutic decision-mak- ing. The use of metformin (Glucophage) as an adjunct to insulin therapy provides effective glycemic control without sig- nificant weight gain. 18,19 The incidence of heart disease and ischemic heart mortality is up to four times higher in people with diabetes. Ischemic heart disease, other heart dis- ease, and cerebrovascular disease account for 40, 15, and 10% of all deaths in this population, respectively (Figure 1). 20 A population-based survey of almost 3,000 people 21 identified high prevalence rates for a constellation of disorders known as syndrome X, meta- bolic syndrome, and insulin resistance syndrome interchangeablyabdominal obesity, type 2 diabetes, glucose intoler- ance, hypertension, hypertriglyc- eridemia, and hypercholesterolemia that far exceeded the rates for each disorder alone or in pairs. For each of these conditions, fasting and post-glu- cose hyperinsulinemia was a common thread that suggested the presence of insulin resistance. When insulin-resistant subjects were compared to control sub- jects, significantly lower HDL choles- terol levels were also seen. Table 1. Glucose Concentrations and Insulin Secretion in Control and Diabetic Subjects Under Three Conditions Condition Control Patients With P Subjects Diabetes Fasting Glucose (mg/dl) 95.2 2.1 221.4 19.4 <0.0001 Insulin secretion (nmol/m 2 /24 hours) 71.7 9.5 82.7 11.5 NS 24-Hour Study Glucose (mg/dl) 109.7 1.9 282.3 25.6 <0.0001 Insulin secretion (nmol/m 2 /24 hours) 220.5 30.4 201.7 19.7 NS Hyperglycemic Clamp Study Glucose (mg/dl) 303.6 4.5 299.8 1.0 NS Insulin secretion (nmol/m 2 /24 hours) 80.6 11.7 24.1 4.1 <0.001 Adapted with permission from Ref. 9. F E A T U R E A R T I C L E Volume 21, Number 1, 2003CLINICAL DIABETES 16 years; the absolute reduction in mortali- ty was 11%. 23 Other studies 2426 have reported improvement or neutral effects on other cardiovascular risk factorstotal choles- terol, LDL cholesterol, HDL cholesterol, triglycerides, or hypertensionwith insulin, even among obese patients. Considering the comorbidity of dia- Because of the connection among hyperinsulinemia, insulin resistance, and cardiovascular risk factors, the UKPDS 17 compared cardiovascular events among patients randomized to conventional lifestyle and dietary management and those on a tight glycemic control regi- men with sulfonylureas, metformin (in overweight patients), or insulin. No adverse effects on cardiovascular out- comes were seen with any of the treat- ments, including insulin. The Diabetes Mellitus Insulin Glu- cose Infusion in Acute Myocardial Infarction study 22,23 assessed the effect of acute insulin-glucose infusion fol- lowed by long-term intensive (multi- dose) insulin treatment in diabetic patients who have had an acute myocardial infarction. Among patients who had received an acute infusion, there was a significant decrease in glu- cose. After 1 year, there was a signifi- cant reduction in mortality in the group who received intensive insulin treat- ment, particularly in patients who had a low cardiovascular risk profile and were insulin naive. 22 These effects per- sisted after a mean follow-up of 3.4 betes and several cardiovascular risk fac- tors, ADA 14 recommends the following in addition to lifestyle alterations: blood pressure measurement at routine medical visits; the use of antihypertensive agents in patients with hypertension; testing for lipid disorders at least annually; lower- ing LDL and triglycerides; increasing HDL and using statins as first-line lipid therapy; using fibrates in patients with low HDL; and using aspirin therapy to prevent cardiovascular events. Clinicians often cite hypoglycemia as an adverse effect that might preclude the use of insulin. Indeed, in the DCCT study of type 1 diabetes, 4 tighter control produced a risk of severe hypoglycemia three times higher than that of conven- tional therapy (Figure 2). This must be viewed, however, in the context of sub- stantially reduced microvascular and neurological complications. Further- more, the rates of severe hypoglycemia are quite low in type 2 diabetes. In the Kumamoto study of type 2 diabetes, 6 average A1C results were 7.1 and 9.4% for tight and conventional groups, respectively. However, only mild hypo- glycemic reactions occurred and at simi- lar rates in both groups. The UKPDS 17 found that the rate of major hypoglycemic episodes (defined as an episode in which help from another Table 2. ADA Guidelines for Glycemic Control for Patients With Diabetes Normal Goal Additional action suggested * Plasma values (mg/dl)
Average preprandial glucose <110 90130 <90/>150
Average bedtime glucose <120 110150 <110/>180 Whole blood values (mg/dl)
Average preprandial glucose <100 80120 <80/>140
Average bedtime glucose <110 100140 <100/>160 A1C <6 <7 >8 The values shown in this table are by necessity generalized to the entire population of individuals with diabetes. Patients with comorbid diseases, the very young and older adults, and others with unusual conditions or circumstances may warrant different treatment goals. These values are for non- pregnant adults. *Values above/below these levels are not goals nor are they acceptable in most patients. They are an indication for a significant change in the treatment plan. Additional action suggested depends on individual patient circumstances. Such actions may include enhanced diabetes self-management edu- cation, comanagement with a diabetes team, referral to an endocrinologist, change in pharmacologi- cal therapy, initiation of or increase in self-monitoring of blood glucose, or more frequent contact with the patient. A1C is referenced to a nondiabetic range of 4.06.0% (mean 5.0%, SD 5%). Values calibrated to plasma glucose. Measurement of capillary blood glucose. Reprinted with permission from Ref. 14. 13% 13% 4% 5% 65% 40% 15% 10% Diabetes Malignant neoplasms Pneumonia/influenza All other Ischemic heart disease Other heart disease Cerebrovascular disease Figure 1. Cardiovascular and cerebrovascular diseases account for 65% of all deaths in patients with diabetes. Adapted from Ref. 20. F E A T U R E A R T I C L E 17 CLINICAL DIABETESVolume 21, Number 1, 2003 concentration that result from the inges- tion of food. In people with diabetes, however, bolus and basal glucose levels are increased; thus, strategies for insulin replacement must focus on mimicking the phases of insulin secretion. Figure 3 shows available insulins by onset, peak, and usual effective duration. 27 Prandial (Bolus) Insulin Prandial forms of insulin mimic the nor- mal first-phase response. These regular insulin or rapid-acting insulin analogs are administered 3060 minutes (regu- lar) or 1015 minutes (lispro [Humalog] or aspart [Novolog]) before food con- sumption. They must also mimic the second-phase response, requiring a more prolonged duration of action to control prolonged glucose elevation after the meal. 28 Although prandial forms offer flexibility in that they can be injected just before a meal, most patients also require daily basal insulin injections. 29 Basal Insulin Both intermediate (NPH and lente) and long-acting (ultralente and glargine [Lantus]) insulins have been used to person or medical intervention was nec- essary) was higher for patients taking insulin (2.3%) than for patients undergo- ing any other intensive therapy or con- ventional treatment (<1%). The rate of any hypoglycemic episode (including episodes that the patient was able to treat unaided) was 36.5% with insulin treat- ment, compared to 11, 17.7, and 1.2% for chlorpropamide, glibenclamide, and diet, respectively. In a secondary analy- sis of obese patients on intensive glycemic control, the rate of major hypo- glycemic events per year for intensive insulin treatment was 2.5% versus <1% for other treatments. Despite the increased risk of mild hypoglycemia, aggressive therapy that combines patient education and self- management with a form of exogenous insulin that closely mimics normal insulin secretion can help to reduce the morbidity and mortality associated with type 2 diabetes. Restoring Natural Insulin Patterns Nondiabetic pancreases self-regulate the amount of insulin secreted, acting in response to changes in blood glucose mimic physiological basal insulin secre- tion, with varying results. An insulin that mimics basal secretion should be slowly and evenly absorbed with no peak, have consistent bioavailability, and have a long half-life that permits once-daily administration. 30,31 This has not been the case with most basal insulin products. NPH and lente have early peaks with rapid waning of action; this may con- tribute to both nighttime hypoglycemia and the dawn phenomenon, a pre- breakfast rise in plasma glucose. There is also variability in the absorption of NPH and lente. 29,32 Data on ultralente vary; in one study of type 1 diabetes, 30 the onset of action of human ultralente was 24 hours, and there was a broad, variable peak 612 hours after injection. The authors concluded that this product did not provide a constant basal insulin concentration. Basal insulin in type 1 diabetes. The pharmacokinetics and pharmacodynam- ics of the insulin analog glargine were compared to those of NPH, ultralente, and continuous subcutaneous insulin infusion (CSII) of lispro in 20 type 1 dia- betic patients using an isoglycemic 24- hour clamp. 33 Glargine was absorbed slowly and produced no pronounced peaks over a 24-hour period. Its onset of action was ~1.5 hours, compared with 0.8 hours for NPH, 1 hour for ultralente, and 0.5 hours for CSII. Its concentra- tion/action profile was similar to CSII, with lower intersubject variability than with NPH and ultralente. These factors make glargine an excellent choice for basal insulin replacement. In another study of type 1 diabetes, 34 256 patients were randomized to receive NPH (once daily at bedtime or twice dai- ly before breakfast and at bedtime) or glargine once daily at bedtime. After 1 week and sustained throughout the 4- week study, fasting plasma glucose was significantly lower in the pooled glargine groups than in the NPH group (165.6 vs. 203.4 mg/dl, respectively; P = 0.0001). Patients who had been taking NPH twice daily before the study were more likely to demonstrate greater improvement if Figure 2. Rate of severe hypoglycemia in patients receiving intensive therapy. As tighter glycemic control is attained, the risk of severe hypoglycemia increases. Points, which correspond to more than 400 patient-years, indicate crude rates within deciles of the mean glycosylated hemoglobin (A1C) values during the trial. Copyright 1988 Massachusetts Medical Society. All rights reserved. Adapted with permission, 2002. 120 100 80 60 40 20 0 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 Glycosylated Hemoglobin (%) R a t e
o f
S e v e r e
H y p o g l y c e m i a ( p e r
1 0 0
p a t i e n t - y e a r s ) F E A T U R E A R T I C L E Volume 21, Number 1, 2003CLINICAL DIABETES 18 high- and low-dose NPH alone in restoring glycemic control. 37 Combina- tion therapy with an intermediate-acting insulin at bedtime plus metformin was superior to bedtime insulin plus gly- buride and metformin, bedtime insulin plus glyburide, and insulin twice daily and produced no weight gain. 18 The addition of evening NPH to existing oral agents was similar in efficacy to morning NPH plus an existing antidia- betic agent, a two-injection regimen of 70/30 insulin, multiple injections, and oral hypoglycemic agents alone; howev- er, this regimen did not induce as much weight gain and hyperinsulinemia. 38 Recent clinical trials suggest that glargine provides basal insulin glycemic control equal to that of NPH with less risk of hypoglycemia. Glargine has been evaluated in patients with type 2 diabetes in a trial comprising 518 patients who had been receiving NPH with or without regular insulin for postprandial control. 39 This 28-week, multicenter, open-label comparison of NPH once or twice daily and glargine once daily at bedtime reported similar decreases in A1C but a lower risk of nocturnal hypoglycemia with glargine compared with NPH (26.5 randomized to a glargine group than were patients previously on once-daily NPH. The longer duration of glargine also provided a statistically significant advantage in reducing the likelihood of the dawn phenomenon. Basal insulin in type 2 diabetes. The management of type 2 diabetes has tradi- tionally followed a stepped approach of lifestyle changes, to oral agents, to com- binations of oral agents, to insulin. Along the way, however, complications resulting from poor glycemic control may occur, some of which might have been reduced or possibly avoided with the early introduction of insulin. 35 Many studies have evaluated how to use insulin effectively for the treatment of type 2 diabetes. Two- and four-dose regimens of NPH improved glycemic control but caused basal hyperinsuline- mia. 36 The addition of 70/30 insulin (a premixed formulation with 30% fast- acting insulin and 70% intermediate- acting insulin) before supper to glimepiride (Amaryl) restored glycemic control more quickly than did 70/30 insulin alone, without producing severe hypoglycemia. 25 The addition of NPH to glipizide (Glucotrol) was superior to vs. 35.5%; P = 0.016). There was signifi- cantly less weight gain with glargine than with NPH (0.4 vs. 1.4 kg; P = 0.0007). A 6-month, multicenter, random- ized, open-label trial 40 compared the addition of glargine or NPH to an oral therapy regimen to restore glycemic control to a target A1C 7% in 756 insulin-nave patients with type 2 dia- betes. A1C results were lower in both treatment groups and 7% in 58% of patients. At the end of the study, the mean glargine dose was higher than that of NPH; however, symptomatic hypo- glycemia rates, particularly nocturnal hypoglycemia, were significantly lower in the glargine group. Risk was reduced by 21% for any incidence of hypo- glycemia and by 42% for nocturnal hypoglycemia (Table 3). Other studies comparing glargine to NPH at bedtime reported that similar control was achieved with each agent; however, there were significantly less hypoglycemia 41 and significantly lower postdinner glucose concentrations 42 with glargine than with NPH. Among insulin- naive patients and overweight patients who had been taking oral agents with or without insulin, significantly fewer receiving glargine experienced nocturnal hypoglycemia. 43 An Algorithm for Using Insulin There is no single best way to initiate insulin therapy in patients with type 2 diabetes in whom oral treatments no longer maintain adequate control. Clinicians should consider 10 units of basal insulin at bedtime, supper, or in the morning a safe, effective recommen- dation for beginning insulin therapy. This dose can then be titrated based on how well a patient has met individual glycemic goals as measured by fasting blood glucose, postmeal glucose levels, and self-monitoring of blood glucose. In obese, insulin-resistant patients, a higher starting dose may be safely used. Figure 4 44 provides an algorithm that includes recommendations for the use of insulin therapy in type 2 diabetes. Figure 3. The action of human insulins. Onset, peak, and usual effective dura- tions vary among available insulins. In some reports, ultralente has demonstrat- ed a peak concentration after several hours, followed by waning. Values shown are the mean in each range. Adapted with permission from Ref. 27. Glargine Ultralente Lente NPH Regular Lispro Aspart Onset Peak Duration 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours F E A T U R E A R T I C L E 19 CLINICAL DIABETESVolume 21, Number 1, 2003 ance. In the management of diabetes, this is more than a relationship between the patient and a single providerit includes an entire health care team. Other factors also influence compli- ance. On the patients side, the belief that the benefits of therapy are worth the con- sequences, a readiness to change, memo- ry, communication skills, literacy level, knowledge, competence, confidence, skills, and a good support system work together to influence the patients accept- ance of therapy. On the teams side, communication skills, the quality of information and instructions, and a will- ingness to identify and address barriers Compliance Patients with diabetes play an integral role in any treatment strategy. Lifestyle modification; goal setting; self moni- toring; preventing, detecting, and treat- ing acute complications; and using medications correctly are all important components in achieving glycemic control. 45 This makes patient education crucial, particularly when it comes to dispelling myths about insulin therapy. The content areas that must be clearly established for patients are listed in Table 4. The relationship between health care provider and patient is crucial to compli- affect compliance. The regimen itself is also a factor; if it is difficult, costly, or has many side effects, compliance may diminish. 4649 In the treatment of type 2 diabetes with insulin, reluctance to inject oneself and fear of weight gain or hypoglycemia may hinder compliance. 35 Clinicians need to explain to their patients that type 2 diabetes is progressive and that insulin will probably have to be used at some point; therefore, clinicians may need to dispel myths associated with insulin use, allay patient fears, and assure patients that insulin will likely improve symp- toms, enhance quality of life, and pro- vide a sense of well-being. Resistance to insulin on the part of clinicians may also be a significant provider-driven factor in compliance. 50 Concerns regarding hypoglycemia, patients fear of needles, cultural health beliefs, and the time necessary to teach self-injection can all emerge as barriers to insulin use. Table 3. Relative Risk of Hypoglycemic Episodes per Patient-Year Hypoglycemia Glargine NPH(%) P Relative Risk With (%) Glargine (%) All confirmed 13.9 17.7 <0.02 21 Nocturnal confirmed 4.0 6.9 <0.001 42 Adapted with permission from Ref. 40. Test for diabetes A1C 6.5% A1C >6.5% A1C 6.5% A1C >6.5% Reassess for type 2 diabetes MNT, physical activity, risk factor reduction Retest for diabetes in 1 year FPG 126140 mg/dl Or A1C <6.5% Continue therapy: Reassess every 3 months FPG 140160 mg/dl or A1C 6.5%8.0% Continue insulin therapy FPG >160 mg/dl or A1C >8.0% Assess for severe symptoms (polydypsia, polyuria, weight loss) Monotherapy Dose titration period: 312 weeks Insulin therapy, MNT, physical activity, DSME, risk reduction MNT, physical activity, DSME, risk factor reduction, SMBG No more than 12 weeks Add insulin; Dose titration period 312 weeks Adjust management to achieve a target FPG level of 70 to 110 mg/dl; Reassess every 3 months Combination therapy: Dose titration period 312 weeks Suggested combinations: Secretagogues + meformin or TZD or AGI Metformin + TZD Type 1 diabetes or type 2 with perisistent severe symptoms Asymptomatic type 2 Diabetes Yes Yes No No Key to Abbreviations: FPG: Fasting Plasma Glucose TZD: Thiazolidinedione AGI: Alpha-Glucosidase Inhibitor DSME: Diabetes Self- Management Education MNT: Medical Nutrition Therapy SMBG: Self-Monitoring of Blood Glucose Figure 4. An algorithm of treatment for patients with type 2 diabetes. Reprinted with permission from Ref. 44. F E A T U R E A R T I C L E Volume 21, Number 1, 2003CLINICAL DIABETES 20 6 Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complica- tions in Japanese patients with non-insulin- dependent diabetes: a randomized prospective 6- year study. Diabetes Res Clin Pract 28:103117, 1995 7 Wright A, Burden ACF, Paisey RB, Cull CA, Holman RR, for the UK Prospective Diabetes Study Group: Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Dia- betes Study. Diabetes Care 25:330336, 2002 8 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Report of the Expert Committee on the Diagnosis and Classifi- cation of Diabetes Mellitus. Diabetes Care 25 (Suppl. 1):S5S20, 2002 9 Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, VanCauter E: Abnormal patterns of insulin secre- tion in non-insulin-dependent diabetes mellitus. N Engl J Med 318:12311239, 1988 10 DeFronzo RA: Pharmacological therapy for type 2 diabetes mellitus. Ann Intern Med 131:281303, 1999 11 Weyer C, Bogardus C, Mott DM , Pratley RE: The natural history of insulin secretory dys- function and insulin resistance in the pathogene- sis of type 2 diabetes mellitus. J Clin Invest 104:787794, 1999 12 Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D: Pathophysiology of insulin secre- tion in non-insulin-dependent diabetes mellitus. Diabetes Care 7:491502, 1984 13 Pozzilli P, Di Mario U: Autoimmune dia- betes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definitions, characterization, and potential prevention. Dia- betes Care 24:14601467, 2001 14 American Diabetes Association: Standards of medical care for patients with diabetes melli- tus (Position Statement). Diabetes Care 25 (Suppl. 1):S33S49, 2002 15 Rossetti L, Giaccari A, DeFronzo RA: Glu- cose toxicity. Diabetes Care 13:610630, 1990 16 Garvey WT, Olefsky JM, Griffin J: The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34:222234, 1985 17 U.K. Prospective Diabetes Study Group: Conclusions With the prevalence of type 2 diabetes on the rise and with the recognized need for strict glycemic control in the preven- tion of complications, strategies for aggressive treatment must be put into effect. Such strategies might include the early use of insulin, alone or in combi- nation with other antidiabetic agents. Clinicians must weigh the risks associat- ed with the use of insulin against the benefits. Several studies have clearly shown that basal insulin therapy, partic- ularly using the insulin analog glargine, closely mimics the bodys physiological secretion of basal insulin and may be added to an existing oral regimen, used alone, or used with preprandial insulin. REFERENCES 1 Harris MI, Flegal KM, Cowie CC, Eberhardt MS, Goldstein DE, Little RR, Wiedmeyer H-M, Byrd-Holt DD: Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults: the Third National Health and Nutrition Examination Survey, 19881994. Dia- betes Care 21:518524, 1998 2 Harris MI: Summary. In Diabetes in Ameri- ca. 2nd ed. National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, NIH Publication No. 95-1468, 1995, p. 114 3 Mokad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS: The continuing increase of diabetes in the U.S. (Let- ter). 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Ann Intern Med 130:389396, 1999 19 Avils-Santa L, Sinding J, Raskin P: Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus: a ran- domized, double-blind, placebo-controlled trial. Ann Intern Med 131:182188, 1999 20 Geiss LS, Herman WH, Smith PJ: Mortality in non-insulin dependent diabetes. In Diabetes in America. 2nd ed. National Diabetes Data Group, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, NIH Publication No. 95-1468, 1995, p. 233257 21 Ferrannini E, Haffner SM, Mitchell BD, Stern MP: Hyperinsulinaemia: the key feature of a cardiovascular and metabolic syndrome. Dia- betologia 34:416422, 1991 22 Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L: Ran- domized trial of insulin-glucose infusion fol- lowed by subcutaneous insulin treatment in dia- betic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. 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Octo- ber 30, 1999, p.23 ACKNOWLEDGMENT The research for this article was sup- ported by an unrestricted grant from Aventis. John R. White, Jr., PA-C, PharmD, is a professor at Washington State Universi- ty College of Pharmacy in Spokane. ments in the pharmacological reduction of blood glucose in patients with type 2 diabetes. Clinical Diabetes 19:153159, 2001 32 Atiea JA, Luzio S, Owens DR: The dawn phenomenon and diabetes control in treated NIDDM and IDDM patients. Diabetes Res Clin Pract 16:183190, 1992 33 Lepore M, Pampanelli S, Fanelli C, Porcel- lati F, Bartocci L, DiVincenzo A, Cordoni C, Costa E, Brunetti P, Bolli G: Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 49:21422148, 2000 34 Rosenstock J, Park G, Zimmerman J, U.S. Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group: Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. Dia- betes Care 23:11371142, 2000 35 Nathan DM: Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 347:13421349, 2002 36 Lindstrom TH, Arnqvist HJ, von Schenck HH: Effect of conventional and intensified insulin therapy on free-insulin profiles and glycemic control in NIDDM. Diabetes Care 15:2734, 1992 37 Shank ML, Del Prato S, DeFronzo RA: Bedtime insulin/daytime glipizide: effective ther- apy for sulfonylurea failures in NIDDM. Dia- betes 44:165172, 1995 38 Yki-Jrvinen H, Kauppila M, Kujansuu E, Lahti J, Marjanen T, Niskanen L, Rajala S, Ryysy L, Salo S, Seppl P, Tulokas T, Viikari J, Kar- jalainen J, Taskinen M-R: Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 327:14261433, 1992 39 Rosenstock J, Schwartz S, Clark C, Park GD, Donley DW, Edwards MB: Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 24:631636, 2001 40 Rosenstock J, Riddle M: Treatment to target in type 2 diabetes: consistent risk reduction of hypoglycaemia with basal insulin glargine as compared with NPH insulin in insulin-naive patients on oral agents (Poster). Presented at the 38th annual meeting of the European Association for the Study of Diabetes. Budapest, Hungary, September 15, 2002 41 Fonseca V, Bell D, Mecca T: Less sympto- matic hypoglycemia with insulin glargine com- pared to NPH in patients with type 2 diabetes (Poster). Presented at the 37th annual meeting of the European Association for the Study of Dia- betes. Glasgow, United Kingdom, September 913, 2001 Stephen N. Davis, MD, FRCP, is chief of the Division of Diabetes, Endocrinol- ogy, and Metabolism at Vanderbilt Uni- versity Medical School in Nashville, Tenn. Ramachandiran Cooppan, MD, is an assistant clinical professor at Har- vard Medical School in Boston, Mass. Mayer B. Davidson, MD, is director of the Clinical Trials Unit at Charles R. Drew University in Los Angeles, Calif. Kathryn Mulcahy, RN, MSN, CDE, is program director of the INOVA Dia- betes Center in Fairfax, Va. Gary A. Manko, MD, is president of Clinical Associates, PA, in Reisterstown, Md. Donald Nelinson, PhD, is executive director of the Diabetes Consortium. The Diabetes Consortium, Inc., is a nonprofit, multidisciplinary collabora- tion dedicated to the development and dissemination of professional and patient initiatives implementing optimal diabetes care. For more information, write to: P.O. Box 8262, Parsippany, NJ, 07054-8262, or call 877-462-4356. Note of disclosure: Dr. White has served on an advisory board for Aventis; has received honoraria for speaking engage- ments from Aventis, Takeda, Omron, Pfizer, and TheraSense; and has received research support from Aventis. Dr. Coop- pan has received honoraria from Bristol- Myers Squibb, Pfizer, Aventis, Novartis, Takeda, Eli Lilly, GlaxoSmithKline, and Wyeth-Ayerst. Ms. Mulcahy has served on advisory boards and received hono- raria from Aventis and Novo Nordisk. Dr. Manko has received honoraria from Pharmacia, Wyeth-Ayerst, and Bristol- Myers Squibb. All of these companies manufacture or market insulin or other pharmaceutical products for the treat- ment of type 2 diabetes or its complica- tions.