Type 2 Diabetes ICYMI

Key clinical point: In patients with type 2 diabetes (T2D), the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) was associated with a lower risk for end-stage renal disease (ESRD) and acute renal failure (ARF) and a slower decline in the estimated glomerular filtration rate (eGFR).

Major finding: Over a median follow-up of 3.8 years, the use of SGLT2i vs. DPP4i was associated with a significantly lower risk for ESRD (hazard ratio [HR] 0.51; P < .001) and ARF (HR 0.59; P < .001) and a significantly slower decline in eGFR (−0.060 vs. −0.625 mL/min/1.73m²  per year; P_interaction < .001).

Study details: This retrospective cohort study propensity score matched 6333 patients with T2D receiving an SGLT2i with 25,332 of those receiving a DPP4i.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Au PCM et al. Association between SGLT20iInhibitors vs DPP4 inhibitors and renal outcomes among patients with type 2 diabetes. J Clin Endocrinol Metab. 2022 (Mar 18). Doi:  10.1210/clinem/dgac164

Key clinical point: In patients with type 2 diabetes (T2D), the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) was associated with a lower risk for end-stage renal disease (ESRD) and acute renal failure (ARF) and a slower decline in the estimated glomerular filtration rate (eGFR).

Major finding: Over a median follow-up of 3.8 years, the use of SGLT2i vs. DPP4i was associated with a significantly lower risk for ESRD (hazard ratio [HR] 0.51; P < .001) and ARF (HR 0.59; P < .001) and a significantly slower decline in eGFR (−0.060 vs. −0.625 mL/min/1.73m²  per year; P_interaction < .001).

Study details: This retrospective cohort study propensity score matched 6333 patients with T2D receiving an SGLT2i with 25,332 of those receiving a DPP4i.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Au PCM et al. Association between SGLT20iInhibitors vs DPP4 inhibitors and renal outcomes among patients with type 2 diabetes. J Clin Endocrinol Metab. 2022 (Mar 18). Doi:  10.1210/clinem/dgac164

Key clinical point: In patients with type 2 diabetes (T2D), the use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. dipeptidyl peptidase-4 inhibitors (DPP4i) was associated with a lower risk for end-stage renal disease (ESRD) and acute renal failure (ARF) and a slower decline in the estimated glomerular filtration rate (eGFR).

Major finding: Over a median follow-up of 3.8 years, the use of SGLT2i vs. DPP4i was associated with a significantly lower risk for ESRD (hazard ratio [HR] 0.51; P < .001) and ARF (HR 0.59; P < .001) and a significantly slower decline in eGFR (−0.060 vs. −0.625 mL/min/1.73m²  per year; P_interaction < .001).

Study details: This retrospective cohort study propensity score matched 6333 patients with T2D receiving an SGLT2i with 25,332 of those receiving a DPP4i.

Disclosures: This study did not receive any funding. The authors declared no conflicts of interest.

Source: Au PCM et al. Association between SGLT20iInhibitors vs DPP4 inhibitors and renal outcomes among patients with type 2 diabetes. J Clin Endocrinol Metab. 2022 (Mar 18). Doi:  10.1210/clinem/dgac164

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Resistance training (RT) effectively reduces glycosylated hemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2D), with RT interventions triggering a larger vs. medium or smaller improvement in muscular strength leading to a greater reduction in HbA1c.

Major finding: RT intervention vs. control treatment significantly decreased HbA1c (weighted mean difference −0.39; P < .001), with a larger vs. medium or small effect on muscular strength leading to a greater reduction in HbA1c (β −0.99; P = .0470).

Study details: Findings are from a meta-analysis of 20 trials including 1172 patients with T2DM.

Disclosures: The study received no specific funding. The authors declared no competing interests.

Source: Jansson AK et al. Effect of resistance training on HbA1c in adults with type 2 diabetes mellitus and the moderating effect of changes in muscular strength: a systematic review and meta-analysis. BMJ Open Diabetes Res Care. 2022;10:e002595 (Mar 10). Doi: 10.1136/bmjdrc-2021-002595

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Fenofibrate reduced the composite outcome of heart failure (HF) hospitalizations or cardiovascular death in patients with type 2 diabetes (T2D) treated with simvastatin, predominantly in those who received the standard background glucose-lowering therapy.

Major finding: The composite outcome of HF hospitalization or cardiovascular death was significantly lower with fenofibrate vs. placebo (hazard ratio [HR] 0.82; P = .048), with reduction primarily observed with the standard glucose-lowering strategy (HR 0.64; 95% CI 0.48-0.85), but not with the intensive glucose-lowering strategy (HR 1.02; 95% CI 0.79-1.33; P_interaction = .017).

Study details: Findings are from the ACCORD Lipid trial including 5518 patients with T2D who were randomly assigned to receive simvastatin plus fenofibrate (n = 2765) or simvastatin plus placebo (n = 2753).

Disclosures: The study was funded by national funds through FCT-Portuguese Foundation for

Science and Technology, under the scope of the Cardiovascular R&D Center-UnIC. Some authors declared being consultants and receiving research support or personal fees from various sources.

Source: Ferreira JP et al. Fenofibrate and heart failure outcomes in patients with type 2 diabetes: analysis from ACCORD. Diabetes Care. 2022 (Mar 23). Doi: 10.2337/dc21-1977

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Empagliflozin showed a beneficial effect on cognitive and physical impairment in frail older patients with type 2 diabetes (T2D) and heart failure with preserved ejection fraction (HFpEF).

Major finding: The mean Montreal Cognitive Assessment score significantly improved from baseline to 1 month in the empagliflozin group (19.80 vs. 22.25; P < .001) but not in the metformin (P = .26) and insulin (P = .81) groups, with empagliflozin showing a significant effect on amelioration of cognitive impairment (odds ratio 3.609; P = .03). The 5-meter gait speed improved significantly in the empagliflozin and metformin groups (both P < .05), but not in the insulin group.

Study details: This prospective observational study included 162 frail older patients aged >65 years who had T2D and HFpEF and were treated with empagliflozin (n = 52), metformin (n = 56), or insulin (n = 54).

Disclosures: The study was partly supported by the US National Institute of Diabetes and Digestive and Kidney Diseases, US National Heart, Lung, and Blood Institute, and US National Institute on Aging, among others. The authors declared no conflicts of interest.

Source: Mone P et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022 (Mar 21). Doi: 10.2337/dc21-2434

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

Key clinical point: Dapagliflozin in addition to standard-of-care treatment demonstrated a clinically relevant decrease in glycated hemoglobin (HbA1c) and an acceptable safety profile in young people with type 2 diabetes (T2D).

Major finding: At 24 weeks, the adjusted mean change in HbA1c was not significantly different between the dapagliflozin and placebo groups in the intention-to-treat analysis (between-group difference [Δ] −0.75%; P = .10), but was significantly different in the sensitivity analysis in the per-protocol population (Δ −1.13%; P = .012). No new safety signals or episodes of death or diabetic ketoacidosis were recorded.

Study details: The data come from a phase 3 trial including 72 participants aged 10-24 years with T2D and HbA1c concentration of 6.5%-11% who were randomly assigned to receive oral dapagliflozin (10 mg) or placebo in addition to standard-of-care treatment for 24 weeks followed by dapagliflozin for 28 weeks

Disclosures: The study was funded by AstraZeneca. Some authors declared receiving consulting fees or research grants or serving on advisory boards for various sources, including AstraZeneca. Three authors declared being stockholders or employees of AstraZeneca.

Source: Tamborlane WV, Laffel LM et al. Efficacy and safety of dapagliflozin in children and young adults with type 2 diabetes: a prospective, multicentre, randomised, parallel group, phase 3 study. Lancet Diabetes Endocrinol. 2022 (Apr 1). Doi: 10.1016/S2213-8587(22)00052-3

A weight-loss program can lead to type 2 diabetes remission, even in individuals with a normal body mass index (BMI), via loss of body fat, particularly in the liver and pancreas, shows a U.K. study.

The ReTUNE trial, funded by Diabetes UK, involved 20 people with type 2 diabetes of less than 6 year’s duration and a BMI of 27 kg/m² or lower.

Joel Austell/MDedge News

After 1 year, participants had lost 9% of their body weight.

Their body fat decreased significantly, to the same level as controls without type 2 diabetes, and they experienced decreases in liver fat, total triglycerides, and pancreatic fat.

The research, presented at the 2022 Diabetes UK Professional Conference, also showed this was accompanied by increases in insulin secretion and reductions in hemoglobin A1c and fasting plasma glucose levels.

Lead author Roy Taylor, MD, PhD, professor of medicine and metabolism, Newcastle University, Newcastle upon Tyne, England, said the findings indicate that the “etiology and pathophysiology of type 2 diabetes is the same whether BMI is normal or raised.”

This information should make a profound difference in what doctors advise their patients, Dr. Taylor added.

“One of the dramatic things about dealing with people in this group,” he said, “is they feel very resentful that healthcare professionals tell them not to lose weight.”

Based on the current results, Dr. Taylor believes this is “inappropriate advice, and it’s that personal advice that I think that this study points a way towards.”
 

Weight loss ‘first line of treatment’

These findings support the theory of a personal fat threshold, above which “type 2 diabetes occurs,” said Dr. Taylor. “Weight loss is the first-line treatment for all with type 2 diabetes, irrespective of BMI.”

Dr. Taylor already showed in the DiRECT trial that a calorie-restricted liquid diet followed by gradual food reintroduction and a weight-loss maintenance program can achieve and sustain type 2 diabetes remission at 2 years in people who are overweight or obese.

As reported this news organization, 36% of 300 patients enrolled in the trial attained diabetes remission and maintained it out to 24 months, compared with negligible changes in the control group.

Inspired by the results of DiRECT and the DROPLET study, the National Health Service has been rolling out a low calorie–diet treatment program for people who are overweight and living with diabetes.

Asked during the postpresentation discussion whether the current results could have implications for the NHS program, Dr. Taylor said it remains, in effect, a study and will not change things for now.

Chris Askew, chief executive of Diabetes UK, said in a release: “This game-changing study ... advances our understanding of why type 2 diabetes develops and what can be done to treat it.

“Our ambition is for as many people as possible to have the chance to put their type 2 diabetes into remission and live well for longer.”

Mr. Askew continued: “The findings of ReTUNE potentially take us a significant step closer to achieving this goal by showing that remission isn’t only possible for people of certain body weights.”
 

Weight and body fat decrease led to remission

For ReTUNE, the team recruited 20 individuals with type 2 diabetes of less than 6 year’s duration who had a BMI of 21-27 and compared them with 20 matched controls, with a follow-up of 52 weeks. 

Patients were an average age of 59.0 years, 13 were women, mean BMI was 24.8, and average duration of diabetes was 2.8 years. Mean A1c was 54 mmol/mol.

Fourteen of the patients were taking metformin at enrollment and two were being treated with gliclazide. These medications were stopped when the individuals with type 2 diabetes entered a weight-loss program incremented in 5% steps, followed by 6 weeks of weight stability.

Overall, weight decreased by an average of 9%, while body fat decreased from 32% at baseline to 28% at 1 year (P < .001), the same percentage as that seen in the controls.

Liver fats also decreased significantly from baseline (P < .001) down to approximately the same level as controls at 1 year, a pattern also seen with very low-density lipoprotein cholesterol and triglyceride levels.

Pancreatic fat decreased steadily and significantly over the course of the 52-week follow-up (P < .05), although remained above the level seen in controls.

Insulin secretion increased significantly over the course of the study (P = .005) to finish just over the threshold for the lower range of normal at 52 weeks.

This, Dr. Taylor showed, was enough for the 14 patients who achieved type 2 diabetes remission to see their A1c levels fall significantly during follow-up (P < .001), alongside fasting plasma glucose levels (P < .001).

ReTUNE is funded by Diabetes UK. The authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A weight-loss program can lead to type 2 diabetes remission, even in individuals with a normal body mass index (BMI), via loss of body fat, particularly in the liver and pancreas, shows a U.K. study.

The ReTUNE trial, funded by Diabetes UK, involved 20 people with type 2 diabetes of less than 6 year’s duration and a BMI of 27 kg/m² or lower.

Joel Austell/MDedge News

After 1 year, participants had lost 9% of their body weight.

Their body fat decreased significantly, to the same level as controls without type 2 diabetes, and they experienced decreases in liver fat, total triglycerides, and pancreatic fat.

The research, presented at the 2022 Diabetes UK Professional Conference, also showed this was accompanied by increases in insulin secretion and reductions in hemoglobin A1c and fasting plasma glucose levels.

Lead author Roy Taylor, MD, PhD, professor of medicine and metabolism, Newcastle University, Newcastle upon Tyne, England, said the findings indicate that the “etiology and pathophysiology of type 2 diabetes is the same whether BMI is normal or raised.”

This information should make a profound difference in what doctors advise their patients, Dr. Taylor added.

“One of the dramatic things about dealing with people in this group,” he said, “is they feel very resentful that healthcare professionals tell them not to lose weight.”

Based on the current results, Dr. Taylor believes this is “inappropriate advice, and it’s that personal advice that I think that this study points a way towards.”
 

Weight loss ‘first line of treatment’

These findings support the theory of a personal fat threshold, above which “type 2 diabetes occurs,” said Dr. Taylor. “Weight loss is the first-line treatment for all with type 2 diabetes, irrespective of BMI.”

Dr. Taylor already showed in the DiRECT trial that a calorie-restricted liquid diet followed by gradual food reintroduction and a weight-loss maintenance program can achieve and sustain type 2 diabetes remission at 2 years in people who are overweight or obese.

As reported this news organization, 36% of 300 patients enrolled in the trial attained diabetes remission and maintained it out to 24 months, compared with negligible changes in the control group.

Inspired by the results of DiRECT and the DROPLET study, the National Health Service has been rolling out a low calorie–diet treatment program for people who are overweight and living with diabetes.

Asked during the postpresentation discussion whether the current results could have implications for the NHS program, Dr. Taylor said it remains, in effect, a study and will not change things for now.

Chris Askew, chief executive of Diabetes UK, said in a release: “This game-changing study ... advances our understanding of why type 2 diabetes develops and what can be done to treat it.

“Our ambition is for as many people as possible to have the chance to put their type 2 diabetes into remission and live well for longer.”

Mr. Askew continued: “The findings of ReTUNE potentially take us a significant step closer to achieving this goal by showing that remission isn’t only possible for people of certain body weights.”
 

Weight and body fat decrease led to remission

For ReTUNE, the team recruited 20 individuals with type 2 diabetes of less than 6 year’s duration who had a BMI of 21-27 and compared them with 20 matched controls, with a follow-up of 52 weeks. 

Patients were an average age of 59.0 years, 13 were women, mean BMI was 24.8, and average duration of diabetes was 2.8 years. Mean A1c was 54 mmol/mol.

Fourteen of the patients were taking metformin at enrollment and two were being treated with gliclazide. These medications were stopped when the individuals with type 2 diabetes entered a weight-loss program incremented in 5% steps, followed by 6 weeks of weight stability.

Overall, weight decreased by an average of 9%, while body fat decreased from 32% at baseline to 28% at 1 year (P < .001), the same percentage as that seen in the controls.

Liver fats also decreased significantly from baseline (P < .001) down to approximately the same level as controls at 1 year, a pattern also seen with very low-density lipoprotein cholesterol and triglyceride levels.

Pancreatic fat decreased steadily and significantly over the course of the 52-week follow-up (P < .05), although remained above the level seen in controls.

Insulin secretion increased significantly over the course of the study (P = .005) to finish just over the threshold for the lower range of normal at 52 weeks.

This, Dr. Taylor showed, was enough for the 14 patients who achieved type 2 diabetes remission to see their A1c levels fall significantly during follow-up (P < .001), alongside fasting plasma glucose levels (P < .001).

ReTUNE is funded by Diabetes UK. The authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A weight-loss program can lead to type 2 diabetes remission, even in individuals with a normal body mass index (BMI), via loss of body fat, particularly in the liver and pancreas, shows a U.K. study.

The ReTUNE trial, funded by Diabetes UK, involved 20 people with type 2 diabetes of less than 6 year’s duration and a BMI of 27 kg/m² or lower.

Joel Austell/MDedge News

After 1 year, participants had lost 9% of their body weight.

Their body fat decreased significantly, to the same level as controls without type 2 diabetes, and they experienced decreases in liver fat, total triglycerides, and pancreatic fat.

The research, presented at the 2022 Diabetes UK Professional Conference, also showed this was accompanied by increases in insulin secretion and reductions in hemoglobin A1c and fasting plasma glucose levels.

Lead author Roy Taylor, MD, PhD, professor of medicine and metabolism, Newcastle University, Newcastle upon Tyne, England, said the findings indicate that the “etiology and pathophysiology of type 2 diabetes is the same whether BMI is normal or raised.”

This information should make a profound difference in what doctors advise their patients, Dr. Taylor added.

“One of the dramatic things about dealing with people in this group,” he said, “is they feel very resentful that healthcare professionals tell them not to lose weight.”

Based on the current results, Dr. Taylor believes this is “inappropriate advice, and it’s that personal advice that I think that this study points a way towards.”
 

Weight loss ‘first line of treatment’

These findings support the theory of a personal fat threshold, above which “type 2 diabetes occurs,” said Dr. Taylor. “Weight loss is the first-line treatment for all with type 2 diabetes, irrespective of BMI.”

Dr. Taylor already showed in the DiRECT trial that a calorie-restricted liquid diet followed by gradual food reintroduction and a weight-loss maintenance program can achieve and sustain type 2 diabetes remission at 2 years in people who are overweight or obese.

As reported this news organization, 36% of 300 patients enrolled in the trial attained diabetes remission and maintained it out to 24 months, compared with negligible changes in the control group.

Inspired by the results of DiRECT and the DROPLET study, the National Health Service has been rolling out a low calorie–diet treatment program for people who are overweight and living with diabetes.

Asked during the postpresentation discussion whether the current results could have implications for the NHS program, Dr. Taylor said it remains, in effect, a study and will not change things for now.

Chris Askew, chief executive of Diabetes UK, said in a release: “This game-changing study ... advances our understanding of why type 2 diabetes develops and what can be done to treat it.

“Our ambition is for as many people as possible to have the chance to put their type 2 diabetes into remission and live well for longer.”

Mr. Askew continued: “The findings of ReTUNE potentially take us a significant step closer to achieving this goal by showing that remission isn’t only possible for people of certain body weights.”
 

Weight and body fat decrease led to remission

For ReTUNE, the team recruited 20 individuals with type 2 diabetes of less than 6 year’s duration who had a BMI of 21-27 and compared them with 20 matched controls, with a follow-up of 52 weeks. 

Patients were an average age of 59.0 years, 13 were women, mean BMI was 24.8, and average duration of diabetes was 2.8 years. Mean A1c was 54 mmol/mol.

Fourteen of the patients were taking metformin at enrollment and two were being treated with gliclazide. These medications were stopped when the individuals with type 2 diabetes entered a weight-loss program incremented in 5% steps, followed by 6 weeks of weight stability.

Overall, weight decreased by an average of 9%, while body fat decreased from 32% at baseline to 28% at 1 year (P < .001), the same percentage as that seen in the controls.

Liver fats also decreased significantly from baseline (P < .001) down to approximately the same level as controls at 1 year, a pattern also seen with very low-density lipoprotein cholesterol and triglyceride levels.

Pancreatic fat decreased steadily and significantly over the course of the 52-week follow-up (P < .05), although remained above the level seen in controls.

Insulin secretion increased significantly over the course of the study (P = .005) to finish just over the threshold for the lower range of normal at 52 weeks.

This, Dr. Taylor showed, was enough for the 14 patients who achieved type 2 diabetes remission to see their A1c levels fall significantly during follow-up (P < .001), alongside fasting plasma glucose levels (P < .001).

ReTUNE is funded by Diabetes UK. The authors reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

An artificial intelligence (AI)–based predictive tool may be able to identify type 1 diabetes in children earlier, before they are diagnosed as a result of potentially fatal diabetic ketoacidosis (DKA), suggests a new U.K. study.

The tool was developed by Julia Townson, PhD, senior trial manager in children and young people at Cardiff University, U.K., and colleagues.

Her team had previously shown that children who develop type 1 diabetes have a different pattern of contact with primary care in the 6 months leading up to their diagnosis.

Symptoms of type 1 diabetes include going to the toilet more and being thirsty, tired, and thin, but GPs can still miss these signs.

So they tested different combinations of factors from GP records – such as urinary tract infections or bedwetting, being prescribed antibiotics or family history of type 1 diabetes – in approximately 1 million children in Wales, more than 2,000 of whom had been diagnosed with type 1 diabetes, to train the predictive tool.

In a separate study of around 1.5 million children in England, they found that the algorithm could identify type 1 diabetes in 75% of affected children 11 days earlier than without the tool, if it was set up as an alert at every one in 10 general practice consultations.

Dr. Townson presented her research at the recent Diabetes UK Professional Conference 2022.
 

One-quarter of kids diagnosed with type 1 diabetes are in DKA

During her presentation, Dr. Townson explained that, in the U.K., approximately 25% of children with type 1 diabetes are diagnosed while they are in DKA, a figure that has remained unchanged for 25 years.

“We know that delayed- and misdiagnosis are the most common reasons for a child presenting in DKA at diagnosis,” she said. “And of course, the reason why it’s so important to prevent presentation in DKA is because of the considerable morbidity and potentially mortality associated with it.”

Indeed, with a simple internet search, Dr. Townson was able to identify four children who lost their lives to DKA in the past 8 years in the U.K.

“It’s encouraging to see that this research could save many families a potentially traumatic trip to the hospital by helping family doctors diagnose type 1 diabetes more rapidly,” Conor McKeever, research communications manager at the type 1 diabetes charity JDRF, told this news organization.

“This approach could go hand-in-hand with population screening, which has the potential to identify people at high risk of developing type 1 diabetes before they experience any symptoms,” he added. The hope is that “far fewer families experience DKA at the start of their type 1 diabetes journey.”

“Finding a way to catch the condition and treat it early could help to avoid emergency hospital treatment and save lives,” agreed Lucy Chambers, PhD, head of research communications at Diabetes UK, which funded the research.
 

How to integrate tool into GP systems

“We are now looking to see how this tool might work with primary care computer systems,” Dr. Townson said. She said in an interview that they are exploring “how it could be ‘bolted’ on to the GP’s software system.”

“It works on many different levels, but one level is frequency of consultations in relation to the frequency of previous consultations, so it needs to be able to ‘look’ through the electronic health records, at the time of the consultation, to come up with a predictive score.”

Dr. Townson said it is not clear how “easy it will be to integrate it into current systems, and I do not know of any other machine learning applications which have been used like this in primary care.”

“But we are hopeful, and we have started to contact companies who are involved in providing these systems.”

The research was funded by Diabetes UK, and the Clinical Trials Unit was funded by Health and Care Research Wales. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

An artificial intelligence (AI)–based predictive tool may be able to identify type 1 diabetes in children earlier, before they are diagnosed as a result of potentially fatal diabetic ketoacidosis (DKA), suggests a new U.K. study.

The tool was developed by Julia Townson, PhD, senior trial manager in children and young people at Cardiff University, U.K., and colleagues.

Her team had previously shown that children who develop type 1 diabetes have a different pattern of contact with primary care in the 6 months leading up to their diagnosis.

Symptoms of type 1 diabetes include going to the toilet more and being thirsty, tired, and thin, but GPs can still miss these signs.

So they tested different combinations of factors from GP records – such as urinary tract infections or bedwetting, being prescribed antibiotics or family history of type 1 diabetes – in approximately 1 million children in Wales, more than 2,000 of whom had been diagnosed with type 1 diabetes, to train the predictive tool.

In a separate study of around 1.5 million children in England, they found that the algorithm could identify type 1 diabetes in 75% of affected children 11 days earlier than without the tool, if it was set up as an alert at every one in 10 general practice consultations.

Dr. Townson presented her research at the recent Diabetes UK Professional Conference 2022.
 

One-quarter of kids diagnosed with type 1 diabetes are in DKA

During her presentation, Dr. Townson explained that, in the U.K., approximately 25% of children with type 1 diabetes are diagnosed while they are in DKA, a figure that has remained unchanged for 25 years.

“We know that delayed- and misdiagnosis are the most common reasons for a child presenting in DKA at diagnosis,” she said. “And of course, the reason why it’s so important to prevent presentation in DKA is because of the considerable morbidity and potentially mortality associated with it.”

Indeed, with a simple internet search, Dr. Townson was able to identify four children who lost their lives to DKA in the past 8 years in the U.K.

“It’s encouraging to see that this research could save many families a potentially traumatic trip to the hospital by helping family doctors diagnose type 1 diabetes more rapidly,” Conor McKeever, research communications manager at the type 1 diabetes charity JDRF, told this news organization.

“This approach could go hand-in-hand with population screening, which has the potential to identify people at high risk of developing type 1 diabetes before they experience any symptoms,” he added. The hope is that “far fewer families experience DKA at the start of their type 1 diabetes journey.”

“Finding a way to catch the condition and treat it early could help to avoid emergency hospital treatment and save lives,” agreed Lucy Chambers, PhD, head of research communications at Diabetes UK, which funded the research.
 

How to integrate tool into GP systems

“We are now looking to see how this tool might work with primary care computer systems,” Dr. Townson said. She said in an interview that they are exploring “how it could be ‘bolted’ on to the GP’s software system.”

“It works on many different levels, but one level is frequency of consultations in relation to the frequency of previous consultations, so it needs to be able to ‘look’ through the electronic health records, at the time of the consultation, to come up with a predictive score.”

Dr. Townson said it is not clear how “easy it will be to integrate it into current systems, and I do not know of any other machine learning applications which have been used like this in primary care.”

“But we are hopeful, and we have started to contact companies who are involved in providing these systems.”

The research was funded by Diabetes UK, and the Clinical Trials Unit was funded by Health and Care Research Wales. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

An artificial intelligence (AI)–based predictive tool may be able to identify type 1 diabetes in children earlier, before they are diagnosed as a result of potentially fatal diabetic ketoacidosis (DKA), suggests a new U.K. study.

The tool was developed by Julia Townson, PhD, senior trial manager in children and young people at Cardiff University, U.K., and colleagues.

Her team had previously shown that children who develop type 1 diabetes have a different pattern of contact with primary care in the 6 months leading up to their diagnosis.

Symptoms of type 1 diabetes include going to the toilet more and being thirsty, tired, and thin, but GPs can still miss these signs.

So they tested different combinations of factors from GP records – such as urinary tract infections or bedwetting, being prescribed antibiotics or family history of type 1 diabetes – in approximately 1 million children in Wales, more than 2,000 of whom had been diagnosed with type 1 diabetes, to train the predictive tool.

In a separate study of around 1.5 million children in England, they found that the algorithm could identify type 1 diabetes in 75% of affected children 11 days earlier than without the tool, if it was set up as an alert at every one in 10 general practice consultations.

Dr. Townson presented her research at the recent Diabetes UK Professional Conference 2022.
 

One-quarter of kids diagnosed with type 1 diabetes are in DKA

During her presentation, Dr. Townson explained that, in the U.K., approximately 25% of children with type 1 diabetes are diagnosed while they are in DKA, a figure that has remained unchanged for 25 years.

“We know that delayed- and misdiagnosis are the most common reasons for a child presenting in DKA at diagnosis,” she said. “And of course, the reason why it’s so important to prevent presentation in DKA is because of the considerable morbidity and potentially mortality associated with it.”

Indeed, with a simple internet search, Dr. Townson was able to identify four children who lost their lives to DKA in the past 8 years in the U.K.

“It’s encouraging to see that this research could save many families a potentially traumatic trip to the hospital by helping family doctors diagnose type 1 diabetes more rapidly,” Conor McKeever, research communications manager at the type 1 diabetes charity JDRF, told this news organization.

“This approach could go hand-in-hand with population screening, which has the potential to identify people at high risk of developing type 1 diabetes before they experience any symptoms,” he added. The hope is that “far fewer families experience DKA at the start of their type 1 diabetes journey.”

“Finding a way to catch the condition and treat it early could help to avoid emergency hospital treatment and save lives,” agreed Lucy Chambers, PhD, head of research communications at Diabetes UK, which funded the research.
 

How to integrate tool into GP systems

“We are now looking to see how this tool might work with primary care computer systems,” Dr. Townson said. She said in an interview that they are exploring “how it could be ‘bolted’ on to the GP’s software system.”

“It works on many different levels, but one level is frequency of consultations in relation to the frequency of previous consultations, so it needs to be able to ‘look’ through the electronic health records, at the time of the consultation, to come up with a predictive score.”

Dr. Townson said it is not clear how “easy it will be to integrate it into current systems, and I do not know of any other machine learning applications which have been used like this in primary care.”

“But we are hopeful, and we have started to contact companies who are involved in providing these systems.”

The research was funded by Diabetes UK, and the Clinical Trials Unit was funded by Health and Care Research Wales. No relevant financial relationships were declared.

A version of this article first appeared on Medscape.com.

A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.

The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).

Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter

“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”

The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.

Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”

The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.

Peggy Peterson Photograph

Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.

However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.

Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.


 

A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.

The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).

Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter

“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”

The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.

Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”

The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.

Peggy Peterson Photograph

Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.

However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.

Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.


 

A genetic risk score based on blood pressure has been shown to potentially help determine the increased risk for heart attack or stroke in people with type 2 diabetes, suggesting that glucose control alone won’t be enough to control a person’s genetic risk for other cardiometabolic diseases.

The study analyzed genetic data from 6,335 participants, characterized as a high-risk multiethnic type 2 diabetes population, in the Action to Control Cardiovascular Risk in Diabetes study (ACCORD). Investigators developed a multivariable-adjustable model that found that, with each degree increase in the genetic score, the risk of cardiovascular disease (CVD) events increased 12%. However, the study found no relationship between glycemic control therapy and BP genetic risk score in CVD risk (P < .10).

Researchers at the University of Alabama at Birmingham reported on the risk score in a research letter

“This study highlights that commonly occurring changes in our DNA that cumulatively contribute to a higher risk of BP and hypertension can predispose T2DM [type 2 diabetes mellitus] patients to a higher risk of CVD events,” lead author Pankaj Arora, MD, said in a comment. The genetic risk score used in the study was effective at identifying CVD risks among the study participants even after accounting for conventional CV risk factors, added Dr. Arora, who’s director of the cardiovascular clinical and translational research and cardiovascular genetics clinic programs at UAB. “We recognize that cardiometabolic diseases travel together. Simply controlling the blood glucose level in isolation without considering an individual’s genetic risk for other cardiometabolic diseases may not yield a reduction of CVD risk in T2DM.”

The study used a map of more than 1,000 common genetic variants known to affect BP and compared that with the DNA of study participants to determine their genetic risks. Dr. Arora and colleagues wrote that the “results invigorate the potential implications” of using a BP polygenic risk score to address CVD risks through early intervention with lifestyle modifications such as diet, exercise, smoking cessation, weight management, and BP control in people with high genetic risk.

Gene profiles like the model the UAB researchers developed are still far away from the clinic, Dr. Arora said. “While such gene profiles are being used regularly in cancer management, these gene profiles are not easily available for cardiologists and endocrinologists to order.” He noted that the cardiogenomics clinic at UAB is one of the few centers that provide this kind of gene profiling in the United States. “Studies like this are bringing gene profiling closer to the doorstep of all cardiology and endocrinology clinics.”

The next step for the research is to expand the genetic variants used in the profiles. “We are now trying to develop a gene profile that encompasses more than 1 million common genetic variations and will be more informative,” Dr. Arora said. He added that few randomized clinical trials have shown using a BP genetic risk score in the clinic would improve outcomes of people with T2DM.

Peggy Peterson Photograph

Kiran Musunuru, MD, PhD, MPH, director of the genetic and epigenetic origins of disease program at the University of Pennsylvania’s cardiovascular program in Philadelphia, provided context on what the study adds to the understanding of CVD risk in people with T2DM. “We know that patients with type 2 diabetes are at increased risk of cardiovascular disease, some of which is due to coexisting risk factors like abnormal lipids and hypertension,” he said in a comment. “This study shows that genetic predisposition to high blood pressure is one of the drivers of risk in these patients.” Dr. Musunuru is also chair of the writing group for the American Heart Association scientific statement on the use of genetics and genomics in clinical care.

However, he noted that collecting that kind of genetic data is challenging because few companies offer the tests and few centers do routine genetic testing. “As more studies like this one demonstrate the potential benefits of genetic testing, we can expect to see broader adoption by clinicians,” Dr. Musunuru said.

Dr. Arora receives funding from the National Heart, Lung, and Blood Institute and the Doris Duke Charitable Foundation. The ACCORD study received funding from Abbott Laboratories, Amylin Pharmaceutical, AstraZeneca, Bayer, Closer Healthcare, GlaxoSmithKline Pharmaceuticals, King Pharmaceuticals, Merck, Novartis, Novo Nordisk, Omron Healthcare, Sanofi-Aventis US, and Schering-Plough. Dr. Musunuru has no relevant relationships to disclose.


 

The new heart failure (HF) guidelines released by three North American societies had a lot of catching up to do given the significant, even paradigm-shifting, additions to available treatment options in the last few years.

The landscape now includes both new and repurposed drug therapies that benefit almost without regard to ejection fraction (EF), and evidence-based urgency to engage patients early on with at least four core medication classes, so-called quadruple therapy.

Catherine Hackett/MDedge News

The guideline document offers a roadmap for navigating those key issues and many others and uses some creative tactics. They include the introduction of generalist-friendly labels for the traditional but obscurely named four stages of HF severity that, it is hoped, will have wider reach and expand the use of effective therapies.

It introduces additional disease-staging terminology that characterizes the syndrome as a continuum:  

• “At risk for HF” for stage A, applied to asymptomatic patients with risk factors such as diabetes or hypertension but no known cardiac changes.
• “Pre-HF” for stage B, which adds cardiac structural changes or elevated natriuretic peptides, still in the absence of symptoms.
• “Symptomatic HF” for stage C, that is, structural disease with current or previous symptoms.
• “Advanced HF” for stage D, characterized by severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).

The new terms should be “easier for primary care physicians as well as nonspecialists” to remember and use effectively “and easier to translate to the patients,” compared with the solely alphabetical staging labels appearing in the guidelines for more than 15 years, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.

An emphasis on “at risk for HF” and “pre-HF” in the new document may help efforts to expand primary prevention of HF and management of preclinical HF. The guideline, Dr. Bozkurt said, includes specific treatment recommendations for those early stages.

The document also updates and sometimes introduces “recommendations for advanced heart failure, acute heart failure, and comorbidities – specifically for atrial fibrillation, iron deficiency, sleep apnea, coronary artery disease, and valvular heart disease,” Dr. Bozkurt observed, as well as for cardiomyopathy and HF related to pregnancy and cancer chemotherapy. “So, it’s a very comprehensive guideline.”

Dr. Bozkurt is vice chair of the guideline writing committee and helped introduce the guideline at the annual scientific sessions of the American College of Cardiology. The document, developed by the ACC, the American Heart Association, and the Heart Failure Society of America, was published April 1, 2022, in the societies’ flagship journals, Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure, respectively. It replaces the 2013 guideline from the ACC and AHA and the ACC/AHA/HFSA–focused update from 2017.

“We really need to treat early, and then we need to treat appropriately,” Douglas L. Mann, MD, Washington University in St. Louis, said in an interview. Dr. Mann, who was not involved in development of the new guideline, said he is “enthusiastic” about the new staging terminology.

“I think it makes it easier to convey the message that these people do need medicines, will benefit from medicines, and in some cases heart failure can be preventable,” he said. “I’m in favor of anything that simplifies it and makes it more readily interpretable by busy doctors who aren’t specialists.”

With the new staging terminology and in other ways, the guideline seems to appreciate cardiomyopathy as a journey from preclinical to advanced symptomatic stages – the preclinical “at-risk” stage tightening focus on primary prevention – and updated thinking on classification of HF by EF.

For example, there is new consideration of “HF with improved ejection fraction” (HFimpEF), which suggests the patient may be evolving from HF with reduced EF (HFrEF) to HF with EF that is preserved or mildly reduced, or vice versa.

With HFimpEF, which identifies patients previously with an EF of 40% or lower that improves to beyond 40% at follow-up testing, patients should continue on the medications they had been previously taking for HFrEF, Dr. Bozkurt said.

Patients at risk for HF, in stage A by the older terminology, are characterized by one or more significant HF risk factors, such as hypertension, diabetes, or coronary disease, as they have been in prior guidelines. But the new document, Dr. Bozkurt observed, adds genetic cardiomyopathies and exposure to cardiotoxic agents to the list.

Perhaps surprisingly, the guideline also includes elevated natriuretic peptides as an indicator of “at risk for HF,” with implications for screening. The evidence suggests that, “for patients who are at risk for heart failure, natriuretic peptide-based screening, followed by team-based care, can prevent development of left ventricular dysfunction in heart failure,” Dr. Bozkurt said.

Persons at risk for HF realistically encompass a huge swath of the population given the world prevalence of high blood pressure, obesity, and diabetes. Management of stage A, therefore, focuses on established tenets of primary cardiovascular prevention, such as weight and BP control, exercise, and healthy dietary choices.

They may well be eligible for treatment with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been “game changers,” Dr. Mann said. “Now you can give them to diabetics and it’s going to prevent heart failure and [cardiovascular] events. We didn’t have a drug like that before, so I think that places a lot of emphasis on aggressive treatment of diabetes.”

For patients with symptomatic HF, the document touts multidisciplinary care and early initiation of drugs from each of four drug classes. Such quadruple therapy includes an SGLT2 inhibitor along with a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system (RAS) inhibitor: the “core foundational therapies” for patients with HFrEF, Dr. Bozkurt observed.

Of note, she said, the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) is the preferred RAS inhibitor. But “if the ARNI cannot be used, then use ACE inhibitors.” If the patient is intolerant of ACE inhibitors because of cough or angioedema, then the choice should be an angiotensin-receptor blocker.

“We have very effective therapies offering survival and morbidity benefits as well as improvements in quality of life and reverse remodeling,” Dr. Bozkurt observed. “The most important message is that optimization of therapies, including all of these medication classes, saves lives.”

The guideline also includes, for the first time, a series of “value statements” on cost-effectiveness of different therapies that assign a “high-value” rating to MRAs, hydralazine, and isosorbide dinitrate in otherwise optimally treated self-identified African Americans, and device therapy in appropriately selected patients. The statements hold SGLT2 inhibitors in chronic symptomatic HF and cardiac transplantation in advanced GDMT-resistant HF to be of “intermediate” value.

The value statements, Dr. Bozkurt noted, “are included throughout the document when there is evidence; when there is a high-quality cost-effectiveness study published.”

Dr. Bozkurt disclosed receiving honoraria or consulting fees from Amgen, AstraZeneca, Baxter International, Bristol-Myers Squibb, Sanofi-Aventis, scPharmaceuticals, and Vifor Pharma; serving on a data safety monitoring board for LivaNova USA; and holding other relationships with Abbott Laboratories and Relypsa. Dr. Mann disclosed receiving honoraria or consulting fees from MyoKardia, Novartis, and Novo Nordisk.

A version of this article first appeared on Medscape.com.

The new heart failure (HF) guidelines released by three North American societies had a lot of catching up to do given the significant, even paradigm-shifting, additions to available treatment options in the last few years.

The landscape now includes both new and repurposed drug therapies that benefit almost without regard to ejection fraction (EF), and evidence-based urgency to engage patients early on with at least four core medication classes, so-called quadruple therapy.

Catherine Hackett/MDedge News

The guideline document offers a roadmap for navigating those key issues and many others and uses some creative tactics. They include the introduction of generalist-friendly labels for the traditional but obscurely named four stages of HF severity that, it is hoped, will have wider reach and expand the use of effective therapies.

It introduces additional disease-staging terminology that characterizes the syndrome as a continuum:  

• “At risk for HF” for stage A, applied to asymptomatic patients with risk factors such as diabetes or hypertension but no known cardiac changes.
• “Pre-HF” for stage B, which adds cardiac structural changes or elevated natriuretic peptides, still in the absence of symptoms.
• “Symptomatic HF” for stage C, that is, structural disease with current or previous symptoms.
• “Advanced HF” for stage D, characterized by severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).

The new terms should be “easier for primary care physicians as well as nonspecialists” to remember and use effectively “and easier to translate to the patients,” compared with the solely alphabetical staging labels appearing in the guidelines for more than 15 years, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.

An emphasis on “at risk for HF” and “pre-HF” in the new document may help efforts to expand primary prevention of HF and management of preclinical HF. The guideline, Dr. Bozkurt said, includes specific treatment recommendations for those early stages.

The document also updates and sometimes introduces “recommendations for advanced heart failure, acute heart failure, and comorbidities – specifically for atrial fibrillation, iron deficiency, sleep apnea, coronary artery disease, and valvular heart disease,” Dr. Bozkurt observed, as well as for cardiomyopathy and HF related to pregnancy and cancer chemotherapy. “So, it’s a very comprehensive guideline.”

Dr. Bozkurt is vice chair of the guideline writing committee and helped introduce the guideline at the annual scientific sessions of the American College of Cardiology. The document, developed by the ACC, the American Heart Association, and the Heart Failure Society of America, was published April 1, 2022, in the societies’ flagship journals, Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure, respectively. It replaces the 2013 guideline from the ACC and AHA and the ACC/AHA/HFSA–focused update from 2017.

“We really need to treat early, and then we need to treat appropriately,” Douglas L. Mann, MD, Washington University in St. Louis, said in an interview. Dr. Mann, who was not involved in development of the new guideline, said he is “enthusiastic” about the new staging terminology.

“I think it makes it easier to convey the message that these people do need medicines, will benefit from medicines, and in some cases heart failure can be preventable,” he said. “I’m in favor of anything that simplifies it and makes it more readily interpretable by busy doctors who aren’t specialists.”

With the new staging terminology and in other ways, the guideline seems to appreciate cardiomyopathy as a journey from preclinical to advanced symptomatic stages – the preclinical “at-risk” stage tightening focus on primary prevention – and updated thinking on classification of HF by EF.

For example, there is new consideration of “HF with improved ejection fraction” (HFimpEF), which suggests the patient may be evolving from HF with reduced EF (HFrEF) to HF with EF that is preserved or mildly reduced, or vice versa.

With HFimpEF, which identifies patients previously with an EF of 40% or lower that improves to beyond 40% at follow-up testing, patients should continue on the medications they had been previously taking for HFrEF, Dr. Bozkurt said.

Patients at risk for HF, in stage A by the older terminology, are characterized by one or more significant HF risk factors, such as hypertension, diabetes, or coronary disease, as they have been in prior guidelines. But the new document, Dr. Bozkurt observed, adds genetic cardiomyopathies and exposure to cardiotoxic agents to the list.

Perhaps surprisingly, the guideline also includes elevated natriuretic peptides as an indicator of “at risk for HF,” with implications for screening. The evidence suggests that, “for patients who are at risk for heart failure, natriuretic peptide-based screening, followed by team-based care, can prevent development of left ventricular dysfunction in heart failure,” Dr. Bozkurt said.

Persons at risk for HF realistically encompass a huge swath of the population given the world prevalence of high blood pressure, obesity, and diabetes. Management of stage A, therefore, focuses on established tenets of primary cardiovascular prevention, such as weight and BP control, exercise, and healthy dietary choices.

They may well be eligible for treatment with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been “game changers,” Dr. Mann said. “Now you can give them to diabetics and it’s going to prevent heart failure and [cardiovascular] events. We didn’t have a drug like that before, so I think that places a lot of emphasis on aggressive treatment of diabetes.”

For patients with symptomatic HF, the document touts multidisciplinary care and early initiation of drugs from each of four drug classes. Such quadruple therapy includes an SGLT2 inhibitor along with a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system (RAS) inhibitor: the “core foundational therapies” for patients with HFrEF, Dr. Bozkurt observed.

Of note, she said, the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) is the preferred RAS inhibitor. But “if the ARNI cannot be used, then use ACE inhibitors.” If the patient is intolerant of ACE inhibitors because of cough or angioedema, then the choice should be an angiotensin-receptor blocker.

“We have very effective therapies offering survival and morbidity benefits as well as improvements in quality of life and reverse remodeling,” Dr. Bozkurt observed. “The most important message is that optimization of therapies, including all of these medication classes, saves lives.”

The guideline also includes, for the first time, a series of “value statements” on cost-effectiveness of different therapies that assign a “high-value” rating to MRAs, hydralazine, and isosorbide dinitrate in otherwise optimally treated self-identified African Americans, and device therapy in appropriately selected patients. The statements hold SGLT2 inhibitors in chronic symptomatic HF and cardiac transplantation in advanced GDMT-resistant HF to be of “intermediate” value.

The value statements, Dr. Bozkurt noted, “are included throughout the document when there is evidence; when there is a high-quality cost-effectiveness study published.”

Dr. Bozkurt disclosed receiving honoraria or consulting fees from Amgen, AstraZeneca, Baxter International, Bristol-Myers Squibb, Sanofi-Aventis, scPharmaceuticals, and Vifor Pharma; serving on a data safety monitoring board for LivaNova USA; and holding other relationships with Abbott Laboratories and Relypsa. Dr. Mann disclosed receiving honoraria or consulting fees from MyoKardia, Novartis, and Novo Nordisk.

A version of this article first appeared on Medscape.com.

The new heart failure (HF) guidelines released by three North American societies had a lot of catching up to do given the significant, even paradigm-shifting, additions to available treatment options in the last few years.

The landscape now includes both new and repurposed drug therapies that benefit almost without regard to ejection fraction (EF), and evidence-based urgency to engage patients early on with at least four core medication classes, so-called quadruple therapy.

Catherine Hackett/MDedge News

The guideline document offers a roadmap for navigating those key issues and many others and uses some creative tactics. They include the introduction of generalist-friendly labels for the traditional but obscurely named four stages of HF severity that, it is hoped, will have wider reach and expand the use of effective therapies.

It introduces additional disease-staging terminology that characterizes the syndrome as a continuum:  

• “At risk for HF” for stage A, applied to asymptomatic patients with risk factors such as diabetes or hypertension but no known cardiac changes.
• “Pre-HF” for stage B, which adds cardiac structural changes or elevated natriuretic peptides, still in the absence of symptoms.
• “Symptomatic HF” for stage C, that is, structural disease with current or previous symptoms.
• “Advanced HF” for stage D, characterized by severe debilitating symptoms or repeated hospitalizations even with guideline-directed medical therapy (GDMT).

The new terms should be “easier for primary care physicians as well as nonspecialists” to remember and use effectively “and easier to translate to the patients,” compared with the solely alphabetical staging labels appearing in the guidelines for more than 15 years, Biykem Bozkurt, MD, PhD, Baylor College of Medicine, Houston, said in an interview.

An emphasis on “at risk for HF” and “pre-HF” in the new document may help efforts to expand primary prevention of HF and management of preclinical HF. The guideline, Dr. Bozkurt said, includes specific treatment recommendations for those early stages.

The document also updates and sometimes introduces “recommendations for advanced heart failure, acute heart failure, and comorbidities – specifically for atrial fibrillation, iron deficiency, sleep apnea, coronary artery disease, and valvular heart disease,” Dr. Bozkurt observed, as well as for cardiomyopathy and HF related to pregnancy and cancer chemotherapy. “So, it’s a very comprehensive guideline.”

Dr. Bozkurt is vice chair of the guideline writing committee and helped introduce the guideline at the annual scientific sessions of the American College of Cardiology. The document, developed by the ACC, the American Heart Association, and the Heart Failure Society of America, was published April 1, 2022, in the societies’ flagship journals, Journal of the American College of Cardiology, Circulation, and the Journal of Cardiac Failure, respectively. It replaces the 2013 guideline from the ACC and AHA and the ACC/AHA/HFSA–focused update from 2017.

“We really need to treat early, and then we need to treat appropriately,” Douglas L. Mann, MD, Washington University in St. Louis, said in an interview. Dr. Mann, who was not involved in development of the new guideline, said he is “enthusiastic” about the new staging terminology.

“I think it makes it easier to convey the message that these people do need medicines, will benefit from medicines, and in some cases heart failure can be preventable,” he said. “I’m in favor of anything that simplifies it and makes it more readily interpretable by busy doctors who aren’t specialists.”

With the new staging terminology and in other ways, the guideline seems to appreciate cardiomyopathy as a journey from preclinical to advanced symptomatic stages – the preclinical “at-risk” stage tightening focus on primary prevention – and updated thinking on classification of HF by EF.

For example, there is new consideration of “HF with improved ejection fraction” (HFimpEF), which suggests the patient may be evolving from HF with reduced EF (HFrEF) to HF with EF that is preserved or mildly reduced, or vice versa.

With HFimpEF, which identifies patients previously with an EF of 40% or lower that improves to beyond 40% at follow-up testing, patients should continue on the medications they had been previously taking for HFrEF, Dr. Bozkurt said.

Patients at risk for HF, in stage A by the older terminology, are characterized by one or more significant HF risk factors, such as hypertension, diabetes, or coronary disease, as they have been in prior guidelines. But the new document, Dr. Bozkurt observed, adds genetic cardiomyopathies and exposure to cardiotoxic agents to the list.

Perhaps surprisingly, the guideline also includes elevated natriuretic peptides as an indicator of “at risk for HF,” with implications for screening. The evidence suggests that, “for patients who are at risk for heart failure, natriuretic peptide-based screening, followed by team-based care, can prevent development of left ventricular dysfunction in heart failure,” Dr. Bozkurt said.

Persons at risk for HF realistically encompass a huge swath of the population given the world prevalence of high blood pressure, obesity, and diabetes. Management of stage A, therefore, focuses on established tenets of primary cardiovascular prevention, such as weight and BP control, exercise, and healthy dietary choices.

They may well be eligible for treatment with sodium-glucose transporter 2 (SGLT2) inhibitors, which have been “game changers,” Dr. Mann said. “Now you can give them to diabetics and it’s going to prevent heart failure and [cardiovascular] events. We didn’t have a drug like that before, so I think that places a lot of emphasis on aggressive treatment of diabetes.”

For patients with symptomatic HF, the document touts multidisciplinary care and early initiation of drugs from each of four drug classes. Such quadruple therapy includes an SGLT2 inhibitor along with a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system (RAS) inhibitor: the “core foundational therapies” for patients with HFrEF, Dr. Bozkurt observed.

Of note, she said, the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) is the preferred RAS inhibitor. But “if the ARNI cannot be used, then use ACE inhibitors.” If the patient is intolerant of ACE inhibitors because of cough or angioedema, then the choice should be an angiotensin-receptor blocker.

“We have very effective therapies offering survival and morbidity benefits as well as improvements in quality of life and reverse remodeling,” Dr. Bozkurt observed. “The most important message is that optimization of therapies, including all of these medication classes, saves lives.”

The guideline also includes, for the first time, a series of “value statements” on cost-effectiveness of different therapies that assign a “high-value” rating to MRAs, hydralazine, and isosorbide dinitrate in otherwise optimally treated self-identified African Americans, and device therapy in appropriately selected patients. The statements hold SGLT2 inhibitors in chronic symptomatic HF and cardiac transplantation in advanced GDMT-resistant HF to be of “intermediate” value.

The value statements, Dr. Bozkurt noted, “are included throughout the document when there is evidence; when there is a high-quality cost-effectiveness study published.”

Dr. Bozkurt disclosed receiving honoraria or consulting fees from Amgen, AstraZeneca, Baxter International, Bristol-Myers Squibb, Sanofi-Aventis, scPharmaceuticals, and Vifor Pharma; serving on a data safety monitoring board for LivaNova USA; and holding other relationships with Abbott Laboratories and Relypsa. Dr. Mann disclosed receiving honoraria or consulting fees from MyoKardia, Novartis, and Novo Nordisk.

A version of this article first appeared on Medscape.com.

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.
 

WASHINGTON – Results from new analyses further fleshed out the potent effect by the investigational SGLT1&2 inhibitor sotagliflozin on major cardiovascular adverse events in patients with type 2 diabetes, chronic kidney disease, and at high risk for cardiovascular disease in the SCORED trial that randomized more than 10,000 patients.

In prespecified, secondary analyses of the SCORED results, treatment with sotagliflozin during a median of 16 months was linked to a significant 21% risk reduction relative to placebo for the combined incidence of total major adverse cardiovascular events (MACE), which included cardiovascular death, first and recurrent episodes of nonfatal MI, and nonfatal stroke among the 5,144 randomized patients who entered the trial with a history of cardiovascular disease (CVD), Deepak L. Bhatt, MD, said at the annual scientific sessions of the American College of Cardiology.

Mitchel L. Zoler/MDedge News

Among the 5,440 patients in the study who did not have a history of CVD (although they did have at least one major risk factor or at least two minor risk factors), treatment with sotagliflozin was linked to a significant 26% relative risk reduction in total MACE events.

Part of these overall MACE benefits resulted from similar improvements from sotagliflozin treatment on the individual outcomes of total nonfatal MI and total nonfatal strokes. Treatment with sotagliflozin cut these MIs by a significant 31% in patients with a history of CVD relative to patients who received placebo, and by a relative 34% in those without a CVD event in their history, a difference compared with placebo that fell short of significance, said Dr. Bhatt, professor of medicine at Harvard Medical School and executive director of interventional cardiovascular programs at Brigham and Women’s Health, both in Boston.

Treatment with sotagliflozin also cut total nonfatal strokes by 31% relative to placebo in patients with a history of CVD, and by a relative 38% in those without a CVD history. Both differences fell short of significance.
 

An early MACE benefit and a stroke benefit

“This stroke benefit has not been clearly seen” with any agent from the closely related sodium-glucose cotransport-2 (SGLT2) inhibitor class, and “the MACE benefit appeared very early,” within 3 months from the start of sotagliflozin treatment, “which may be because of the SGLT1 inhibition,” Dr. Bhatt said during his report.

The SGLT1 receptor is the primary mechanism cells in the gut use to absorb glucose and galactose in the human gastrointestinal tract, Dr. Bhatt explained, while the SGLT2 receptor appears on kidney cells and is the major player in the reabsorption of filtered glucose. The SGLT2 inhibitor class includes the agents canagliflozin (Invokana), dapagliflozin (Farxiga), and empagliflozin (Jardiance), while sotagliflozin inhibits both SGLT1 and SGLT2.

Main results from SCORED appeared in a report first released in late 2020, and showed that for the study’s primary endpoint treatment with sotagliflozin linked with a significant 26% relative risk reduction for the composite of cardiovascular deaths, hospitalizations for heart failure, and urgent visits for heart failure (N Engl J Med. 2021 Jan 14;384[2]:129-39). Patient follow-up in SCORED was not as long as originally planned when the study stopped early due to a loss of funding from a sponsor that was triggered by the COVID-19 pandemic.

MACE results ‘heterogeneous’ from SGLT2 inhibitors

Sotagliflozin and agents from the SGLT2 inhibitor class “have been consistent” in their benefits for reducing cardiovascular death and hospitalization for heart failure, but for MACE, the results from the SGLT2 inhibitors “have been more heterogeneous,” and the effect of sotagliflozin on MACE “were different in SCORED,” commented Michelle L. O’Donoghue, MD, MPH, a cardiologist at Brigham and Women’s Hospital in Boston who was not involved with this work.

Mitchel L. Zoler/MDedge News

“The results suggest a benefit [from sotagliflozin] on atherosclerotic events, which could be a potential advantage” compared with the SGLT2 inhibitors, “but the heterogeneity of this effect” among these agents means that more confirmatory data are needed for sotagliflozin, Dr. O’Donoghue said in an interview.

“There is a lot of enthusiasm for the concept” of combined inhibition of the SGLT1 and 2 receptors, and if more evidence for unique benefits of this effect accumulate “it may lead to increased enthusiasm for sotagliflozin,” she said. “A lot will also depend on pricing decisions” for sotagliflozin, if it receives U.S. marketing approval from the Food and Drug Administration. Decisions about which agent from the SGLT2 inhibitor class to prescribe “are often being made based on price right now,” Dr. O’Donoghue said.

Lexicon Pharmaceuticals, the company developing sotagliflozin, has announced plans to resubmit its new drug application for sotagliflozin to the FDA later in 2022, with the agency’s approval decision likely occurring late in 2022 or sometime during 2023. In February, the company withdrew its December 2021 application to correct a “technical issue” it had found.

An additional analysis reported by Dr. Bhatt used combined data from SCORED as well as several additional randomized trials of sotagliflozin involving a total of more than 20,000 patients that showed a significant 21% reduction in the incidence of MACE compared with placebo.

During his talk, Dr. Bhatt said that sotagliflozin was potentially superior to the agents that inhibit only SGLT2. In an interview, he based this tentative assessment on at least four attributes of sotagliflozin that have emerged from trial results:

• The drug’s ability to significantly reduce MACE and to have this effect apparent within a few months of treatment onset;
• The significantly reduced rate of stroke with sotagliflozin (when patients are not subdivided into those with or without a history of CVD) that has not yet been seen with any SGLT2 inhibitor;
• The ability of sotagliflozin to reduce hemoglobin A1c levels in patients with type 2 diabetes even when their estimated glomerular filtration rate is less than 30 mL/min per 1.73 m², an effect not seen with SGLT2 inhibitors and possibly explained by sotagliflozin having an effect on gut absorption of glucose in addition to its SGLT2 inhibitory effect in the kidney;
• And the proven ability of sotagliflozin to be safe and effective when initiated in patients hospitalized for heart failure, a property that so far has only also been shown for the SGLT2 inhibitor empagliflozin in the EMPULSE trial (Nature Med. 2022 Mar;28: 568-74).

SCORED was sponsored by Sanofi and Lexicon Pharmaceuticals, the companies originally developing sotagliflozin, although with the withdrawal of Sanofi’s support, further development is now sponsored entirely by Lexicon. Dr. Bhatt received research funding from Sanofi and Lexicon that was paid to Brigham and Women’s Health, and he has been an advisor to numerous companies. Dr. O’Donoghue has been a consultant to Amgen, Janssen, and Novartis, and has received research funding from Amgen, AZ MedImmune, Intarcia, Janssen, Merck, and Novartis.