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Timely Addition of Insulin to Oral Therapy for Type 2 Diabetes

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Timely Addition of Insulin to Oral Therapy for Type 2 Diabetes EDITORIAL Timely Addition of Insulin to Oral Therapy for Type 2 Diabetes he U.K. Prospective Diabetes Study betes to treatment with diet alone, insulin (usually by 20–50%) the requirement for (UKPDS) has shaped our view of the alone, or a sulfonylurea alone initially, but exogenous insulin, which cannot be T management of type 2 diabetes insulin was added when fasting blood adapted to varying needs after injection, more than any other trial. It proved that glucose was persistently Ͼ108 mg/dl. especially during exercise, when mobili- glycemic control limits retinopathy (and The sulfonylureas used were glipizide or zation of insulin from subcutaneous de- probably other microvascular complica- chlorpropamide, perhaps because earlier pots can inappropriately increase. tions) as much for type 2 diabetic patients in the trial, glyburide was associated with Ongoing sulfonylurea treatment may also as had previously been shown for type 1 more hypoglycemia. Insulin was given enhance the opportunity for normal diabetic patients (1). It defined the pro- first as ultralente alone, with mealtime downregulation of endogenous insulin gressive natural history of type 2 diabetes, regular insulin added subsequently as when blood glucose declines. These with declining ␤-cell function over time needed. As in the main UKPDS protocol, mechanisms could lead to smaller within- and a need for progressively more active both pharmacotherapeutic regimens out- and between-day variations of blood glu- treatment to maintain glycemic control performed diet alone. However, the regi- cose as well as less risk of hypoglycemia at (2). In addition, it has offered important men mandating the timely addition of any mean level of glycemia, resulting in insights into the effects of several forms of insulin to a sulfonylurea proved superior the opportunity to achieve lower HbA1c treatment. to insulin alone. The median HbA1c over values without excessive hypoglycemia, For example, newly diagnosed pa- 6 years was 0.5% lower with the progres- as was seen in this UKPDS substudy. tients entering the UKPDS who did not sive (monotherapy to combined therapy) In theory, these mechanisms might need immediate insulin therapy received regimen, which was associated with sim- apply not just to sulfonylureas but also to intensive dietary therapy, but only 15% of ilar weight gain but less hypoglycemia metformin and thiazolidinediones, in them were able to reach target levels of compared with insulin alone. The advan- slightly differing ways, when they are glycemic control (fasting blood glucose tage in glycemic control was quantitively combined with insulin therapy. A recent Յ108 mg/dl) after 3 months, and the re- very like that seen in smaller and shorter physiologic study (9) of concurrent use of sults were even worse after a year (3). This studies, performed later in the course of metformin or troglitazone with very in- disappointing result indicates that life- type 2 diabetes (7,8), which also com- tensive insulin therapy, delivered as con- style intervention alone will only occasion- pared sulfonylurea/insulin therapy with tinuous subcutaneous insulin infusion, ally be successful for patients presenting aggressively titrated insulin-only therapy. showed that the insulin dosage that was with overt diabetes. The UKPDS also re- Experience from the main UKPDS pre- needed declined ϳ30% with metformin assured us that insulin and sulfonylureas dicts that this much glycemic benefit and 50% with the thiazolidinedione, do not increase cardiovascular mortality, should reduce microvascular events by whereas C-peptide levels were un- as had been feared. It showed that gly- 10–15%. changed. Under these conditions of in- buride caused more hypoglycemia than However, oral agent/insulin combi- creased tissue responsiveness to insulin, chlorpropamide and glipizide (1) and nations are still not very widely used. appropriate modulations of endogenous that metformin (4) was the one drug used Aside from previous lack of evidence from insulin secretion should be more effective that did not cause weight gain compared large trials reporting that combined ther- in attenuating both increases and de- with therapy based on lifestyle. These in- apy is better than insulin alone, accep- creases of blood glucose. With met- sights have helped us deploy these treat- tance of combinations has been hindered formin, which acts mainly at the liver, the ments more effectively. by lack of a clear physiologic rationale. clinical result should be less risk of hypo- One of the main conclusions the The UKPDS investigators endorse the the- glycemia. With thiazolidinediones, which UKPDS investigators themselves have ory that injected long-acting insulin can act mainly at muscle and fat, a reduction drawn from their findings is that combi- improve overnight glucose control suffi- of postprandial hyperglycemia may be nations of treatments will routinely be ciently to reduce glucose toxicity (and li- just as important. The ability of met- needed for type 2 diabetes (5). In this is- potoxicity), thereby allowing a formin to improve the effectiveness of sue of Diabetes Care, they report the re- sulfonylurea to have its full effect poten- multiple injections of insulin for type 2 sults of a 6-year substudy using a tiating mealtime insulin secretion. An- diabetes was apparent in a small 6-month predefined combined regimen (Glucose other possibility is that chronic use of clinical study (10) in which optimized Study 2) that was motivated in part by the sulfonylureas increases the contribution treatment achieved HbA1c 6.5% with findings described above and conducted of endogenous insulin secretion to regu- metformin plus insulin but only 7.5% toward the end of the overall trial (6). In lation of basal glucose production, lead- with placebo plus insulin. This study also eight centers, 826 patients were random- ing to greater glycemic stability. This confirmed another advantage of using ized shortly after diagnosis of type 2 dia- effect might derive partly from reducing metformin with insulin—limitation of the DIABETES CARE, VOLUME 25, NUMBER 2, FEBRUARY 2002 395 Editorial weight gain usually seen with intensifica- cular morbidity and mortality in type 2 sponse of fasting plasma glucose to diet tion of insulin treatment. diabetes. The glycemic targets in such tri- therapy in newly presenting type II dia- betic patients. Metabolism 39:905–912, The UKPDS report may underesti- als will have to correspond to HbA1c mate the benefits of combined oral agent/ Յ6.5%—a range that was not maintained 1990 4. UK Prospective Diabetes Study Group: insulin therapy because the agents used in in the UKPDS in either the main mono- Effect of intensive blood-glucose control therapy protocol or the early combined this substudy that started over a decade with metformin on complications in ago are being replaced by better versions. therapy substudy discussed here. The me- overweight patients with type 2 diabetes Chlorpropamide and conventional glipi- dian HbA1c of 6.6% that was shown with (UKPDS 34). Lancet 352:854–865, 1998 zide are now rarely used, whereas early addition of ultralente insulin to 5. Turner RC, Cull CA, Frighi V, Holman glimepiride and extended-release glipiz- glipizide or chlorpropamide in the RR, the UK Prospective Diabetes Study ide are gaining on glyburide, which is still UKPDS sets a challenge for the newer Group: Glycemic control with diet, sulfo- the most widely used sulfonylurea in the studies to match or surpass using multiple nylurea, metformin, or insulin in patients U.S., partly because of its very low cost. combinations of newer agents. For clini- with type 2 diabetes mellitus: progressive Bovine ultralente insulin is gone, and hu- cal practice in the meantime, this latest requirement for multiple therapies (UKPDS report from the UKPDS documents the 49): J Am Med Assoc 281:2005–2012, man ultralente insulin is likely to be sup- 1999 planted by insulin glargine, a long-acting effectiveness of the timely addition of in- sulin to an oral regimen to defend HbA 6. Wright A, Burden ACF, Paisey, RB, Cull, analog that promises to supplement basal 1c CA, Holman, RR, for the UK Prospective insulin more reliably. Moreover, met- 7.0%, which is a widely accepted target Diabetes Study Group: Sulfonylurea inad- formin, rosiglitazone, and pioglitazone based on microvascular end point trials. equacy: efficacy of addition of insulin over are now available in the U.S. 6 years in patients with type 2 diabetes in MATTHEW C. RIDDLE, MD Using the newer products, current the U.K. Prospective Diabetes Study. Dia- betes Care 25:330–336, 2002 and future trials should expand our un- From the Division of Endocrinology, Diabetes, and derstanding of the effectiveness of oral Clinical Nutrition, Department of Medicine, Oregon 7. Riddle MC, Hart J, Bingham P, Garrison C, McDaniel P: Combined therapy for agent/insulin combination regimens. For Health and Science University, Portland, Oregon. Address correspondence to Matthew C. Riddle, obese type 2 diabetes: suppertime mixed example, one study is comparing the abil- MD, Section of Diabetes L-345, Oregon Health and insulin with daytime sulfonylurea. Am J ity of bedtime NPH insulin versus bed- Science University, 3181 SW Sam Jackson Park Rd., Med Sci 303:151–156, 1992 time glargine to reestablish optimal Portland, OR 97201. E-mail: [email protected]. 8. Shank ML, DelPrato S, DeFronzo RA: glycemic control while one or two oral M.C.R. has received consulting fees from Amylin, Bedtime insulin/daytime glipizide: effec- Aventis, GlaxoSmithKline, Novo Nordisk, Ortho- tive therapy for sulfonylurea failures in agents are continued. A preliminary re- McNeil (Johnson & Johnson), and Pfizer; lecture port, which included data from Ͼ300 pa- honoraria from Amylin, Aventis, Bristol-Myers NIDDM. Diabetes 44:165–172, 1995 tients (11) and pooled data from the two Squibb, GlaxoSmithKline, Novo Nordisk, and 9. Yu JG, Kruszynska YT, Mulford MI, Olef- randomized treatment groups, showed Pfizer; and grant/research support from Aventis, sky JM: A comparison of troglitazone and that remarkably good control is possible Pfizer, and GlaxoSmithKline.
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