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May 22, 2009 - Abstract Objectives (1) To determine the prevalence of metformin prescribing in type 2 diabetes with a contrain- dication and (2) to explore ...
Pharm World Sci (2009) 31:481–486 DOI 10.1007/s11096-009-9303-2

RESEARCH ARTICLE

Prescribing metformin in type 2 diabetes with a contraindication: prevalence and outcome Juraporn Pongwecharak Æ Nawatsanan Tengmeesri Æ Nongluck Malanusorn Æ Matshamon Panthong Æ Nantida Pawangkapin

Received: 13 July 2008 / Accepted: 14 April 2009 / Published online: 22 May 2009  Springer Science+Business Media B.V. 2009

Abstract Objectives (1) To determine the prevalence of metformin prescribing in type 2 diabetes with a contraindication and (2) to explore whether metformin use on top of contraindications modified the risks of lactic acidosis, hospitalization, and death in type 2 diabetes. Setting Ambulatory diabetic clinics of the secondary-level care General Hospital of Hatyai district, Songkhla province, South Thailand. Method A cross-sectional study was carried out for the objective (1). A retrospective cohort study was applied to meet the objective (2). Out-patient medical case notes were reviewed for metformin use, number of hospitalizations, lactic acidosis cases, death cases, and the presence of contraindications, which were limited to: (1) chronic renal impairments, (2) chronic liver diseases, and (3) cardiac failure. Only documented diagnoses of the above conditions were counted. Main outcome measure The prevalence of metformin use in type 2 diabetes with a contraindication; odds ratios (ORs) of the occurrences of lactic acidosis, hospitalization, and death in type 2 diabetes with a contraindication modified by metformin use. Results A total of 1,630 type 2 diabetic outpatients were identified; 19.3% (315/1,630) had at least one contraindication to metformin use, with chronic renal impairment being the most frequent risk (78%, 246/315). Of those with a contraindication, 84.4% (266/315) were metformin users. Compared to non-metformin users, there were no significant differences in the number of hospitalizations and deaths. No cases of lactic acidosis were evident. Metformin use in the presence of contraindications did not affect the

J. Pongwecharak (&)  N. Tengmeesri  N. Malanusorn  M. Panthong  N. Pawangkapin Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hatyai, Songkhla 90112, Thailand e-mail: [email protected]

risks of hospitalization (OR 0.73, 95% confidence interval [CI] 0.38–1.4, P = 0.34) or death (OR 0.58, 95% CI 0.11– 3.15, P = 0.53). Other patient factors, such as the female gender or having diabetes-related complications, had significant influences on both outcomes. Conclusion The prevalence of type 2 diabetes receiving metformin despite having a contraindication was over 80%. However, metformin use in such conditions did not appear to increase the risks of hospitalization and death. No lactic acidosis was reported. Other patient factors than metformin affect the risks of hospitalization and death. Keywords Contraindication  Death  Hospitalization  Lactic acidosis  Metformin  Renal impairments  Thailand  Type 2 diabetes

Impact of findings on practice •



Research is needed (1) to verify if prescribers are actually aware of the contraindication-list when they decide to prescribe metformin; (2) to explore the effects of specific contraindication (other than cardiac failure) to metformin use on clinical outcomes. Given the established benefits of metformin in type-2 diabetes but also the lack of data against or in favour of its use when some contraindications exist, its use in patients should not be deterred but the possible adverse effects should be closely monitored.

Introduction Metformin is the only oral antidiabetic agent proven to reduce diabetes-related and total mortality in obese type 2

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diabetes [1]. It has now been recommended as an agent of choice in the treatment of type 2 diabetes regardless of obesity [2]. Its predecessor, phenformin, was abandoned due to fatal cases of lactic acidosis. The use of metformin, with adherence to the contraindications and warnings, confirmed its safety in both post-marketing surveillance studies [3, 4] and several clinical studies [5, 6], where there was no excess risk of lactic acid associated with its use, compared to those not taking any agent. In usual practice, metformin has been widely prescribed for diabetic patients with a known contraindicated condition, but, apparently, no lactic acidosis cases were observed [7, 8]. This observation raised the issue of product labeling revisions to exclude some particular conditions from being unnecessarily marked as a contraindication. At present, cardiac failure is no longer listed as a contraindication, as advised to manufacturers by the USFDA [9]. Cardiac failure alone may not put the patients at risk of developing metformin-associated lactic acidosis [8, 10]. In fact, metformin use was associated with fewer deaths or hospitalizations in diabetes with heart failure [11, 12]. On the other hand, cases of metformin-associated lactic acidosis continued to be reported sporadically [13–18]; concern over the risk thus remained. In Thailand, there are 28 metformin products with full prescribing information. They were the generic and the original products, excluding combinations. The contraindications present in their prescribing information vary in detail and coverage, although they shared some similarities [19] (Table 1). They can be classified as: (1) chronic

Table 1 Contraindications to the use of metformin in the prescribing information of metformin products marketed in Thailand Contraindications present in prescribing information

Number of products (N = 28)

Ketoacidosis

26

Renal impairments

24

Cardiac failure

20

History of lactic acidosis (or conditions predisposed to it)

11

Alcoholism (acute or chronic)

19

Precoma/diabetic coma

16

Chronic liver diseases

17

Hypoxemia

12

Shock

6

Stress/Trauma Severe infection

8 8

Miscellaneous (i.e., recent or acute myocardial infarction, septicemia, acute porphyria, thyroid impairment, pulmonary insufficiency, dehydration, pregnancy, lactation)

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18

conditions, i.e., renal impairments, liver diseases, cardiac failure, chronic alcoholism, and history of lactic acidosis or conditions predisposing to it; (2) acute conditions, i.e., precoma/diabetic coma, ketoacidosis, shock, severe infection, and stress/trauma. A few products also included recent myocardial infarction or acute myocardial infarction. Other less common contraindications present in the prescribing information included hypoxemia, pulmonary insufficiency, dehydration, pregnancy, lactation, thyroid impairment, and acute porphyria. The contraindications were not well defined; for example, only seven out of all products defined renal impairment as severe. A decision to prescribe metformin may, thus, rely on the physician’s clinical judgment, provided that they study the prescribing information carefully.

Aim of the study To determine the prevalence of metformin use in the presence of contraindications, and to explore if metformin use on top of contraindications affects the risks of lactic acidosis, hospitalization, and death.

Methods The study took place in April 2006 in the outpatient diabetic clinic of the secondary-level care General Hospital in Hatyai district, Songkhla, Thailand. Type 2 diabetic patients’ medical case notes were selected (N = 1,630). They were reviewed back to the dates when diabetes mellitus was first diagnosed for each patient and whether or not they had been started on metformin at any time since their diagnoses. The presence of concurrent contraindications to metformin use was also identified at the time when metfomin was instituted. Contraindications of interest were defined as a risk factor predisposing to metformin-associated lactic acidosis, following those in the product information. Specifically for the study, they were limited to conditions involving three major organ systems, i.e., (1) chronic liver diseases; (2) chronic renal impairments; and (3) cardiac failure. The presence of contraindications was counted if they were documented in the medical case notes. Diabetes-related complications, i.e., nephropathy, retinopathy, neuropathy, foot ulcer, and amputation, were also noted if evidenced in the medical case notes at any time point. Hospitalizations, lactic acidosis cases, and deaths were the outcomes observed since metformin had begun for each patient up to the time when the study started. The medical case notes and hospital death registries linked by hospital numbers were examined in order to identify the death outcome.

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3.97 ± 3.09 (2.4 months up to 35 years), totaling to 5,497.6 years of metformin use. A total of 315 patients had a contraindication. Among these, 266 (84.4%) were receiving metformin as part of their antidiabetic regimens. However, fewer patients in the metformin user group (18.2%) had a contraindication compared to their counterparts (28.5%, P = 0.01). Chronic renal impairments were significantly more frequent in the non-metformin user group than in the metformin user group.

SPSS for Windows version 13.0 was used for the data analysis. Binary logistic regression was used to estimate the odds of the outcomes predicted by metformin. Student’s t-test or the Chi-square test was used to compare the quantitative or qualitative characteristics of the two groups of patients who had contraindications, i.e., metformin users vs. non-metformin users. A significant level was set at a Pvalue of less than 0.05.

Results Prevalence of metformin prescribed in type 2 diabetes with a contraindication

Effects of metformin use in the presence of contraindications on the risks of lactic acidosis, hospitalization, and death

Table 2 describes the demographic and characteristics of the type 2 diabetic patients (N = 1,630) by metformin use and the prevalence of metformin prescribing in those with contraindications. The duration of metformin use was

Table 3 compares the characteristics and the outcomes studied in type 2 diabetic patients with contraindications who were metformin users and non-users. No case of lactic acidosis was found. Both groups were similar in their

Table 2 Demographic and characteristics of type 2 diabetic patients stratified by metformin use Characteristics

Metformin users (N = 1,458)

Male (%)

502 (34.4)

Age (SD), years [range]

Non-metformin users (N = 172) 62 (36.0)

61.05 (11.57) [22–92]

63.84 (13.7) [23–91]

Time since diagnosis (SD), years [range]

6.72 (4.8) [0.02–40]

5.54 (4.6) [0.5–29]

Diabetes-related complications (%)

564 (38.7)

Combined antidiabetic regimens that included metformin (%)

0.67 0.012 0.002 0.21

1281 (87.9)





177 (12.1)





Metformin monotherapy (%) Duration of metformin use (SD), years [range] Daily dose of metformin (SD), mg [range]

58 (33.7)

P-value

3.97 (3.09) [0.02–35]





1,521.78 (815.1) [250–5,100]





Presence of at least one contraindication (%)

266 (18.2)

Chronic liver diseases (%) Cardiac failure (%) Chronic renal impairments (%) Patients with at least one hospitalization (%)

49 (28.5)

0.01

19 (1.3)

2 (1.2)

1.0

66 (4.5) 203 (13.9)

10 (5.8) 43 (25)

0.45 \0.001

498 (34.2)

71 (41.3)

0.06

The characteristics in bold indicate a significant difference between the groups

Table 3 Comparison of the characteristics and outcomes between metformin users and non-metformin users in the presence of contraindications Characteristics

Metformin users with contraindications (N = 266)

Non-metformin users with contraindications (N = 49)

P-value

Female (%)

168 (63.2)

30 (61.2)

0.8

Age (SD), years

64.97 (10.57)

66.2 (12.02)

0.48

Time since diagnosis (SD), years

751 (5.6)

7.46 (5.94)

0.95

Diabetes-related complication (%)

113 (42.5)

19 (38.8)

0.63

Patients with hospitalization (%)

138 (51.9)

28 (57.1)

0.5

Deaths (%)

7 (2.6)

2 (4.1)

0.58

Number of hospitalizations per patient (SD) Lactic acidosis case

1.4 (2.19) None

2.04 (3.03) None

0.16 –

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Table 4 Probability of hospitalization and death in type 2 diabetes patients with a contraindication (N = 315) predicted by metformin use adjusted by other characteristics Modifiers

Hospitalization Odds ratio [95%CI]

Death P-value

Odds ratio [95%CI]

P-value 0.53

Metformin use

0.73 [0.38, 1.40]

0.34

0.58 [0.11, 3.15]

Female

1.91 [1.16, 3.12]

0.01

1.3 [0.24, 6.9]

0.77

Age (years) Time since diagnosis (years)

0.99 [0.96, 1.01] 1.03 [0.98, 1.07]

0.24 0.16

1.09 [0.997 1.18] 0.96 [0.83, 1.11]

0.06 0.59

Diabetes-related complications

1.66 [0.996, 2.76]

0.05

1.86 [0.41, 8.51]

0.43

1.0 [0.999,1.0]

0.07

1.01 [0.91, 1.12]

0.87

Daily dose of metformin (mg) Duration of metformin use (years)

1.0 [0.998, 1.00] 1.25 [0.91, 1.73]

0.66 0.17

The variable in bold indicates a significant influence on the outcome

Table 5 Probability of hospitalization and death in type 2 diabetes patients with chronic renal impairments (N = 246) predicted by metformin use adjusted by other characteristics Modifiers

Hospitalization Odds ratio [95%CI]

Metformin use Female Age (years) Time since diagnosis (years) Diabetes-related complications Daily dose of metformin (mg) Duration of metformin use (years)

Death P-value

Odds ratio [95%CI]

P-value

0.63 [0.31, 1.31]

0.22

0.39 [0.06, 2.5]

0.32

2.26 [1.3, 4.0]

0.005

2.6 [0.27, 25.4]

0.41

0.997 [0.97, 1.03]

0.86

1.11 [0.996 1.23]

0.06

1.02 [0.98, 1.08]

0.33

0.96 [0.82, 1.13]

0.64

2.7 [1.54, 4.7] 1.0 [0.999,1.0]

0.001 0.07

1.96 [0.30, 12.6] 1.0 [0.998, 1.002]

0.48 0.85

1.01 [0.90, 1.13]

0.89

1.24 [0.85, 1.81]

0.26

The variables in bold indicate a significant influence on the outcome

characteristics and outcomes. Metformin use in the presence of contraindications, adjusted for other variables, did not affect hospitalizations and deaths (see Table 4). Specifically, in chronic renal impairments, which constituted most of the contraindications, both outcomes remained unaffected by metformin use (see Table 5).

Discussion Prevalence of metformin prescribed in type 2 diabetes with a contraindication The present study reported the prevalence of prescribing metformin in type 2 diabetes patients with existing contraindications to be over 80%, which was in line with the prevalences of 19–94% reported elsewhere [7, 8, 20, 21]. However, it was noted that contraindications were significantly less frequent in those started on metformin compared to those who were not. It was not known if this was due to prescribers’ awareness of the contraindications and avoiding metformin use in the patients.

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Effects of metformin use in the presence of contraindications on the risks of lactic acidosis, hospitalization, and death No cases of lactic acidosis were found in the study. Our small sample size could be an explanation, considering that the pooled incidence of metformin-associated lactic acidosis is 6–8 cases per 100,000 patient-years [6]. In addition, the number of patients considered to have contraindications to metformin use was too small (N = 315) to observe for the event within the time-frame studied. Non-metformin users with similar contraindications tended to be hospitalized more often and had more deaths than their counterparts, but the differences were not statistically significant. Metformin use did not appear to influence both hospitalization and death in patients with contraindications. Other patient characteristics, i.e., female gender and diabetes-related complications, increased the odds of the outcomes. Studies to date have rarely examined the outcome of metformin-users with other contraindications, except for cardiac failure. They showed that hospital admission or mortality was lowered in metformin users in

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the presence of cardiac failure [8, 11, 12], which was found to improve with metformin use [8, 12]. A large number of patients with contraindications in the present study had chronic renal impairments (246/315), but we did not find that metformin use on top of such conditions posed any risk for hospitalization and death. However, it should not be interpreted that metformin use in chronic renal impairments is safe. The degree of their severity should be taken into account. Mild renal impairment in metformin users was not shown to increase the lactic acid level, and no cases of lactic acidosis were found in such conditions [22]. Serum creatinine levels of greater than 1.4 mg/dl or 1.5 mg/dl for females and males, respectively, are the recommended cut points for the avoidance of metformin use [23]. We did not obtain complete data on serum creatinine or its clearance but relied upon documented diagnosis only. The number of patients whose degrees of renal impairments were severe enough to avoid metformin use was, therefore, unknown. Indeed, the listed contraindications in metformin prescribing information, such as liver impairments and renal impairments, were generally broad as to the extent of impairments in which metformin must not be used. Renal impairments should be guided by creatinine clearance rather than using the serum creatinine cut point alone, as metformin is known to be excreted unchanged renally. A study showed that the presence of contraindications resulted in withholding as well as dosage adjustment of metformin in most patients [24], while they were disregarded in the other studies [25, 26]. The present study did not investigate if the presence of a specific contraindication would have influenced the initial dosage of metformin. Limitations of the study The retrospective nature of the study could render incomplete data. The study population was from the secondarylevel care hospital only, therefore, its generalizability may be limited in terms of the hospital population of diabetic patients and the prescribing pattern of metformin. The study shared some similarities with the demographic data from the 2003 national cross-sectional survey in tertiary–level care and university hospitals [27] in percentages of male patients (34.6 vs. 33.8%) and patient ages (61.35 ± 11.84 vs. 60.9 ± 11.5 years), respectively. However, metformin monotherapy (10.9 vs. 29.2%) and metformin-combined therapy (78.6 vs. 89%) were less common in the present study than those from the tertiary-level care and university hospitals. The size of the study population was insufficient to detect cases of lactic acidosis, if any. Confounding factors such as alcohol intake, obesity, other concurrent medications, glycemic control, as well as comorbidities other than the contraindications studied could not be excluded.

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Despite a number of drawbacks, the present study is one of a few studies ever attempted to examine at the outcomes of metformin use concurrent with contraindications in type 2 diabetes mellitus. Conclusion Metformin use on top of contraindications was widespread, i.e., over 80% of type 2 diabetes patients with documented chronic liver diseases, chronic renal impairments, or cardiac failure were found to be started on metformin. However, no cases of lactic acidosis were established. Metformin use did not increase the odds of hospitalization and death in type 2 diabetes patients with contraindications. Acknowledgements We are grateful to Miss Jaruwee Kanjanakeereethamrong of the Department of Pharmacy at Songkhla General Hospital for coordinating the data collection. Our thanks are also extended to Mr. Murray John McMurdo for the language proofreading. Funding This research project was supported by the annual research grant from the Faculty of Pharmaceutical Sciences and Prince of Songkla University. Conflict of interest statement

None.

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