C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n / P s y c h o s o c i a l R e s e a r c h
Secondary Failure of Metformin
Monotherapy in Clinical Practice
8% to define initial success and secondary HRISTOPHER CONNER, PHARMD, PHD
studies have examined the potential ben-efits of immediate versus delayed met-formin initiation used with a modern A1C OBJECTIVE — We sought to document the secondary failure rate of metformin mono-
therapy in a clinical practice setting and to explore factors that predict therapeutic failure.
although metformin fails at a rate of ϳ4%per year in clinical trials (7), the failure RESEARCH DESIGN AND METHODS — We studied 1,799 type 2 diabetic patients
rate in the real world of clinical practice who, between 2004 and 2006, lowered their A1C to Ͻ7% after initiating metformin mono- therapy as their first-ever anti-hyperglycemic drug. We examined all A1C values recorded through 31 December 2008 (2–5 years of follow-up), defining secondary failure as a subsequent A1C Ն7.5% or the addition or substitution of another anti-hyperglycemic agent. We usedlogistic regression to identify factors associated with the probability of secondary failure.
therapy experienced by unselected pa-tients in a nonresearch setting who had a RESULTS — Of the 1,799 patients studied, 42% (n ϭ 748) experienced secondary failure; the
mean failure rate was 17% per year. However, patients who initiated metformin within 3 months ering their A1C to Ͻ7% with metformin.
of diabetes diagnosis failed at an age-and A1C-adjusted rate of 12.2% (10.5–14.4%) per year, and We then sought to identify factors associ- patients who initiated while A1C was Ͻ7% failed at an adjusted rate of 12.3% per year. An ated with slower loss of glycemic control.
interaction term between duration of diagnosed diabetes and A1C was not significant. Age, duration, and A1C at initiation were the only factors that predicted secondary failure.
ducted within a managed care plan usingelectronic medical records with substan- CONCLUSIONS — Although metformin failure may occur more rapidly in clinical practice
than in clinical trails, initiating it soon after diabetes diagnosis and while A1C is low mightpreserve ␤-cell function, prolong the effectiveness of metformin, reduce lifetime glycemic bur- cluding built-in alerts for A1C testing.
den, and prevent diabetes complications. Our findings support the current treatment algorithmfor hyperglycemia management that recommends metformin initiation when diabetes is first RESEARCH DESIGN AND
Diabetes Care 33:501–506, 2010
Study siteKaiser Permanente Northwest (KPNW) is TheDiabetesPreventionProgramand Association for the Study of Diabetes anonprofitgroup-modelHMOthatpro-
therapy can slow the deterioration of gly- rently with lifestyle intervention at di- uses electronic health care utilization data to track and facilitate operations. An elec- progression to diabetes. This suggests that tronic medical record, in use since 1996, initiation of metformin as soon as diabetes allows the attending clinician to record as many as 20 International Classification of trajectory of loss in insulin secretory ca- perglycemia appears to improve the effec- Diseases, Ninth Revision, Clinical Modifica- pacity and glycemic control, delaying the tiveness and durability of the therapy, but tion (ICD-9-CM) coded diagnoses at each in these studies, duration of diabetes (de- ambulatory patient contact and up to nine lay in initiation of therapy) did not predict discharge diagnoses for inpatient hospital the clinician at each contact. A single re- choice, and they used an A1C cut point of gional laboratory performs nearly allKPNW laboratory tests, and the results ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● From the 1Kaiser Permanente Center for Health Research, Portland, Oregon; and 2Novo Nordisk, Seattle, Corresponding author: Gregory A. Nichols, [email protected]
Received 18 September 2009 and accepted 19 December 2009. Published ahead of print at http://care. on 29 December 2009. DOI: 10.2337/dc09-1749.
2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.
org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. DIABETES CARE, VOLUME 33, NUMBER 3, MARCH 2010 Secondary failure of metformin monotherapy
Table 1—Characteristics of patients who did and did not experience secondary failure of
metformin monotherapy after achieving A1C <7%
monotherapy as their first-ever anti-hyperglycemic drug between 1 January KPNW members for at least 1 year beforetheir first metformin dispense. We ex- months of therapy, defined as 1) receipt of only a single metformin dispense, 2) re- ceipt of less than a 90-day supply, or 3) ary failure after initial success, we then We defined secondary failure as 1) the ad- hyperglycemic agent or 2) a subsequent A1C Ն7.5%, a level slightly above the ac- used this higher threshold to provide cer- Data are means Ϯ SD or percent, unless otherwise indicated.
above 7.0% and to account for recentlypublished trials that report adverse effectsor no beneficial effects of glycemic control potential covariate. Because the duration of potential possession varied in our data depending on time to failure or censoring, period, a rate of 17.0% (15.8 –18.2%) per definitions of failure (A1C Ͼ7.5% or ad- ratio using person-specific denominators.
P ϭ 0.008), longer duration of diabetes before therapy (26.5 vs. 21.4 months, P Ͻ to assess the independent contribution of tiation (8.2 vs. 7.9%, P Ͻ 0.001) were including medication possession ratio, to the probability of experiencing secondary failure. All candidate predictors were en- months. Individuals who did not fail were followed for a mean of 27.6 months (P Ͻ those that were statistically significant (P Ͻ 0.05) were retained in the final blood pressure, lipid levels, and estimated densities to estimate the secondary failure the last values recorded on or before the rate per 1,000 person-years but report the index date. Average daily dose of the ini- figures as percent per year to facilitate stratified by baseline A1C, the secondary tween diabetes diagnosis and the start of failure rates were adjusted for age, sex, supply. The analysis period for estimating and duration of diabetes. When stratified longer. Failure was less likely among in- curred first. Patients who left the health (P value for ␹2 of distribution Ͻ0.001).
plan were censored as of their termination date. To control for different patterns of RESULTS — Of the 1,799 patients
tients, we calculated a measure of adher- ence, the medication possession ratio, as a first-ever anti-hyperglycemic, 42% (n ϭ DIABETES CARE, VOLUME 33, NUMBER 3, MARCH 2010 Brown, Conner, and Nichols
Table 2—Distribution of diabetes duration and A1C at metformin initiation and parsimonious
logistic regression of the probability of secondary failure of metformin
failure (odds ratio 1.56, 95% CI 1.12–2.18), and patients who initiated 36 ormore months after diagnosis were more than twice as likely to fail (2.20, 1.68 – metformin initiation of 7–7.9, 8 – 8.9, and 1.54 –2.72) more likely to experience sec- ondary failure, respectively, relative to was not significant. The multivariable sta- (c statistic ϭ 0.613) and adequate fit (Hosmer-Lemeshow ␹2 ϭ 8.3, P ϭ *P ϭ 0.008. †␹2 for distribution P Ͻ 0.001.
patients who initiated metformin within 3months of diabetes diagnosis each year, was lower (P value for ␹2 of distribution tients (Fig. 1). Patients who started met- three of the 20 patient characteristics de- dictors of the odds of secondary failure of those who initiated in 4 –11 months were Figure 1—Kaplan-Meier plot of secondary failure of metformin monotherapy by categories of duration of diabetes at metformin initiation adjustedfor age and A1C at initiation and the percent per year (95% CIs) experiencing secondary failure. DIABETES CARE, VOLUME 33, NUMBER 3, MARCH 2010 Secondary failure of metformin monotherapy
Figure 2—Kaplan-Meier plot of secondary failure of metformin monotherapy by categories of A1C at metformin initiation adjusted for age anddiabetes duration at initiation and the percent per year (95% CIs) experiencing secondary failure. CONCLUSIONS — In this observa-
tional cohort study of 1,799 patients who related end point, microvascular disease, myocardial infarction, and all-cause mor- correlates to an A1C of ϳ8% (8), whereas that initiating metformin within 3 months of diabetes diagnosis was associated with also included the addition or substitution a substantial reduction in the odds of sec- of other anti-hyperglycemic agents within ondary loss of glycemic control. This re- beneficial “legacy effect” in cardiovascular sult is consistent with the hypothesis that disease prevention. A recent joint state- ment of trialists and scientific associations ␤-cell function and supports the current screened volunteers treated by research further supports this point of view (12).
ADA/EASD hyperglycemia treatment al- between real-world “effectiveness” stud- formin initiation and preservation of gly- formin therapy as soon as type 2 diabetes ies and trials of clinical efficacy are not therefore have significant health and eco- secondary failure. Importantly, only sub- jects with the shortest diabetes duration gression (A1C Ն7% or initiation of ther- fidence intervals among the other catego- bidities did not affect this finding, nor did analyses examining the two definitions of other predictors including A1C at initia- difference in the probability of failure.
tion, BMI, blood pressure, lipids, adher- rate. However, it is important to note that failure rate of 17%, substantially greater DIABETES CARE, VOLUME 33, NUMBER 3, MARCH 2010 Brown, Conner, and Nichols
tes mellitus by changes in lifestyle amongsubjects with impaired glucose tolerance.
sample, 780 (23%) patients either did not refill their initial dispense, refilled sporad- nents of tight glycemic control. Further- Diabetes Prevention Programme (IDPP).
tiation. Another 709 patients were unable cians wishing to optimize their patients’ metformin may be less tolerable, less ef- typically requires ongoing therapeutic ad- (16). As therapies lose their effectiveness, long delays frequently result in substan- lengthened effectiveness of the drug, pos- sibly resulting from more effective preser- ment of therapy: a consensus statement of effectiveness requires therapeutic adher- of Diabetes. Diabetes Care 2009;32:193–203 thereby delaying the need for therapeutic among all patients. This is likely due to burden associated with its failure. Further the study design, which limited the study successful initial metformin therapy. Dia- sample to patients who had initially suc- analysis of secondary failure of successful Acknowledgments — This research was
consistent with a previous study in which funded by Novo Nordisk. G.A.N. and J.B.B.
received funding from Novo Nordisk to con- duct the study reported in this article. By con- Lachin JM, O’Neill MC, Zinman B, Viberti greater odds of therapy intensification af- tract, they were the final deciders regarding the design and interpretation of the results. In bility of rosiglitazone, metformin, or gly- addition to Novo Nordisk, they have received funding from other firms that manufacture drugs marketed to treat diabetes, including 8. American Diabetes Association. Standards of medical care in diabetes–2009. Diabetes levels. If so, it would be expected that they Takeda Pharmaceuticals North America, and Novartis Pharmaceuticals. C.C. is an employee 9. Kent DM, Hayward RA. Limitations of ap- of and holds stock in Novo Nordisk. No other plying summary results of clinical trials to potential conflicts of interest relevant to this individual patients: the need for risk strat- tients with longer duration of diabetes be- This study was presented at the 69th Scien- 10. Pani LN, Nathan DM, Grant RW. Clinical tific Sessions of the American Diabetes Associ- in good control for much of that untreated ation, New Orleans, Louisiana, 5–9 June period, in which case their total time in who initiated metformin immediately.
Our objective was to assess the success of metformin therapy in drug-naïve patients intensive glucose control in type 2 diabe-tes. N Engl J Med 2008;359:1577–1589 Nathan DM, Diabetes Prevention Pro-gram Research Group: Reduction in the 12. Skyler JS, Bergenstal R, Bonow RO, Buse J, incidence of type 2 diabetes with lifestyle 2. Tuomilehto J, Lindstro¨m J, Eriksson JG, Valle TT, Ha¨ma¨la¨inen H, Ilanne-Parikka DIABETES CARE, VOLUME 33, NUMBER 3, MARCH 2010 Secondary failure of metformin monotherapy
of cardiovascular events: implications of RR. Glycemic control with diet, sulfonyl- 14. Bailey CJ, Turner RC. Metformin. N Engl with type 2 diabetes mellitus: progressive 15. Grant R, Adams AS, Trinacty CM, Zhang entific statement of the American College quent clinical inertia in type 2 diabetes 17. Brown JB, Nichols GA, Perry A. The bur- den of treatment failure in type 2 diabetes.



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