Correspondence

New Treatments for Diabetes

N Engl J Med 2007; 356:2219-2223May 24, 2007

Article

To the Editor:

In his Perspective article on diabetes, Nathan (Feb. 1 issue)1 suggests that a newly approved dipeptidyl peptidase IV (DPP-IV) inhibitor, sitagliptin, “is one of the less effective glycemia-lowering drugs.” This contention may reflect a misunderstanding of the relationship between a change in the glycated hemoglobin level and the baseline value. Our meta-analysis showed that for existing oral agents, with a baseline glycated hemoglobin level between 9.0% and 9.9%, the mean decrease was 1.0 percentage point, whereas for a baseline level between 8.0% and 8.9%, the mean decrease was 0.6 percentage point.2 The smaller decreases in the glycated hemoglobin level with sitagliptin, then, are explained by a lower baseline value than those reported in older studies of metformin, sulfonylureas, and thiazolidinediones.

To illustrate this point, we have added data from published placebo-controlled trials of sitagliptin3 and vildagliptin4 to our original analysis (Figure 1Figure 1Changes in Glycated Hemoglobin Levels According to Baseline Levels in Six Placebo-Controlled Studies of Sitagliptin and Vildagliptin, as Compared with 73 Studies of Other Agents between 1991 and 2002.). Furthermore, head-to-head comparisons show that DPP-IV inhibitors have a glucose-lowering effect that is similar to that of the sulfonylurea glipizide, with a considerably lower likelihood of causing hypoglycemia,5 and to that of the thiazolidinediones, without causing weight gain.6 We conclude that these new agents, which are effective in combination with insulin sensitizers, will help more persons with diabetes to achieve the difficult goal of improved glycemic control.

Zachary T. Bloomgarden, M.D.
Mt. Sinai School of Medicine, New York, NY 10029
zbloomgard@aol.com

Silvio E. Inzucchi, M.D.
Yale University School of Medicine, New Haven, CT 06520

Dr. Bloomgarden reports serving on speaker panels for Takeda, GlaxoSmithKline, Novo Nordisk, Eli Lilly, Amylin, Merck, and Novartis and serving as a consultant for Merck. Dr. Inzucchi reports serving as an adviser to Merck, Takeda, Pfizer, and Novartis; receiving consulting fees from Merck; receiving honoraria from Merck and Takeda; and receiving research funding from Eli Lilly. No other potential conflict of interest relevant to this letter was reported.

6 References

1. 1

   Nathan DM. Finding new treatments for diabetes -- how many, how fast . . . how good? N Engl J Med 2007;356:437-440
   Full Text | Web of Science | Medline

2. 2

   Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care 2006;29:2137-2139
   CrossRef | Web of Science | Medline

3. 3

   Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006;49:2564-2571
   CrossRef | Web of Science | Medline

4. 4

   Ristic S, Byiers S, Foley J, Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005;7:692-698
   CrossRef | Web of Science | Medline

5. 5

   Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194-205
   CrossRef | Web of Science | Medline

6. 6

   Rosenstock J, Baron MA, Camisasca RP, Cressier F, Couturier A, Dejager S. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab 2007;9:175-185
   CrossRef | Web of Science | Medline

To the Editor:

In the article by Nathan, important inaccuracies concerning the review and approval process of the Food and Drug Administration (FDA) should be clarified. The 1962 amendment to the Food, Drug, and Cosmetic Act (FDCA) requires that drug approval be based on “substantial evidence,” a requirement that is generally fulfilled by data from adequate and well-controlled studies.1 Approval of antidiabetic therapies typically relies on evidence from several well-controlled clinical studies, including a minimum 6-month, placebo-controlled period that continues into an extension period exceeding 1 year to further assess safety and durability of effect. This was the case with the sitagliptin approval, which was based not only on the four phase 3 studies cited by Nathan but also on an extensive nonclinical and phase 1 and 2 clinical development program. Overall, 3276 patients took sitagliptin in 34 studies, with a cumulative exposure of 1339 patient-years — far in excess of the 641 patient-years cited by Nathan.2 However, since even a large clinical program cannot elucidate all safety issues, the FDA closely monitors the safety of all drugs after approval and takes regulatory action that is consistent with new safety information.

Nathan implies that newer antidiabetic therapies have little clinical value if they are less potent than older agents; this suggests that superior efficacy is now necessary in drug approval. A demand for superior efficacy is not permitted under the FDCA, which calls for the determination of the safety and efficacy of a drug on its own merits. Furthermore, superiority is not the only consideration in selecting a drug for a given patient in the clinic, since relative safety, tolerability, and individual response are important factors in any clinical judgment.

We agree that the failure to use effective therapies and implement lifestyle and dietary modifications contributes to inadequate glycemic control in many persons with diabetes. Comparative clinical trials of available therapies may better inform prescribers and patients and partially address these failures. Well-designed trials of multiple agents probably will not be conducted by manufacturers, and the FDA has limited authority to demand such trials. Any such trials probably would be conducted through an alliance of academic institutions and government agencies. Such efforts to show the comparative safety, effectiveness, and costs of therapies would be more conducive to public health than regulatory measures, which might significantly hinder the development of new therapies that offer choices when other available therapies are contraindicated, are poorly tolerated, or do not meet individual needs.

Ilan Irony, M.D.
Mary H. Parks, M.D.
Robert J. Meyer, M.D.
Food and Drug Administration, Silver Spring, MD 20993-0002
ilan.irony@fda.hhs.gov

2 References

1. 1

   21 C.F.R. subpart D, § 314.126 (2006).
   

2. 2

   FDA reviews for Januvia (sitagliptin phosphate). (Accessed May 3, 2007, at http://www.fda.gov/cder/foi/nda/2006/021995s000TOC.htm.)
   

To the Editor:

Nathan's caution against the use of new treatments seems surprising, given not only the increasing prevalence of diabetes but also our declining ability to achieve control of diabetes, as evidenced by the rising average glycated hemoglobin level in the past decade.1 Our inability to achieve diabetes control is probably due to a lack of effective and durable treatments. Nathan's suggestion that we continue to use primarily insulin, sulfonylureas, and biguanides (a suggestion that is also made in his recent American Diabetes Association [ADA] guideline2 and that is similar to the ADA's recommendations a decade ago3) is flawed, since data from the United Kingdom Prospective Diabetes Study (UKPDS) show that these treatments all fail to achieve control over time.4 A Diabetes Outcome Progression Trial, one of the largest studies involving persons with type 2 diabetes, showed that rosiglitazone resulted in a 32% reduction in the risk of treatment failure as compared with metformin and in a 63% reduction as compared with glyburide5 — results that Nathan dismissed in his editorial accompanying the report on this trial. The management of type 2 diabetes should focus on achieving as well as sustaining normoglycemia. Might some combination of a glitazone, gliptin, and rimonabant achieve this outcome? We may never find out if others insist on doing the same old thing.

Matthew L. Mintz, M.D.
George Washington University School of Medicine, Washington, DC 20037
mmintz@mfa.gwu.edu

Dr. Mintz reports receiving lecture fees from GlaxoSmithKline, Takeda, and Pfizer. No other potential conflict of interest relevant to this letter was reported.

5 References

1. 1

   Saydah SH, Fradkin J, Cowie CC. Poor control of risk factors for vascular disease among adults with previously diagnosed diabetes. JAMA 2004;291:335-342
   CrossRef | Web of Science | Medline

2. 2

   Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia 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. Diabetes Care 2006;29:1963-1972[Erratum, Diabetes Care 2006;29:2816-8.]
   CrossRef | Web of Science | Medline

3. 3

   The pharmacological treatment of hyperglycemia in NIDDM. Diabetes Care 1995;18:1510-1518
   Web of Science | Medline

4. 4

   Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005-2012
   CrossRef | Web of Science | Medline

5. 5

   Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443[Erratum, N Engl J Med 2007;356:1387-8.]
   Full Text | Web of Science | Medline

To the Editor:

Nathan criticizes the rapid approval of new drugs for hypoglycemia, stating that the current available treatment is adequate. We think this is inaccurate. Despite existing drugs, the diabetes epidemic is increasing, with relatively few patients achieving glycemic control.1 Furthermore, as shown in the UKPDS, adherence to glycemic control requires high-dose drug combinations and insulin with resulting side effects.2 Thus, we believe that new and effective drugs are needed, with future treatment based on metformin combinations.

Regarding the quick FDA approval of sitagliptin, we would like to clarify that although the only published report at the time was ours, the results of other trials have already been presented at the ADA meeting (June 9 to 13, 2006). Furthermore, trials show that metformin–sitagliptin combinations more than doubled the effect of metformin,3 with a possible beta-cell protective effect4 and negligible side effects (in contrast to the hepatotoxicity of troglitazone that was noticed before its FDA approval). Thus, the new gliptins are a welcome addition to our armamentarium. In combination with metformin or other drugs for hypoglycemia, the gliptins offer a safe and effective option for the treatment of diabetes.

Itamar Raz, M.D.
Roy Eldor, M.D.
Hadassah–Hebrew University, 91120 Jerusalem, Israel
eldorroy@yahoo.com

4 References

1. 1

   Resnick HE, Foster GL, Bardsley J, Ratner RE. Achievement of American Diabetes Association clinical practice recommendations among U.S. adults with diabetes, 1999-2002: the National Health and Nutrition Examination Survey. Diabetes Care 2006;29:531-537
   CrossRef | Web of Science | Medline

2. 2

   Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999;281:2005-2012
   CrossRef | Web of Science | Medline

3. 3

   Williams-Herman D, Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J. Initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin provides substantial glycemic improvement and HbA1c goal attainment in patients with type 2 diabetes mellitus. Diabet Med 2006;23:Suppl 4:265-410
   Web of Science | Medline

4. 4

   Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab 2007;9:186-193
   CrossRef | Web of Science | Medline

Author/Editor Response

Bloomgarden and Inzucchi note the potential importance of initial glycated hemoglobin levels in judging the relative effectiveness of new diabetes medications.1 Although their figure shows a correlation of baseline glycated hemoglobin levels with a glucose-lowering effect, it explains only 14% of the variance. Despite this modest correlation, they suggest that, considered in this light, the DPP-IV inhibitors are not as ineffective as I proposed. However, the scant data available at the time I wrote the Perspective article did not provide any direct proof that sitagliptin is as effective as less expensive agents. If pharmaceutical company–sponsored investigators want to claim similar effects of newer drugs as compared with older ones, they should perform more head-to-head comparison studies. The recently published study cited by Bloomgarden and Inzucchi was an efficacy analysis of glipizide as compared with sitagliptin in which almost one third of the subjects who underwent randomization were excluded from the primary analysis.2 More patients in the sitagliptin-treatment group discontinued therapy “for lack of efficacy.” In the intention-to-treat analysis, sitagliptin lowered glycated hemoglobin levels by 0.51%.

Irony and colleagues point to “important inaccuracies” in my Perspective article regarding the FDA approval process. They note that the FDA considered data from 30 studies, in addition to the 4 published clinical trials I considered, and that the total cumulative exposure was 1339 patient-years, “far in excess of the 641 patient-years” that I cited. First, I did not suggest that the FDA considered only peer-reviewed, published data. I only noted the paucity of peer-reviewed data from clinical trials for clinicians to consider. Second, even if the FDA considers 1339 patient-years of exposure to be a major improvement, the average exposure in the studies was about 5 months — for a drug that may be taken by millions of patients for many years. I join Irony et al. in decrying the limited studies that directly compare therapeutic agents.

Mintz suggests that my curmudgeonly critiques of new glucose-lowering agents, including the DPP-IV inhibitors and thiazolidinediones3 (as well as inhaled insulin4), will inhibit our ability to maintain lower glycemia over time. I would counter that the introduction of more expensive, less effective medications does not contribute to the well-being of the population of patients with diabetes. If combinations of new medications with older ones are proposed to improve long-term diabetes control, at an expense similar to or less than that of older combinations, they should be tested.

Finally, Raz and Eldor note that data published in abstracts suggest that combination therapy with metformin has a synergistic effect. I urge peer-reviewed publication of such studies, assuming they include active comparison treatments so that the additive effects of the newer agents can be compared with older combinations.

David M. Nathan, M.D.
Massachusetts General Hospital, Boston, MA 02114
dnathan@partners.org

4 References

1. 1

   Bloomgarden ZT, Dodis R, Viscoli CM, Holmboe ES, Inzucchi SE. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. Diabetes Care 2006;29:2137-2139
   CrossRef | Web of Science | Medline

2. 2

   Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the dipeptilyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007;9:194-205
   CrossRef | Web of Science | Medline

3. 3

   Nathan DM. Thiazolidinediones for initial treatment of type 2 diabetes? N Engl J Med 2006;355:2477-2480
   Full Text | Web of Science | Medline

4. 4

   Nathan DM. No time to inhale: arguments against inhaled insulin in 2007. Diabetes Care 2007;30:442-443
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   C. F. Deacon. (2011) Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes, Obesity and Metabolism 13:1, 7-18
   CrossRef