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Intensifying Treatment in Poorly Controlled Type 2 Diabetes Mellitus: Case Reports
Supplement issue
Intensifying Treatment in Poorly Controlled Type 2 Diabetes Mellitus: Case Reports Joseph Tibaldi, MD Department of Endocrinology, Flushing Hospital Medical Center, Flushing, New York, USA
ABSTRACT There is no single correct treatment option for all patients with type 2 diabetes mellitus. Duration of diabetes and stage of the disease, level of control, lifestyle habits, and attitude toward disease management all affect the choice of treatment for any given individual. Indeed, the above factors should be especially considered when considering initiating insulin therapy in these patients. Basal insulin and premixed insulin remain the most common formulations used when initiating insulin in patients with type 2 diabetes and, as demonstrated in this article, both of these insulin strategies can be effective in controlling hyperglycemia when therapy is individualized to the patient. © 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, S30 –S34 KEYWORDS: Control; Hyperglycemia; Treatment Intensification; Type 2 Diabetes
Depending on the degree of hyperglycemia and stage of the disease, there are various treatment options for patients with type 2 diabetes mellitus. The healthcare provider must partner with the patient, explore the various options with their attendant benefits and limitations, and then act to prevent the clinical inertia that unfortunately is common with diabetes treatment. The genuine cases presented here demonstrate a range of patient needs, as well as lifestyle and potential response issues, that require consideration when tailoring treatment to individual requirements.
CASE STUDIES Case 1: Jane A 74-year-old woman presented for her yearly physical examination with her primary care physician. She had a prior history of a myocardial infarction 6 years earlier, complicated by transient congestive heart failure, as well as type 2 diabetes for 9 years. Her medications included aspirin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), an angiotensin-converting enzyme (ACE)
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Joseph Tibaldi, MD, Queens Diabetes and Endocrinology Associates, 59-45 161 Street, Flushing, New York 11365, USA. E-mail address: [email protected]
0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.03.024
inhibitor, extended-release glipizide 10 mg/day, and metformin 1,000 mg twice a day. Her 2 main complaints were increasing arthritis in her hands and decreasing vision due to cataracts. Jane stated that her ophthalmologist had said the cataracts were not yet “ripe” for removal. Her physical examination was only notable in that she had gained 4 lb (1.8 kg) in the last year, now bringing her body mass index (BMI) to 31. Laboratory findings from routine blood tests that had been done the week before the examination were reviewed. Jane’s fasting lipid profile revealed a low-density lipoprotein level of 60 mg/dL (1 mg/dL ⫽ 0.02586 mmol/L) but a triglyceride level of 267 mg/dL (1 mg/dL ⫽ 0.01129 mmol/L). Her urine microalbumin remained negative and she was congratulated that, in 9 years, she had no evidence of microvascular complications. However, her glycosylated hemoglobin (HbA1c) level was 8.2%; 4 months previously it was 8.0%, up from 7.0% a year earlier. Her blood glucose records revealed a fairly flat curve of moderate hyperglycemia throughout the day with blood glucose values between 170 and 220 mg/dL (1 mg/dL ⫽ 0.05551 mmol/L), reflecting her 3 balanced meals. She was advised that something had to be done to address her elevated glycemic levels. Results from the landmark United Kingdom Prospective Diabetes Study (UKPDS), a large intervention study in patients with type 2 diabetes, suggested that by reducing her HbA1c from 8.2% back to 7.0% Jane would decrease her risk of developing microvas-
Tibaldi
Intensifying Treatment in Type 2 Diabetes
cular disease by approximately 44% and decrease her risk of any diabetes-related adverse outcome or death by about 25%.1 When insulin was mentioned, Jane burst into tears. She related how a friend who started insulin had gained 21 lb (9.5 kg), at least in part because “she always had to eat to prevent her sugar from going too low.” To prevent weight gain, Jane always exercised in the form of a daily walk and ate 3 balanced meals per day. She had followed this routine faithfully since her retirement. In addition, she expressed concern that she lived alone and that her arthritis and cataracts would not allow her to self-administer insulin. Jane’s physician discussed the point that progression to insulin use does not indicate failure, because the natural history of type 2 diabetes dictates that, after ⱖ10 years insulin is required to maintain good blood glucose control and to stay healthy.2 Sensing Jane’s severe apprehension, the physician requested permission to administer a mock injection. An insulin pen device with a 30-gauge pen needle was used with a test fluid: Jane was amazed that she really did not feel it. She was then given the device and asked to dial 10 U. The device featured a large-dose scale and audible clicks upon dose adjustment allowing her to perform this task easily despite her arthritis and poor vision.
Case 2: John John is a 48-year-old man with type 2 diabetes who returned to see his family physician after a hiatus of 1 year. He noted that his new job, involving frequent travel, meant that finding time for “his health” was proving difficult. He was now in a situation whereby small meals during the day left him famished by evening, at which time he would return home and consume a large dinner. He felt that this dietary pattern, as well as decreased exercise, had led to a 5 lb (2.3 kg) weight gain and deterioration of his glycemic control. A year ago John’s HbA1c was 6.7% on extended release glipizide 10 mg/day and metformin 1,000 mg/day. He was also taking a statin, aspirin, and an ACE inhibitor. No evidence of microvascular disease was noted on his physical examination; the only change was an increase in the varicosities and edema in his legs, which he attributed to being “on his feet all day.” Laboratory work showed that his HbA1c level had increased to 8.5%. This finding was consistent with self-measured blood sugars: fasting blood glucose was 200 mg/dL and predinner glucose was 120 to 130 mg/dL, but bedtime ranged from 310 to 330 mg/dL. John realized that his meal patterns should change, but with the restrictions of the new job he thought he could not achieve this. His grandmother had had numerous complications due to diabetes and John understood that these complications were preventable; however the thought of insulin scared him.
Case 3: Sam Upon receiving a diagnosis of type 2 diabetes 2 years earlier at the age of 33, Sam decided to take a proactive approach
S31 to the management of his disease, immediately attending an American Diabetes Association (ADA) educational course for people with diabetes. He was fortunate to have been diagnosed before complications occurred and wanted to keep it that way. Despite his best intentions, Sam had difficulty with portion control and gained rather than lost weight on his medication (a combination tablet of metformin and glyburide). Sam’s current fasting glucose readings were on the order of 140 to 150 mg/dL, but his postprandial glucose levels would often reach 220 to 250 mg/dL. Sam was aware that his current HbA1c of 7.5% represented an increased risk for diabetic complications and that something needed to be done.
Case 4: Gloria Gloria, a 71-year-old woman, was shocked to learn she had diabetes. She was slim, exercised regularly, and knew no one who had the disease. She had been placed quickly on triple therapy (rosiglitazone 4 mg/day, glimepiride 8 mg/ day, metformin 1,000 mg twice daily) but with poor results. A glutamic acid decarboxylase– 65 antibody test was moderately positive, indicating that she had latent autoimmune diabetes in adulthood. Insulin was started and oral hypoglycemic agents were stopped. She was quickly advanced to a multiple injection insulin regimen with glargine 10 U at bedtime plus glulisine 2 to 4 U with meals administered with a pen device. Gloria was taught carbohydrate counting and was meticulous in testing. She was able to obtain reasonable fasting glucose values in the 85–120 mg/dL range, and adequate prelunch glucose values in the same range. However, her predinner glucose values, taken at about 7 PM were always ⬎200 mg/dL, despite increasing the lunchtime dose of glulisine to achieve postprandial values of about 140 mg/dL.
INSULIN: TO START OR NOT TO START? WHAT ARE THE CONSIDERATIONS? The patient is an important ally in selecting insulin as a therapy. The patient must be made aware that in most cases, treatment of type 2 diabetes eventually progresses to insulin therapy. Some individuals are apprehensive about the presumed pain of injections, a fear that can readily be allayed by a mock injection, as in the case of Jane. Perceived inability to administer injections because of physical impediments, such as Jane’s arthritis, can also be addressed by showing the patient how to use insulin pens. In the discussion with the patient, the physician must assess how willing the patient is to follow recommendations, that is, would he/she only consider 1 injection or could he/she administer insulin 4 times a day? The usual patient preference is to add another pill, rather than an injection, to their existing oral regimen. The limitations and side effects of the medicines must be considered: ●
sulfonylureas may show their maximal effects at lower doses than prescribing guidelines suggest3
S32 ● ●
90% of the biologic effect of glipizide is at 10 mg, of glyburide at 5 mg, and of glimepiride is at 4 mg4-6 the maximal dose of metformin is 1,000 mg twice a day7
Going above these doses does not help an individual. Thiazolidinediones (TZDs) are commonly added to complete triple therapy but HbA1c reductions are typically on the order of 1.0% to 1.5%, and side effects such as edema or weight gain may occur.8 Recently, concerns about the cardiovascular safety of TZDs have been raised, and currently warnings for risk of causing or escalating congestive heart failure (CHF) have been added to the product labelling.9,10 A recent meta-analysis of 42 randomized, controlled, clinical trials of rosiglitazone found a significant increase in the risk for myocardial infarction (MI) and an increase in death from cardiovascular causes, although significance was borderline and these findings are controversial. Further research is needed to evaluate what (if any) are the cardiovascular risks associated with TZDs.9 In the cases discussed above, Sam would be a good candidate, but must be informed that there is a chance of weight gain if this therapy is chosen. John’s HbA1c is too high for a TZD to allow him to achieve American College of Endocrinology goals of 6.5%. His baseline edema from varicosities may also intensify. Dipeptidyl peptidase– 4 inhibitors are now available and are predominantly postprandial glycemic regulators. They are currently approved by the US Food and Drug Administration (FDA) only for monotherapy or for use in conjunction with metformin or TZDs, but none of the patients presented here fall under these recommendation categories. ␣-Glucosidase inhibitors are also postprandial regulators, so these patients would derive little benefit from such drugs. Moreover, because of their gastrointestinal side effects, ␣-glucosidase inhibitors are not commonly prescribed in the United States. The glucagon-like peptide–1 analogue exenatide is becoming a more popular medicine because of its appetitesuppressing effects and attendant weight loss. However, its effect on HbA1c may be quite limited compared with other antidiabetic therapies (with reductions ⱕ1.3%)11,12; additionally, the fact that it is predominantly a postprandial regulator has to be taken into account when determining which patients are likely candidates for this therapy.13 In the cases above, if Jane were to use the medicine, she would most likely lose weight but not reach her target HbA1c. She would also have to be cognizant of the fact that exenatide is a twice-daily parenteral medicine. Sam, might benefit from this therapy because his HbA1c is within the necessary range and the appetite-suppressing effect of exenatide might help him with portion and, hence, weight control. The starting dose is 5 g twice daily, given subcutaneously, at breakfast and dinner for 1 month, with an increase to 10 g after 1 month assuming there are no limiting side effects such as nausea or vomiting. Generally the sulfonylurea dose is decreased by 50% when starting exenatide to limit the risk for hypoglycemia.14
The American Journal of Medicine, Vol 121, No 6A, June 2008 Insulin initiation or change of insulin is a possibility with all of these patients. In type 2 diabetes, insulin is usually initiated by adding either a basal or premixed formulation to existing oral antidiabetic therapy. Modern insulins (insulin analogues) are popular because their absorption properties have been designed to achieve favorable pharmacodynamic profiles.15 Basal insulin is currently the most popular choice of therapy, because a dose can be administered at virtually any time on a daily basis and is commonly given in the morning or at nighttime. The goals of basal insulin therapy are to diminish hepatic glucose production, lower the fasting glucose level, and hopefully allow -cells to recover by eliminating glucotoxicity. -Cell recovery and attendant prandial insulin secretion are required to attain glycemic goals; otherwise postprandial blood glucose is likely to remain markedly elevated. Generally, the introduction of basal insulin therapy that is continually titrated to a fasting glucose target lowers HbA1c by about 1.5% regardless of the baseline level of control.16-19 Jane would be a good candidate for basal insulin therapy for many reasons. Her HbA1c, at 8.2%, means there is a reasonable chance for achieving guideline targets with basal insulin. She is afraid of hypoglycemia, but the modern basal insulin analogues, insulin glargine and insulin detemir, have both been shown to incur a significantly lower risk for hypoglycemia than that incurred by the conventional basal insulin preparation, neutral protamine Hagedorn (NPH).16-19 Both of these insulin analogues are available in pen devices, which would suit Jane. In addition, initiation of insulin with insulin detemir has been shown to incur less weight gain than that observed with NPH insulin,17,18 and this advantage appears to increase with baseline BMI. While weight gain of about 6.6 lb (3 kg) was seen over 6 months in all BMI categories with NPH, heavier patients gained progressively less weight with insulin detemir; patients with a BMI ⬎29 gained only 1.1 to 1.3 lb (0.5 to 0.6 kg),17 which is likely to be reassuring for Jane. Basal insulin can be given as 10 U, or 0.1 to 0.2 U/kg, at night. Easy-to-use algorithms have been studied to titrate basal insulin doses.20,21 One such algorithm20 increases the insulin by 2 U every 3 days until fasting blood glucose (FBG) is at goal, typically 100 mg/dL. The oral hypoglycemic agent can be continued. If, 3 to 6 months later, the HbA1c is not at goal then 2 options exist: 1. 10% of the basal dose could be added as a rapid-acting analogue to be taken with the patient’s main meal, and 10% subtracted from the basal dose. The patient would then need to titrate up the prandial insulin dose until the postprandial glucose levels were at the specified goal, typically 140 to 180 mg/dL. The anticipated decrease in HbA1c is 0.5%. Additional prandial injections can be given later if needed. 2. The basal dose can be split in half and administered as 2 doses of an analogue premix at breakfast and at dinner. The predinner dose should be titrated every 3 days until FBG is ⬍110 mg/dL. Once FBG is controlled, the break-
Tibaldi Table 1
Intensifying Treatment in Type 2 Diabetes
S33
Overview of cases
Age (yr) Medication HbA1c BMI category Relevant clinical finding/other considerations
Therapeutic choices
Final choice
Jane
John
Sam
Gloria
74 SU, metformin 8.2 Obese Arthritis, cataracts
48 SU, metformin 8.5 Overweight Varicose veins
35 SU, metformin 7.5 Obese None
71 MDI 7.4 Normal Slim
Stable balanced meals Fear of weight gain and hypoglycemia
Edema
—
GAD-65 positive
Basal, premixed
Basal bolus
CSII
TZD and exenatide
Premixed
TZD, exenatide Basal, premixed
Basal
TZD Premixed
Exenatide
Split basal
Split basal
BMI ⫽ body mass index; CSII ⫽ continuous subcutaneous insulin infusion; GAD-65 ⫽ glutamic acid decarboxylase– 65; MDI ⫽ multiple-dose insulin; SU ⫽ sulfonylurea; TZD ⫽ thiazolidinedione.
fast dose should be titrated in 2-U increments every 3 days until the predinner blood glucose is ⬍110 mg/dL.22 Basal insulin is also a reasonable choice for Sam. Although the anticipated weight loss is greater with exenatide, if Sam were intolerant of drug, then a basal insulin would be an alternative, again noting that less weight gain is likely to occur if insulin detemir is selected. Gloria’s case highlights some potential shortcomings of all basal insulins. The half-life and duration of action is dependent on dose, and there is a slight peak in effect.23 Thus at small doses, the mean duration of action of glargine and detemir may not extend to 24 hours.23 Gloria’s glucose patterns reveal that the basal insulin wears off after lunch. Higher doses could extend the duration of action, but if the peak of action is too great, there is a risk for hypoglycemia. However, both insulin glargine and insulin detemir have demonstrated a relatively flatter time– action profile24-26 and less risk for hypoglycemia compared with NPH insulin.16,19,27 Gloria therefore needs to split her basal dose in half and take it twice a day. Another option for Gloria is to consider an insulin pump. A premixed insulin analogue may be the best choice for John, because his HbA1c is at 8.5%. Therefore, the addition of a basal insulin or of exenatide would be unlikely to achieve an HbA1c of 6.5%. A TZD could possibly reduce his HbA1c to 7.0%, but the preexisting edema would most likely worsen. With his current lifestyle of a large evening dinner followed by very high bedtime glucose levels, a premixed insulin would be beneficial in lowering the evening postprandial glucose as well as the FBG levels. An analogue mix at dinner (12 U) could be added to his current medication, and John could increase the dose every 3 days until his FBG was 80 to 110 mg/dL. After 3 months, if target HbA1c is not attained, an additional dose could be given at breakfast starting with 6 U to be titrated up every
3 days by 2 U until the predinner glucose is 80 to 110 mg/dL. Diabetes inevitably progresses, however, and at some future stage a second injection will likely be needed.28 If postlunch glucose levels are high, for instance in the case of a patient consuming a large lunch, a third dose of analogue mix can be added at lunch, starting with 3 U and slowly titrating the dose up based on glucose readings taken before dinner. In the majority of cases, however, a third shot is not required. The premix choice may be a viable option for Jane and Sam, but weight gain is a consideration in both cases. The achievement of excellent HbA1c levels, for example, a 2.8% reduction to 6.9% with biphasic insulin aspart 30 (BIAsp 30) used twice daily in the INITIATE (Initiation of Insulin to Reach A1c Target) study22 came with an increase in weight of around 12 lb (5.4 kg). In the PREFER (Predictable and for Every Patient Reliable) study, again using twice-daily BIAsp 30, a reduction in HbA1c from 8.4% to 7.07% was demonstrated, but the increase in weight was 4.6 lb (2.1 kg).29 While initiation of a premix regimen offers both Jane and Sam the opportunity to make substantial improvements in their glycemic control, they will need to become adept at carbohydrate and calorie counting and make dietary changes if they are to avoid further weight gain.
SUMMARY Each of the cases presented here it is possible to make additional treatment interventions to improve the patient’s glycemic control. With careful consideration of each patient’s individual needs and the options available, and with appropriate counseling, choices can be made that may help to maximize patient acceptance of therapy and therefore the chances of success (Table 1).
S34
The American Journal of Medicine, Vol 121, No 6A, June 2008
AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: Joseph Tibaldi, MD, is a member of the Speakers’ Bureau for Daichi Sankyo, GlaxoSmithKline, Merck & Co., Novartis, Novo Nordisk A/S, and sanofi-aventis.
References 1. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405412. 2. Wright A, Burden AC, Paisey RB, et al, 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 UK Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25: 330-336. 3. Melander A, Donnelly R, Rydberg T. Is there a concentration-effect relationship for sulphonylureas? Clin Pharmacokinet. 1998;34:181188. 4. Stenman S, Melander A, Groop P-H, Groop LC. What is the benefit of increasing the sulfonylurea dose? Am Intern Med. 1993;118:169-172. 5. Hermann LS, Schersten B, Melander A. Antihyperglycaemic efficacy, response prediction, and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination. Diabet Med. 1993;11:953-960. 6. Goldberg RB, Holvey SM, Schneider J, for the Glimepiride Protocol #201 Study Group. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. Diabetes Care. 1996;19:849-856. 7. Garber A, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, doseresponse trial. Am J Med. 1997;103:491-497. 8. Noble J, Baerlocher MO, Silverberg J. Management of type 2 diabetes mellitus: role of thiazolidinediones. Can Fam Physician. 2005;51:683687. 9. Nissen SE, Wolsky K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [published correction appears in N Engl J Med. 2007;357:100]. N Engl J Med. 2007;356: 2457-2471. 10. Highlights of prescribing information for Avandia. Research Triangle Park, NC: GlaxoSmithKline. Available at: http://www.fda.gov/cder/ foi/label/2007/021071s031lbl.pdf. Accessed December 13, 2007. 11. Nathan DM, Buse JB, Davidson MB, et al, for the Professional Practice Committee, American Diabetes Association and the European Association for the Study of Diabetes. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2006;49:1711-1721. 12. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419-428. 13. Mikhail N. Exenatide: a novel approach for treatment of type 2 diabetes. South Med J. 2006;99:1271-1279. 14. Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes
15. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. Lindholm A. New insulins in the treatment of diabetes mellitus. Best Pract Res Clin Gastroenterol. 2002;16:475-492. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The Treat-to-Target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086. Hermansen K, Davies M, Derezinski T, et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetes Care. 2006;29:1269-1274. Philis-Tsimikas A, Charpentier G, Clauson P, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28:1569-1581. Eliaschewitz FG, Calvo C, Valbuean H, et al, for the HOE 901/4013 LA Study Group. Therapy in type 2 diabetes: insuling glargine vs. NPH insulin both in combination with glimepride. Arch Med Res. 2006;37:495-501. Davies M, Storms F, Dhutler S, et al, for the ATLANTUS Study Group. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28:1282-1288. Shapiro AMJ, Meneghini L, Koenen C, et al. PREDICTIVE 303: a 26-week multi-centre, randomized, open-label study to evaluate the efficacy and safety of a simplified self-adjusted dosing guideline using once-daily insulin detemir in patients with type 2 diabetes. Diabet Med. 2006;23 (suppl 4):337. Poster 934. Raskin P, Allen E, Hollander P, et al, for the INITIATE study group. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260-265. Klein O, Lynge J, Endahl L, et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9:290-299. Lepore M, Pampanelli S, Fanelli C, et al. 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. 2000;49: 2142-2148. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005;28:1107-1112. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-1620. Massi Benedetti M, Humburg E, Dressler A, et al, for the 3002 Study Group. A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes. Horm Metab Res. 2003;35:189-196. Garber A, Wahlen J, Wahl T, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (the 1-2-3 Study). Diabetes Obes Metab. 2006;8:58-66. Liebl A, Prager R, Kaiser M, et al, on behalf of the PREFER study group. Biphasic insulin aspart 30 (BIAsp30), insulin detemir (IDet) and insulin aspart (IAsp) allow patients with type 2 diabetes to reach A1C target: the PREFER Study [abstract]. Diabetes Care. 2006; 55(suppl 1):A123.
Intensifying Treatment in Poorly Controlled Type 2 Diabetes Mellitus: Case Reports Joseph Tibaldi, MD Department of Endocrinology, Flushing Hospital Medical Center, Flushing, New York, USA
ABSTRACT There is no single correct treatment option for all patients with type 2 diabetes mellitus. Duration of diabetes and stage of the disease, level of control, lifestyle habits, and attitude toward disease management all affect the choice of treatment for any given individual. Indeed, the above factors should be especially considered when considering initiating insulin therapy in these patients. Basal insulin and premixed insulin remain the most common formulations used when initiating insulin in patients with type 2 diabetes and, as demonstrated in this article, both of these insulin strategies can be effective in controlling hyperglycemia when therapy is individualized to the patient. © 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, S30 –S34 KEYWORDS: Control; Hyperglycemia; Treatment Intensification; Type 2 Diabetes
Depending on the degree of hyperglycemia and stage of the disease, there are various treatment options for patients with type 2 diabetes mellitus. The healthcare provider must partner with the patient, explore the various options with their attendant benefits and limitations, and then act to prevent the clinical inertia that unfortunately is common with diabetes treatment. The genuine cases presented here demonstrate a range of patient needs, as well as lifestyle and potential response issues, that require consideration when tailoring treatment to individual requirements.
CASE STUDIES Case 1: Jane A 74-year-old woman presented for her yearly physical examination with her primary care physician. She had a prior history of a myocardial infarction 6 years earlier, complicated by transient congestive heart failure, as well as type 2 diabetes for 9 years. Her medications included aspirin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin), an angiotensin-converting enzyme (ACE)
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Joseph Tibaldi, MD, Queens Diabetes and Endocrinology Associates, 59-45 161 Street, Flushing, New York 11365, USA. E-mail address: [email protected]
0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.03.024
inhibitor, extended-release glipizide 10 mg/day, and metformin 1,000 mg twice a day. Her 2 main complaints were increasing arthritis in her hands and decreasing vision due to cataracts. Jane stated that her ophthalmologist had said the cataracts were not yet “ripe” for removal. Her physical examination was only notable in that she had gained 4 lb (1.8 kg) in the last year, now bringing her body mass index (BMI) to 31. Laboratory findings from routine blood tests that had been done the week before the examination were reviewed. Jane’s fasting lipid profile revealed a low-density lipoprotein level of 60 mg/dL (1 mg/dL ⫽ 0.02586 mmol/L) but a triglyceride level of 267 mg/dL (1 mg/dL ⫽ 0.01129 mmol/L). Her urine microalbumin remained negative and she was congratulated that, in 9 years, she had no evidence of microvascular complications. However, her glycosylated hemoglobin (HbA1c) level was 8.2%; 4 months previously it was 8.0%, up from 7.0% a year earlier. Her blood glucose records revealed a fairly flat curve of moderate hyperglycemia throughout the day with blood glucose values between 170 and 220 mg/dL (1 mg/dL ⫽ 0.05551 mmol/L), reflecting her 3 balanced meals. She was advised that something had to be done to address her elevated glycemic levels. Results from the landmark United Kingdom Prospective Diabetes Study (UKPDS), a large intervention study in patients with type 2 diabetes, suggested that by reducing her HbA1c from 8.2% back to 7.0% Jane would decrease her risk of developing microvas-
Tibaldi
Intensifying Treatment in Type 2 Diabetes
cular disease by approximately 44% and decrease her risk of any diabetes-related adverse outcome or death by about 25%.1 When insulin was mentioned, Jane burst into tears. She related how a friend who started insulin had gained 21 lb (9.5 kg), at least in part because “she always had to eat to prevent her sugar from going too low.” To prevent weight gain, Jane always exercised in the form of a daily walk and ate 3 balanced meals per day. She had followed this routine faithfully since her retirement. In addition, she expressed concern that she lived alone and that her arthritis and cataracts would not allow her to self-administer insulin. Jane’s physician discussed the point that progression to insulin use does not indicate failure, because the natural history of type 2 diabetes dictates that, after ⱖ10 years insulin is required to maintain good blood glucose control and to stay healthy.2 Sensing Jane’s severe apprehension, the physician requested permission to administer a mock injection. An insulin pen device with a 30-gauge pen needle was used with a test fluid: Jane was amazed that she really did not feel it. She was then given the device and asked to dial 10 U. The device featured a large-dose scale and audible clicks upon dose adjustment allowing her to perform this task easily despite her arthritis and poor vision.
Case 2: John John is a 48-year-old man with type 2 diabetes who returned to see his family physician after a hiatus of 1 year. He noted that his new job, involving frequent travel, meant that finding time for “his health” was proving difficult. He was now in a situation whereby small meals during the day left him famished by evening, at which time he would return home and consume a large dinner. He felt that this dietary pattern, as well as decreased exercise, had led to a 5 lb (2.3 kg) weight gain and deterioration of his glycemic control. A year ago John’s HbA1c was 6.7% on extended release glipizide 10 mg/day and metformin 1,000 mg/day. He was also taking a statin, aspirin, and an ACE inhibitor. No evidence of microvascular disease was noted on his physical examination; the only change was an increase in the varicosities and edema in his legs, which he attributed to being “on his feet all day.” Laboratory work showed that his HbA1c level had increased to 8.5%. This finding was consistent with self-measured blood sugars: fasting blood glucose was 200 mg/dL and predinner glucose was 120 to 130 mg/dL, but bedtime ranged from 310 to 330 mg/dL. John realized that his meal patterns should change, but with the restrictions of the new job he thought he could not achieve this. His grandmother had had numerous complications due to diabetes and John understood that these complications were preventable; however the thought of insulin scared him.
Case 3: Sam Upon receiving a diagnosis of type 2 diabetes 2 years earlier at the age of 33, Sam decided to take a proactive approach
S31 to the management of his disease, immediately attending an American Diabetes Association (ADA) educational course for people with diabetes. He was fortunate to have been diagnosed before complications occurred and wanted to keep it that way. Despite his best intentions, Sam had difficulty with portion control and gained rather than lost weight on his medication (a combination tablet of metformin and glyburide). Sam’s current fasting glucose readings were on the order of 140 to 150 mg/dL, but his postprandial glucose levels would often reach 220 to 250 mg/dL. Sam was aware that his current HbA1c of 7.5% represented an increased risk for diabetic complications and that something needed to be done.
Case 4: Gloria Gloria, a 71-year-old woman, was shocked to learn she had diabetes. She was slim, exercised regularly, and knew no one who had the disease. She had been placed quickly on triple therapy (rosiglitazone 4 mg/day, glimepiride 8 mg/ day, metformin 1,000 mg twice daily) but with poor results. A glutamic acid decarboxylase– 65 antibody test was moderately positive, indicating that she had latent autoimmune diabetes in adulthood. Insulin was started and oral hypoglycemic agents were stopped. She was quickly advanced to a multiple injection insulin regimen with glargine 10 U at bedtime plus glulisine 2 to 4 U with meals administered with a pen device. Gloria was taught carbohydrate counting and was meticulous in testing. She was able to obtain reasonable fasting glucose values in the 85–120 mg/dL range, and adequate prelunch glucose values in the same range. However, her predinner glucose values, taken at about 7 PM were always ⬎200 mg/dL, despite increasing the lunchtime dose of glulisine to achieve postprandial values of about 140 mg/dL.
INSULIN: TO START OR NOT TO START? WHAT ARE THE CONSIDERATIONS? The patient is an important ally in selecting insulin as a therapy. The patient must be made aware that in most cases, treatment of type 2 diabetes eventually progresses to insulin therapy. Some individuals are apprehensive about the presumed pain of injections, a fear that can readily be allayed by a mock injection, as in the case of Jane. Perceived inability to administer injections because of physical impediments, such as Jane’s arthritis, can also be addressed by showing the patient how to use insulin pens. In the discussion with the patient, the physician must assess how willing the patient is to follow recommendations, that is, would he/she only consider 1 injection or could he/she administer insulin 4 times a day? The usual patient preference is to add another pill, rather than an injection, to their existing oral regimen. The limitations and side effects of the medicines must be considered: ●
sulfonylureas may show their maximal effects at lower doses than prescribing guidelines suggest3
S32 ● ●
90% of the biologic effect of glipizide is at 10 mg, of glyburide at 5 mg, and of glimepiride is at 4 mg4-6 the maximal dose of metformin is 1,000 mg twice a day7
Going above these doses does not help an individual. Thiazolidinediones (TZDs) are commonly added to complete triple therapy but HbA1c reductions are typically on the order of 1.0% to 1.5%, and side effects such as edema or weight gain may occur.8 Recently, concerns about the cardiovascular safety of TZDs have been raised, and currently warnings for risk of causing or escalating congestive heart failure (CHF) have been added to the product labelling.9,10 A recent meta-analysis of 42 randomized, controlled, clinical trials of rosiglitazone found a significant increase in the risk for myocardial infarction (MI) and an increase in death from cardiovascular causes, although significance was borderline and these findings are controversial. Further research is needed to evaluate what (if any) are the cardiovascular risks associated with TZDs.9 In the cases discussed above, Sam would be a good candidate, but must be informed that there is a chance of weight gain if this therapy is chosen. John’s HbA1c is too high for a TZD to allow him to achieve American College of Endocrinology goals of 6.5%. His baseline edema from varicosities may also intensify. Dipeptidyl peptidase– 4 inhibitors are now available and are predominantly postprandial glycemic regulators. They are currently approved by the US Food and Drug Administration (FDA) only for monotherapy or for use in conjunction with metformin or TZDs, but none of the patients presented here fall under these recommendation categories. ␣-Glucosidase inhibitors are also postprandial regulators, so these patients would derive little benefit from such drugs. Moreover, because of their gastrointestinal side effects, ␣-glucosidase inhibitors are not commonly prescribed in the United States. The glucagon-like peptide–1 analogue exenatide is becoming a more popular medicine because of its appetitesuppressing effects and attendant weight loss. However, its effect on HbA1c may be quite limited compared with other antidiabetic therapies (with reductions ⱕ1.3%)11,12; additionally, the fact that it is predominantly a postprandial regulator has to be taken into account when determining which patients are likely candidates for this therapy.13 In the cases above, if Jane were to use the medicine, she would most likely lose weight but not reach her target HbA1c. She would also have to be cognizant of the fact that exenatide is a twice-daily parenteral medicine. Sam, might benefit from this therapy because his HbA1c is within the necessary range and the appetite-suppressing effect of exenatide might help him with portion and, hence, weight control. The starting dose is 5 g twice daily, given subcutaneously, at breakfast and dinner for 1 month, with an increase to 10 g after 1 month assuming there are no limiting side effects such as nausea or vomiting. Generally the sulfonylurea dose is decreased by 50% when starting exenatide to limit the risk for hypoglycemia.14
The American Journal of Medicine, Vol 121, No 6A, June 2008 Insulin initiation or change of insulin is a possibility with all of these patients. In type 2 diabetes, insulin is usually initiated by adding either a basal or premixed formulation to existing oral antidiabetic therapy. Modern insulins (insulin analogues) are popular because their absorption properties have been designed to achieve favorable pharmacodynamic profiles.15 Basal insulin is currently the most popular choice of therapy, because a dose can be administered at virtually any time on a daily basis and is commonly given in the morning or at nighttime. The goals of basal insulin therapy are to diminish hepatic glucose production, lower the fasting glucose level, and hopefully allow -cells to recover by eliminating glucotoxicity. -Cell recovery and attendant prandial insulin secretion are required to attain glycemic goals; otherwise postprandial blood glucose is likely to remain markedly elevated. Generally, the introduction of basal insulin therapy that is continually titrated to a fasting glucose target lowers HbA1c by about 1.5% regardless of the baseline level of control.16-19 Jane would be a good candidate for basal insulin therapy for many reasons. Her HbA1c, at 8.2%, means there is a reasonable chance for achieving guideline targets with basal insulin. She is afraid of hypoglycemia, but the modern basal insulin analogues, insulin glargine and insulin detemir, have both been shown to incur a significantly lower risk for hypoglycemia than that incurred by the conventional basal insulin preparation, neutral protamine Hagedorn (NPH).16-19 Both of these insulin analogues are available in pen devices, which would suit Jane. In addition, initiation of insulin with insulin detemir has been shown to incur less weight gain than that observed with NPH insulin,17,18 and this advantage appears to increase with baseline BMI. While weight gain of about 6.6 lb (3 kg) was seen over 6 months in all BMI categories with NPH, heavier patients gained progressively less weight with insulin detemir; patients with a BMI ⬎29 gained only 1.1 to 1.3 lb (0.5 to 0.6 kg),17 which is likely to be reassuring for Jane. Basal insulin can be given as 10 U, or 0.1 to 0.2 U/kg, at night. Easy-to-use algorithms have been studied to titrate basal insulin doses.20,21 One such algorithm20 increases the insulin by 2 U every 3 days until fasting blood glucose (FBG) is at goal, typically 100 mg/dL. The oral hypoglycemic agent can be continued. If, 3 to 6 months later, the HbA1c is not at goal then 2 options exist: 1. 10% of the basal dose could be added as a rapid-acting analogue to be taken with the patient’s main meal, and 10% subtracted from the basal dose. The patient would then need to titrate up the prandial insulin dose until the postprandial glucose levels were at the specified goal, typically 140 to 180 mg/dL. The anticipated decrease in HbA1c is 0.5%. Additional prandial injections can be given later if needed. 2. The basal dose can be split in half and administered as 2 doses of an analogue premix at breakfast and at dinner. The predinner dose should be titrated every 3 days until FBG is ⬍110 mg/dL. Once FBG is controlled, the break-
Tibaldi Table 1
Intensifying Treatment in Type 2 Diabetes
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Overview of cases
Age (yr) Medication HbA1c BMI category Relevant clinical finding/other considerations
Therapeutic choices
Final choice
Jane
John
Sam
Gloria
74 SU, metformin 8.2 Obese Arthritis, cataracts
48 SU, metformin 8.5 Overweight Varicose veins
35 SU, metformin 7.5 Obese None
71 MDI 7.4 Normal Slim
Stable balanced meals Fear of weight gain and hypoglycemia
Edema
—
GAD-65 positive
Basal, premixed
Basal bolus
CSII
TZD and exenatide
Premixed
TZD, exenatide Basal, premixed
Basal
TZD Premixed
Exenatide
Split basal
Split basal
BMI ⫽ body mass index; CSII ⫽ continuous subcutaneous insulin infusion; GAD-65 ⫽ glutamic acid decarboxylase– 65; MDI ⫽ multiple-dose insulin; SU ⫽ sulfonylurea; TZD ⫽ thiazolidinedione.
fast dose should be titrated in 2-U increments every 3 days until the predinner blood glucose is ⬍110 mg/dL.22 Basal insulin is also a reasonable choice for Sam. Although the anticipated weight loss is greater with exenatide, if Sam were intolerant of drug, then a basal insulin would be an alternative, again noting that less weight gain is likely to occur if insulin detemir is selected. Gloria’s case highlights some potential shortcomings of all basal insulins. The half-life and duration of action is dependent on dose, and there is a slight peak in effect.23 Thus at small doses, the mean duration of action of glargine and detemir may not extend to 24 hours.23 Gloria’s glucose patterns reveal that the basal insulin wears off after lunch. Higher doses could extend the duration of action, but if the peak of action is too great, there is a risk for hypoglycemia. However, both insulin glargine and insulin detemir have demonstrated a relatively flatter time– action profile24-26 and less risk for hypoglycemia compared with NPH insulin.16,19,27 Gloria therefore needs to split her basal dose in half and take it twice a day. Another option for Gloria is to consider an insulin pump. A premixed insulin analogue may be the best choice for John, because his HbA1c is at 8.5%. Therefore, the addition of a basal insulin or of exenatide would be unlikely to achieve an HbA1c of 6.5%. A TZD could possibly reduce his HbA1c to 7.0%, but the preexisting edema would most likely worsen. With his current lifestyle of a large evening dinner followed by very high bedtime glucose levels, a premixed insulin would be beneficial in lowering the evening postprandial glucose as well as the FBG levels. An analogue mix at dinner (12 U) could be added to his current medication, and John could increase the dose every 3 days until his FBG was 80 to 110 mg/dL. After 3 months, if target HbA1c is not attained, an additional dose could be given at breakfast starting with 6 U to be titrated up every
3 days by 2 U until the predinner glucose is 80 to 110 mg/dL. Diabetes inevitably progresses, however, and at some future stage a second injection will likely be needed.28 If postlunch glucose levels are high, for instance in the case of a patient consuming a large lunch, a third dose of analogue mix can be added at lunch, starting with 3 U and slowly titrating the dose up based on glucose readings taken before dinner. In the majority of cases, however, a third shot is not required. The premix choice may be a viable option for Jane and Sam, but weight gain is a consideration in both cases. The achievement of excellent HbA1c levels, for example, a 2.8% reduction to 6.9% with biphasic insulin aspart 30 (BIAsp 30) used twice daily in the INITIATE (Initiation of Insulin to Reach A1c Target) study22 came with an increase in weight of around 12 lb (5.4 kg). In the PREFER (Predictable and for Every Patient Reliable) study, again using twice-daily BIAsp 30, a reduction in HbA1c from 8.4% to 7.07% was demonstrated, but the increase in weight was 4.6 lb (2.1 kg).29 While initiation of a premix regimen offers both Jane and Sam the opportunity to make substantial improvements in their glycemic control, they will need to become adept at carbohydrate and calorie counting and make dietary changes if they are to avoid further weight gain.
SUMMARY Each of the cases presented here it is possible to make additional treatment interventions to improve the patient’s glycemic control. With careful consideration of each patient’s individual needs and the options available, and with appropriate counseling, choices can be made that may help to maximize patient acceptance of therapy and therefore the chances of success (Table 1).
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The American Journal of Medicine, Vol 121, No 6A, June 2008
AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: Joseph Tibaldi, MD, is a member of the Speakers’ Bureau for Daichi Sankyo, GlaxoSmithKline, Merck & Co., Novartis, Novo Nordisk A/S, and sanofi-aventis.
References 1. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405412. 2. Wright A, Burden AC, Paisey RB, et al, 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 UK Prospective Diabetes Study (UKPDS 57). Diabetes Care. 2002;25: 330-336. 3. Melander A, Donnelly R, Rydberg T. Is there a concentration-effect relationship for sulphonylureas? Clin Pharmacokinet. 1998;34:181188. 4. Stenman S, Melander A, Groop P-H, Groop LC. What is the benefit of increasing the sulfonylurea dose? Am Intern Med. 1993;118:169-172. 5. Hermann LS, Schersten B, Melander A. Antihyperglycaemic efficacy, response prediction, and dose-response relations of treatment with metformin and sulphonylurea, alone and in primary combination. Diabet Med. 1993;11:953-960. 6. Goldberg RB, Holvey SM, Schneider J, for the Glimepiride Protocol #201 Study Group. A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. Diabetes Care. 1996;19:849-856. 7. Garber A, Duncan TG, Goodman AM, et al. Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, doseresponse trial. Am J Med. 1997;103:491-497. 8. Noble J, Baerlocher MO, Silverberg J. Management of type 2 diabetes mellitus: role of thiazolidinediones. Can Fam Physician. 2005;51:683687. 9. Nissen SE, Wolsky K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes [published correction appears in N Engl J Med. 2007;357:100]. N Engl J Med. 2007;356: 2457-2471. 10. Highlights of prescribing information for Avandia. Research Triangle Park, NC: GlaxoSmithKline. Available at: http://www.fda.gov/cder/ foi/label/2007/021071s031lbl.pdf. Accessed December 13, 2007. 11. Nathan DM, Buse JB, Davidson MB, et al, for the Professional Practice Committee, American Diabetes Association and the European Association for the Study of Diabetes. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia. 2006;49:1711-1721. 12. Ratner RE, Maggs D, Nielsen LL, et al. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2006;8:419-428. 13. Mikhail N. Exenatide: a novel approach for treatment of type 2 diabetes. South Med J. 2006;99:1271-1279. 14. Nauck MA, Duran S, Kim D, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes
15. 16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-267. Lindholm A. New insulins in the treatment of diabetes mellitus. Best Pract Res Clin Gastroenterol. 2002;16:475-492. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The Treat-to-Target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26:3080-3086. Hermansen K, Davies M, Derezinski T, et al. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naïve people with type 2 diabetes. Diabetes Care. 2006;29:1269-1274. Philis-Tsimikas A, Charpentier G, Clauson P, et al. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28:1569-1581. Eliaschewitz FG, Calvo C, Valbuean H, et al, for the HOE 901/4013 LA Study Group. Therapy in type 2 diabetes: insuling glargine vs. NPH insulin both in combination with glimepride. Arch Med Res. 2006;37:495-501. Davies M, Storms F, Dhutler S, et al, for the ATLANTUS Study Group. Improvement of glycemic control in subjects with poorly controlled type 2 diabetes: comparison of two treatment algorithms using insulin glargine. Diabetes Care. 2005;28:1282-1288. Shapiro AMJ, Meneghini L, Koenen C, et al. PREDICTIVE 303: a 26-week multi-centre, randomized, open-label study to evaluate the efficacy and safety of a simplified self-adjusted dosing guideline using once-daily insulin detemir in patients with type 2 diabetes. Diabet Med. 2006;23 (suppl 4):337. Poster 934. Raskin P, Allen E, Hollander P, et al, for the INITIATE study group. Initiating insulin therapy in type 2 diabetes: a comparison of biphasic and basal insulin analogs. Diabetes Care. 2005;28:260-265. Klein O, Lynge J, Endahl L, et al. Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007;9:290-299. Lepore M, Pampanelli S, Fanelli C, et al. 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. 2000;49: 2142-2148. Plank J, Bodenlenz M, Sinner F, et al. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir. Diabetes Care. 2005;28:1107-1112. Heise T, Nosek L, Ronn BB, et al. Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes. Diabetes. 2004;53:1614-1620. Massi Benedetti M, Humburg E, Dressler A, et al, for the 3002 Study Group. A one-year, randomised, multicentre trial comparing insulin glargine with NPH insulin in combination with oral agents in patients with type 2 diabetes. Horm Metab Res. 2003;35:189-196. Garber A, Wahlen J, Wahl T, et al. Attainment of glycaemic goals in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (the 1-2-3 Study). Diabetes Obes Metab. 2006;8:58-66. Liebl A, Prager R, Kaiser M, et al, on behalf of the PREFER study group. Biphasic insulin aspart 30 (BIAsp30), insulin detemir (IDet) and insulin aspart (IAsp) allow patients with type 2 diabetes to reach A1C target: the PREFER Study [abstract]. Diabetes Care. 2006; 55(suppl 1):A123.