Correspondence
Initial Management of Glycemia in Type 2 Diabetes
N Engl J Med 2003; 348:760-761February 20, 2003
- Article
To the Editor:
In his Clinical Practice article (Oct. 24 issue),1 Nathan states that “although combination therapy with a sulfonylurea (or glitinides) and insulin has been approved for use, I do not recommend it.” The author bases his recommendation on the principle that combination therapy should involve agents with different primary modes of action, but often we use agents with the same mode of action but different pharmacokinetic profiles — a clear example being insulin mixtures.
In most patients with type 2 diabetes, sulfonylureas can be viewed as an “endogenous insulin injection.” That being the case, the combination of a long-acting insulin such as insulin glargine or a neutral protamine Hagedorn preparation with a glitinide for postprandial control makes perfect sense, and initial studies have been supportive.2
Moreover, the recently published United Kingdom Prospective Diabetes Study (UKPDS 57)3 showed that the addition of insulin in patients with diabetes that is not optimally controlled by sulfonylurea therapy, as compared with insulin alone, leads to better glycemic control (glycosylated hemoglobin, 6.6 percent vs. 7.1 percent; proportion with <7 percent glycosylated hemoglobin, 47 percent vs. 35 percent). This control was achieved with similar weight gain and, more importantly, with a lower incidence of major hypoglycemic episodes. The combination of insulin and sulfonylurea should still be recommended for selected patients.
3 ReferencesSalomon Banarer, M.D.
University of Louisville, Louisville, KY 40292
sbanarer@im.wustl. edu 1
Nathan DM . Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med 2002;347:1342-1349
Full Text | Web of Science | Medline2
de Luis DA ,Aller R ,Cuellar L , et al. Effect of repaglinide addition to NPH insulin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:1844-1845
CrossRef | Web of Science | Medline3
Wright A ,Burden AC ,Paisey RB ,Cull CA ,Holman RR . Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002;25:330-336[Erratum, Diabetes Care 2002;25:1268.]
CrossRef | Web of Science | Medline
To the Editor:
Nathan mentions that multiple combinations of therapies have proved efficacious in controlling type 2 diabetes mellitus, including thiazolidinediones and insulin. What was not mentioned in the article was that three recent randomized, controlled trials (two trials involving rosiglitazone and one trial involving pioglitazone) found that subjects without a history of heart failure who received thiazolidinediones in addition to insulin had an increased risk of development of overt heart failure as compared with subjects who received insulin alone.1,2 This fact deserves mention so that readers may consider adjusting their practice accordingly.
2 ReferencesRenato A. Apolito, M.D.
Columbia University College of Physicians and Surgeons, New York, NY 10032
apolitre@hotmail.com 1
Summary. Rockville, Md.: Food and Drug Administration, April 2002. (Accessed January 30, 2003, at http://www.fda.gov/medwatch/SAFETY/2002/summary-actos-avandia.pdf.)
2
Avandia (rosiglitazone maleate). Research Triangle Park, N.C.: GlaxoSmithKline, 2003. (Accessed January 30, 2003, at http://www.avandia.com/.)
Author/Editor Response
Dr. Banarer takes exception to my recommendation that insulin and sulfonylureas (or glitinides) not be used for combination therapy since they have similar modes of action and are not likely to have additive hypoglycemic effects. Many studies have demonstrated that the combination of insulin and sulfonylureas results in a “significant but modest improvement in glycemic control” as compared with insulin alone.1 However, almost all studies have failed to use insulin aggressively, raising the possibility that the same effect could be achieved with more insulin.2
According to the report from UKPDS cited by Dr. Banarer, early addition of insulin in subjects randomly assigned to sulfonylurea treatment resulted in a mean glycosylated hemoglobin level that was 0.5 percentage point lower than the mean level achieved in patients assigned to insulin treatment; however, neither of these groups was treated intensively with insulin.3 Specifically, both groups received a single-injection “basal” insulin (bovine or human ultralente insulin) at substantially lower doses (0.24 to 0.30 U per kilogram of body weight per day) than those required in most studies of intensive therapy and without the routine benefit of rapid-acting insulins. The study cited to support the addition of repaglinide to insulin, published as a letter to the editor, was an unmasked, uncontrolled study that did not allow adjustment of insulin doses.4 In my opinion, the addition to insulin of sulfonylureas or glitinides, with their added cost, side effects, and drug interactions, is not merited for most patients.
Dr. Apolito points out that the two currently available thiazolidinediones, when used in combination with insulin, may exacerbate or cause congestive heart failure. Fluid retention, a possibility included as a footnote in Table 2 of my article and noted in the package inserts for both thiazolidinediones, can occur with or without concurrent insulin therapy. When used as monotherapy, the thiazolidinediones increase the incidence of edema by a factor of three to four, from approximately 1 percent with placebo to 5 percent with rosiglitazone or pioglitazone. A similar relative increase in the frequency of edema has been seen with combination therapy when thiazolidinediones are combined with other oral hypoglycemic agents. Although only pioglitazone is currently approved for use with insulin, clinical trials of insulin combined with rosiglitazone or pioglitazone have shown an increase by a factor of two to three in the incidence of edema, from 5 to 7 percent with insulin monotherapy to 15 percent with combination therapy. The risk of congestive heart failure is also increased with combination therapy, albeit at lower absolute rates. The thiazolidinediones are not currently recommended for use in patients with New York Heart Association class III or IV status and should be used cautiously in combination with all other hypoglycemic medications, including insulin.
4 ReferencesDavid M. Nathan, M.D.
Massachusetts General Hospital, Boston, MA 02114
dnathan@partners.org 1
Pugh JA ,Wagner ML ,Sawyer J ,Ramirez G ,Tuley M ,Friedberg SJ . Is combination sulfonylurea and insulin therapy useful in NIDDM patients? A metaanalysis. Diabetes Care 1992;15:953-959
CrossRef | Web of Science | Medline2
Genuth S . Treating diabetes with both insulin and sulfonylurea drugs: what is the value? Clin Diabetes 1987;5:73-793
Wright A ,Burden AC ,Paisey RB ,Cull CA ,Holman RR . Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002;25:330-336[Erratum, Diabetes Care 2002;25:1268.]
CrossRef | Web of Science | Medline4
de Luis DA ,Aller R ,Cuellar L , et al. Effect of repaglinide addition to NPH insulin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24:1844-1845
CrossRef | Web of Science | Medline
