Sangeeta R. Kashyap, MD

A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass. 

Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.

The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
 

Ask Patients About Alcohol Use

It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).

The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.

Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely. 

Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group. 

There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.

A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.

Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.

Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
 

Back to Our Patient: 

Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines. 

With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.

Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.

A version of this article appeared on Medscape.com.

A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass. 

Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.

The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
 

Ask Patients About Alcohol Use

It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).

The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.

Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely. 

Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group. 

There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.

A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.

Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.

Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
 

Back to Our Patient: 

Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines. 

With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.

Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.

A version of this article appeared on Medscape.com.

A 50-year-old woman with a history of class 3 obesity, gastroesophageal reflux disease, prediabetes, metabolic dysfunction–associated steatotic liver disease, asthma, and depression returns to our weight management clinic with weight regain 4 years after Roux-en-Y gastric bypass. 

Her initial body weight was 389 lb (176.8 kg; body mass index [BMI], 65), and her nadir weight after surgery was 183 lb (83.2 kg; BMI, 30.5), representing a total weight loss of 53%. During the initial 2 years after surgery, she experienced multiple life stressors and was treated with venlafaxine for mild depression. She regained 25 lb (11.4 kg). Over the next 2 years, she gained another 20 lb (9.1 kg), for a total of 45 lb (20.5 kg) above nadir.

The patient reported increased nighttime consumption of alcohol including vodka, wine, and beer of over 20 drinks per week for the past 2 years. Her laboratory profile showed an elevated fasting glucose level (106 mg/dL, formerly 98 mg/dL), an elevated gamma-glutamyl transferase (GGT) level, and iron deficiency anemia. She admitted to regularly missing doses of postbariatric vitamins and minerals.
 

Ask Patients About Alcohol Use

It’s important to ask patients with significant weight regain after metabolic and bariatric surgery (MBS) about alcohol intake, because patients who have MBS are at an increased risk of developing alcohol use disorder (AUD).

The American Society for Metabolic and Bariatric Surgery recommends screening for alcohol intake both before and after MBS. Underreporting of alcohol consumption is common, but an elevated GGT level or elevated liver enzyme levels can indicate alcohol use. Depression and anxiety exacerbated by life stressors often accompany excessive alcohol intake.

Some antiobesity medications that regulate appetite may also help limit excessive alcohol intake. Naltrexone is used both for the treatment of AUD and for weight management, often in combination with bupropion). In a patient with weight regain and AUD, naltrexone alone would be a reasonable treatment option, although weight loss would probably be modest. The addition of bupropion to naltrexone would probably produce more weight loss; average total body weight loss with bupropion-naltrexone in clinical trials was about 6%. One cautionary note on bupropion: A patient’s seizure history should be elicited, because people with AUD are at increased risk for seizures in the withdrawal stage and bupropion can make those seizures more likely. 

Glucagon-like peptide 1 (GLP-1) receptor agonists (eg, liraglutide and semaglutide) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide receptor agonists) (eg, tirzepatide) are second-generation antiobesity medications that produce more weight loss than first-generation agents such as bupropion/naltrexone. Of note, prior bariatric surgery was an exclusion criterion in the clinical trials assessing the efficacy of these agents for weight loss. The use of GLP-1 receptor agonists after MBS in people with inadequate weight loss or weight regain has been an area of active research. The BARI-OPTIMISE randomized clinical trial published in 2023 assessed the safety and efficacy of liraglutide 3.0 mg daily in patients with inadequate weight loss after MBS. The mean body weight reduction was 8.82% in the liraglutide group vs 0.54% in the placebo group. 

There is also emerging interest in the potential of GLP-1 receptor agonists in AUD. These medications act on the central nervous system to influence reward pathways. In rodents, studies have shown that GLP-1 receptor agonist administration reduces alcohol intake, although most studies have focused on short-term effects.

A series of experiments assessed the effects of semaglutide on alcohol intake in rodents. The authors found that semaglutide lowered the alcohol-induced release of dopamine and enhanced dopamine metabolism within the nucleus accumbens.

Evidence in humans is still limited, with only one published randomized controlled trial to date. In the 26-week study, weekly exenatide was not superior to placebo in reducing the number of heavy drinking days in patients with AUD who also received cognitive-behavioral therapy. An exploratory analysis in a subgroup of patients with obesity and AUD showed that exenatide reduced alcohol consumption. Of note, exenatide is rarely used in clinical practice because it does not produce substantial weight loss.

Liraglutide was chosen for this patient because of the established efficacy for this agent in patients with a history of MBS. In addition, patients often anecdotally report reduced desire for alcohol while taking a GLP-1 receptor agonist. Although GLP-1 receptor agonists have been shown to reduce alcohol intake in animal studies, their efficacy and safety in humans with AUD are not yet well established.
 

Back to Our Patient: 

Given the patient’s weight regain, an upper gastrointestinal series was performed to rule out gastro-gastric fistula or other anatomic abnormalities. After fistula was ruled out, she was prescribed liraglutide for weight management, which was titrated from 0.6 mg/d to 3 mg/d per the prescribing guidelines. 

With the use of liraglutide over the next year, the patient maintained a stable weight of 200 lb (90.9 kg) and noted that along with reduced appetite, her cravings for alcohol had diminished and she no longer felt the urge to drink alcohol at night. Her fasting glucose and GGT levels normalized. She began to see a nutritionist regularly and was planning to rejoin a bariatric support group.

Dr. Schmitz is an instructor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine, New York. She has disclosed no relevant financial relationships. Dr. Kashyap is a assistant chief of clinical affairs, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell New York Presbyterian, New York. She disclosed ties to GI Dynamics.

A version of this article appeared on Medscape.com.

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.

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.

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

• Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
• Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

• Colorectal cancer RR 0.93, 95% CI 0.87–1.00
• Lung cancer RR 0.91, 95% CI 0.84–0.98
• Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

• Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
• Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

• Colorectal cancer RR 0.93, 95% CI 0.87–1.00
• Lung cancer RR 0.91, 95% CI 0.84–0.98
• Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.

In the last quarter century, many new drugs have become available for treating type 2 diabetes mellitus. The American Association of Clinical Endocrinologists incorporated these new agents in its updated glycemic control algorithm in 2013.¹ Because diabetes affects 25.8 million Americans and can lead to blindness, renal failure, cardiovascular disease, and amputation, agents that help us treat it more effectively are valuable.²

One of the barriers to effective treatment is the side effects of the agents. Because some of these drugs have been in use for only a short time, concerns of potential adverse effects have arisen. Cancer is one such concern, especially since type 2 diabetes mellitus by itself increases the risk of cancer by 20% to 50% compared with no diabetes.³

Type 2 diabetes has been linked to risk of cancers of the pancreas,⁴ colorectum,^5,6 liver,⁷ kidney,^8,9 breast,¹⁰ bladder,¹¹ and endometri-um,¹² as well as to hematologic malignancies such as non-Hodgkin lymphoma.¹³ The risk of bladder cancer appears to depend on how long the patient has had type 2 diabetes. Newton et al,¹⁴ in a prospective cohort study, found that those who had diabetes for more than 15 years and used insulin had the highest risk of bladder cancer. On the other hand, the risk of prostate cancer is actually lower in people with diabetes,¹⁵ particularly in those who have had diabetes for longer than 4 years.¹⁶

Cancer and type 2 diabetes share many risk factors and underlying pathophysiologic mechanisms. Nonmodifiable risk factors for both diseases include advanced age, male sex, ethnicity (African American men appear to be most vulnerable to both cancer and diabetes),^17,18 and family history. Modifiable risk factors include lower socioeconomic status, obesity, and alcohol consumption. These common risk factors lead to hyperinsulinemia and insulin resistance, changes in mitochondrial function, low-grade inflammation, and oxidative stress,³ which promote both diabetes and cancer. Diabetes therapy may influence several of these processes.

Several classes of diabetes drugs, including exogenous insulin,^19–22 insulin secretagogues,^23–25 and incretin-based therapies,^26–28 have been under scrutiny because of their potential influences on cancer development in a population already at risk (Table 1).

INSULIN ANALOGUES: MIXED EVIDENCE

Insulin promotes cell division by binding to insulin receptor isoform A and insulin-like growth factor 1 receptors.²⁹ Because endogenous hyperinsulinemia has been linked to cancer risk, growth, and proliferation, some speculate that exogenous insulin may also increase cancer risk.

In 2009, a retrospective study by Hemkens et al linked the long-acting insulin analogue glargine to risk of cancer.¹⁹ This finding set off a tumult of controversy within the medical community and concern among patients. Several limitations of the study were brought to light, including a short duration of follow-up, and several other studies have refuted the study’s findings.^20,21

More recently, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial²² found no higher cancer risk with glargine use than with placebo. This study enrolled 12,537 participants from 573 sites in 40 countries. Specifically, risks with glargine use were as follows:

• Any cancer—hazard ratio 1.00, 95% confidence interval (CI) 0.88–1.13, P = .97
• Cancer death—hazard ratio 0.94, 95% CI 0.77–1.15, P = .52.

However, the study was designed to assess cardiovascular outcomes, not cancer risk. Furthermore, the participants were not typical of patients seen in clinical practice: their insulin doses were lower (the median insulin dose was 0.4 units/kg/day by year 6, whereas in clinical practice, those with type 2 diabetes mellitus often use more than 1 unit/kg/day, depending on duration of diabetes, diet, and exercise regimen), and their baseline median hemoglobin A_1c level was only 6.4%. And one may argue that the median follow-up of 6.2 years was too short for cancer to develop.²²

In vitro studies indicate that long-acting analogue insulin therapy may promote cancer cell growth more than endogenous insulin,³⁰ but epidemiologic data have not unequivocally substantiated this.^20–22 There is no clear evidence that analogue insulin therapy raises cancer risk above that of human recombinant insulin, and starting insulin therapy should not be delayed because of concerns about cancer risk, particularly in uncontrolled diabetes.

INSULIN SECRETAGOGUES

Sulfonylureas: Higher risk

Before 1995, only two classes of diabetes drugs were approved by the US Food and Drug Administration (FDA)—insulin and sulfonylureas.

Sulfonylureas lower blood sugar levels by binding to sulfonylurea receptors and inhibiting adenosine triphosphate-dependent potassium channels. The resulting change in resting potential causes an influx of calcium, ultimately leading to insulin secretion.

Sulfonylureas are effective, and because of their low cost, physicians often pick them as a second-line agent after metformin.

The main disadvantage of sulfonylureas is the risk of hypoglycemia, particularly in patients with renal failure, the elderly, and diabetic patients who are unaware of when they are hypoglycemic. Other potential drawbacks are that they impair cardiac ischemic preconditioning³¹ and possibly increase cancer risk.^21,32 (Ischemic preconditioning is the process in which transient episodes of ischemia “condition” the myocardium so that it better withstands future episodes with minimal anginal pain and tissue injury.³³) Of the sulfonylureas, glyburide has been most implicated in cardiovascular risk.³²

In a retrospective cohort study of 62,809 patients from a general-practice database in the United Kingdom, Currie et al²¹ found that sulfonylurea monotherapy was associated with a 36% higher risk of cancer (95% CI 1.19–1.54, P < .001) than metformin monotherapy. Prescribing bias may have influenced the results: practitioners are more likely to prescribe sulfonylureas to leaner patients, who have a greater likelihood of occult cancer. However, other studies also found that the cancer death rate is higher in those who take a sulfonylurea alone than in those who use metformin alone.^23,24

Some evidence indicates that long-acting sulfonylurea formulations (eg, glyburide) likely hold the most danger, certainly in regard to hypoglycemia, but it is less clear if this translates to cancer concerns.³¹

Meglitinides: Limited evidence

Meglitinides, the other class of insulin secretagogues, are less commonly used but are similar to sulfonylureas in the way they increase endogenous insulin levels. The data are limited regarding cancer risk and meglitinide therapy, but the magnitude of the association is similar to that with sulfonylurea therapy.²⁵

INSULIN SENSITIZERS

There are currently two classes of insulin sensitizers: biguanides and thiazolidinediones (TZDs, also known as glitazones). These drugs show less risk of both cancer incidence and cancer death than insulin secretagogues such as sulfonylureas.^21,23,24 In fact, they may decrease cancer potential by alteration of signaling via the AKT/mTOR (v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin) pathway.³⁴

Metformin, a biguanide, is the oral drug of choice

Metformin is the only biguanide currently available in the United States. It was approved by the FDA in 1995, although it had been in clinical use since the 1950s. Inexpensive and familiar, it is the oral antihyperglycemic of choice if there are no contraindications to it, such as renal dysfunction (creatinine ≥ 1.4 mg/dL in women and ≥ 1.5 mg/dL in men), acute decompensated heart failure, or pulmonary or hepatic insufficiency, all of which may lead to an increased risk of lactic acidosis.¹

Metformin lowers blood sugar levels primarily by inhibiting hepatic glucose production (gluconeogenesis) and by improving peripheral insulin sensitivity. It directly activates AMP-activated protein kinase (AMPK), which affects insulin signaling and glucose and fat metabolism.³⁵ It may exert further beneficial effects by acutely increasing glucagon-like peptide-1 (GLP-1) levels and inducing islet incretin-receptor gene expression.³⁶ Although the exact mechanisms have not been fully elucidated, metformin’s insulin-sensitizing properties are likely from favorable effects on insulin receptor expression, tyrosine kinase activity, and influences on the incretin pathway.^36,37 These effects also mitigate carcinogenesis, both directly (via AMPK and liver kinase B1, a tumor-suppressor gene) and indirectly (via reduction of hyperinsulinemia).³⁵

Overall, biguanide therapy is associated with a lower cancer incidence or, at worst, no effect on cancer incidence. In vitro studies demonstrate that metformin both suppresses cancer cell growth and induces apoptosis, resulting in fewer live cancer cells.³⁴ Several retrospective studies found lower cancer risk in metformin users than in patients receiving antidiabetes drugs other than insulin-sensitizing agents,^{21,23,25,38–40} while others have shown no effect.⁴¹ Use of metformin was specifically associated with lower risk of cancers of the liver, colon and rectum, and lung.⁴² Further, metformin users have a lower cancer mortality rate than nonusers.^24,43

Thiazolidinediones

TZDs, such as pioglitazone, work by binding to peroxisome proliferator-activated gamma receptors in the cell nucleus, altering gene transcription.⁴⁴ They reduce insulin resistance and levels of endogenous insulin levels and free fatty acids.⁴⁴

Concern over bladder cancer risk with TZD use, particularly with pioglitazone, has increased in the last few years, as various cohort studies found a statistically significant increased risk with this agent.⁴⁴ The risk appears to rise with cumulative dose.^45,46

Randomized controlled trials also found an increased risk of bladder cancer with TZD therapy, although the difference was not statistically significant.^47–49 In a mean follow-up of 8.7 years, the Prospective Pioglitazone Clinical Trial in Macrovascular Events reported 23 cases of bladder cancer in the pioglitazone group vs 22 cases in the placebo group, for rates of 0.9% vs 0.8% (relative risk [RR] 1.06, 95% CI 0.59–1.89).⁴⁹

On the other hand, the risk of cancer of the breast, colon, and lung has been found to be lower with TZD use.⁴⁷ In vitro studies support the clinical data, showing that TZDs inhibit growth of human cancer cells derived from cancers of the lung, colon, breast, stomach, ovary, and prostate.^50–53

Home et al⁵⁴ compared rosiglitazone against a sulfonylurea in patients already taking metformin in the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD) trial. Malignancies developed in 6.7% of the sulfonylurea group compared with 5.1% of the rosiglitazone group, for a hazard ratio of 1.33 (95% CI 0.94–1.88).

Both ADOPT (A Diabetes Outcome Progression Trial) and the RECORD trial found rosiglitazone comparable to metformin in terms of cancer risk.⁵⁴

Colmers et al⁴⁷ pooled data from four randomized controlled trials, seven cohort studies, and nine case-control studies to assess the risk of cancer with TZD use in type 2 diabetes. Both the randomized and observational data showed neutral overall cancer risk with TZDs. However, pooled data from observational studies showed significantly lower risk with TZD use in terms of:

• Colorectal cancer RR 0.93, 95% CI 0.87–1.00
• Lung cancer RR 0.91, 95% CI 0.84–0.98
• Breast cancer RR 0.89, 95% CI 0.81–0.98.

INCRETIN-BASED THERAPIES

Incretins are hormones released from the gut in response to food ingestion, triggering release of insulin before blood glucose levels rise. Their action explains why insulin secretion increases more after an oral glucose load than after an intravenous glucose load, a phenomenon called the incretin effect.⁵⁵

There are two incretin hormones: glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). They have short a half-life because they are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV).⁵⁵ Available incretin-based therapies are GLP-1 receptor agonists and DPP-IV inhibitors.

When used as monotherapy, incretin-based therapies do not cause hypoglycemia because their effect is glucose-dependent.⁵⁵ GLP-1 receptor antagonists have the added benefit of inducing weight loss, but DPP-IV inhibitors are considered to be weight-neutral.

GLP-1 receptor agonists

Exenatide, the first of the GLP-1 receptor agonists, was approved in 2005. The original formulation (Byetta) is taken by injection twice daily, and timing in conjunction with food intake is important: it should be taken within 60 minutes before the morning and evening meals. Extended-release exenatide (Bydureon) is a once-weekly formulation taken without regard to timing of food intake. Exenatide (either twice-daily Byetta or once-weekly Bydureon) should not be used in those with creatinine clearance less than 30 mL/min or end-stage renal disease and should be used with caution in patients with renal transplantation.

Liraglutide (Victoza), a once-daily formulation, can be injected irrespective of food intake. The dose does not have to be adjusted for renal function, although it should be used with caution in those with renal impairment, including end-stage renal disease. Approval for a 3-mg formulation is pending with the FDA as a weight-loss drug on the basis of promising results in a randomized phase 3 trial.⁵⁶

Albiglutide (Tanzeum), a once-weekly GLP-1 receptor antagonist, was recently approved by the FDA.

DPP-IV inhibitors

Whereas GLP-1 receptor agonists are injected, the DPP-IV inhibitors have the advantage of being oral agents.

Sitagliptin (Januvia), the first DPP-IV inhibitor, became available in the United States in 2006. Since then, three more have become available: saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina).

Concerns about thyroid cancer with incretin drugs

Concerns of increased risk of cancer, particularly of the thyroid and pancreas, have been raised since GLP-1 receptor agonists and DPP-IV inhibitors became available.

Studies in rodents have shown C-cell hyperplasia, sometimes resulting in increased incidence of thyroid carcinoma, and dose-dependent rises in serum calcitonin, particularly with liraglutide.²⁶ This has raised concern about an increased risk of medullary thyroid carcinoma in humans. However, the density of C cells in rodents is up to 45 times greater than in humans, and C cells also express functional GLP-1 receptors.²⁶

Gier et al²⁷ assessed the expression of calcitonin and human GLP-1 receptors in normal C cells, C cell hyperplasia, and medullary cancer. In this study, calcitonin and GLP-1 receptor were co-expressed in medullary thyroid cancer (10 of 12 cases) and C-cell hyperplasia (9 of 9 cases) more commonly than in normal C cells (5 of 15 cases). Further, GLP-1 receptor was expressed in 3 of 17 cases of papillary thyroid cancer.

Calcitonin, a polypeptide hormone produced by thyroid C cells and used as a medullary thyroid cancer biomarker, was increased in a slightly higher percentage of patients treated with liraglutide than in controls, without an increase above the normal range.⁵⁷

A meta-analysis by Alves et al⁵⁸ of 25 studies found that neither exenatide (no cases reported) nor liraglutide (odds ratio 1.54, 95% CI 0.40–6.02) was associated with increased thyroid cancer risk.

MacConell et al⁵⁹ pooled the results of 19 placebo-controlled trials of twice-daily exenatide and found a thyroid cancer incidence rate of 0.3 per 100 patient-years (< 0.1%) vs 0 per 100 patient-years in pooled comparators.

Concerns about pancreatic cancer with incretin drugs

Increased risk of acute pancreatitis is a potential side effect of both DPP-IV inhibitors and GLP-1 receptor agonists and has led to speculation that this translates to an increased risk of pancreatic cancer.

In a point-counterpoint debate, Butler et al²⁸ argued that incretin-based medications have questionable safety, with increased rates of pancreatitis possibly leading to pancreatic cancer. In counterpoint, Nauck⁶⁰ argued that the risk of pancreatitis or cancer is extremely low, and clinical cases are unsubstantiated.

Bailey⁶¹ outlined the complexities and difficulties in drawing firm conclusions from individual clinical trials regarding possible adverse effects of diabetes drugs. The trials are typically designed to assess hemoglobin A_1c reduction at varying doses and are typically restricted in patient selection, patient numbers, and drug-exposure duration, which may introduce allocation and ascertainment biases. The attempt to draw firm conclusions from such trials can be problematic and can lead to increased alarm, warranted or not.

Type 2 diabetes mellitus itself is associated with an increased incidence of pancreatic cancer, and whether incretin therapy enhances this risk is still controversial. Whether more episodes of acute pancreatitis without chronic pancreatitis can be extrapolated to an increased incidence of pancreatic cancer is doubtful. A normal pancreatic duct cell may take up to 12 years to become a tumor cell from which pancreatic carcinoma develops, another 7 years to develop metastatic capacity, and another 3 years before a diagnosis is made from clinical symptoms (which are usually accompanied by metastases).⁶²

The risks and benefits of incretin therapies remain a contentious issue, and there are no clear prospective data at this time on increased pancreatic cancer incidence. Long-term prospective studies designed to analyze these specific outcomes (pancreatitis, pancreatic cancer, and medullary thyroid cancer) need to be undertaken.⁶³

OTHER DIABETES THERAPIES

Alpha glucosidase inhibitors

Oral glucosidase inhibitors ameliorate hyperglycemia by inhibiting alpha glucosidase enzymes in the brush border of the small intestines, preventing conversion of polysaccharides to monosaccharides.⁶⁴ This slows digestion of carbohydrates and glucose release into the bloodstream and blunts the postprandial hyperglycemic excursion.

The two alpha glucosidase inhibitors currently available in the United States are acarbose and miglitol, and although data are limited, they do not appear to increase the risk of cancer.^65,66

Sodium-glucose-linked cotransporter 2 inhibitors

The newest class of oral diabetes agents to be approved are the sodium-glucose-linked cotransporter 2 (SGLT2) inhibitors canagliflozin (Invokana) and dapagliflozin (Farxiga).

SGLT2 is a protein in the S1 segment of the proximal renal tubules responsible for over 90% of renal glucose reabsorption. SGLT2 inhibitors lower serum glucose levels by promoting glycosuria and have also been shown to have favorable effects on blood pressure and weight.^67,68

Canagliflozin was the first of its class to gain FDA approval in the United States. It has not been found to be associated with increased cancer risk.⁶⁸

Dapagliflozin, originally approved in Europe, was approved in the United States on January 8, 2014. Because of a possible increased incidence of breast and bladder malignancies, the FDA advisory committee initially recommended against approval and required further data. In those who were treated, nine cases of bladder cancer and nine cases of breast cancer were reported, compared with one case of bladder cancer and no cases of breast cancer in the control group; however, the difference was not statistically significant.⁶⁸

Since SGLT2 inhibitors are still new, data on long-term outcomes are lacking. Early clinical data do not show a significant increase in cancer risk.

WHAT THIS MEANS IN PRACTICE

Many studies have found associations between diabetes, obesity, hyperinsulinemia, and cancer risk. In the last decade, concerns implicating antihyperglycemic agents in cancer development have arisen but have not been well substantiated. At this time, there are no definitive prospective data indicating that the currently available type 2 diabetes therapies increase the incidence of cancer beyond the inherent increased risk in this population. What, then, is one to do?

Educate. Lifestyle modification, including weight management, should continue to be emphasized in diabetes education, as no therapy is completely effective without adjunct modifications in diet and physical activity. Epidemiologic studies have shown the benefits of lifestyle modifications, which ameliorate many of the adverse metabolic conditions that coexist in type 2 diabetes and cancer.

Screen for cancer. Given the associations between diabetes and malignancy, cancer screening is especially important in this high-risk population.

Customize therapy to individual patients. Those with a personal history of bladder cancer should avoid pioglitazone, and those who have had pancreatic cancer should avoid sitagliptin until definitive clinical data become available.

Moreover, patients with a personal or family history of medullary thyroid cancer should not receive GLP-1 receptor agonists. These agents should also probably be avoided in patients with a personal history of differentiated thyroid carcinoma or a history of familial nonmedullary thyroid carcinoma. Until we have further elucidating data, it is not possible to say whether a family history of any of the other types of cancer should represent a contraindication to the use of any of these agents.

Discuss. The multitude of diabetes therapies warrants physician-patient discussions that carefully weigh the risks and benefits of additional agents to optimize glycemic control and metabolic factors in individual patients.

Eighty percent of people with type 2 diabetes mellitus are obese or overweight.¹ Excess adipose tissue can lead to endocrine dysregulation,² contributing to the pathogenesis of type 2 diabetes, and obesity is one of the strongest predictors of this disease.³

For obese people with type 2 diabetes, diet and exercise can lead to weight loss and many other benefits, such as better glycemic control, less insulin resistance, lower risk of diabetes-related comorbidities and complications, fewer diabetic medications needed, and lower health care costs.^4–7 Intensive lifestyle interventions have also been shown to induce partial remission of diabetes and to prevent the onset of type 2 diabetes in people at high risk of it.^5–7

A very-low-calorie diet is one of many dietary options available to patients with type 2 diabetes who are overweight or obese. The protein-sparing modified fast (PSMF) is a type of very-low-calorie diet with a high protein content and simultaneous restriction of carbohydrate and fat.^8,9 It was developed in the 1970s, and since then various permutations have been used in weight loss and health care clinics worldwide.

MOSTLY PROTEIN, VERY LITTLE CARBOHYDRATE AND FAT

The PSMF is a medically supervised diet that provides less than 800 kcal/day during an initial intensive phase of about 6 months, followed by the gradual reintroduction of calories during a refeeding phase of about 6 to 8 weeks.¹⁰

During the intensive phase, patients obtain most of their calories from protein, approximately 1.2 to 1.5 g/kg of ideal body weight per day. At the same time, carbohydrate intake is restricted to less than 20 to 50 g/day; additional fats outside of protein sources are not allowed.⁹ Thus, the PSMF shares features of both very-low-calorie diets and very-low-carbohydrate ketogenic diets (eg, the Atkins diet), though some differences exist among the three (Figure 1).

Patients rapidly lose weight during the intensive phase, typically between 1 and 3 kg per week, with even greater losses during the first 2 weeks.8,9 Weight loss typically plateaus within 6 months, at which point patients begin the refeeding period. During refeeding, complex carbohydrates and low-glycemic, high-fiber cereals, fruits, vegetables, and fats are gradually reintroduced. Meanwhile, protein intake is reduced to individually tailored amounts as part of a weight-maintenance diet.

LIPOLYSIS, KETOSIS, DIURESIS

Modified from Baker S, et al. Effects and clinical potential of very-low-calorie diets (VLCDS) in type 2 diabetes. Diabetes Res Clin Pract 2009; 85:235–242.

The specific macronutrient composition of the PSMF during the intensive phase is designed so that patients enter ketosis and lose as much fat as they can while preserving lean body mass.^9,11 Figure 2 illustrates the mechanisms of ketosis and the metabolic impact of the PSMF.

With dietary carbohydrate restriction, serum glucose and insulin levels decline and glycogen stores are depleted. The drop in serum insulin allows lipolysis to occur, resulting in loss of adipose tissue and production of ketone bodies in the liver. Ketone bodies become the primary source of energy for the brain and other tissues during fasting and have metabolic and neuroprotective benefits.^12,13

Some studies suggest that ketosis also suppresses appetite, helping curb total caloric intake throughout the diet.¹⁴ Protein itself may increase satiety.¹⁵

Glycogen in the liver is bound to water, so the depletion of glycogen also results in loss of attached water. As a result, diuresis contributes significantly to the initial weight loss within the first 2 weeks on the PSMF.⁹

WHO IS A CANDIDATE FOR THE PSMF?

The PSMF is indicated only for adults with a body mass index (BMI) of at least 30 kg/m² or a BMI of at least 27 kg/m² and at least one comorbidity such as type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, osteoarthritis, or fatty liver.¹² Patients must also be sufficiently committed and motivated to make the intensive dietary and behavioral changes the program calls for.

The PSMF should be considered when more conventional low-calorie approaches to weight loss fail or when patients become discouraged by the slower results seen with traditional diets.⁸ Patients undergoing a PSMF are usually encouraged by the initial period of rapid weight loss, and such diets have lower dropout rates.¹⁶

This diet may also be recommended for obese patients who have poorly controlled type 2 diabetes and growing resistance to medications, to bring down the blood glucose level. Another use is before bariatric surgery to reduce the risk of obesity-related complications.⁸ Patients who regain weight after bariatric surgery may also benefit.

MEAL REPLACEMENTS OR A DIET PLAN?

The PSMF program at Cleveland Clinic is based on modified preparation and selection of conventional foods. Details of the program are described in Table 1. Protein sources must be of high biologic value, containing the right mix of essential amino acids (eg, lean meat, fish, poultry, egg whites).⁹

Some commercially available very-low-calorie diets (eg, OPTIFAST, Medifast) that are advertised as PSMFs consist mainly of meal replacements. In the program at Cleveland Clinic, meal replacements in the form of commercial high-protein shakes or bars can be used occasionally for convenience and to maintain adherence to the diet.

However, preparation of PSMF meals from natural, conventional foods is thought to play an important role in long-term behavior modification and so is strongly encouraged. Patients learn low-fat cooking methods, portion control, and how to make appropriate choices in shopping, eating, and dining out. These lessons are valuable for those who struggle with long-term weight loss. Learning these behaviors through the program may help ease the transition to the weight-maintenance phase and beyond. For some patients, cooking is also a source of enjoyment, as is the sight, smell, and taste of nonliquid foods.¹⁰

In addition, patients appreciate being able to eat the same foods as others in their household, except for omitting high-carbohydrate foods. It has also been reported that patients on a food-based PSMF were significantly less hungry and preoccupied with eating than those on a liquid formula diet.¹⁷

CONTRAINDICATIONS AND SAFETY CONCERNS

Contraindications to the PSMF include a BMI less than 27 kg/m², recent myocardial infarction, angina, significant arrhythmia, decompensated congestive heart failure, cerebrovascular insufficiency or recent stroke, end-stage renal disease, liver failure, malignancy, major psychiatric illness, pregnancy or lactation, and wasting disorders. It is also not recommended for patients under age 16 or over age 65.

In view of the risk of diabetic ketoacidosis and the difficulty of titrating required doses ofinsulin, patients with type 1 diabetes mellitus are usually not advised to undergo a low-carbohydrate or very-low-calorie diet.^8,12 However, we and others have found that the PSMF can be used in some obese patients with type 1 diabetes if it is combined with appropriate education and careful monitoring.¹²

Major concerns about the safety of the PSMF stem from experiences with the first very-low-calorie diets in the 1970s, which were associated with fatal cardiac arrhythmias and sudden death.¹⁸ These early diets used liquid formulas with hydrolyzed collagen protein of poor biologic value and were deficient in many vitamins and minerals. Today’s very-low-calorie diets use protein sources of high biologic value (chiefly animal, soy, and egg for the PSMF) and are supplemented with necessary vitamins and minerals, reducing the risk of electrolyte and cardiac abnormalities.^9,19,20 Furthermore, before starting the PSMF all patients must have an electrocardiogram to be sure they have no arrhythmias (eg, heart block, QT interval prolongation) or ischemia.

Relative contraindications

A known history of cholelithiasis is a relative contraindication to a very-low-calorie diet and may be of concern for some patients and providers. While obesity itself is already a risk factor for gallstones, gallstone formation has also been associated with bile stasis, which occurs from rapid weight loss with liquid formula diets of low fat intake (< 10 g/day).²¹ However, in the PSMF, fat intake from protein sources, though low (45–70 g/day), is considered high enough to allow adequate gallbladder contraction, thus decreasing the risk of gallstone formation.²²

Gout is another relative contraindication, as hyperuricemia with risk of gout is also linked to high-protein diets.⁹ Palgi et al²³ found that uric acid levels rose by a mean of 0.4 mg/dL during the diet. The risk of gout, however, seemed to be small, occurring in fewer than 1% of patients in the study. Furthermore, in a recent study by Li et al,²⁴ uric acid levels were found to significantly decrease in patients on a high-protein, very-low-calorie diet. Nonetheless, uric acid levels should be monitored regularly in patients on the PSMF.

SIDE EFFECTS OF THE DIET

Common side effects of the PSMF include headache, fatigue, orthostatic hypotension, muscle cramps, cold intolerance, constipation, diarrhea, fatigue, halitosis, menstrual changes, and hair thinning. Most of these are transient and may be alleviated by adjusting fluid, salt, and supplement intake. Other side effects may disappear as the patient is weaned off the diet.^8,9

REGULAR FOLLOW-UP WITH HEALTH CARE PROVIDERS

Current PSMF programs are considered safe when used in combination with regular follow-up with health care providers.^8,12

At Cleveland Clinic, patients meet with a dietitian twice in the first month and monthly thereafter (or more frequently if needed) for weight monitoring and education on nutrition and behavior modification (Table 1). Since the PSMF does not provide complete nutrition, daily supplementation with vitamins and minerals is required.

Daily exercise is encouraged throughout the program to increase fitness and to help keep the weight off during the refeeding phase and after.

Patients also meet every 6 to 8 weeks with the referring nurse practitioner or physician for further monitoring and evaluation of vital signs, laboratory results, and side effects. The PSMF protocol at Cleveland Clinic enables both primary care physicians and specialists (including nurse practitioners) within our network to monitor the patient’s status. Use of a common electronic medical record system is particularly valuable for easy communication between providers. If a primary care physician feels unable to appropriately counsel and supervise a patient in the PSMF program, referral to an endocrinologist or weight loss specialist is recommended.

In addition to baseline electrocardiography and monitoring of uric acid levels, a comprehensive metabolic panel is drawn at baseline, twice in the first month, and monthly thereafter to check for electrolyte imbalances and metabolic and tissue dysfunction such as dehydration, excessive protein loss, and liver or kidney injury.

Patients should not attempt the PSMF without medical supervision. Many patients have friends or family members who want to try the PSMF along with them, but this can be dangerous, especially for those with hypertension or type 2 diabetes. The medications prescribed for these conditions can result in hypotension or hypoglycemia during the PSMF.

Although there are no standard guidelines for adjusting medication use before starting a patient on the PSMF, it is logical to taper off or discontinue antihypertensive agents in patients with tightly controlled hypertension to avoid possible dehydration and hypotension during the first few diuresis-inducing weeks of the diet. In particular, diuretic agents should be discontinued to prevent further electrolyte imbalance and fluid shifts.

Similarly, in patients with tightly controlled type 2 diabetes (hemoglobin A_1c < 7.0%), oral hypoglycemic agents and insulin therapy should be reduced before starting the diet to avoid potential hypoglycemia. During the course of the diet, providers should then adjust medication dosages based on follow-up vital signs and laboratory results and daily glucose monitoring.⁸

EFFECTS OF THE PSMF IN PATIENTS WITH TYPE 2 DIABETES

Though few formal studies have been done, the PSMF may have major effects on hyperglycemia, cardiovascular risk factors, and diabetic nephropathy in obese patients with type 2 diabetes, at least in the short term (Table 2).

Weight loss

In one of the first PSMF studies,²³ in 668 patients with or without type 2 diabetes (baseline weight 98 kg), the mean weight loss was 21 kg after the intensive phase and 19 kg by the end of the refeeding phase.

In another observational report,²⁵ 25% to 30% of patients lost even more weight, averaging 38.6 kg of weight loss. Typically, the higher the baseline weight, the greater the weight loss during the PSMF.²³

Patients with type 2 diabetes lost a similar amount of weight (8.5 kg) compared with those without diabetes (9.4 kg, P = .64) in a study of meal-replacement PSMF (using OPTIFAST shakes and bars).²⁶ In a large meal-replacement study of 2,093 patients, Li et al²⁴ found that weight loss was similar between diabetic, prediabetic, and nondiabetic patients. Weight loss was also closely maintained in those patients who stayed on the diet for 12 months.

In a PSMF study in which all the participants had type 2 diabetes, the mean weight loss was 18.6 kg. Although the patients regained some of this weight, at 1 year they still weighed 8.6 kg less than at baseline. However, a conventional, balanced, low-calorie diet resulted in similar amounts of weight loss after 1 year.²⁷ Furthermore, a second round of the PSMF did not result in significant additional weight loss but rather weight maintenance.²⁸

Fat loss and smaller waist circumference

Most of the weight lost during a PSMF is from fat tissue.^11,26 Abdominal (visceral) fat may be lost first, which is desirable for patients with type 2 diabetes, since a higher degree of abdominal fat is linked to insulin resistance.^2,29

After a meal-replacement PSMF, waist circumference decreased significantly in patients both with and without type 2 diabetes.^24,26 However, in one study, less fat was lost per unit of change of BMI in the group with type 2 diabetes than in the nondiabetic group.²⁶ Since insulin inhibits lipolysis, it is possible that exogenous insulin use in diabetic patients may prevent greater reductions in fat mass, though this is likely not the only mechanism.²⁶

Lower fasting serum glucose

Fasting serum glucose levels decreased significantly from baseline in patients with type 2 diabetes after a PSMF in all studies that measured this variable.^{23–28,30,31} Changes in fasting glucose are immediate and are associated with caloric restriction rather than weight loss itself.^30,32 Furthermore, the observed decrease in serum glucose is even more impressive in view of the withdrawal or reduction of doses of insulin and oral hypoglycemic agents before starting the diet.

In a study that compared glycemic control in a PSMF diet vs a balanced low-calorie diet, the fasting serum glucose in the PSMF group declined 46%, from 255.9 mg/dL at baseline to 138.7 mg/dL at 20 weeks (P = .001). After 1 year, it had risen back to 187.4 mg/dL, which was still 27% lower than at baseline (P = .023). These results compared favorably with those in the low-calorie diet group (P < .05), which saw fasting serum glucose decline 27% after 20 weeks (from 230.6 mg/dL at baseline to 167.6 mg/dL) and then rise to 5% over baseline (243.2 mg/dL) after 1 year.²⁷

In a later study, the decrease in fasting serum glucose was not maintained at 1 year, but a significantly higher percentage (55%) of participants in the PSMF group were still able to remain free of diabetic medications compared with those who followed a balanced low-calorie diet (31%, P = .01).²⁸

Decrease in hemoglobin A_1c

Declines in fasting serum glucose corresponded with short-term declines in hemoglobin A_1c in several reports.^27–31 Hemoglobin A_1c declined significantly from an average of 10.4% to 7.3% (P = .001) after PSMF intervention in patients with type 2 diabetes. In contrast, hemoglobin A_1c in the low-calorie diet control group declined from 10.4% to 8.6%.²⁷ One year later, hemoglobin A_1c remained lower than at baseline in the PSMF group (final 9.2%) and continued to compare favorably against the control group (final 11.8%, between-group P = .001). However, these 1-year post-intervention improvements were not seen in a second, more intensive study.²⁸

Less insulin resistance

In several studies, fasting serum insulin levels declined along with serum glucose levels, implying decreased insulin resistance.^{25,27,28,30,31} In addition, insulin output was enhanced during glucose challenge after completion of the PSMF, suggesting possible improved (though still impaired) pancreatic beta-cell capacity.^25,27,30

Improved lipid profile

The most common effect of the PSMF on the lipid profile is a significant decrease in triglycerides in patients both with and without type 2 diabetes.^8,23,24,28 In addition, high-density lipoprotein cholesterol increased in two studies following PSMF intervention or after 1-year of follow-up.^24,27,28 Total cholesterol and low-density lipoprotein cholesterol levels also improved after the PSMF, but these changes were not always maintained at follow-up visits.^8,24,28

Lower blood pressure

Improvements in both systolic and diastolic blood pressure were noted in two studies, with mean decreases of 6 mm Hg to 13 mm Hg systolic and 8 mm Hg diastolic after PSMF intervention.^23,28 In a third study, reductions in blood pressure were less dramatic, and only changes in diastolic but not systolic blood pressure remained significant at 12 months.²⁴ While improvements were not observed in a fourth study, patients in this study also had impaired kidney function caused by diabetic nephropathy, and changes in medication were not taken into account.³¹

Kidney function tests

In a small study, Friedman et al showed that 12 weeks of the PSMF in six patients with advanced diabetic nephropathy (stage 3B or stage 4 chronic kidney disease) led to a loss of 12% of body weight (P = .03) as well as significant reductions in serum creatinine and cystatin C levels (P < .05).³¹ In addition, albuminuria decreased by 30% (P = .08). Side effects were minimal, and the diet was well tolerated despite its high protein content, which is a concern in patients with impaired kidney function.

Thus, weight loss via the PSMF may still be beneficial in type 2 diabetic patients with chronic kidney disease and may even improve the course of progression of diabetic nephropathy.

Long-term weight loss is elusive

Long-term weight loss has been an elusive goal for many diet programs. In a study using a very-low-calorie diet in obese patients with type 2 diabetes, substantial weight loss was maintained in half of the patients at 3 years after the intervention, but nearly all of the patients had regained most of their weight after 5 years.³³

While commitment to behavior modification, maintenance of physical activity, and continued follow-up are all critical factors in sustaining weight loss, new and innovative approaches to battle weight regain are needed.³⁴

Yet despite considerable weight regain in most patients, the Look AHEAD (Action for Health in Diabetes) study showed that participants in intensive lifestyle intervention programs still achieved greater weight loss after 4 years than those receiving standard care.³⁵ Whether this holds true for those in intensive PSMF programs is unknown. In addition, conclusive PSMF studies regarding glycemic control, lipids, and blood pressure beyond 1 year of follow-up are lacking.

A VIABLE OPTION FOR MANY

Adherence to a very-low-calorie, ketogenic PSMF program results in major short-term health benefits for obese patients with type 2 diabetes. These benefits include significant weight loss, often more than 18 kg, within 6 months.^23–28 In addition, significant improvements in fasting glucose^{23–28,30–32} and hemoglobin A_1c levels^27–31 are linked to the caloric and carbohydrate restriction of the PSMF. Insulin resistance was also attenuated, with possible partial restoration of pancreatic beta-cell capacity.^{25,27,28,30,31} In some studies, the PSMF resulted in lower systolic and diastolic blood pressure^23,24,28 and triglyceride levels.^8,23,24,28 One small study also suggested a possible improvement of diabetic nephropathy.³¹ Lastly, improvements in glycemia and hypertension were associated with a reduction in the need for antidiabetic and antihypertensive drugs.³⁶

Still, weight loss and many of the associated improvements partially return to baseline levels 1 year after the intervention. Thus, more long-term studies are needed to explore factors for better weight maintenance after the PSMF.

Also, only a few studies have compared the effect of the PSMF between patients with or without type 2 diabetes. One study suggested that fat loss may be reduced in patients with type 2 diabetes.²⁶

In conclusion, despite some risks and safety concerns, PSMF is a viable option for many obese, type 2 diabetic patients as a method of short-term weight loss, with evidence for improvement of glycemic control and cardiovascular risk factors for up to 1 year. To strengthen support for the PSMF, however, further research is warranted on the diet’s long-term effects in patients with type 2 diabetes and also in nondiabetic patients.
 

Acknowledgments: Many thanks to Cheryl Reitz, RD, LD, CDE, and Dawn Noe, RD, LD, CDE, for providing their expertise on the PSMF protocols carried out at Cleveland Clinic. Additional thanks to Tejas Kashyap for his initial assistance with this review.

Eighty percent of people with type 2 diabetes mellitus are obese or overweight.¹ Excess adipose tissue can lead to endocrine dysregulation,² contributing to the pathogenesis of type 2 diabetes, and obesity is one of the strongest predictors of this disease.³

For obese people with type 2 diabetes, diet and exercise can lead to weight loss and many other benefits, such as better glycemic control, less insulin resistance, lower risk of diabetes-related comorbidities and complications, fewer diabetic medications needed, and lower health care costs.^4–7 Intensive lifestyle interventions have also been shown to induce partial remission of diabetes and to prevent the onset of type 2 diabetes in people at high risk of it.^5–7

A very-low-calorie diet is one of many dietary options available to patients with type 2 diabetes who are overweight or obese. The protein-sparing modified fast (PSMF) is a type of very-low-calorie diet with a high protein content and simultaneous restriction of carbohydrate and fat.^8,9 It was developed in the 1970s, and since then various permutations have been used in weight loss and health care clinics worldwide.

MOSTLY PROTEIN, VERY LITTLE CARBOHYDRATE AND FAT

The PSMF is a medically supervised diet that provides less than 800 kcal/day during an initial intensive phase of about 6 months, followed by the gradual reintroduction of calories during a refeeding phase of about 6 to 8 weeks.¹⁰

During the intensive phase, patients obtain most of their calories from protein, approximately 1.2 to 1.5 g/kg of ideal body weight per day. At the same time, carbohydrate intake is restricted to less than 20 to 50 g/day; additional fats outside of protein sources are not allowed.⁹ Thus, the PSMF shares features of both very-low-calorie diets and very-low-carbohydrate ketogenic diets (eg, the Atkins diet), though some differences exist among the three (Figure 1).

Patients rapidly lose weight during the intensive phase, typically between 1 and 3 kg per week, with even greater losses during the first 2 weeks.8,9 Weight loss typically plateaus within 6 months, at which point patients begin the refeeding period. During refeeding, complex carbohydrates and low-glycemic, high-fiber cereals, fruits, vegetables, and fats are gradually reintroduced. Meanwhile, protein intake is reduced to individually tailored amounts as part of a weight-maintenance diet.

LIPOLYSIS, KETOSIS, DIURESIS

Modified from Baker S, et al. Effects and clinical potential of very-low-calorie diets (VLCDS) in type 2 diabetes. Diabetes Res Clin Pract 2009; 85:235–242.

The specific macronutrient composition of the PSMF during the intensive phase is designed so that patients enter ketosis and lose as much fat as they can while preserving lean body mass.^9,11 Figure 2 illustrates the mechanisms of ketosis and the metabolic impact of the PSMF.

With dietary carbohydrate restriction, serum glucose and insulin levels decline and glycogen stores are depleted. The drop in serum insulin allows lipolysis to occur, resulting in loss of adipose tissue and production of ketone bodies in the liver. Ketone bodies become the primary source of energy for the brain and other tissues during fasting and have metabolic and neuroprotective benefits.^12,13

Some studies suggest that ketosis also suppresses appetite, helping curb total caloric intake throughout the diet.¹⁴ Protein itself may increase satiety.¹⁵

Glycogen in the liver is bound to water, so the depletion of glycogen also results in loss of attached water. As a result, diuresis contributes significantly to the initial weight loss within the first 2 weeks on the PSMF.⁹

WHO IS A CANDIDATE FOR THE PSMF?

The PSMF is indicated only for adults with a body mass index (BMI) of at least 30 kg/m² or a BMI of at least 27 kg/m² and at least one comorbidity such as type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, osteoarthritis, or fatty liver.¹² Patients must also be sufficiently committed and motivated to make the intensive dietary and behavioral changes the program calls for.

The PSMF should be considered when more conventional low-calorie approaches to weight loss fail or when patients become discouraged by the slower results seen with traditional diets.⁸ Patients undergoing a PSMF are usually encouraged by the initial period of rapid weight loss, and such diets have lower dropout rates.¹⁶

This diet may also be recommended for obese patients who have poorly controlled type 2 diabetes and growing resistance to medications, to bring down the blood glucose level. Another use is before bariatric surgery to reduce the risk of obesity-related complications.⁸ Patients who regain weight after bariatric surgery may also benefit.

MEAL REPLACEMENTS OR A DIET PLAN?

The PSMF program at Cleveland Clinic is based on modified preparation and selection of conventional foods. Details of the program are described in Table 1. Protein sources must be of high biologic value, containing the right mix of essential amino acids (eg, lean meat, fish, poultry, egg whites).⁹

Some commercially available very-low-calorie diets (eg, OPTIFAST, Medifast) that are advertised as PSMFs consist mainly of meal replacements. In the program at Cleveland Clinic, meal replacements in the form of commercial high-protein shakes or bars can be used occasionally for convenience and to maintain adherence to the diet.

However, preparation of PSMF meals from natural, conventional foods is thought to play an important role in long-term behavior modification and so is strongly encouraged. Patients learn low-fat cooking methods, portion control, and how to make appropriate choices in shopping, eating, and dining out. These lessons are valuable for those who struggle with long-term weight loss. Learning these behaviors through the program may help ease the transition to the weight-maintenance phase and beyond. For some patients, cooking is also a source of enjoyment, as is the sight, smell, and taste of nonliquid foods.¹⁰

In addition, patients appreciate being able to eat the same foods as others in their household, except for omitting high-carbohydrate foods. It has also been reported that patients on a food-based PSMF were significantly less hungry and preoccupied with eating than those on a liquid formula diet.¹⁷

CONTRAINDICATIONS AND SAFETY CONCERNS

Contraindications to the PSMF include a BMI less than 27 kg/m², recent myocardial infarction, angina, significant arrhythmia, decompensated congestive heart failure, cerebrovascular insufficiency or recent stroke, end-stage renal disease, liver failure, malignancy, major psychiatric illness, pregnancy or lactation, and wasting disorders. It is also not recommended for patients under age 16 or over age 65.

In view of the risk of diabetic ketoacidosis and the difficulty of titrating required doses ofinsulin, patients with type 1 diabetes mellitus are usually not advised to undergo a low-carbohydrate or very-low-calorie diet.^8,12 However, we and others have found that the PSMF can be used in some obese patients with type 1 diabetes if it is combined with appropriate education and careful monitoring.¹²

Major concerns about the safety of the PSMF stem from experiences with the first very-low-calorie diets in the 1970s, which were associated with fatal cardiac arrhythmias and sudden death.¹⁸ These early diets used liquid formulas with hydrolyzed collagen protein of poor biologic value and were deficient in many vitamins and minerals. Today’s very-low-calorie diets use protein sources of high biologic value (chiefly animal, soy, and egg for the PSMF) and are supplemented with necessary vitamins and minerals, reducing the risk of electrolyte and cardiac abnormalities.^9,19,20 Furthermore, before starting the PSMF all patients must have an electrocardiogram to be sure they have no arrhythmias (eg, heart block, QT interval prolongation) or ischemia.

Relative contraindications

A known history of cholelithiasis is a relative contraindication to a very-low-calorie diet and may be of concern for some patients and providers. While obesity itself is already a risk factor for gallstones, gallstone formation has also been associated with bile stasis, which occurs from rapid weight loss with liquid formula diets of low fat intake (< 10 g/day).²¹ However, in the PSMF, fat intake from protein sources, though low (45–70 g/day), is considered high enough to allow adequate gallbladder contraction, thus decreasing the risk of gallstone formation.²²

Gout is another relative contraindication, as hyperuricemia with risk of gout is also linked to high-protein diets.⁹ Palgi et al²³ found that uric acid levels rose by a mean of 0.4 mg/dL during the diet. The risk of gout, however, seemed to be small, occurring in fewer than 1% of patients in the study. Furthermore, in a recent study by Li et al,²⁴ uric acid levels were found to significantly decrease in patients on a high-protein, very-low-calorie diet. Nonetheless, uric acid levels should be monitored regularly in patients on the PSMF.

SIDE EFFECTS OF THE DIET

Common side effects of the PSMF include headache, fatigue, orthostatic hypotension, muscle cramps, cold intolerance, constipation, diarrhea, fatigue, halitosis, menstrual changes, and hair thinning. Most of these are transient and may be alleviated by adjusting fluid, salt, and supplement intake. Other side effects may disappear as the patient is weaned off the diet.^8,9

REGULAR FOLLOW-UP WITH HEALTH CARE PROVIDERS

Current PSMF programs are considered safe when used in combination with regular follow-up with health care providers.^8,12

At Cleveland Clinic, patients meet with a dietitian twice in the first month and monthly thereafter (or more frequently if needed) for weight monitoring and education on nutrition and behavior modification (Table 1). Since the PSMF does not provide complete nutrition, daily supplementation with vitamins and minerals is required.

Daily exercise is encouraged throughout the program to increase fitness and to help keep the weight off during the refeeding phase and after.

Patients also meet every 6 to 8 weeks with the referring nurse practitioner or physician for further monitoring and evaluation of vital signs, laboratory results, and side effects. The PSMF protocol at Cleveland Clinic enables both primary care physicians and specialists (including nurse practitioners) within our network to monitor the patient’s status. Use of a common electronic medical record system is particularly valuable for easy communication between providers. If a primary care physician feels unable to appropriately counsel and supervise a patient in the PSMF program, referral to an endocrinologist or weight loss specialist is recommended.

In addition to baseline electrocardiography and monitoring of uric acid levels, a comprehensive metabolic panel is drawn at baseline, twice in the first month, and monthly thereafter to check for electrolyte imbalances and metabolic and tissue dysfunction such as dehydration, excessive protein loss, and liver or kidney injury.

Patients should not attempt the PSMF without medical supervision. Many patients have friends or family members who want to try the PSMF along with them, but this can be dangerous, especially for those with hypertension or type 2 diabetes. The medications prescribed for these conditions can result in hypotension or hypoglycemia during the PSMF.

Although there are no standard guidelines for adjusting medication use before starting a patient on the PSMF, it is logical to taper off or discontinue antihypertensive agents in patients with tightly controlled hypertension to avoid possible dehydration and hypotension during the first few diuresis-inducing weeks of the diet. In particular, diuretic agents should be discontinued to prevent further electrolyte imbalance and fluid shifts.

Similarly, in patients with tightly controlled type 2 diabetes (hemoglobin A_1c < 7.0%), oral hypoglycemic agents and insulin therapy should be reduced before starting the diet to avoid potential hypoglycemia. During the course of the diet, providers should then adjust medication dosages based on follow-up vital signs and laboratory results and daily glucose monitoring.⁸

EFFECTS OF THE PSMF IN PATIENTS WITH TYPE 2 DIABETES

Though few formal studies have been done, the PSMF may have major effects on hyperglycemia, cardiovascular risk factors, and diabetic nephropathy in obese patients with type 2 diabetes, at least in the short term (Table 2).

Weight loss

In one of the first PSMF studies,²³ in 668 patients with or without type 2 diabetes (baseline weight 98 kg), the mean weight loss was 21 kg after the intensive phase and 19 kg by the end of the refeeding phase.

In another observational report,²⁵ 25% to 30% of patients lost even more weight, averaging 38.6 kg of weight loss. Typically, the higher the baseline weight, the greater the weight loss during the PSMF.²³

Patients with type 2 diabetes lost a similar amount of weight (8.5 kg) compared with those without diabetes (9.4 kg, P = .64) in a study of meal-replacement PSMF (using OPTIFAST shakes and bars).²⁶ In a large meal-replacement study of 2,093 patients, Li et al²⁴ found that weight loss was similar between diabetic, prediabetic, and nondiabetic patients. Weight loss was also closely maintained in those patients who stayed on the diet for 12 months.

In a PSMF study in which all the participants had type 2 diabetes, the mean weight loss was 18.6 kg. Although the patients regained some of this weight, at 1 year they still weighed 8.6 kg less than at baseline. However, a conventional, balanced, low-calorie diet resulted in similar amounts of weight loss after 1 year.²⁷ Furthermore, a second round of the PSMF did not result in significant additional weight loss but rather weight maintenance.²⁸

Fat loss and smaller waist circumference

Most of the weight lost during a PSMF is from fat tissue.^11,26 Abdominal (visceral) fat may be lost first, which is desirable for patients with type 2 diabetes, since a higher degree of abdominal fat is linked to insulin resistance.^2,29

After a meal-replacement PSMF, waist circumference decreased significantly in patients both with and without type 2 diabetes.^24,26 However, in one study, less fat was lost per unit of change of BMI in the group with type 2 diabetes than in the nondiabetic group.²⁶ Since insulin inhibits lipolysis, it is possible that exogenous insulin use in diabetic patients may prevent greater reductions in fat mass, though this is likely not the only mechanism.²⁶

Lower fasting serum glucose

Fasting serum glucose levels decreased significantly from baseline in patients with type 2 diabetes after a PSMF in all studies that measured this variable.^{23–28,30,31} Changes in fasting glucose are immediate and are associated with caloric restriction rather than weight loss itself.^30,32 Furthermore, the observed decrease in serum glucose is even more impressive in view of the withdrawal or reduction of doses of insulin and oral hypoglycemic agents before starting the diet.

In a study that compared glycemic control in a PSMF diet vs a balanced low-calorie diet, the fasting serum glucose in the PSMF group declined 46%, from 255.9 mg/dL at baseline to 138.7 mg/dL at 20 weeks (P = .001). After 1 year, it had risen back to 187.4 mg/dL, which was still 27% lower than at baseline (P = .023). These results compared favorably with those in the low-calorie diet group (P < .05), which saw fasting serum glucose decline 27% after 20 weeks (from 230.6 mg/dL at baseline to 167.6 mg/dL) and then rise to 5% over baseline (243.2 mg/dL) after 1 year.²⁷

In a later study, the decrease in fasting serum glucose was not maintained at 1 year, but a significantly higher percentage (55%) of participants in the PSMF group were still able to remain free of diabetic medications compared with those who followed a balanced low-calorie diet (31%, P = .01).²⁸

Decrease in hemoglobin A_1c

Declines in fasting serum glucose corresponded with short-term declines in hemoglobin A_1c in several reports.^27–31 Hemoglobin A_1c declined significantly from an average of 10.4% to 7.3% (P = .001) after PSMF intervention in patients with type 2 diabetes. In contrast, hemoglobin A_1c in the low-calorie diet control group declined from 10.4% to 8.6%.²⁷ One year later, hemoglobin A_1c remained lower than at baseline in the PSMF group (final 9.2%) and continued to compare favorably against the control group (final 11.8%, between-group P = .001). However, these 1-year post-intervention improvements were not seen in a second, more intensive study.²⁸

Less insulin resistance

In several studies, fasting serum insulin levels declined along with serum glucose levels, implying decreased insulin resistance.^{25,27,28,30,31} In addition, insulin output was enhanced during glucose challenge after completion of the PSMF, suggesting possible improved (though still impaired) pancreatic beta-cell capacity.^25,27,30

Improved lipid profile

The most common effect of the PSMF on the lipid profile is a significant decrease in triglycerides in patients both with and without type 2 diabetes.^8,23,24,28 In addition, high-density lipoprotein cholesterol increased in two studies following PSMF intervention or after 1-year of follow-up.^24,27,28 Total cholesterol and low-density lipoprotein cholesterol levels also improved after the PSMF, but these changes were not always maintained at follow-up visits.^8,24,28

Lower blood pressure

Improvements in both systolic and diastolic blood pressure were noted in two studies, with mean decreases of 6 mm Hg to 13 mm Hg systolic and 8 mm Hg diastolic after PSMF intervention.^23,28 In a third study, reductions in blood pressure were less dramatic, and only changes in diastolic but not systolic blood pressure remained significant at 12 months.²⁴ While improvements were not observed in a fourth study, patients in this study also had impaired kidney function caused by diabetic nephropathy, and changes in medication were not taken into account.³¹

Kidney function tests

In a small study, Friedman et al showed that 12 weeks of the PSMF in six patients with advanced diabetic nephropathy (stage 3B or stage 4 chronic kidney disease) led to a loss of 12% of body weight (P = .03) as well as significant reductions in serum creatinine and cystatin C levels (P < .05).³¹ In addition, albuminuria decreased by 30% (P = .08). Side effects were minimal, and the diet was well tolerated despite its high protein content, which is a concern in patients with impaired kidney function.

Thus, weight loss via the PSMF may still be beneficial in type 2 diabetic patients with chronic kidney disease and may even improve the course of progression of diabetic nephropathy.

Long-term weight loss is elusive

Long-term weight loss has been an elusive goal for many diet programs. In a study using a very-low-calorie diet in obese patients with type 2 diabetes, substantial weight loss was maintained in half of the patients at 3 years after the intervention, but nearly all of the patients had regained most of their weight after 5 years.³³

While commitment to behavior modification, maintenance of physical activity, and continued follow-up are all critical factors in sustaining weight loss, new and innovative approaches to battle weight regain are needed.³⁴

Yet despite considerable weight regain in most patients, the Look AHEAD (Action for Health in Diabetes) study showed that participants in intensive lifestyle intervention programs still achieved greater weight loss after 4 years than those receiving standard care.³⁵ Whether this holds true for those in intensive PSMF programs is unknown. In addition, conclusive PSMF studies regarding glycemic control, lipids, and blood pressure beyond 1 year of follow-up are lacking.

A VIABLE OPTION FOR MANY

Adherence to a very-low-calorie, ketogenic PSMF program results in major short-term health benefits for obese patients with type 2 diabetes. These benefits include significant weight loss, often more than 18 kg, within 6 months.^23–28 In addition, significant improvements in fasting glucose^{23–28,30–32} and hemoglobin A_1c levels^27–31 are linked to the caloric and carbohydrate restriction of the PSMF. Insulin resistance was also attenuated, with possible partial restoration of pancreatic beta-cell capacity.^{25,27,28,30,31} In some studies, the PSMF resulted in lower systolic and diastolic blood pressure^23,24,28 and triglyceride levels.^8,23,24,28 One small study also suggested a possible improvement of diabetic nephropathy.³¹ Lastly, improvements in glycemia and hypertension were associated with a reduction in the need for antidiabetic and antihypertensive drugs.³⁶

Still, weight loss and many of the associated improvements partially return to baseline levels 1 year after the intervention. Thus, more long-term studies are needed to explore factors for better weight maintenance after the PSMF.

Also, only a few studies have compared the effect of the PSMF between patients with or without type 2 diabetes. One study suggested that fat loss may be reduced in patients with type 2 diabetes.²⁶

In conclusion, despite some risks and safety concerns, PSMF is a viable option for many obese, type 2 diabetic patients as a method of short-term weight loss, with evidence for improvement of glycemic control and cardiovascular risk factors for up to 1 year. To strengthen support for the PSMF, however, further research is warranted on the diet’s long-term effects in patients with type 2 diabetes and also in nondiabetic patients.
 

Acknowledgments: Many thanks to Cheryl Reitz, RD, LD, CDE, and Dawn Noe, RD, LD, CDE, for providing their expertise on the PSMF protocols carried out at Cleveland Clinic. Additional thanks to Tejas Kashyap for his initial assistance with this review.

Eighty percent of people with type 2 diabetes mellitus are obese or overweight.¹ Excess adipose tissue can lead to endocrine dysregulation,² contributing to the pathogenesis of type 2 diabetes, and obesity is one of the strongest predictors of this disease.³

For obese people with type 2 diabetes, diet and exercise can lead to weight loss and many other benefits, such as better glycemic control, less insulin resistance, lower risk of diabetes-related comorbidities and complications, fewer diabetic medications needed, and lower health care costs.^4–7 Intensive lifestyle interventions have also been shown to induce partial remission of diabetes and to prevent the onset of type 2 diabetes in people at high risk of it.^5–7

A very-low-calorie diet is one of many dietary options available to patients with type 2 diabetes who are overweight or obese. The protein-sparing modified fast (PSMF) is a type of very-low-calorie diet with a high protein content and simultaneous restriction of carbohydrate and fat.^8,9 It was developed in the 1970s, and since then various permutations have been used in weight loss and health care clinics worldwide.

MOSTLY PROTEIN, VERY LITTLE CARBOHYDRATE AND FAT

The PSMF is a medically supervised diet that provides less than 800 kcal/day during an initial intensive phase of about 6 months, followed by the gradual reintroduction of calories during a refeeding phase of about 6 to 8 weeks.¹⁰

During the intensive phase, patients obtain most of their calories from protein, approximately 1.2 to 1.5 g/kg of ideal body weight per day. At the same time, carbohydrate intake is restricted to less than 20 to 50 g/day; additional fats outside of protein sources are not allowed.⁹ Thus, the PSMF shares features of both very-low-calorie diets and very-low-carbohydrate ketogenic diets (eg, the Atkins diet), though some differences exist among the three (Figure 1).

Patients rapidly lose weight during the intensive phase, typically between 1 and 3 kg per week, with even greater losses during the first 2 weeks.8,9 Weight loss typically plateaus within 6 months, at which point patients begin the refeeding period. During refeeding, complex carbohydrates and low-glycemic, high-fiber cereals, fruits, vegetables, and fats are gradually reintroduced. Meanwhile, protein intake is reduced to individually tailored amounts as part of a weight-maintenance diet.

LIPOLYSIS, KETOSIS, DIURESIS

Modified from Baker S, et al. Effects and clinical potential of very-low-calorie diets (VLCDS) in type 2 diabetes. Diabetes Res Clin Pract 2009; 85:235–242.

The specific macronutrient composition of the PSMF during the intensive phase is designed so that patients enter ketosis and lose as much fat as they can while preserving lean body mass.^9,11 Figure 2 illustrates the mechanisms of ketosis and the metabolic impact of the PSMF.

With dietary carbohydrate restriction, serum glucose and insulin levels decline and glycogen stores are depleted. The drop in serum insulin allows lipolysis to occur, resulting in loss of adipose tissue and production of ketone bodies in the liver. Ketone bodies become the primary source of energy for the brain and other tissues during fasting and have metabolic and neuroprotective benefits.^12,13

Some studies suggest that ketosis also suppresses appetite, helping curb total caloric intake throughout the diet.¹⁴ Protein itself may increase satiety.¹⁵

Glycogen in the liver is bound to water, so the depletion of glycogen also results in loss of attached water. As a result, diuresis contributes significantly to the initial weight loss within the first 2 weeks on the PSMF.⁹

WHO IS A CANDIDATE FOR THE PSMF?

The PSMF is indicated only for adults with a body mass index (BMI) of at least 30 kg/m² or a BMI of at least 27 kg/m² and at least one comorbidity such as type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea, osteoarthritis, or fatty liver.¹² Patients must also be sufficiently committed and motivated to make the intensive dietary and behavioral changes the program calls for.

The PSMF should be considered when more conventional low-calorie approaches to weight loss fail or when patients become discouraged by the slower results seen with traditional diets.⁸ Patients undergoing a PSMF are usually encouraged by the initial period of rapid weight loss, and such diets have lower dropout rates.¹⁶

This diet may also be recommended for obese patients who have poorly controlled type 2 diabetes and growing resistance to medications, to bring down the blood glucose level. Another use is before bariatric surgery to reduce the risk of obesity-related complications.⁸ Patients who regain weight after bariatric surgery may also benefit.

MEAL REPLACEMENTS OR A DIET PLAN?

The PSMF program at Cleveland Clinic is based on modified preparation and selection of conventional foods. Details of the program are described in Table 1. Protein sources must be of high biologic value, containing the right mix of essential amino acids (eg, lean meat, fish, poultry, egg whites).⁹

Some commercially available very-low-calorie diets (eg, OPTIFAST, Medifast) that are advertised as PSMFs consist mainly of meal replacements. In the program at Cleveland Clinic, meal replacements in the form of commercial high-protein shakes or bars can be used occasionally for convenience and to maintain adherence to the diet.

However, preparation of PSMF meals from natural, conventional foods is thought to play an important role in long-term behavior modification and so is strongly encouraged. Patients learn low-fat cooking methods, portion control, and how to make appropriate choices in shopping, eating, and dining out. These lessons are valuable for those who struggle with long-term weight loss. Learning these behaviors through the program may help ease the transition to the weight-maintenance phase and beyond. For some patients, cooking is also a source of enjoyment, as is the sight, smell, and taste of nonliquid foods.¹⁰

In addition, patients appreciate being able to eat the same foods as others in their household, except for omitting high-carbohydrate foods. It has also been reported that patients on a food-based PSMF were significantly less hungry and preoccupied with eating than those on a liquid formula diet.¹⁷

CONTRAINDICATIONS AND SAFETY CONCERNS

Contraindications to the PSMF include a BMI less than 27 kg/m², recent myocardial infarction, angina, significant arrhythmia, decompensated congestive heart failure, cerebrovascular insufficiency or recent stroke, end-stage renal disease, liver failure, malignancy, major psychiatric illness, pregnancy or lactation, and wasting disorders. It is also not recommended for patients under age 16 or over age 65.

In view of the risk of diabetic ketoacidosis and the difficulty of titrating required doses ofinsulin, patients with type 1 diabetes mellitus are usually not advised to undergo a low-carbohydrate or very-low-calorie diet.^8,12 However, we and others have found that the PSMF can be used in some obese patients with type 1 diabetes if it is combined with appropriate education and careful monitoring.¹²

Major concerns about the safety of the PSMF stem from experiences with the first very-low-calorie diets in the 1970s, which were associated with fatal cardiac arrhythmias and sudden death.¹⁸ These early diets used liquid formulas with hydrolyzed collagen protein of poor biologic value and were deficient in many vitamins and minerals. Today’s very-low-calorie diets use protein sources of high biologic value (chiefly animal, soy, and egg for the PSMF) and are supplemented with necessary vitamins and minerals, reducing the risk of electrolyte and cardiac abnormalities.^9,19,20 Furthermore, before starting the PSMF all patients must have an electrocardiogram to be sure they have no arrhythmias (eg, heart block, QT interval prolongation) or ischemia.

Relative contraindications

A known history of cholelithiasis is a relative contraindication to a very-low-calorie diet and may be of concern for some patients and providers. While obesity itself is already a risk factor for gallstones, gallstone formation has also been associated with bile stasis, which occurs from rapid weight loss with liquid formula diets of low fat intake (< 10 g/day).²¹ However, in the PSMF, fat intake from protein sources, though low (45–70 g/day), is considered high enough to allow adequate gallbladder contraction, thus decreasing the risk of gallstone formation.²²

Gout is another relative contraindication, as hyperuricemia with risk of gout is also linked to high-protein diets.⁹ Palgi et al²³ found that uric acid levels rose by a mean of 0.4 mg/dL during the diet. The risk of gout, however, seemed to be small, occurring in fewer than 1% of patients in the study. Furthermore, in a recent study by Li et al,²⁴ uric acid levels were found to significantly decrease in patients on a high-protein, very-low-calorie diet. Nonetheless, uric acid levels should be monitored regularly in patients on the PSMF.

SIDE EFFECTS OF THE DIET

Common side effects of the PSMF include headache, fatigue, orthostatic hypotension, muscle cramps, cold intolerance, constipation, diarrhea, fatigue, halitosis, menstrual changes, and hair thinning. Most of these are transient and may be alleviated by adjusting fluid, salt, and supplement intake. Other side effects may disappear as the patient is weaned off the diet.^8,9

REGULAR FOLLOW-UP WITH HEALTH CARE PROVIDERS

Current PSMF programs are considered safe when used in combination with regular follow-up with health care providers.^8,12

At Cleveland Clinic, patients meet with a dietitian twice in the first month and monthly thereafter (or more frequently if needed) for weight monitoring and education on nutrition and behavior modification (Table 1). Since the PSMF does not provide complete nutrition, daily supplementation with vitamins and minerals is required.

Daily exercise is encouraged throughout the program to increase fitness and to help keep the weight off during the refeeding phase and after.

Patients also meet every 6 to 8 weeks with the referring nurse practitioner or physician for further monitoring and evaluation of vital signs, laboratory results, and side effects. The PSMF protocol at Cleveland Clinic enables both primary care physicians and specialists (including nurse practitioners) within our network to monitor the patient’s status. Use of a common electronic medical record system is particularly valuable for easy communication between providers. If a primary care physician feels unable to appropriately counsel and supervise a patient in the PSMF program, referral to an endocrinologist or weight loss specialist is recommended.

In addition to baseline electrocardiography and monitoring of uric acid levels, a comprehensive metabolic panel is drawn at baseline, twice in the first month, and monthly thereafter to check for electrolyte imbalances and metabolic and tissue dysfunction such as dehydration, excessive protein loss, and liver or kidney injury.

Patients should not attempt the PSMF without medical supervision. Many patients have friends or family members who want to try the PSMF along with them, but this can be dangerous, especially for those with hypertension or type 2 diabetes. The medications prescribed for these conditions can result in hypotension or hypoglycemia during the PSMF.

Although there are no standard guidelines for adjusting medication use before starting a patient on the PSMF, it is logical to taper off or discontinue antihypertensive agents in patients with tightly controlled hypertension to avoid possible dehydration and hypotension during the first few diuresis-inducing weeks of the diet. In particular, diuretic agents should be discontinued to prevent further electrolyte imbalance and fluid shifts.

Similarly, in patients with tightly controlled type 2 diabetes (hemoglobin A_1c < 7.0%), oral hypoglycemic agents and insulin therapy should be reduced before starting the diet to avoid potential hypoglycemia. During the course of the diet, providers should then adjust medication dosages based on follow-up vital signs and laboratory results and daily glucose monitoring.⁸

EFFECTS OF THE PSMF IN PATIENTS WITH TYPE 2 DIABETES

Though few formal studies have been done, the PSMF may have major effects on hyperglycemia, cardiovascular risk factors, and diabetic nephropathy in obese patients with type 2 diabetes, at least in the short term (Table 2).

Weight loss

In one of the first PSMF studies,²³ in 668 patients with or without type 2 diabetes (baseline weight 98 kg), the mean weight loss was 21 kg after the intensive phase and 19 kg by the end of the refeeding phase.

In another observational report,²⁵ 25% to 30% of patients lost even more weight, averaging 38.6 kg of weight loss. Typically, the higher the baseline weight, the greater the weight loss during the PSMF.²³

Patients with type 2 diabetes lost a similar amount of weight (8.5 kg) compared with those without diabetes (9.4 kg, P = .64) in a study of meal-replacement PSMF (using OPTIFAST shakes and bars).²⁶ In a large meal-replacement study of 2,093 patients, Li et al²⁴ found that weight loss was similar between diabetic, prediabetic, and nondiabetic patients. Weight loss was also closely maintained in those patients who stayed on the diet for 12 months.

In a PSMF study in which all the participants had type 2 diabetes, the mean weight loss was 18.6 kg. Although the patients regained some of this weight, at 1 year they still weighed 8.6 kg less than at baseline. However, a conventional, balanced, low-calorie diet resulted in similar amounts of weight loss after 1 year.²⁷ Furthermore, a second round of the PSMF did not result in significant additional weight loss but rather weight maintenance.²⁸

Fat loss and smaller waist circumference

Most of the weight lost during a PSMF is from fat tissue.^11,26 Abdominal (visceral) fat may be lost first, which is desirable for patients with type 2 diabetes, since a higher degree of abdominal fat is linked to insulin resistance.^2,29

After a meal-replacement PSMF, waist circumference decreased significantly in patients both with and without type 2 diabetes.^24,26 However, in one study, less fat was lost per unit of change of BMI in the group with type 2 diabetes than in the nondiabetic group.²⁶ Since insulin inhibits lipolysis, it is possible that exogenous insulin use in diabetic patients may prevent greater reductions in fat mass, though this is likely not the only mechanism.²⁶

Lower fasting serum glucose

Fasting serum glucose levels decreased significantly from baseline in patients with type 2 diabetes after a PSMF in all studies that measured this variable.^{23–28,30,31} Changes in fasting glucose are immediate and are associated with caloric restriction rather than weight loss itself.^30,32 Furthermore, the observed decrease in serum glucose is even more impressive in view of the withdrawal or reduction of doses of insulin and oral hypoglycemic agents before starting the diet.

In a study that compared glycemic control in a PSMF diet vs a balanced low-calorie diet, the fasting serum glucose in the PSMF group declined 46%, from 255.9 mg/dL at baseline to 138.7 mg/dL at 20 weeks (P = .001). After 1 year, it had risen back to 187.4 mg/dL, which was still 27% lower than at baseline (P = .023). These results compared favorably with those in the low-calorie diet group (P < .05), which saw fasting serum glucose decline 27% after 20 weeks (from 230.6 mg/dL at baseline to 167.6 mg/dL) and then rise to 5% over baseline (243.2 mg/dL) after 1 year.²⁷

In a later study, the decrease in fasting serum glucose was not maintained at 1 year, but a significantly higher percentage (55%) of participants in the PSMF group were still able to remain free of diabetic medications compared with those who followed a balanced low-calorie diet (31%, P = .01).²⁸

Decrease in hemoglobin A_1c

Declines in fasting serum glucose corresponded with short-term declines in hemoglobin A_1c in several reports.^27–31 Hemoglobin A_1c declined significantly from an average of 10.4% to 7.3% (P = .001) after PSMF intervention in patients with type 2 diabetes. In contrast, hemoglobin A_1c in the low-calorie diet control group declined from 10.4% to 8.6%.²⁷ One year later, hemoglobin A_1c remained lower than at baseline in the PSMF group (final 9.2%) and continued to compare favorably against the control group (final 11.8%, between-group P = .001). However, these 1-year post-intervention improvements were not seen in a second, more intensive study.²⁸

Less insulin resistance

In several studies, fasting serum insulin levels declined along with serum glucose levels, implying decreased insulin resistance.^{25,27,28,30,31} In addition, insulin output was enhanced during glucose challenge after completion of the PSMF, suggesting possible improved (though still impaired) pancreatic beta-cell capacity.^25,27,30

Improved lipid profile

The most common effect of the PSMF on the lipid profile is a significant decrease in triglycerides in patients both with and without type 2 diabetes.^8,23,24,28 In addition, high-density lipoprotein cholesterol increased in two studies following PSMF intervention or after 1-year of follow-up.^24,27,28 Total cholesterol and low-density lipoprotein cholesterol levels also improved after the PSMF, but these changes were not always maintained at follow-up visits.^8,24,28

Lower blood pressure

Improvements in both systolic and diastolic blood pressure were noted in two studies, with mean decreases of 6 mm Hg to 13 mm Hg systolic and 8 mm Hg diastolic after PSMF intervention.^23,28 In a third study, reductions in blood pressure were less dramatic, and only changes in diastolic but not systolic blood pressure remained significant at 12 months.²⁴ While improvements were not observed in a fourth study, patients in this study also had impaired kidney function caused by diabetic nephropathy, and changes in medication were not taken into account.³¹

Kidney function tests

In a small study, Friedman et al showed that 12 weeks of the PSMF in six patients with advanced diabetic nephropathy (stage 3B or stage 4 chronic kidney disease) led to a loss of 12% of body weight (P = .03) as well as significant reductions in serum creatinine and cystatin C levels (P < .05).³¹ In addition, albuminuria decreased by 30% (P = .08). Side effects were minimal, and the diet was well tolerated despite its high protein content, which is a concern in patients with impaired kidney function.

Thus, weight loss via the PSMF may still be beneficial in type 2 diabetic patients with chronic kidney disease and may even improve the course of progression of diabetic nephropathy.

Long-term weight loss is elusive

Long-term weight loss has been an elusive goal for many diet programs. In a study using a very-low-calorie diet in obese patients with type 2 diabetes, substantial weight loss was maintained in half of the patients at 3 years after the intervention, but nearly all of the patients had regained most of their weight after 5 years.³³

While commitment to behavior modification, maintenance of physical activity, and continued follow-up are all critical factors in sustaining weight loss, new and innovative approaches to battle weight regain are needed.³⁴

Yet despite considerable weight regain in most patients, the Look AHEAD (Action for Health in Diabetes) study showed that participants in intensive lifestyle intervention programs still achieved greater weight loss after 4 years than those receiving standard care.³⁵ Whether this holds true for those in intensive PSMF programs is unknown. In addition, conclusive PSMF studies regarding glycemic control, lipids, and blood pressure beyond 1 year of follow-up are lacking.

A VIABLE OPTION FOR MANY

Adherence to a very-low-calorie, ketogenic PSMF program results in major short-term health benefits for obese patients with type 2 diabetes. These benefits include significant weight loss, often more than 18 kg, within 6 months.^23–28 In addition, significant improvements in fasting glucose^{23–28,30–32} and hemoglobin A_1c levels^27–31 are linked to the caloric and carbohydrate restriction of the PSMF. Insulin resistance was also attenuated, with possible partial restoration of pancreatic beta-cell capacity.^{25,27,28,30,31} In some studies, the PSMF resulted in lower systolic and diastolic blood pressure^23,24,28 and triglyceride levels.^8,23,24,28 One small study also suggested a possible improvement of diabetic nephropathy.³¹ Lastly, improvements in glycemia and hypertension were associated with a reduction in the need for antidiabetic and antihypertensive drugs.³⁶

Still, weight loss and many of the associated improvements partially return to baseline levels 1 year after the intervention. Thus, more long-term studies are needed to explore factors for better weight maintenance after the PSMF.

Also, only a few studies have compared the effect of the PSMF between patients with or without type 2 diabetes. One study suggested that fat loss may be reduced in patients with type 2 diabetes.²⁶

In conclusion, despite some risks and safety concerns, PSMF is a viable option for many obese, type 2 diabetic patients as a method of short-term weight loss, with evidence for improvement of glycemic control and cardiovascular risk factors for up to 1 year. To strengthen support for the PSMF, however, further research is warranted on the diet’s long-term effects in patients with type 2 diabetes and also in nondiabetic patients.
 

Acknowledgments: Many thanks to Cheryl Reitz, RD, LD, CDE, and Dawn Noe, RD, LD, CDE, for providing their expertise on the PSMF protocols carried out at Cleveland Clinic. Additional thanks to Tejas Kashyap for his initial assistance with this review.