Slight Hyperglycemia Risk Shouldn't Deter Statin Use

The Food and Drug Administration's announcement that the labeling of statins will now note their potential for raising a patient’s blood sugar and glycosylated hemoglobin levels is a reminder that, despite their relative safety, statin treatment poses some level of risk and hence should not be prescribed indiscriminately, experts said.

On the other hand, the risk for blood sugar elevation is modest enough that for the vast majority of patients who have significant cardiovascular disease (CVD) risk, the potential benefit from statin treatment continues to far outweigh the risk patients might face from statin-induced hyperglycemia, according to several experts interviewed for this article. Patients with cardiovascular disease risk who could remain on statins include those who have already had a cardiovascular event, the secondary prevention population, and patients who already have diabetes, considered a coronary risk equivalent because of the sizeable risk that diabetes confers for a future cardiovascular event.

"It would be a mistake to say that anyone at high risk for diabetes should be denied a statin because these people are also at high risk for cardiovascular disease."

Boosted hyperglycemia that pushes a person’s fasting plasma glucose level to 126 mg/dL or above, the range diagnosed as type 2 diabetes, "is probably the most frequent quantifiable harm from statins" but is still uncommon, noted Dr. Jennifer G. Robinson, professor of medicine and epidemiology at the University of Iowa in Iowa City. She estimated that of the 10%-15% of patients who will develop type 2 diabetes over a period of several years on statin treatment, roughly 1 new case of diabetes out of every 500 incident cases will be attributable to statin treatment, based on the risk information available today.

"It's not very much. It should not change any clinician’s day to day practice in any way," said Dr. Robinson, who is also a vice-chair of the Adult Treatment Panel IV, the group assembled by the National Heart, Lung, and Blood Institute to issue new U.S. cholesterol management guidelines, expected later this year. "It just means that you don’t give a statin to everyone, not someone with a 1% risk for a cardiovascular event over the next 10 years," she said.

Primary prevention poses the most complicated issues, when physicians prescribe statins to people who have not yet had any cardiovascular event. Prescribers face the difficult question of when the risk for incident hyperglycemia triggered by a statin starts to outweigh the benefit from cardiovascular risk reduction. Further muddying the question of whom to exclude from primary prevention with statin treatment are the unknowns that shroud the effect: How do statins cause this? Which patients are most susceptible? Do different statins pose varying levels of hyperglycemia risk?

"As increasingly large populations become candidates for statin treatment, with new guidelines and new methods for CVD risk-prediction modeling, it will be very important to look at the benefit to risk ratio of treatment, including the risk for developing diabetes," said Dr. JoAnn E. Manson, professor of medicine at Harvard Medical School and chief of preventive medicine at Brigham and Women’s Hospital in Boston.

Relatively low-risk groups of patients who are increasingly prescribed statins include adolescents, young adults, and middle-aged women, she noted. "The key is the absolute risk of CVD in these groups, more than their relative risk. In a population with a low absolute risk of CVD events, we need to look very carefully to see where the crossover occurs from net benefit to net risk of treatment."

A problem for the time being is that no good way exists for identifying what factors, beyond borderline high blood glucose at baseline, help identify patients at increased risk for developing diabetes while on statin treatment. Additional research and guidance about what level of fasting plasma glucose at baseline, before a statin regimen starts, should trigger concern, and how often plasma glucose should be monitored once a patient is on a statin, will be helpful, Dr. Manson said.

"Professional societies and expert groups should make clear recommendations about the need for routine vs. targeted glucose testing, as well as the frequency. Consensus guidelines don’t yet exist. The new statin label eliminates testing liver function. Will this be replaced by excessive testing of blood glucose, a practice that could be burdensome to patients and clinicians and drive up health care costs?" she said in an interview.

The dilemma physicians also face when deciding whether to prescribe a statin to patients toward the low end of the cardiovascular risk spectrum is that the same risk factors that might flag patients with a high risk for insulin resistance, hyperglycemia, and the development of type 2 diabetes – factors such as obesity, inadequate physical activity, elements of metabolic syndrome, and a "prediabetic" fasting plasma glucose level of 110-125 mg/dL – also function as cardiovascular disease risk factors.

"It would be a mistake to say that anyone at high risk for diabetes should be denied a statin because these people are also at high risk for cardiovascular disease," Dr. Manson said. She recommended that patients on statin treatment at least be told to be on the alert for developing new symptoms of diabetes: frequent thirst, frequent urination, and blurred vision. "And lifestyle modifications should be intensified to reduce both diabetes and CVD risk."

"The excess risk for diabetes is concentrated in the people with fasting blood sugars in the 115- to 125-mg/dL range" said Dr. Roger S. Blumenthal, professor of medicine and director of preventive medicine at Johns Hopkins Medical Institutions in Baltimore. "A lot of those people are clearly insulin resistant. We almost always have a fasting plasma glucose [when patients are about to start on a statin] as part of a basic lipid profile. With physicians aware of the association, I think this will focus more attention on vulnerable patients in the 115- to 125-mg/dL range, who are headed for diabetes if they don’t make significant improvements in their diet and exercise habits. It’s reasonable to look at glucose and tell patients that a statin might potentially raise their blood sugar by 5-7 mg/dL, but exercising and dropping some excess weight will significantly improve their blood sugar."

Targeted use of plasma glucose testing in statin recipients who seem to have the greatest risk for developing diabetes also received endorsement from Dr. Prakash Deedwania, professor of medicine at the University of California, San Francisco, in Fresno. He suggested possibly doing annual testing of patients with metabolic syndrome, those who are obese, those with a family history of diabetes, and patients who have previously shown impaired glucose tolerance on a tolerance test.

If a patient’s fasting plasma glucose began to creep up on a statin regimen, "I’d look for other reasons, such as did they gain weight?" he said. Seeing a possible hyperglycemic effect should also prompt a reassessment of whether the patient benefited from the statin, and whether they have made necessary lifestyle changes like improved diet and increased exercise. Rising blood sugar could be used to help motivate a patient to do better on lifestyle measures, and trigger a reevaluation of whether the patient is, on balance, benefiting from the statin, he said. Changing the statin used or the dosage is tricky, because no evidence exists now to support such steps.

But because the biggest signal for the prodiabetic effect of statins came in results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) (N. Engl. J. Med. 2008;359:2195-207), the current perception among at least some physicians is that rosuvastatin (Crestor) poses the biggest hyperglycemic risk. "Some physicians might consider changing [the prescribed statin] from rosuvastatin to simvastatin or atorvastatin," Dr. Blumenthal said.

The FDA took the right step in adding the hyperglycemia information to statin labeling, said Dr. Deedwania. "They give the data, and leave it up to physicians to make their own conclusions."

As a consequence of the FDA’s actions "a lot more physicians will pay attention to glucose as they put patients on statins. The evidence is consistent, and most now agree that it’s real," said Dr. Stephen J. Nicholls, a cardiologist at the Cleveland Clinic. "But these are not completely healthy people with low glucose levels who suddenly, on a statin, become diabetic. What this reinforces is that while there will continue to be a lot of people who require statin treatment, the cornerstone of treatment is lifestyle change: diet, exercise, and weight loss. There is a continuum of risk: Patients at higher risk will benefit from a statin; for patients at very low risk use lifestyle. And if you put a patient on a statin, you need to keep an eye on them."

Dr. Robinson, Dr. Manson, and Dr. Blumenthal said that they had no relevant financial disclosures. Dr. Deedwania said that he has been a consultant to Pfizer, Amarin, and Amgen. Dr. Nicholls said he has received research support from AstraZeneca and has been a consultant to AstraZeneca, Merck, and Pfizer.

The Food and Drug Administration's announcement that the labeling of statins will now note their potential for raising a patient’s blood sugar and glycosylated hemoglobin levels is a reminder that, despite their relative safety, statin treatment poses some level of risk and hence should not be prescribed indiscriminately, experts said.

On the other hand, the risk for blood sugar elevation is modest enough that for the vast majority of patients who have significant cardiovascular disease (CVD) risk, the potential benefit from statin treatment continues to far outweigh the risk patients might face from statin-induced hyperglycemia, according to several experts interviewed for this article. Patients with cardiovascular disease risk who could remain on statins include those who have already had a cardiovascular event, the secondary prevention population, and patients who already have diabetes, considered a coronary risk equivalent because of the sizeable risk that diabetes confers for a future cardiovascular event.

"It would be a mistake to say that anyone at high risk for diabetes should be denied a statin because these people are also at high risk for cardiovascular disease."

Boosted hyperglycemia that pushes a person’s fasting plasma glucose level to 126 mg/dL or above, the range diagnosed as type 2 diabetes, "is probably the most frequent quantifiable harm from statins" but is still uncommon, noted Dr. Jennifer G. Robinson, professor of medicine and epidemiology at the University of Iowa in Iowa City. She estimated that of the 10%-15% of patients who will develop type 2 diabetes over a period of several years on statin treatment, roughly 1 new case of diabetes out of every 500 incident cases will be attributable to statin treatment, based on the risk information available today.

"It's not very much. It should not change any clinician’s day to day practice in any way," said Dr. Robinson, who is also a vice-chair of the Adult Treatment Panel IV, the group assembled by the National Heart, Lung, and Blood Institute to issue new U.S. cholesterol management guidelines, expected later this year. "It just means that you don’t give a statin to everyone, not someone with a 1% risk for a cardiovascular event over the next 10 years," she said.

Primary prevention poses the most complicated issues, when physicians prescribe statins to people who have not yet had any cardiovascular event. Prescribers face the difficult question of when the risk for incident hyperglycemia triggered by a statin starts to outweigh the benefit from cardiovascular risk reduction. Further muddying the question of whom to exclude from primary prevention with statin treatment are the unknowns that shroud the effect: How do statins cause this? Which patients are most susceptible? Do different statins pose varying levels of hyperglycemia risk?

"As increasingly large populations become candidates for statin treatment, with new guidelines and new methods for CVD risk-prediction modeling, it will be very important to look at the benefit to risk ratio of treatment, including the risk for developing diabetes," said Dr. JoAnn E. Manson, professor of medicine at Harvard Medical School and chief of preventive medicine at Brigham and Women’s Hospital in Boston.

Relatively low-risk groups of patients who are increasingly prescribed statins include adolescents, young adults, and middle-aged women, she noted. "The key is the absolute risk of CVD in these groups, more than their relative risk. In a population with a low absolute risk of CVD events, we need to look very carefully to see where the crossover occurs from net benefit to net risk of treatment."

A problem for the time being is that no good way exists for identifying what factors, beyond borderline high blood glucose at baseline, help identify patients at increased risk for developing diabetes while on statin treatment. Additional research and guidance about what level of fasting plasma glucose at baseline, before a statin regimen starts, should trigger concern, and how often plasma glucose should be monitored once a patient is on a statin, will be helpful, Dr. Manson said.

"Professional societies and expert groups should make clear recommendations about the need for routine vs. targeted glucose testing, as well as the frequency. Consensus guidelines don’t yet exist. The new statin label eliminates testing liver function. Will this be replaced by excessive testing of blood glucose, a practice that could be burdensome to patients and clinicians and drive up health care costs?" she said in an interview.

The dilemma physicians also face when deciding whether to prescribe a statin to patients toward the low end of the cardiovascular risk spectrum is that the same risk factors that might flag patients with a high risk for insulin resistance, hyperglycemia, and the development of type 2 diabetes – factors such as obesity, inadequate physical activity, elements of metabolic syndrome, and a "prediabetic" fasting plasma glucose level of 110-125 mg/dL – also function as cardiovascular disease risk factors.

"It would be a mistake to say that anyone at high risk for diabetes should be denied a statin because these people are also at high risk for cardiovascular disease," Dr. Manson said. She recommended that patients on statin treatment at least be told to be on the alert for developing new symptoms of diabetes: frequent thirst, frequent urination, and blurred vision. "And lifestyle modifications should be intensified to reduce both diabetes and CVD risk."

"The excess risk for diabetes is concentrated in the people with fasting blood sugars in the 115- to 125-mg/dL range" said Dr. Roger S. Blumenthal, professor of medicine and director of preventive medicine at Johns Hopkins Medical Institutions in Baltimore. "A lot of those people are clearly insulin resistant. We almost always have a fasting plasma glucose [when patients are about to start on a statin] as part of a basic lipid profile. With physicians aware of the association, I think this will focus more attention on vulnerable patients in the 115- to 125-mg/dL range, who are headed for diabetes if they don’t make significant improvements in their diet and exercise habits. It’s reasonable to look at glucose and tell patients that a statin might potentially raise their blood sugar by 5-7 mg/dL, but exercising and dropping some excess weight will significantly improve their blood sugar."

Targeted use of plasma glucose testing in statin recipients who seem to have the greatest risk for developing diabetes also received endorsement from Dr. Prakash Deedwania, professor of medicine at the University of California, San Francisco, in Fresno. He suggested possibly doing annual testing of patients with metabolic syndrome, those who are obese, those with a family history of diabetes, and patients who have previously shown impaired glucose tolerance on a tolerance test.

If a patient’s fasting plasma glucose began to creep up on a statin regimen, "I’d look for other reasons, such as did they gain weight?" he said. Seeing a possible hyperglycemic effect should also prompt a reassessment of whether the patient benefited from the statin, and whether they have made necessary lifestyle changes like improved diet and increased exercise. Rising blood sugar could be used to help motivate a patient to do better on lifestyle measures, and trigger a reevaluation of whether the patient is, on balance, benefiting from the statin, he said. Changing the statin used or the dosage is tricky, because no evidence exists now to support such steps.

But because the biggest signal for the prodiabetic effect of statins came in results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) (N. Engl. J. Med. 2008;359:2195-207), the current perception among at least some physicians is that rosuvastatin (Crestor) poses the biggest hyperglycemic risk. "Some physicians might consider changing [the prescribed statin] from rosuvastatin to simvastatin or atorvastatin," Dr. Blumenthal said.

The FDA took the right step in adding the hyperglycemia information to statin labeling, said Dr. Deedwania. "They give the data, and leave it up to physicians to make their own conclusions."

As a consequence of the FDA’s actions "a lot more physicians will pay attention to glucose as they put patients on statins. The evidence is consistent, and most now agree that it’s real," said Dr. Stephen J. Nicholls, a cardiologist at the Cleveland Clinic. "But these are not completely healthy people with low glucose levels who suddenly, on a statin, become diabetic. What this reinforces is that while there will continue to be a lot of people who require statin treatment, the cornerstone of treatment is lifestyle change: diet, exercise, and weight loss. There is a continuum of risk: Patients at higher risk will benefit from a statin; for patients at very low risk use lifestyle. And if you put a patient on a statin, you need to keep an eye on them."

Dr. Robinson, Dr. Manson, and Dr. Blumenthal said that they had no relevant financial disclosures. Dr. Deedwania said that he has been a consultant to Pfizer, Amarin, and Amgen. Dr. Nicholls said he has received research support from AstraZeneca and has been a consultant to AstraZeneca, Merck, and Pfizer.

The Food and Drug Administration's announcement that the labeling of statins will now note their potential for raising a patient’s blood sugar and glycosylated hemoglobin levels is a reminder that, despite their relative safety, statin treatment poses some level of risk and hence should not be prescribed indiscriminately, experts said.

On the other hand, the risk for blood sugar elevation is modest enough that for the vast majority of patients who have significant cardiovascular disease (CVD) risk, the potential benefit from statin treatment continues to far outweigh the risk patients might face from statin-induced hyperglycemia, according to several experts interviewed for this article. Patients with cardiovascular disease risk who could remain on statins include those who have already had a cardiovascular event, the secondary prevention population, and patients who already have diabetes, considered a coronary risk equivalent because of the sizeable risk that diabetes confers for a future cardiovascular event.

"It would be a mistake to say that anyone at high risk for diabetes should be denied a statin because these people are also at high risk for cardiovascular disease."

Boosted hyperglycemia that pushes a person’s fasting plasma glucose level to 126 mg/dL or above, the range diagnosed as type 2 diabetes, "is probably the most frequent quantifiable harm from statins" but is still uncommon, noted Dr. Jennifer G. Robinson, professor of medicine and epidemiology at the University of Iowa in Iowa City. She estimated that of the 10%-15% of patients who will develop type 2 diabetes over a period of several years on statin treatment, roughly 1 new case of diabetes out of every 500 incident cases will be attributable to statin treatment, based on the risk information available today.

"It's not very much. It should not change any clinician’s day to day practice in any way," said Dr. Robinson, who is also a vice-chair of the Adult Treatment Panel IV, the group assembled by the National Heart, Lung, and Blood Institute to issue new U.S. cholesterol management guidelines, expected later this year. "It just means that you don’t give a statin to everyone, not someone with a 1% risk for a cardiovascular event over the next 10 years," she said.

Primary prevention poses the most complicated issues, when physicians prescribe statins to people who have not yet had any cardiovascular event. Prescribers face the difficult question of when the risk for incident hyperglycemia triggered by a statin starts to outweigh the benefit from cardiovascular risk reduction. Further muddying the question of whom to exclude from primary prevention with statin treatment are the unknowns that shroud the effect: How do statins cause this? Which patients are most susceptible? Do different statins pose varying levels of hyperglycemia risk?

"As increasingly large populations become candidates for statin treatment, with new guidelines and new methods for CVD risk-prediction modeling, it will be very important to look at the benefit to risk ratio of treatment, including the risk for developing diabetes," said Dr. JoAnn E. Manson, professor of medicine at Harvard Medical School and chief of preventive medicine at Brigham and Women’s Hospital in Boston.

Relatively low-risk groups of patients who are increasingly prescribed statins include adolescents, young adults, and middle-aged women, she noted. "The key is the absolute risk of CVD in these groups, more than their relative risk. In a population with a low absolute risk of CVD events, we need to look very carefully to see where the crossover occurs from net benefit to net risk of treatment."

A problem for the time being is that no good way exists for identifying what factors, beyond borderline high blood glucose at baseline, help identify patients at increased risk for developing diabetes while on statin treatment. Additional research and guidance about what level of fasting plasma glucose at baseline, before a statin regimen starts, should trigger concern, and how often plasma glucose should be monitored once a patient is on a statin, will be helpful, Dr. Manson said.

"Professional societies and expert groups should make clear recommendations about the need for routine vs. targeted glucose testing, as well as the frequency. Consensus guidelines don’t yet exist. The new statin label eliminates testing liver function. Will this be replaced by excessive testing of blood glucose, a practice that could be burdensome to patients and clinicians and drive up health care costs?" she said in an interview.

The dilemma physicians also face when deciding whether to prescribe a statin to patients toward the low end of the cardiovascular risk spectrum is that the same risk factors that might flag patients with a high risk for insulin resistance, hyperglycemia, and the development of type 2 diabetes – factors such as obesity, inadequate physical activity, elements of metabolic syndrome, and a "prediabetic" fasting plasma glucose level of 110-125 mg/dL – also function as cardiovascular disease risk factors.

"It would be a mistake to say that anyone at high risk for diabetes should be denied a statin because these people are also at high risk for cardiovascular disease," Dr. Manson said. She recommended that patients on statin treatment at least be told to be on the alert for developing new symptoms of diabetes: frequent thirst, frequent urination, and blurred vision. "And lifestyle modifications should be intensified to reduce both diabetes and CVD risk."

"The excess risk for diabetes is concentrated in the people with fasting blood sugars in the 115- to 125-mg/dL range" said Dr. Roger S. Blumenthal, professor of medicine and director of preventive medicine at Johns Hopkins Medical Institutions in Baltimore. "A lot of those people are clearly insulin resistant. We almost always have a fasting plasma glucose [when patients are about to start on a statin] as part of a basic lipid profile. With physicians aware of the association, I think this will focus more attention on vulnerable patients in the 115- to 125-mg/dL range, who are headed for diabetes if they don’t make significant improvements in their diet and exercise habits. It’s reasonable to look at glucose and tell patients that a statin might potentially raise their blood sugar by 5-7 mg/dL, but exercising and dropping some excess weight will significantly improve their blood sugar."

Targeted use of plasma glucose testing in statin recipients who seem to have the greatest risk for developing diabetes also received endorsement from Dr. Prakash Deedwania, professor of medicine at the University of California, San Francisco, in Fresno. He suggested possibly doing annual testing of patients with metabolic syndrome, those who are obese, those with a family history of diabetes, and patients who have previously shown impaired glucose tolerance on a tolerance test.

If a patient’s fasting plasma glucose began to creep up on a statin regimen, "I’d look for other reasons, such as did they gain weight?" he said. Seeing a possible hyperglycemic effect should also prompt a reassessment of whether the patient benefited from the statin, and whether they have made necessary lifestyle changes like improved diet and increased exercise. Rising blood sugar could be used to help motivate a patient to do better on lifestyle measures, and trigger a reevaluation of whether the patient is, on balance, benefiting from the statin, he said. Changing the statin used or the dosage is tricky, because no evidence exists now to support such steps.

But because the biggest signal for the prodiabetic effect of statins came in results from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) (N. Engl. J. Med. 2008;359:2195-207), the current perception among at least some physicians is that rosuvastatin (Crestor) poses the biggest hyperglycemic risk. "Some physicians might consider changing [the prescribed statin] from rosuvastatin to simvastatin or atorvastatin," Dr. Blumenthal said.

The FDA took the right step in adding the hyperglycemia information to statin labeling, said Dr. Deedwania. "They give the data, and leave it up to physicians to make their own conclusions."

As a consequence of the FDA’s actions "a lot more physicians will pay attention to glucose as they put patients on statins. The evidence is consistent, and most now agree that it’s real," said Dr. Stephen J. Nicholls, a cardiologist at the Cleveland Clinic. "But these are not completely healthy people with low glucose levels who suddenly, on a statin, become diabetic. What this reinforces is that while there will continue to be a lot of people who require statin treatment, the cornerstone of treatment is lifestyle change: diet, exercise, and weight loss. There is a continuum of risk: Patients at higher risk will benefit from a statin; for patients at very low risk use lifestyle. And if you put a patient on a statin, you need to keep an eye on them."

Dr. Robinson, Dr. Manson, and Dr. Blumenthal said that they had no relevant financial disclosures. Dr. Deedwania said that he has been a consultant to Pfizer, Amarin, and Amgen. Dr. Nicholls said he has received research support from AstraZeneca and has been a consultant to AstraZeneca, Merck, and Pfizer.