Letters To The Editor

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

In Reply: Dr. Fountas et al highlight further data on insulin therapy and cancer risk, specifically in regard to insulin detemir and insulin degludec. Detemir first gained US Food and Drug Administration (FDA) approval in 2005 as a basal insulin, dosed once or twice daily.¹ Compared with regular human insulin, detemir has demonstrated proliferative and antiapoptotic activities in vitro in various cancer cell lines—eg, HCT-116 (colorectal cancer), PC-3 (prostate cancer), and MCF-7 (breast adenocarcinoma).² But clinically, detemir has not demonstrated increased cancer risk compared with other basal insulins in randomized controlled trials or cohort studies.^3–5

Degludec (U-200 insulin) is equal to twice the concentration of the usual U-100 insulin therapies presently available. In February 2013, the drug application for insulin degludec failed to obtain FDA approval, and the FDA requested additional data on cardiovascular safety. Thus, degludec is not currently available in the United States.⁶

Besides ameliorating nocturnal hypoglycemia,⁷ U-200 insulin may mitigate potential mitogenic effects.⁸ However, there are still very few data on degludec compared with the amount of data on insulin glargine. Insulin analogues with a decreased dissociation rate from the insulin receptor are associated with higher mitogenic potency than metabolic potency compared with human insulin.^9,10 Degludec, like detemir, has an elevated dissociation rate from the insulin receptor, a low affinity for IGF-1 receptors, and a low mitogenic activity in vitro.⁸

At this juncture, neither detemir nor degludec has been associated with higher cancer risk, but these therapies are relatively new. And as Dr. Fountas et al indicated, their safety, particularly in regard to cancer risk in diabetes patients, should continue to be assessed.

To the Editor: I would like to add three points to the excellent review of diabetes therapy and cancer risk by Drs. Sun, Kashyap, and Nasr in the October 2014 issue of Cleveland Clinic Journal of Medicine.¹

First, a recent 10-year prospective observational study of more than 190,000 patients showed no increase in bladder cancer with exposure to or long-term use of pioglitazone vs comparator when smoking status was controlled. Although publicly released, these 10-year data have not yet been published.

Second, a recent paper² from the US Food and Drug Administration and European Medicine Agency reviewed the pancreatic safety of incretin-based therapies. They concluded that there is no evidence that these agents increase the risk of pancreatitis or of pancreatic cancer. So I believe that the authors’ comment that pancreatitis is a “potential side effect” of these agents is not quite accurate.

Lastly, the authors cite no substantial evidence that would support their statement to avoid using glucagon-like protein 1 (GLP-1) receptor agonists in those with a personal history of differentiated thyroid cancer. Indeed these patients, if adequately treated, should have no remnant thyroid tissue. The rodent data indicate an effect of GLP-1 agonists on rodent C cells, not thyroid follicular cells.³ In addition, the prescribing information for these agents does not advise such a limitation on their use.

To the Editor: I would like to add three points to the excellent review of diabetes therapy and cancer risk by Drs. Sun, Kashyap, and Nasr in the October 2014 issue of Cleveland Clinic Journal of Medicine.¹

First, a recent 10-year prospective observational study of more than 190,000 patients showed no increase in bladder cancer with exposure to or long-term use of pioglitazone vs comparator when smoking status was controlled. Although publicly released, these 10-year data have not yet been published.

Second, a recent paper² from the US Food and Drug Administration and European Medicine Agency reviewed the pancreatic safety of incretin-based therapies. They concluded that there is no evidence that these agents increase the risk of pancreatitis or of pancreatic cancer. So I believe that the authors’ comment that pancreatitis is a “potential side effect” of these agents is not quite accurate.

Lastly, the authors cite no substantial evidence that would support their statement to avoid using glucagon-like protein 1 (GLP-1) receptor agonists in those with a personal history of differentiated thyroid cancer. Indeed these patients, if adequately treated, should have no remnant thyroid tissue. The rodent data indicate an effect of GLP-1 agonists on rodent C cells, not thyroid follicular cells.³ In addition, the prescribing information for these agents does not advise such a limitation on their use.

To the Editor: I would like to add three points to the excellent review of diabetes therapy and cancer risk by Drs. Sun, Kashyap, and Nasr in the October 2014 issue of Cleveland Clinic Journal of Medicine.¹

First, a recent 10-year prospective observational study of more than 190,000 patients showed no increase in bladder cancer with exposure to or long-term use of pioglitazone vs comparator when smoking status was controlled. Although publicly released, these 10-year data have not yet been published.

Second, a recent paper² from the US Food and Drug Administration and European Medicine Agency reviewed the pancreatic safety of incretin-based therapies. They concluded that there is no evidence that these agents increase the risk of pancreatitis or of pancreatic cancer. So I believe that the authors’ comment that pancreatitis is a “potential side effect” of these agents is not quite accurate.

Lastly, the authors cite no substantial evidence that would support their statement to avoid using glucagon-like protein 1 (GLP-1) receptor agonists in those with a personal history of differentiated thyroid cancer. Indeed these patients, if adequately treated, should have no remnant thyroid tissue. The rodent data indicate an effect of GLP-1 agonists on rodent C cells, not thyroid follicular cells.³ In addition, the prescribing information for these agents does not advise such a limitation on their use.

In Reply: In regard to Dr. Weiss’s first point, the Kaiser Permanente Northern California diabetes registry study aimed to assess the association between bladder cancer and pioglitazone in 193,099 patients. In their 2011 interim 5-year analysis, Lewis et al reported a modest but statistically significant increased risk of bladder cancer in patients with type 2 diabetes mellitus who used pioglitazone for 2 or more years.¹

We appreciate Dr. Weiss’s comment on the 10-year study conclusion data. As Dr. Weiss has indicated, the recent Takeda news release² showed that the primary analysis found no association between pioglitazone use and bladder cancer risk. Furthermore, no association was found between bladder cancer risk and duration of use, higher cumulative doses, or time since initiation of pioglitazone.²

Regarding Dr. Weiss’s second point, we agree that at this time the cumulative data are not supportive of pancreatitis as per Egan et al.³ Recent publication of the SAVOR-TIMI trial⁴ of saxagliptin documented no increased risk of pancreatitis or pancreatic cancer over 2.1 years of follow-up in more than 16,000 patients over the age of 40 with type 2 diabetes. However, since amylase and lipase levels were not routinely checked in study participants, subclinical and asymptomatic cases may not have been recognized.⁴ Therefore, we stand by our statement that pancreatitis is a potential side effect.

It is important to recognize that although the observational data reviewed by both agencies (the US Food and Drug Administration and European Medicine Agency) in the publication by Egan et al³ are reassuring, we cannot yet say with absolute certainty that there is no associated risk. In fact, the concluding statements of the publication are as follows: “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.”³

On September 18, 2014, the newest approved GLP-1 receptor agonist, dulaglutide, was approved with a boxed warning that it causes thyroid C-cell tumors in rats, that whether it causes thyroid C-cell tumors including medullary thyroid carcinoma (MTC) in humans is unknown, and that since relevance to humans could not be determined from clinical or nonclinical studies, dulaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia syndrome type 2.⁵

It is important to recognize that despite these controversies, which have not been well-supported to date, incretin-based therapies have numerous metabolic benefits, including favorable glycemic and weight effects.

In regard to Dr. Weiss’s last point, we would like to point out the study by Gier et al⁶ in which GLP-1 receptor expression was found in 3 of 17 cases of human papillary thyroid cancer. The implication is that abnormal thyroid tissue does not behave the same way as normal tissue.

Furthermore, Dr. Weiss brings up the point that patients with thyroid cancer, if it is adequately treated, should have no remnant thyroid tissue. Certainly, adequate treatment would be an easy call to make if a stimulated thyroglobulin level is below the assay’s detection limit and there is no imaging evidence of residual thyroid cancer. For example, in someone with a history of thyroid cancer diagnosed more than 10 years ago without biochemical or imaging evidence of disease, any potential concerns of GLP-1 receptor agonist use in regards to thyroid cancer would be nominal. But not everyone with thyroid cancer falls into this category.

We do not suggest that these potential risks preclude the use of these agents in all patients, but rather that a discussion should occur between physician and patient. Diabetes therapy, as in treatment of other medical conditions, should be tailored to the individual patient, and all potential risk and benefits should be disclosed and considered.

In Reply: In regard to Dr. Weiss’s first point, the Kaiser Permanente Northern California diabetes registry study aimed to assess the association between bladder cancer and pioglitazone in 193,099 patients. In their 2011 interim 5-year analysis, Lewis et al reported a modest but statistically significant increased risk of bladder cancer in patients with type 2 diabetes mellitus who used pioglitazone for 2 or more years.¹

We appreciate Dr. Weiss’s comment on the 10-year study conclusion data. As Dr. Weiss has indicated, the recent Takeda news release² showed that the primary analysis found no association between pioglitazone use and bladder cancer risk. Furthermore, no association was found between bladder cancer risk and duration of use, higher cumulative doses, or time since initiation of pioglitazone.²

Regarding Dr. Weiss’s second point, we agree that at this time the cumulative data are not supportive of pancreatitis as per Egan et al.³ Recent publication of the SAVOR-TIMI trial⁴ of saxagliptin documented no increased risk of pancreatitis or pancreatic cancer over 2.1 years of follow-up in more than 16,000 patients over the age of 40 with type 2 diabetes. However, since amylase and lipase levels were not routinely checked in study participants, subclinical and asymptomatic cases may not have been recognized.⁴ Therefore, we stand by our statement that pancreatitis is a potential side effect.

It is important to recognize that although the observational data reviewed by both agencies (the US Food and Drug Administration and European Medicine Agency) in the publication by Egan et al³ are reassuring, we cannot yet say with absolute certainty that there is no associated risk. In fact, the concluding statements of the publication are as follows: “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.”³

On September 18, 2014, the newest approved GLP-1 receptor agonist, dulaglutide, was approved with a boxed warning that it causes thyroid C-cell tumors in rats, that whether it causes thyroid C-cell tumors including medullary thyroid carcinoma (MTC) in humans is unknown, and that since relevance to humans could not be determined from clinical or nonclinical studies, dulaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia syndrome type 2.⁵

It is important to recognize that despite these controversies, which have not been well-supported to date, incretin-based therapies have numerous metabolic benefits, including favorable glycemic and weight effects.

In regard to Dr. Weiss’s last point, we would like to point out the study by Gier et al⁶ in which GLP-1 receptor expression was found in 3 of 17 cases of human papillary thyroid cancer. The implication is that abnormal thyroid tissue does not behave the same way as normal tissue.

Furthermore, Dr. Weiss brings up the point that patients with thyroid cancer, if it is adequately treated, should have no remnant thyroid tissue. Certainly, adequate treatment would be an easy call to make if a stimulated thyroglobulin level is below the assay’s detection limit and there is no imaging evidence of residual thyroid cancer. For example, in someone with a history of thyroid cancer diagnosed more than 10 years ago without biochemical or imaging evidence of disease, any potential concerns of GLP-1 receptor agonist use in regards to thyroid cancer would be nominal. But not everyone with thyroid cancer falls into this category.

We do not suggest that these potential risks preclude the use of these agents in all patients, but rather that a discussion should occur between physician and patient. Diabetes therapy, as in treatment of other medical conditions, should be tailored to the individual patient, and all potential risk and benefits should be disclosed and considered.

In Reply: In regard to Dr. Weiss’s first point, the Kaiser Permanente Northern California diabetes registry study aimed to assess the association between bladder cancer and pioglitazone in 193,099 patients. In their 2011 interim 5-year analysis, Lewis et al reported a modest but statistically significant increased risk of bladder cancer in patients with type 2 diabetes mellitus who used pioglitazone for 2 or more years.¹

We appreciate Dr. Weiss’s comment on the 10-year study conclusion data. As Dr. Weiss has indicated, the recent Takeda news release² showed that the primary analysis found no association between pioglitazone use and bladder cancer risk. Furthermore, no association was found between bladder cancer risk and duration of use, higher cumulative doses, or time since initiation of pioglitazone.²

Regarding Dr. Weiss’s second point, we agree that at this time the cumulative data are not supportive of pancreatitis as per Egan et al.³ Recent publication of the SAVOR-TIMI trial⁴ of saxagliptin documented no increased risk of pancreatitis or pancreatic cancer over 2.1 years of follow-up in more than 16,000 patients over the age of 40 with type 2 diabetes. However, since amylase and lipase levels were not routinely checked in study participants, subclinical and asymptomatic cases may not have been recognized.⁴ Therefore, we stand by our statement that pancreatitis is a potential side effect.

It is important to recognize that although the observational data reviewed by both agencies (the US Food and Drug Administration and European Medicine Agency) in the publication by Egan et al³ are reassuring, we cannot yet say with absolute certainty that there is no associated risk. In fact, the concluding statements of the publication are as follows: “Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.”³

On September 18, 2014, the newest approved GLP-1 receptor agonist, dulaglutide, was approved with a boxed warning that it causes thyroid C-cell tumors in rats, that whether it causes thyroid C-cell tumors including medullary thyroid carcinoma (MTC) in humans is unknown, and that since relevance to humans could not be determined from clinical or nonclinical studies, dulaglutide is contraindicated in patients with a personal or family history of MTC, as well as in patients with multiple endocrine neoplasia syndrome type 2.⁵

It is important to recognize that despite these controversies, which have not been well-supported to date, incretin-based therapies have numerous metabolic benefits, including favorable glycemic and weight effects.

In regard to Dr. Weiss’s last point, we would like to point out the study by Gier et al⁶ in which GLP-1 receptor expression was found in 3 of 17 cases of human papillary thyroid cancer. The implication is that abnormal thyroid tissue does not behave the same way as normal tissue.

Furthermore, Dr. Weiss brings up the point that patients with thyroid cancer, if it is adequately treated, should have no remnant thyroid tissue. Certainly, adequate treatment would be an easy call to make if a stimulated thyroglobulin level is below the assay’s detection limit and there is no imaging evidence of residual thyroid cancer. For example, in someone with a history of thyroid cancer diagnosed more than 10 years ago without biochemical or imaging evidence of disease, any potential concerns of GLP-1 receptor agonist use in regards to thyroid cancer would be nominal. But not everyone with thyroid cancer falls into this category.

We do not suggest that these potential risks preclude the use of these agents in all patients, but rather that a discussion should occur between physician and patient. Diabetes therapy, as in treatment of other medical conditions, should be tailored to the individual patient, and all potential risk and benefits should be disclosed and considered.

To the Editor: In their article about the care of patients with advanced chronic kidney disease, Sakhuja et al¹ mentioned that metformin is contraindicated in chronic kidney disease.

Metformin is a good and useful drug. Not only is it one of the cheapest antidiabetic medications, it is the only one shown to reduce cardiovascular mortality rates in type 2 diabetes mellitus.

Although metformin is thought to increase the risk of lactic acidosis, a Cochrane review² found that the incidence of lactic acidosis was only 4.3 cases per 100,000 patient-years in patients taking metformin, compared with 5.4 cases per 100,000 patient-years in patients not taking metformin. Furthermore, in a large registry of patients with type 2 diabetes and atherothrombosis,³ the rate of all-cause mortality was 24% lower in metformin users than in nonusers, and in those who had moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m²) the difference was 36%.³

A trial by Rachmani et al⁴ raised questions about the standard contraindications to metformin. The authors reviewed 393 patients who had at least one contraindication to metformin but who were receiving it anyway. Their serum creatinine levels ranged from 1.5 to 2.5 mg/dL. There were no cases of lactic acidosis reported. The patients were then randomized either to continue taking metformin or to stop taking it. At 2 years, the group that had stopped taking it had gained more weight, and their glycemic control was worse.

In the Cochrane analysis,² although individual creatinine levels were not available, 53% of the studies reviewed did not exclude patients with serum creatinine levels higher than 1.5 mg/dL. This equated to 37,360 patient-years of metformin use in studies that included patients with chronic kidney disease, and did not lead to lactic acidosis.

Even though metformin’s US package insert says that it is contraindicated if the serum creatinine level is 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women or if the creatinine clearance is “abnormal,” in view of the available evidence, many countries (eg, the United Kingdom, Australia, the Netherlands) now allow metformin to be used in patients with glomerular filtration rates as low as 30 mL/min/1.73m², with lower doses if the glomerular filtration rate is lower than 45.⁵

The current contraindication to metformin in chronic kidney disease needs to be reviewed. In poor countries like India, this cheap medicine may be the only option available for treating type 2 diabetes mellitus, and it remains the first-line therapy for type 2 diabetes mellitus as recommended by the International Diabetes Federation, the American Diabetes Association, and the European Association for the Study of Diabetes.⁵

To the Editor: In their article about the care of patients with advanced chronic kidney disease, Sakhuja et al¹ mentioned that metformin is contraindicated in chronic kidney disease.

Metformin is a good and useful drug. Not only is it one of the cheapest antidiabetic medications, it is the only one shown to reduce cardiovascular mortality rates in type 2 diabetes mellitus.

Although metformin is thought to increase the risk of lactic acidosis, a Cochrane review² found that the incidence of lactic acidosis was only 4.3 cases per 100,000 patient-years in patients taking metformin, compared with 5.4 cases per 100,000 patient-years in patients not taking metformin. Furthermore, in a large registry of patients with type 2 diabetes and atherothrombosis,³ the rate of all-cause mortality was 24% lower in metformin users than in nonusers, and in those who had moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m²) the difference was 36%.³

A trial by Rachmani et al⁴ raised questions about the standard contraindications to metformin. The authors reviewed 393 patients who had at least one contraindication to metformin but who were receiving it anyway. Their serum creatinine levels ranged from 1.5 to 2.5 mg/dL. There were no cases of lactic acidosis reported. The patients were then randomized either to continue taking metformin or to stop taking it. At 2 years, the group that had stopped taking it had gained more weight, and their glycemic control was worse.

In the Cochrane analysis,² although individual creatinine levels were not available, 53% of the studies reviewed did not exclude patients with serum creatinine levels higher than 1.5 mg/dL. This equated to 37,360 patient-years of metformin use in studies that included patients with chronic kidney disease, and did not lead to lactic acidosis.

Even though metformin’s US package insert says that it is contraindicated if the serum creatinine level is 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women or if the creatinine clearance is “abnormal,” in view of the available evidence, many countries (eg, the United Kingdom, Australia, the Netherlands) now allow metformin to be used in patients with glomerular filtration rates as low as 30 mL/min/1.73m², with lower doses if the glomerular filtration rate is lower than 45.⁵

The current contraindication to metformin in chronic kidney disease needs to be reviewed. In poor countries like India, this cheap medicine may be the only option available for treating type 2 diabetes mellitus, and it remains the first-line therapy for type 2 diabetes mellitus as recommended by the International Diabetes Federation, the American Diabetes Association, and the European Association for the Study of Diabetes.⁵

To the Editor: In their article about the care of patients with advanced chronic kidney disease, Sakhuja et al¹ mentioned that metformin is contraindicated in chronic kidney disease.

Metformin is a good and useful drug. Not only is it one of the cheapest antidiabetic medications, it is the only one shown to reduce cardiovascular mortality rates in type 2 diabetes mellitus.

Although metformin is thought to increase the risk of lactic acidosis, a Cochrane review² found that the incidence of lactic acidosis was only 4.3 cases per 100,000 patient-years in patients taking metformin, compared with 5.4 cases per 100,000 patient-years in patients not taking metformin. Furthermore, in a large registry of patients with type 2 diabetes and atherothrombosis,³ the rate of all-cause mortality was 24% lower in metformin users than in nonusers, and in those who had moderate renal impairment (creatinine clearance 30–59 mL/min/1.73 m²) the difference was 36%.³

A trial by Rachmani et al⁴ raised questions about the standard contraindications to metformin. The authors reviewed 393 patients who had at least one contraindication to metformin but who were receiving it anyway. Their serum creatinine levels ranged from 1.5 to 2.5 mg/dL. There were no cases of lactic acidosis reported. The patients were then randomized either to continue taking metformin or to stop taking it. At 2 years, the group that had stopped taking it had gained more weight, and their glycemic control was worse.

In the Cochrane analysis,² although individual creatinine levels were not available, 53% of the studies reviewed did not exclude patients with serum creatinine levels higher than 1.5 mg/dL. This equated to 37,360 patient-years of metformin use in studies that included patients with chronic kidney disease, and did not lead to lactic acidosis.

Even though metformin’s US package insert says that it is contraindicated if the serum creatinine level is 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women or if the creatinine clearance is “abnormal,” in view of the available evidence, many countries (eg, the United Kingdom, Australia, the Netherlands) now allow metformin to be used in patients with glomerular filtration rates as low as 30 mL/min/1.73m², with lower doses if the glomerular filtration rate is lower than 45.⁵

The current contraindication to metformin in chronic kidney disease needs to be reviewed. In poor countries like India, this cheap medicine may be the only option available for treating type 2 diabetes mellitus, and it remains the first-line therapy for type 2 diabetes mellitus as recommended by the International Diabetes Federation, the American Diabetes Association, and the European Association for the Study of Diabetes.⁵

In Reply: We appreciate Dr. Imam’s comments regarding using metformin in those with chronic kidney disease.

The US Food and Drug Administration currently lists metformin as contraindicated in those with mild to moderate renal insufficiency, with serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females. This contraindication is based on the pharmacokinetics of the medication and, likely, the association of a similar medication, phenformin, with lactic acidosis, which eventually led to its withdrawal from the market. However, lactic acidosis is much less frequent with metformin than with phenformin.¹

We agree that metformin is an invaluable medication for diabetes mellitus not requiring insulin. We also agree that lactic acidosis is rare, especially in those with mild renal insufficiency. However, lactic acidosis does occur in patients with chronic kidney disease while on metformin and, however rare, when it does occur it is a life-threatening event.²

The clearance of metformin is strongly dependent on kidney function,³ and therefore guidelines still recommend reducing the dose in those with moderate renal insufficiency and recommend considering stopping the medication in those with severe renal insufficiency—the population we were talking about in our article.⁴ We are aware of changes to the guidelines that have been made by various groups, and in many circumstances we ourselves take an individualized approach, weighing the risks and benefits of continued therapy with the patient and his or her primary care provider. That being said, we did not believe that such nuanced recommendations were appropriate for our article, especially since they are contrary to marketing restrictions for the drug.

In Reply: We appreciate Dr. Imam’s comments regarding using metformin in those with chronic kidney disease.

The US Food and Drug Administration currently lists metformin as contraindicated in those with mild to moderate renal insufficiency, with serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females. This contraindication is based on the pharmacokinetics of the medication and, likely, the association of a similar medication, phenformin, with lactic acidosis, which eventually led to its withdrawal from the market. However, lactic acidosis is much less frequent with metformin than with phenformin.¹

We agree that metformin is an invaluable medication for diabetes mellitus not requiring insulin. We also agree that lactic acidosis is rare, especially in those with mild renal insufficiency. However, lactic acidosis does occur in patients with chronic kidney disease while on metformin and, however rare, when it does occur it is a life-threatening event.²

The clearance of metformin is strongly dependent on kidney function,³ and therefore guidelines still recommend reducing the dose in those with moderate renal insufficiency and recommend considering stopping the medication in those with severe renal insufficiency—the population we were talking about in our article.⁴ We are aware of changes to the guidelines that have been made by various groups, and in many circumstances we ourselves take an individualized approach, weighing the risks and benefits of continued therapy with the patient and his or her primary care provider. That being said, we did not believe that such nuanced recommendations were appropriate for our article, especially since they are contrary to marketing restrictions for the drug.

In Reply: We appreciate Dr. Imam’s comments regarding using metformin in those with chronic kidney disease.

The US Food and Drug Administration currently lists metformin as contraindicated in those with mild to moderate renal insufficiency, with serum creatinine levels greater than or equal to 1.5 mg/dL in males and greater than or equal to 1.4 mg/dL in females. This contraindication is based on the pharmacokinetics of the medication and, likely, the association of a similar medication, phenformin, with lactic acidosis, which eventually led to its withdrawal from the market. However, lactic acidosis is much less frequent with metformin than with phenformin.¹

We agree that metformin is an invaluable medication for diabetes mellitus not requiring insulin. We also agree that lactic acidosis is rare, especially in those with mild renal insufficiency. However, lactic acidosis does occur in patients with chronic kidney disease while on metformin and, however rare, when it does occur it is a life-threatening event.²

The clearance of metformin is strongly dependent on kidney function,³ and therefore guidelines still recommend reducing the dose in those with moderate renal insufficiency and recommend considering stopping the medication in those with severe renal insufficiency—the population we were talking about in our article.⁴ We are aware of changes to the guidelines that have been made by various groups, and in many circumstances we ourselves take an individualized approach, weighing the risks and benefits of continued therapy with the patient and his or her primary care provider. That being said, we did not believe that such nuanced recommendations were appropriate for our article, especially since they are contrary to marketing restrictions for the drug.

To the Editor: I was delighted to see an article addressing the overuse of stress tests in asymptomatic individuals.¹ I still think, however, that one could really look at the issue a little further. In truly asymptomatic individuals, even those with established coronary heart disease, what is the value of the “annual stress echocardiogram,” often done in cardiologist’s offices? I was perturbed a bit by the statement, “a physician may consider ordering exercise electrocardiography in asymptomatic adults at intermediate risk of coronary heart disease.” Are there data to suggest the number needed to treat or the number needed to harm? I was sobered by the results of the Detection of Ischemia in Asymptomatic Diabetics trial,² which showed no benefit in screening patients with type 2 diabetes with stress myocardial perfusion imaging (a technique probably more costly but more accurate than stress echocardiography).

I understand that bold statements about the lack of usefulness of the stress test in asymptomatic individuals might be misinterpreted by payers as a justification for denying coverage, but it would provide more help for those of us in primary care who are trying to dissuade patients from inappropriate and potentially harmful testing.

To the Editor: I was delighted to see an article addressing the overuse of stress tests in asymptomatic individuals.¹ I still think, however, that one could really look at the issue a little further. In truly asymptomatic individuals, even those with established coronary heart disease, what is the value of the “annual stress echocardiogram,” often done in cardiologist’s offices? I was perturbed a bit by the statement, “a physician may consider ordering exercise electrocardiography in asymptomatic adults at intermediate risk of coronary heart disease.” Are there data to suggest the number needed to treat or the number needed to harm? I was sobered by the results of the Detection of Ischemia in Asymptomatic Diabetics trial,² which showed no benefit in screening patients with type 2 diabetes with stress myocardial perfusion imaging (a technique probably more costly but more accurate than stress echocardiography).

I understand that bold statements about the lack of usefulness of the stress test in asymptomatic individuals might be misinterpreted by payers as a justification for denying coverage, but it would provide more help for those of us in primary care who are trying to dissuade patients from inappropriate and potentially harmful testing.

To the Editor: I was delighted to see an article addressing the overuse of stress tests in asymptomatic individuals.¹ I still think, however, that one could really look at the issue a little further. In truly asymptomatic individuals, even those with established coronary heart disease, what is the value of the “annual stress echocardiogram,” often done in cardiologist’s offices? I was perturbed a bit by the statement, “a physician may consider ordering exercise electrocardiography in asymptomatic adults at intermediate risk of coronary heart disease.” Are there data to suggest the number needed to treat or the number needed to harm? I was sobered by the results of the Detection of Ischemia in Asymptomatic Diabetics trial,² which showed no benefit in screening patients with type 2 diabetes with stress myocardial perfusion imaging (a technique probably more costly but more accurate than stress echocardiography).

I understand that bold statements about the lack of usefulness of the stress test in asymptomatic individuals might be misinterpreted by payers as a justification for denying coverage, but it would provide more help for those of us in primary care who are trying to dissuade patients from inappropriate and potentially harmful testing.

In Reply: Thanks so much for sharing your thoughts on our article. We share your frustration with the lack of evidence to support the decision to avoid stress testing in all asymptomatic individuals. In fact, there is no direct evidence that the identification and treatment of screening-detected, asymptomatic coronary artery disease will decrease mortality risk and improve outcomes in patients with no history of coronary artery disease.

The focus of our article was to review the available evidence and guidelines on stress testing low-risk, asymptomatic patients. The statement in the article that you cite, “a physician may consider ordering exercise electrocardiography in asymptomatic adults with intermediate risk of coronary heart disease,” was pulled from the 2010 American College of Cardiology/American Heart Association guideline¹ in an attempt to summarize recent guidelines on this issue. Unfortunately, there is currently insufficient evidence to recommend for or against screening in patients at intermediate risk for coronary heart disease. As a result, the decision to perform stress testing in an asymptomatic patient at intermediate risk should include an informed discussion between the physician and patient. In contrast, there is considerable evidence supporting the recommendation not to screen in asymptomatic low-risk individuals, which is the main conclusion of our article.

In Reply: Thanks so much for sharing your thoughts on our article. We share your frustration with the lack of evidence to support the decision to avoid stress testing in all asymptomatic individuals. In fact, there is no direct evidence that the identification and treatment of screening-detected, asymptomatic coronary artery disease will decrease mortality risk and improve outcomes in patients with no history of coronary artery disease.

The focus of our article was to review the available evidence and guidelines on stress testing low-risk, asymptomatic patients. The statement in the article that you cite, “a physician may consider ordering exercise electrocardiography in asymptomatic adults with intermediate risk of coronary heart disease,” was pulled from the 2010 American College of Cardiology/American Heart Association guideline¹ in an attempt to summarize recent guidelines on this issue. Unfortunately, there is currently insufficient evidence to recommend for or against screening in patients at intermediate risk for coronary heart disease. As a result, the decision to perform stress testing in an asymptomatic patient at intermediate risk should include an informed discussion between the physician and patient. In contrast, there is considerable evidence supporting the recommendation not to screen in asymptomatic low-risk individuals, which is the main conclusion of our article.

In Reply: Thanks so much for sharing your thoughts on our article. We share your frustration with the lack of evidence to support the decision to avoid stress testing in all asymptomatic individuals. In fact, there is no direct evidence that the identification and treatment of screening-detected, asymptomatic coronary artery disease will decrease mortality risk and improve outcomes in patients with no history of coronary artery disease.

The focus of our article was to review the available evidence and guidelines on stress testing low-risk, asymptomatic patients. The statement in the article that you cite, “a physician may consider ordering exercise electrocardiography in asymptomatic adults with intermediate risk of coronary heart disease,” was pulled from the 2010 American College of Cardiology/American Heart Association guideline¹ in an attempt to summarize recent guidelines on this issue. Unfortunately, there is currently insufficient evidence to recommend for or against screening in patients at intermediate risk for coronary heart disease. As a result, the decision to perform stress testing in an asymptomatic patient at intermediate risk should include an informed discussion between the physician and patient. In contrast, there is considerable evidence supporting the recommendation not to screen in asymptomatic low-risk individuals, which is the main conclusion of our article.

To the Editor: We read with interest the article by Drs. Buitrago et al in the May 2014 issue of Cleveland Clinic Journal of Medicine, “Syncope during a pharmacologic nuclear stress test.”¹ It highlights a known, serious interaction between adenosine and dipyridamole (the latter contained in the aspirin-dipyridamole combination Aggrenox) and associated asystole in patients undergoing pharmacologic cardiac stress testing. This interaction is known in the cardiology literature, as it was noted in the current guidelines for pharmacologic stress testing.² However, I would like to discuss a few points with the authors for a better understanding of the case.

First, the underlying rhythm before the development of complete atrioventricular (AV) dissociation and asystole was significant for second-degree AV block (Mobitz type I, Wenckebach). Second- or third-degree AV block is considered a contraindication to adenosine because of the risk of exacerbating these conditions. This underlying AV nodal disease made dipyridamole not the only culprit. In addition, the patient had been on two agents (labetalol and clonidine) that have AV nodal-blocking properties. Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia are another reason for delayed conduction and PR prolongation, and electrolyte levels should be checked and corrected properly before the stress test or coronary angiography. It would have been helpful if the authors had discussed these points for a better understanding of the drug-drug interaction.

Because of the increasing trend to admit patients with chest pain to observation units to rule out myocardial infarction, the case has a valuable teaching point, especially for hospitalists and emergency physicians in charge of patients admitted with chest pain.³ Since cardiologists rarely get involved in the care of these patients, careful review of medications before scheduling stress testing is of ultimate importance and should be emphasized in the discussion.

Lastly, the number of combined medications that are available commercially is increasing, which puts patients at higher risk of drug interactions. Hospitalists and internists taking care of patients, especially elderly patients, admitted from nursing homes and taking multiple medications should pay extra attention when reviewing medications with brand names.^4,5 Furthermore, a 12-lead electrocardiogram should be reviewed, with special attention to the PR interval and QT segment. A pharmacy consultation could be valuable, especially in patients taking multiple drugs.⁶

To the Editor: We read with interest the article by Drs. Buitrago et al in the May 2014 issue of Cleveland Clinic Journal of Medicine, “Syncope during a pharmacologic nuclear stress test.”¹ It highlights a known, serious interaction between adenosine and dipyridamole (the latter contained in the aspirin-dipyridamole combination Aggrenox) and associated asystole in patients undergoing pharmacologic cardiac stress testing. This interaction is known in the cardiology literature, as it was noted in the current guidelines for pharmacologic stress testing.² However, I would like to discuss a few points with the authors for a better understanding of the case.

First, the underlying rhythm before the development of complete atrioventricular (AV) dissociation and asystole was significant for second-degree AV block (Mobitz type I, Wenckebach). Second- or third-degree AV block is considered a contraindication to adenosine because of the risk of exacerbating these conditions. This underlying AV nodal disease made dipyridamole not the only culprit. In addition, the patient had been on two agents (labetalol and clonidine) that have AV nodal-blocking properties. Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia are another reason for delayed conduction and PR prolongation, and electrolyte levels should be checked and corrected properly before the stress test or coronary angiography. It would have been helpful if the authors had discussed these points for a better understanding of the drug-drug interaction.

Because of the increasing trend to admit patients with chest pain to observation units to rule out myocardial infarction, the case has a valuable teaching point, especially for hospitalists and emergency physicians in charge of patients admitted with chest pain.³ Since cardiologists rarely get involved in the care of these patients, careful review of medications before scheduling stress testing is of ultimate importance and should be emphasized in the discussion.

Lastly, the number of combined medications that are available commercially is increasing, which puts patients at higher risk of drug interactions. Hospitalists and internists taking care of patients, especially elderly patients, admitted from nursing homes and taking multiple medications should pay extra attention when reviewing medications with brand names.^4,5 Furthermore, a 12-lead electrocardiogram should be reviewed, with special attention to the PR interval and QT segment. A pharmacy consultation could be valuable, especially in patients taking multiple drugs.⁶

To the Editor: We read with interest the article by Drs. Buitrago et al in the May 2014 issue of Cleveland Clinic Journal of Medicine, “Syncope during a pharmacologic nuclear stress test.”¹ It highlights a known, serious interaction between adenosine and dipyridamole (the latter contained in the aspirin-dipyridamole combination Aggrenox) and associated asystole in patients undergoing pharmacologic cardiac stress testing. This interaction is known in the cardiology literature, as it was noted in the current guidelines for pharmacologic stress testing.² However, I would like to discuss a few points with the authors for a better understanding of the case.

First, the underlying rhythm before the development of complete atrioventricular (AV) dissociation and asystole was significant for second-degree AV block (Mobitz type I, Wenckebach). Second- or third-degree AV block is considered a contraindication to adenosine because of the risk of exacerbating these conditions. This underlying AV nodal disease made dipyridamole not the only culprit. In addition, the patient had been on two agents (labetalol and clonidine) that have AV nodal-blocking properties. Electrolyte imbalances such as hypokalemia, hypomagnesemia, and hypocalcemia are another reason for delayed conduction and PR prolongation, and electrolyte levels should be checked and corrected properly before the stress test or coronary angiography. It would have been helpful if the authors had discussed these points for a better understanding of the drug-drug interaction.

Because of the increasing trend to admit patients with chest pain to observation units to rule out myocardial infarction, the case has a valuable teaching point, especially for hospitalists and emergency physicians in charge of patients admitted with chest pain.³ Since cardiologists rarely get involved in the care of these patients, careful review of medications before scheduling stress testing is of ultimate importance and should be emphasized in the discussion.

Lastly, the number of combined medications that are available commercially is increasing, which puts patients at higher risk of drug interactions. Hospitalists and internists taking care of patients, especially elderly patients, admitted from nursing homes and taking multiple medications should pay extra attention when reviewing medications with brand names.^4,5 Furthermore, a 12-lead electrocardiogram should be reviewed, with special attention to the PR interval and QT segment. A pharmacy consultation could be valuable, especially in patients taking multiple drugs.⁶