Clinical Edge Journal Scan

Key clinical point: Women with type 2 diabetes (T2D) and a history of gestational diabetes (GD) are at a higher risk for myocardial infarction (MI) and coronary artery disease compared with those with T2D and no GD history.

Major finding: Among women with T2D, those with a history of GD had a significantly higher risk for MI (adjusted odds ratio [aOR] 2.53; 95% CI 1.18-5.40) and a borderline increased risk for coronary artery disease (aOR 2.15; 95% CI 1.00-4.66) compared with those without GD history.

Study details: This cross-sectional study included 2494 women aged ≥20 years with T2D, of which 385 (15.4%) had a history of GD.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Cui Y et al. Impact of prior gestational diabetes on long-term type 2 diabetes complications. J Diabetes Complications. 2022;36(9):108282 (Aug 2). Doi: 10.1016/j.jdiacomp.2022.108282

Key clinical point: Women with type 2 diabetes (T2D) and a history of gestational diabetes (GD) are at a higher risk for myocardial infarction (MI) and coronary artery disease compared with those with T2D and no GD history.

Major finding: Among women with T2D, those with a history of GD had a significantly higher risk for MI (adjusted odds ratio [aOR] 2.53; 95% CI 1.18-5.40) and a borderline increased risk for coronary artery disease (aOR 2.15; 95% CI 1.00-4.66) compared with those without GD history.

Study details: This cross-sectional study included 2494 women aged ≥20 years with T2D, of which 385 (15.4%) had a history of GD.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Cui Y et al. Impact of prior gestational diabetes on long-term type 2 diabetes complications. J Diabetes Complications. 2022;36(9):108282 (Aug 2). Doi: 10.1016/j.jdiacomp.2022.108282

Key clinical point: Women with type 2 diabetes (T2D) and a history of gestational diabetes (GD) are at a higher risk for myocardial infarction (MI) and coronary artery disease compared with those with T2D and no GD history.

Major finding: Among women with T2D, those with a history of GD had a significantly higher risk for MI (adjusted odds ratio [aOR] 2.53; 95% CI 1.18-5.40) and a borderline increased risk for coronary artery disease (aOR 2.15; 95% CI 1.00-4.66) compared with those without GD history.

Study details: This cross-sectional study included 2494 women aged ≥20 years with T2D, of which 385 (15.4%) had a history of GD.

Disclosures: This study received no specific funding. The authors declared no conflicts of interest.

Source: Cui Y et al. Impact of prior gestational diabetes on long-term type 2 diabetes complications. J Diabetes Complications. 2022;36(9):108282 (Aug 2). Doi: 10.1016/j.jdiacomp.2022.108282

Key clinical point: Patients with type 2 diabetes (T2D) who initiated dulaglutide and liraglutide showed good treatment persistence and similar improvement in glycemic control along with weight loss at 12 months.

Major finding: At 12 months, a high probability of treatment persistence (0.88; 95% CI 0.86-0.90, and 0.83; 95% CI 0.80-0.85, respectively) and a significant reduction in the mean glycated hemoglobin level (−1.18% and −1.15%, respectively) were observed in patients initiating dulaglutide and liraglutide, along with body weight reduction in both the dulaglutide (−3.2 kg) and liraglutide (−3.4 kg) groups.

Study details: The data come from a prospective observational study, TROPHIES, including 2005 patients with T2D who initiated the first injectable treatment with dulaglutide (n = 1014) or liraglutide (n = 991).

Disclosures: This study was funded by Eli Lilly and Company. The authors declared receiving research support, speaker’s fees, or travel support or serving as a clinical investigator or consultant for various sources, including Eli Lilly. Six authors declared being full-time employees and shareholders of Eli Lilly.

Source: Guerci B et al. The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in type 2 diabetes patients (TROPHIES): Patient disposition, clinical characteristics, and treatment persistence at 12 months diabetes Obes Metab. 2022 (Jul 25). Doi: 10.1111/dom.14823

Key clinical point: Patients with type 2 diabetes (T2D) who initiated dulaglutide and liraglutide showed good treatment persistence and similar improvement in glycemic control along with weight loss at 12 months.

Major finding: At 12 months, a high probability of treatment persistence (0.88; 95% CI 0.86-0.90, and 0.83; 95% CI 0.80-0.85, respectively) and a significant reduction in the mean glycated hemoglobin level (−1.18% and −1.15%, respectively) were observed in patients initiating dulaglutide and liraglutide, along with body weight reduction in both the dulaglutide (−3.2 kg) and liraglutide (−3.4 kg) groups.

Study details: The data come from a prospective observational study, TROPHIES, including 2005 patients with T2D who initiated the first injectable treatment with dulaglutide (n = 1014) or liraglutide (n = 991).

Disclosures: This study was funded by Eli Lilly and Company. The authors declared receiving research support, speaker’s fees, or travel support or serving as a clinical investigator or consultant for various sources, including Eli Lilly. Six authors declared being full-time employees and shareholders of Eli Lilly.

Source: Guerci B et al. The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in type 2 diabetes patients (TROPHIES): Patient disposition, clinical characteristics, and treatment persistence at 12 months diabetes Obes Metab. 2022 (Jul 25). Doi: 10.1111/dom.14823

Key clinical point: Patients with type 2 diabetes (T2D) who initiated dulaglutide and liraglutide showed good treatment persistence and similar improvement in glycemic control along with weight loss at 12 months.

Major finding: At 12 months, a high probability of treatment persistence (0.88; 95% CI 0.86-0.90, and 0.83; 95% CI 0.80-0.85, respectively) and a significant reduction in the mean glycated hemoglobin level (−1.18% and −1.15%, respectively) were observed in patients initiating dulaglutide and liraglutide, along with body weight reduction in both the dulaglutide (−3.2 kg) and liraglutide (−3.4 kg) groups.

Study details: The data come from a prospective observational study, TROPHIES, including 2005 patients with T2D who initiated the first injectable treatment with dulaglutide (n = 1014) or liraglutide (n = 991).

Disclosures: This study was funded by Eli Lilly and Company. The authors declared receiving research support, speaker’s fees, or travel support or serving as a clinical investigator or consultant for various sources, including Eli Lilly. Six authors declared being full-time employees and shareholders of Eli Lilly.

Source: Guerci B et al. The real-world observational prospective study of health outcomes with dulaglutide and liraglutide in type 2 diabetes patients (TROPHIES): Patient disposition, clinical characteristics, and treatment persistence at 12 months diabetes Obes Metab. 2022 (Jul 25). Doi: 10.1111/dom.14823

Key clinical point: Switching from low-dose to high-dose empagliflozin led to significant clinical benefits in patients with type 2 diabetes (T2D) and inadequate glycemic control.

Major finding: Increasing the dose of empagliflozin from 10 mg to 25 mg for 6 months significantly improved the fasting plasma glucose and glycated hemoglobin levels by −12.7 mg/dL and −13%, respectively (P < .01), along with a significant reduction in body weight (−0.6 kg), triglyceride level (−22.1 mg/dL), and c-glutamyl transpeptidase level (−6.6 U/L; P < .01) and increase in hematocrit by 0.9% after 3 months.

Study details: This was a retrospective study including 52 patients with T2D and inadequate glycemic control whose dose of empagliflozin was increased from 10 mg to 25 mg once daily.

Disclosures: This study was sponsored by Shimazu Corporation, Kyoto, Japan. The authors declared no conflicts of interest.

Source: Matsumura T et al. Clinical benefit of switching from low-dose to high-dose empagliflozin in patients with type 2 diabetes. Diabetes Ther. 2022 (Jul 15). Doi: 10.1007/s13300-022-01296-y

Key clinical point: Switching from low-dose to high-dose empagliflozin led to significant clinical benefits in patients with type 2 diabetes (T2D) and inadequate glycemic control.

Major finding: Increasing the dose of empagliflozin from 10 mg to 25 mg for 6 months significantly improved the fasting plasma glucose and glycated hemoglobin levels by −12.7 mg/dL and −13%, respectively (P < .01), along with a significant reduction in body weight (−0.6 kg), triglyceride level (−22.1 mg/dL), and c-glutamyl transpeptidase level (−6.6 U/L; P < .01) and increase in hematocrit by 0.9% after 3 months.

Study details: This was a retrospective study including 52 patients with T2D and inadequate glycemic control whose dose of empagliflozin was increased from 10 mg to 25 mg once daily.

Disclosures: This study was sponsored by Shimazu Corporation, Kyoto, Japan. The authors declared no conflicts of interest.

Source: Matsumura T et al. Clinical benefit of switching from low-dose to high-dose empagliflozin in patients with type 2 diabetes. Diabetes Ther. 2022 (Jul 15). Doi: 10.1007/s13300-022-01296-y

Key clinical point: Switching from low-dose to high-dose empagliflozin led to significant clinical benefits in patients with type 2 diabetes (T2D) and inadequate glycemic control.

Major finding: Increasing the dose of empagliflozin from 10 mg to 25 mg for 6 months significantly improved the fasting plasma glucose and glycated hemoglobin levels by −12.7 mg/dL and −13%, respectively (P < .01), along with a significant reduction in body weight (−0.6 kg), triglyceride level (−22.1 mg/dL), and c-glutamyl transpeptidase level (−6.6 U/L; P < .01) and increase in hematocrit by 0.9% after 3 months.

Study details: This was a retrospective study including 52 patients with T2D and inadequate glycemic control whose dose of empagliflozin was increased from 10 mg to 25 mg once daily.

Disclosures: This study was sponsored by Shimazu Corporation, Kyoto, Japan. The authors declared no conflicts of interest.

Source: Matsumura T et al. Clinical benefit of switching from low-dose to high-dose empagliflozin in patients with type 2 diabetes. Diabetes Ther. 2022 (Jul 15). Doi: 10.1007/s13300-022-01296-y

Key clinical point: Dapagliflozin consistently reduced the risk for cardiovascular (CV) death or hospitalization for heart failure (HHF) and kidney disease progression irrespective of the background CV medication in patients with type 2 diabetes (T2D) with a consistent safety profile.

Major finding: Dapagliflozin vs placebo led to a consistent reduction in the composite of CV death/HHF, HHF alone, and kidney-specific outcomes irrespective of the background CV medications (P_interaction > .05), with patients not using diuretics showing better kidney specific outcomes (P_interaction  =  .003). Serious adverse events were not significantly different between the dapagliflozin and placebo groups.

Study details: Findings are from a prespecified secondary analysis of the DECLARE-TIMI 58 trial including 17,160 patients with T2D and either atherosclerotic disease or multiple CV risk factors.

Disclosures: The DECLAR-TIMI 58 trial was supported by AstraZeneca. One author reported being an employee and shareholder of AstraZeneca. Some authors reported receiving research funding or support, honoraria, personal fees, or consulting or speaker fees, or serving as advisory board members for various sources, including AstraZeneca.

Source: Oyama K et al. Efficacy and safety of dapagliflozin according to background use of cardiovascular medications in patients with type 2 diabetes: A prespecified secondary analysis of a randomized clinical trial. JAMA Cardiol. 2022 (Jul 20). Doi: 10.1001/jamacardio.2022.2006

Key clinical point: Dapagliflozin consistently reduced the risk for cardiovascular (CV) death or hospitalization for heart failure (HHF) and kidney disease progression irrespective of the background CV medication in patients with type 2 diabetes (T2D) with a consistent safety profile.

Major finding: Dapagliflozin vs placebo led to a consistent reduction in the composite of CV death/HHF, HHF alone, and kidney-specific outcomes irrespective of the background CV medications (P_interaction > .05), with patients not using diuretics showing better kidney specific outcomes (P_interaction  =  .003). Serious adverse events were not significantly different between the dapagliflozin and placebo groups.

Study details: Findings are from a prespecified secondary analysis of the DECLARE-TIMI 58 trial including 17,160 patients with T2D and either atherosclerotic disease or multiple CV risk factors.

Disclosures: The DECLAR-TIMI 58 trial was supported by AstraZeneca. One author reported being an employee and shareholder of AstraZeneca. Some authors reported receiving research funding or support, honoraria, personal fees, or consulting or speaker fees, or serving as advisory board members for various sources, including AstraZeneca.

Source: Oyama K et al. Efficacy and safety of dapagliflozin according to background use of cardiovascular medications in patients with type 2 diabetes: A prespecified secondary analysis of a randomized clinical trial. JAMA Cardiol. 2022 (Jul 20). Doi: 10.1001/jamacardio.2022.2006

Key clinical point: Dapagliflozin consistently reduced the risk for cardiovascular (CV) death or hospitalization for heart failure (HHF) and kidney disease progression irrespective of the background CV medication in patients with type 2 diabetes (T2D) with a consistent safety profile.

Major finding: Dapagliflozin vs placebo led to a consistent reduction in the composite of CV death/HHF, HHF alone, and kidney-specific outcomes irrespective of the background CV medications (P_interaction > .05), with patients not using diuretics showing better kidney specific outcomes (P_interaction  =  .003). Serious adverse events were not significantly different between the dapagliflozin and placebo groups.

Study details: Findings are from a prespecified secondary analysis of the DECLARE-TIMI 58 trial including 17,160 patients with T2D and either atherosclerotic disease or multiple CV risk factors.

Disclosures: The DECLAR-TIMI 58 trial was supported by AstraZeneca. One author reported being an employee and shareholder of AstraZeneca. Some authors reported receiving research funding or support, honoraria, personal fees, or consulting or speaker fees, or serving as advisory board members for various sources, including AstraZeneca.

Source: Oyama K et al. Efficacy and safety of dapagliflozin according to background use of cardiovascular medications in patients with type 2 diabetes: A prespecified secondary analysis of a randomized clinical trial. JAMA Cardiol. 2022 (Jul 20). Doi: 10.1001/jamacardio.2022.2006

Key clinical point: Initiation of 300 units/mL insulin glargine (Gla-300) or 100 units/mL degludec (Deg-100) was associated with similar improvements in glycemic control, no weight gain, and low rates of hypoglycemia in insulin-naive patients with type 2 diabetes (T2D).

Major finding: After 6 months, both Gla-300 and Deg-100 led to a significant and similar reduction in glycated hemoglobin (between group difference [Δ] −0.01%; P  =  .49) and fasting blood glucose (Δ −2.09 mg/dL; P  =  .74) levels, with no significant changes in body weight in both treatment groups. Overall, the incidence of hypoglycemia was low, with no severe episodes reported.

Study details: This was a retrospective study including insulin-naive patients with T2D who initiated Gla-300 and were propensity matched with those who initiated Deg-100 (n = 357).

Disclosures: This study was funded by Sanofi S.r.l., Milan, Italy. Some authors declared receiving lecture fees, consulting fees, research funding, or speaking honoraria from various sources, including Sanofi. M Larosa declared being an employee and holding stock in Sanofi.

Source: Fadini GP et al. Comparative effectiveness and safety of glargine 300 U/mL versus degludec 100 U/mL in insulin-naïve patients with type 2 diabetes. A multicenter retrospective real-world study (RESTORE-2 NAIVE STUDY). Acta Diabetol. 2022 (Jul 21). Doi: 10.1007/s00592-022-01925-9

Key clinical point: Initiation of 300 units/mL insulin glargine (Gla-300) or 100 units/mL degludec (Deg-100) was associated with similar improvements in glycemic control, no weight gain, and low rates of hypoglycemia in insulin-naive patients with type 2 diabetes (T2D).

Major finding: After 6 months, both Gla-300 and Deg-100 led to a significant and similar reduction in glycated hemoglobin (between group difference [Δ] −0.01%; P  =  .49) and fasting blood glucose (Δ −2.09 mg/dL; P  =  .74) levels, with no significant changes in body weight in both treatment groups. Overall, the incidence of hypoglycemia was low, with no severe episodes reported.

Study details: This was a retrospective study including insulin-naive patients with T2D who initiated Gla-300 and were propensity matched with those who initiated Deg-100 (n = 357).

Disclosures: This study was funded by Sanofi S.r.l., Milan, Italy. Some authors declared receiving lecture fees, consulting fees, research funding, or speaking honoraria from various sources, including Sanofi. M Larosa declared being an employee and holding stock in Sanofi.

Source: Fadini GP et al. Comparative effectiveness and safety of glargine 300 U/mL versus degludec 100 U/mL in insulin-naïve patients with type 2 diabetes. A multicenter retrospective real-world study (RESTORE-2 NAIVE STUDY). Acta Diabetol. 2022 (Jul 21). Doi: 10.1007/s00592-022-01925-9

Key clinical point: Initiation of 300 units/mL insulin glargine (Gla-300) or 100 units/mL degludec (Deg-100) was associated with similar improvements in glycemic control, no weight gain, and low rates of hypoglycemia in insulin-naive patients with type 2 diabetes (T2D).

Major finding: After 6 months, both Gla-300 and Deg-100 led to a significant and similar reduction in glycated hemoglobin (between group difference [Δ] −0.01%; P  =  .49) and fasting blood glucose (Δ −2.09 mg/dL; P  =  .74) levels, with no significant changes in body weight in both treatment groups. Overall, the incidence of hypoglycemia was low, with no severe episodes reported.

Study details: This was a retrospective study including insulin-naive patients with T2D who initiated Gla-300 and were propensity matched with those who initiated Deg-100 (n = 357).

Disclosures: This study was funded by Sanofi S.r.l., Milan, Italy. Some authors declared receiving lecture fees, consulting fees, research funding, or speaking honoraria from various sources, including Sanofi. M Larosa declared being an employee and holding stock in Sanofi.

Source: Fadini GP et al. Comparative effectiveness and safety of glargine 300 U/mL versus degludec 100 U/mL in insulin-naïve patients with type 2 diabetes. A multicenter retrospective real-world study (RESTORE-2 NAIVE STUDY). Acta Diabetol. 2022 (Jul 21). Doi: 10.1007/s00592-022-01925-9

Key clinical point: Dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) did not increase the risk for fracture in patients with type 2 diabetes (T2D) compared with other antidiabetic agents or placebo.

Major finding: DPP-4i was not associated with a higher risk for total fracture compared with insulin (odds ratio [OR] 0.86; 95% CI 0.39-1.90), metformin (OR 1.41; 95% CI 0.48-4.19), sulfonylureas (OR 0.77; 95% CI 0.50-1.20), thiazolidinediones (OR 0.82; 95% CI 0.27-2.44), α-glucosidase inhibitor (OR 4.92; 95% CI 0.23-103.83), and placebo (OR 1.04; 95% CI 0.84-1.29), with findings being similar for GLP-1 RA and SGLT-2i.

Study details: The data come from a systematic review and network meta-analysis of 177 randomized controlled trials including 165,081 patients with T2D.

Disclosures: This study was supported by the National Natural Science Foundation, China, and others. The authors declared no conflicts of interest.

Source: Chai S et al. Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and network meta-analysis combining 177 randomized controlled trials with a median follow-up of 26 weeks. Front Pharmacol. 2022;13:825417 (Jul 1). Doi:  10.3389/fphar.2022.825417

Key clinical point: Dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) did not increase the risk for fracture in patients with type 2 diabetes (T2D) compared with other antidiabetic agents or placebo.

Major finding: DPP-4i was not associated with a higher risk for total fracture compared with insulin (odds ratio [OR] 0.86; 95% CI 0.39-1.90), metformin (OR 1.41; 95% CI 0.48-4.19), sulfonylureas (OR 0.77; 95% CI 0.50-1.20), thiazolidinediones (OR 0.82; 95% CI 0.27-2.44), α-glucosidase inhibitor (OR 4.92; 95% CI 0.23-103.83), and placebo (OR 1.04; 95% CI 0.84-1.29), with findings being similar for GLP-1 RA and SGLT-2i.

Study details: The data come from a systematic review and network meta-analysis of 177 randomized controlled trials including 165,081 patients with T2D.

Disclosures: This study was supported by the National Natural Science Foundation, China, and others. The authors declared no conflicts of interest.

Source: Chai S et al. Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and network meta-analysis combining 177 randomized controlled trials with a median follow-up of 26 weeks. Front Pharmacol. 2022;13:825417 (Jul 1). Doi:  10.3389/fphar.2022.825417

Key clinical point: Dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) did not increase the risk for fracture in patients with type 2 diabetes (T2D) compared with other antidiabetic agents or placebo.

Major finding: DPP-4i was not associated with a higher risk for total fracture compared with insulin (odds ratio [OR] 0.86; 95% CI 0.39-1.90), metformin (OR 1.41; 95% CI 0.48-4.19), sulfonylureas (OR 0.77; 95% CI 0.50-1.20), thiazolidinediones (OR 0.82; 95% CI 0.27-2.44), α-glucosidase inhibitor (OR 4.92; 95% CI 0.23-103.83), and placebo (OR 1.04; 95% CI 0.84-1.29), with findings being similar for GLP-1 RA and SGLT-2i.

Study details: The data come from a systematic review and network meta-analysis of 177 randomized controlled trials including 165,081 patients with T2D.

Disclosures: This study was supported by the National Natural Science Foundation, China, and others. The authors declared no conflicts of interest.

Source: Chai S et al. Risk of fracture with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, or sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes mellitus: A systematic review and network meta-analysis combining 177 randomized controlled trials with a median follow-up of 26 weeks. Front Pharmacol. 2022;13:825417 (Jul 1). Doi:  10.3389/fphar.2022.825417

Key clinical point: Dipeptidyl peptidase 4 inhibitors (DPP-4i), but not glucagon-like peptide 1 receptor agonists (GLP-1 RA), significantly increased the risk for acute liver injury in patients with type 2 diabetes (T2D) compared with sodium-glucose cotransporter-2 inhibitors (SGLT-2i).

Major finding: Compared with SGLT-2i, DPP-4i (hazard ratio [HR] 1.53; 95% CI 1.02-2.30), but not GLP-1 RA (HR 1.11; 95% CI 0.57-2.16), were associated with a higher risk for acute liver injury; however, the risk was significantly higher in women receiving DPP-4i (HR 3.22; 95% CI 1.67-6.21) and GLP-1 RA (HR 3.23; 95% CI 1.44-7.25).

Study details: Findings are from a population-based study including 2 new-user, active-comparator cohorts; the first cohort included 106,310 and 27,277 new users of DPP-4i and SGLT-2i, respectively, and the second cohort included 9470 and 26,936 new users of GLP-1 RA and SGLT-2i, respectively.

Disclosures: This study was funded by a Canadian Institutes of Health Research Foundation Scheme grant. L Azoulay declared receiving consulting fees from Janssen Pharmaceuticals and Pfizer outside this work.

Source: Pradhan R et al. Incretin-based drugs and the risk of acute liver injury among patients with type 2 diabetes. Diabetes Care. 2022 (Jul 22). Doi: 10.2337/dc22-0712

Key clinical point: Dipeptidyl peptidase 4 inhibitors (DPP-4i), but not glucagon-like peptide 1 receptor agonists (GLP-1 RA), significantly increased the risk for acute liver injury in patients with type 2 diabetes (T2D) compared with sodium-glucose cotransporter-2 inhibitors (SGLT-2i).

Major finding: Compared with SGLT-2i, DPP-4i (hazard ratio [HR] 1.53; 95% CI 1.02-2.30), but not GLP-1 RA (HR 1.11; 95% CI 0.57-2.16), were associated with a higher risk for acute liver injury; however, the risk was significantly higher in women receiving DPP-4i (HR 3.22; 95% CI 1.67-6.21) and GLP-1 RA (HR 3.23; 95% CI 1.44-7.25).

Study details: Findings are from a population-based study including 2 new-user, active-comparator cohorts; the first cohort included 106,310 and 27,277 new users of DPP-4i and SGLT-2i, respectively, and the second cohort included 9470 and 26,936 new users of GLP-1 RA and SGLT-2i, respectively.

Disclosures: This study was funded by a Canadian Institutes of Health Research Foundation Scheme grant. L Azoulay declared receiving consulting fees from Janssen Pharmaceuticals and Pfizer outside this work.

Source: Pradhan R et al. Incretin-based drugs and the risk of acute liver injury among patients with type 2 diabetes. Diabetes Care. 2022 (Jul 22). Doi: 10.2337/dc22-0712

Key clinical point: Dipeptidyl peptidase 4 inhibitors (DPP-4i), but not glucagon-like peptide 1 receptor agonists (GLP-1 RA), significantly increased the risk for acute liver injury in patients with type 2 diabetes (T2D) compared with sodium-glucose cotransporter-2 inhibitors (SGLT-2i).

Major finding: Compared with SGLT-2i, DPP-4i (hazard ratio [HR] 1.53; 95% CI 1.02-2.30), but not GLP-1 RA (HR 1.11; 95% CI 0.57-2.16), were associated with a higher risk for acute liver injury; however, the risk was significantly higher in women receiving DPP-4i (HR 3.22; 95% CI 1.67-6.21) and GLP-1 RA (HR 3.23; 95% CI 1.44-7.25).

Study details: Findings are from a population-based study including 2 new-user, active-comparator cohorts; the first cohort included 106,310 and 27,277 new users of DPP-4i and SGLT-2i, respectively, and the second cohort included 9470 and 26,936 new users of GLP-1 RA and SGLT-2i, respectively.

Disclosures: This study was funded by a Canadian Institutes of Health Research Foundation Scheme grant. L Azoulay declared receiving consulting fees from Janssen Pharmaceuticals and Pfizer outside this work.

Source: Pradhan R et al. Incretin-based drugs and the risk of acute liver injury among patients with type 2 diabetes. Diabetes Care. 2022 (Jul 22). Doi: 10.2337/dc22-0712

Key clinical point: Once-weekly exenatide was superior to placebo in improving glycemic control and was well tolerated in youth with type 2 diabetes (T2D) who were suboptimally controlled with current treatments. It had a safety profile similar to that in adults.

Major finding: At 24 weeks, the least squares mean change in the glycated hemoglobin level in the exenatide vs placebo group was −0.36% vs 0.49%, respectively, with a between-group difference of −0.85% (P  =  .012) showing the superiority of exenatide over placebo. Adverse events were reported by 61.0% and 73.9% of participants in the exenatide and placebo groups, respectively.

Study details: Findings are from a multicenter, parallel-group, phase 3 study including 72 patients with T2D suboptimally controlled with current treatments who were randomly assigned to receive once-weekly exenatide (n = 49) or placebo (n = 23).

Disclosures: This study was funded by AstraZeneca. N Shehadeh and O Doehring declared receiving support from AstraZeneca. The other authors declared being employees or holding stocks in AstraZeneca.

Source: Tamborlane WV et al. Once-weekly exenatide in youth with type 2 diabetes. Diabetes Care. 2022;45(8):1833–1840 (Jul 26). Doi: 10.2337/dc21-2275

Key clinical point: Once-weekly exenatide was superior to placebo in improving glycemic control and was well tolerated in youth with type 2 diabetes (T2D) who were suboptimally controlled with current treatments. It had a safety profile similar to that in adults.

Major finding: At 24 weeks, the least squares mean change in the glycated hemoglobin level in the exenatide vs placebo group was −0.36% vs 0.49%, respectively, with a between-group difference of −0.85% (P  =  .012) showing the superiority of exenatide over placebo. Adverse events were reported by 61.0% and 73.9% of participants in the exenatide and placebo groups, respectively.

Study details: Findings are from a multicenter, parallel-group, phase 3 study including 72 patients with T2D suboptimally controlled with current treatments who were randomly assigned to receive once-weekly exenatide (n = 49) or placebo (n = 23).

Disclosures: This study was funded by AstraZeneca. N Shehadeh and O Doehring declared receiving support from AstraZeneca. The other authors declared being employees or holding stocks in AstraZeneca.

Source: Tamborlane WV et al. Once-weekly exenatide in youth with type 2 diabetes. Diabetes Care. 2022;45(8):1833–1840 (Jul 26). Doi: 10.2337/dc21-2275

Key clinical point: Once-weekly exenatide was superior to placebo in improving glycemic control and was well tolerated in youth with type 2 diabetes (T2D) who were suboptimally controlled with current treatments. It had a safety profile similar to that in adults.

Major finding: At 24 weeks, the least squares mean change in the glycated hemoglobin level in the exenatide vs placebo group was −0.36% vs 0.49%, respectively, with a between-group difference of −0.85% (P  =  .012) showing the superiority of exenatide over placebo. Adverse events were reported by 61.0% and 73.9% of participants in the exenatide and placebo groups, respectively.

Study details: Findings are from a multicenter, parallel-group, phase 3 study including 72 patients with T2D suboptimally controlled with current treatments who were randomly assigned to receive once-weekly exenatide (n = 49) or placebo (n = 23).

Disclosures: This study was funded by AstraZeneca. N Shehadeh and O Doehring declared receiving support from AstraZeneca. The other authors declared being employees or holding stocks in AstraZeneca.

Source: Tamborlane WV et al. Once-weekly exenatide in youth with type 2 diabetes. Diabetes Care. 2022;45(8):1833–1840 (Jul 26). Doi: 10.2337/dc21-2275

Surgical resection plays a critical role in the management of early-stage gastric cancer. Depending on the tumor stage and location, there are different surgical approaches. Complications associated with surgical resection can significantly affect quality of life and ability to receive subsequent treatment. With recent advances in minimally invasive approaches, laparoscopic resections are emerging as an attractive option for patients undergoing oncologic surgeries.

The KLASS-02 trial was a multicenter, randomized, controlled, noninferiority clinical trial, which enrolled 1050 patients with locally advanced gastric cancer. Of the enrolled patients, 974 patients underwent R0 resection either by laparoscopic (n = 492) or open (n = 482) distal gastrectomy. In the previous readout of this study with 3 years of follow-up, laparoscopic distal gastrectomy had noninferior oncologic outcomes compared with open surgery for locally advanced gastric cancer. Son and colleagues are now reporting 5-year follow-up results. Overall survival (OS; 88.9% vs 88.7%; P = .30) and relapse-free survival (79.5% vs 81.1%; P = .658) rates were similar in both surgical groups. The pattern of recurrences was similar between the two groups as well, with peroneal (42.1% of patients) and hematogenous (20.8%) being the most frequent ones. However, patients who underwent laparoscopic vs open distal gastrectomy had a significantly lower late complication rate (6.5% vs 11.0%; P = .01). This study demonstrates that laparoscopic distal gastrectomy is an appropriate alternative to open distal gastrectomy and should be offered to patients who are treated in centers with experience in performing these types of operations.

Peritoneal metastasis is a common site for the spread of gastric cancer. As such, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of this disease has been explored in a number of studies. The effectiveness of prophylactic HIPEC during resection of early-stage gastric cancer remains unknown.

Shen and colleagues conducted a propensity score-matching analysis looking at the efficacy and safety of HIPEC in this setting. The study evaluated outcomes of 395 patients with locally advanced gastric cancer who underwent resection with (n = 146) or without HIPEC (n = 248). In the HIPEC group, OS compared favorably to the surgery-only group (69.9% vs 40.8%, P = .049) and 2-year relapse-free survival was higher with HIPEC (60.7% vs 31.6%, P = .049).

Previously, the CYTO-CHIP propensity score analysis study performed in France demonstrated that HIPEC in addition to cytoreductive surgery resulted in improved OS in patients with advanced gastric cancer and peritoneal metastasis compared to cytoreduction surgery alone.¹ However, with both of these reports, interpretation of the results carries inherent limitations that are associated with retrospective study design. Prior prospective studies, on the other hand, had mixed results. An ongoing phase 3 prospective study of D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP) will hopefully provide a definitive answer regarding the benefit of HIPEC in early-stage gastric cancer management (NCT01882933). Ultimately, going forward, the role of HIPEC in early-stage disease will need to be examined in a prospective study with carefully selected patients, using the latest biomarkers and systemic therapies.

Mismatch repair protein deficient (dMMR) or microsatellite unstable gastric cancer (MSI-H) have distinct biologic behaviors and treatment responses. They are much more responsive to immune checkpoint inhibitors in the metastatic setting. In early-stage disease, exploratory analysis of patients with MSI-H tumors previously enrolled in the perioperative MAGIC trial, revealed that patients with MSI-H tumors had a better prognosis when treated with surgery alone, and they potentially experienced detrimental effects from chemotherapy.²

The GERCOR NEONIPIGA single-arm phase 2 study enrolled 32 patients with resectable dMMR/MSI-H gastric and gastroesophageal junction tumors.³ Patients were treated with 240-mg neoadjuvant nivolumab once every 2 weeks six times and 1-mg/kg ipilimumab once every 6 weeks twice, followed by surgery and 480-mg adjuvant nivolumab once every 4 weeks nine times. Twenty-nine patients underwent resection. All resections were with negative margins (R0). Pathologic complete response was seen in 17 (58.6%) of patients. As of the February 2022 data cutoff, with a median duration of follow-up of 14.9 months, 30 out of 31 patients with early-stage disease remained alive and without recurrence or progression (one evaluable patient had metastatic disease).

These results certainly support further investigation of immunotherapy use in this patient population. However, in the absence of prospective randomized data, the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) remains the standard of care in those who can tolerate it. For patients with MSI-H tumors who are not candidates for combination chemotherapy or whose tumors are progressing on chemotherapy, neoadjuvant immunotherapy is certainly a good option to consider.

Additional References

1. Bonnot P-E et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): A propensity score analysis. J Clin Oncol. 2019;37:2028-2040. Doi: 10.1200/JCO.18.01688

2. Smyth EC et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197-1203. Doi: 10.1001/jamaoncol.2016.6762

3. André T et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022 (Aug 15. Doi: 10.1200/JCO.22.00686

Surgical resection plays a critical role in the management of early-stage gastric cancer. Depending on the tumor stage and location, there are different surgical approaches. Complications associated with surgical resection can significantly affect quality of life and ability to receive subsequent treatment. With recent advances in minimally invasive approaches, laparoscopic resections are emerging as an attractive option for patients undergoing oncologic surgeries.

The KLASS-02 trial was a multicenter, randomized, controlled, noninferiority clinical trial, which enrolled 1050 patients with locally advanced gastric cancer. Of the enrolled patients, 974 patients underwent R0 resection either by laparoscopic (n = 492) or open (n = 482) distal gastrectomy. In the previous readout of this study with 3 years of follow-up, laparoscopic distal gastrectomy had noninferior oncologic outcomes compared with open surgery for locally advanced gastric cancer. Son and colleagues are now reporting 5-year follow-up results. Overall survival (OS; 88.9% vs 88.7%; P = .30) and relapse-free survival (79.5% vs 81.1%; P = .658) rates were similar in both surgical groups. The pattern of recurrences was similar between the two groups as well, with peroneal (42.1% of patients) and hematogenous (20.8%) being the most frequent ones. However, patients who underwent laparoscopic vs open distal gastrectomy had a significantly lower late complication rate (6.5% vs 11.0%; P = .01). This study demonstrates that laparoscopic distal gastrectomy is an appropriate alternative to open distal gastrectomy and should be offered to patients who are treated in centers with experience in performing these types of operations.

Peritoneal metastasis is a common site for the spread of gastric cancer. As such, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of this disease has been explored in a number of studies. The effectiveness of prophylactic HIPEC during resection of early-stage gastric cancer remains unknown.

Shen and colleagues conducted a propensity score-matching analysis looking at the efficacy and safety of HIPEC in this setting. The study evaluated outcomes of 395 patients with locally advanced gastric cancer who underwent resection with (n = 146) or without HIPEC (n = 248). In the HIPEC group, OS compared favorably to the surgery-only group (69.9% vs 40.8%, P = .049) and 2-year relapse-free survival was higher with HIPEC (60.7% vs 31.6%, P = .049).

Previously, the CYTO-CHIP propensity score analysis study performed in France demonstrated that HIPEC in addition to cytoreductive surgery resulted in improved OS in patients with advanced gastric cancer and peritoneal metastasis compared to cytoreduction surgery alone.¹ However, with both of these reports, interpretation of the results carries inherent limitations that are associated with retrospective study design. Prior prospective studies, on the other hand, had mixed results. An ongoing phase 3 prospective study of D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP) will hopefully provide a definitive answer regarding the benefit of HIPEC in early-stage gastric cancer management (NCT01882933). Ultimately, going forward, the role of HIPEC in early-stage disease will need to be examined in a prospective study with carefully selected patients, using the latest biomarkers and systemic therapies.

Mismatch repair protein deficient (dMMR) or microsatellite unstable gastric cancer (MSI-H) have distinct biologic behaviors and treatment responses. They are much more responsive to immune checkpoint inhibitors in the metastatic setting. In early-stage disease, exploratory analysis of patients with MSI-H tumors previously enrolled in the perioperative MAGIC trial, revealed that patients with MSI-H tumors had a better prognosis when treated with surgery alone, and they potentially experienced detrimental effects from chemotherapy.²

The GERCOR NEONIPIGA single-arm phase 2 study enrolled 32 patients with resectable dMMR/MSI-H gastric and gastroesophageal junction tumors.³ Patients were treated with 240-mg neoadjuvant nivolumab once every 2 weeks six times and 1-mg/kg ipilimumab once every 6 weeks twice, followed by surgery and 480-mg adjuvant nivolumab once every 4 weeks nine times. Twenty-nine patients underwent resection. All resections were with negative margins (R0). Pathologic complete response was seen in 17 (58.6%) of patients. As of the February 2022 data cutoff, with a median duration of follow-up of 14.9 months, 30 out of 31 patients with early-stage disease remained alive and without recurrence or progression (one evaluable patient had metastatic disease).

These results certainly support further investigation of immunotherapy use in this patient population. However, in the absence of prospective randomized data, the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) remains the standard of care in those who can tolerate it. For patients with MSI-H tumors who are not candidates for combination chemotherapy or whose tumors are progressing on chemotherapy, neoadjuvant immunotherapy is certainly a good option to consider.

Additional References

1. Bonnot P-E et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): A propensity score analysis. J Clin Oncol. 2019;37:2028-2040. Doi: 10.1200/JCO.18.01688

2. Smyth EC et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197-1203. Doi: 10.1001/jamaoncol.2016.6762

3. André T et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022 (Aug 15. Doi: 10.1200/JCO.22.00686

Surgical resection plays a critical role in the management of early-stage gastric cancer. Depending on the tumor stage and location, there are different surgical approaches. Complications associated with surgical resection can significantly affect quality of life and ability to receive subsequent treatment. With recent advances in minimally invasive approaches, laparoscopic resections are emerging as an attractive option for patients undergoing oncologic surgeries.

The KLASS-02 trial was a multicenter, randomized, controlled, noninferiority clinical trial, which enrolled 1050 patients with locally advanced gastric cancer. Of the enrolled patients, 974 patients underwent R0 resection either by laparoscopic (n = 492) or open (n = 482) distal gastrectomy. In the previous readout of this study with 3 years of follow-up, laparoscopic distal gastrectomy had noninferior oncologic outcomes compared with open surgery for locally advanced gastric cancer. Son and colleagues are now reporting 5-year follow-up results. Overall survival (OS; 88.9% vs 88.7%; P = .30) and relapse-free survival (79.5% vs 81.1%; P = .658) rates were similar in both surgical groups. The pattern of recurrences was similar between the two groups as well, with peroneal (42.1% of patients) and hematogenous (20.8%) being the most frequent ones. However, patients who underwent laparoscopic vs open distal gastrectomy had a significantly lower late complication rate (6.5% vs 11.0%; P = .01). This study demonstrates that laparoscopic distal gastrectomy is an appropriate alternative to open distal gastrectomy and should be offered to patients who are treated in centers with experience in performing these types of operations.

Peritoneal metastasis is a common site for the spread of gastric cancer. As such, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of this disease has been explored in a number of studies. The effectiveness of prophylactic HIPEC during resection of early-stage gastric cancer remains unknown.

Shen and colleagues conducted a propensity score-matching analysis looking at the efficacy and safety of HIPEC in this setting. The study evaluated outcomes of 395 patients with locally advanced gastric cancer who underwent resection with (n = 146) or without HIPEC (n = 248). In the HIPEC group, OS compared favorably to the surgery-only group (69.9% vs 40.8%, P = .049) and 2-year relapse-free survival was higher with HIPEC (60.7% vs 31.6%, P = .049).

Previously, the CYTO-CHIP propensity score analysis study performed in France demonstrated that HIPEC in addition to cytoreductive surgery resulted in improved OS in patients with advanced gastric cancer and peritoneal metastasis compared to cytoreduction surgery alone.¹ However, with both of these reports, interpretation of the results carries inherent limitations that are associated with retrospective study design. Prior prospective studies, on the other hand, had mixed results. An ongoing phase 3 prospective study of D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP) will hopefully provide a definitive answer regarding the benefit of HIPEC in early-stage gastric cancer management (NCT01882933). Ultimately, going forward, the role of HIPEC in early-stage disease will need to be examined in a prospective study with carefully selected patients, using the latest biomarkers and systemic therapies.

Mismatch repair protein deficient (dMMR) or microsatellite unstable gastric cancer (MSI-H) have distinct biologic behaviors and treatment responses. They are much more responsive to immune checkpoint inhibitors in the metastatic setting. In early-stage disease, exploratory analysis of patients with MSI-H tumors previously enrolled in the perioperative MAGIC trial, revealed that patients with MSI-H tumors had a better prognosis when treated with surgery alone, and they potentially experienced detrimental effects from chemotherapy.²

The GERCOR NEONIPIGA single-arm phase 2 study enrolled 32 patients with resectable dMMR/MSI-H gastric and gastroesophageal junction tumors.³ Patients were treated with 240-mg neoadjuvant nivolumab once every 2 weeks six times and 1-mg/kg ipilimumab once every 6 weeks twice, followed by surgery and 480-mg adjuvant nivolumab once every 4 weeks nine times. Twenty-nine patients underwent resection. All resections were with negative margins (R0). Pathologic complete response was seen in 17 (58.6%) of patients. As of the February 2022 data cutoff, with a median duration of follow-up of 14.9 months, 30 out of 31 patients with early-stage disease remained alive and without recurrence or progression (one evaluable patient had metastatic disease).

These results certainly support further investigation of immunotherapy use in this patient population. However, in the absence of prospective randomized data, the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) remains the standard of care in those who can tolerate it. For patients with MSI-H tumors who are not candidates for combination chemotherapy or whose tumors are progressing on chemotherapy, neoadjuvant immunotherapy is certainly a good option to consider.

Additional References

1. Bonnot P-E et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): A propensity score analysis. J Clin Oncol. 2019;37:2028-2040. Doi: 10.1200/JCO.18.01688

2. Smyth EC et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197-1203. Doi: 10.1001/jamaoncol.2016.6762

3. André T et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022 (Aug 15. Doi: 10.1200/JCO.22.00686

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.