EASD: Evolocumab shows ‘promising efficacy’ in type 2 diabetes

STOCKHOLM – Evolocumab, used in addition to the standard of care, lowered low-density lipoprotein cholesterol (LDL-C) and improved other lipid parameters in people with type 2 diabetes just as effectively as it did in those without, with no apparent detrimental effects on glycemic control, judging from findings from two open-label extension studies.

According to analysis of 1-year data derived from two multicenter, open-label extension studies of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, the mean percentage change from baseline in LDL-C with evolocumab was –56.4% in subjects with and –52.2% in subjects without type 2 diabetes. By comparison, there were 3.4% and 6% increases in LDL-C in diabetic and nondiabetic individuals who received standard of care alone.

Similar changes from baseline in non–high-density lipoprotein cholesterol were seen, with –46.4% and –43.9% decreases and 4.3% and 5.6% rises in the diabetic and nondiabetic groups who were or were not treated with evolocumab in addition to standard of care. Triglycerides were also reduced with evolocumab (–13% in diabetic and –7.8% in nondiabetics) vs. the standard of care (1.6% and 3.0% increases, respectively). And, reductions in lipoprotein (a) were observed with evolocumab (–27.5% and –25.1) but not with standard of care alone.

These effects were comparable among a variety of subgroups of patients with type 2 diabetes, said the presenting study investigator Dr. Naveed Sattar, at the annual meeting of the European Association for the Study of Diabetes. The reductions were “comparable among type 2 diabetes subgroups stratified by gender, statin intensity, insulin use, presence or absence of CVD, hemoglobin A_1c, and eGFR [epidermal growth factor receptor], with some caveats for HbA_1c and eGFR as the numbers were rather small,” he said.

Dr. Sattar, who is professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, said of this analysis: “I think based on these results, evolocumab, basically the PCSK9 inhibitors, has promising efficacy in patients with type 2 diabetes.”

The lipid analysis was based on data from the OSLER-1 and OSLER-2 studies, which altogether recruited 4,802 (75%) of subjects from the phase II and three studies conducted with evolocumab. Participants in these extension trials were randomized to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly in addition to standard of care vs. standard of care alone. There were 852 individuals with type 2 diabetes and 3,950 without diabetes at enrollment into these extension studies.

Glycemic control was looked at in a separate analysis of data from these two studies, with the patients without diabetes at enrollment being categorized into those at high risk (n = 2,432) and those at low risk (n = 1,518) of developing diabetes using standard criteria for the metabolic syndrome, impaired fasting plasma glucose, HbA_1c higher than 6%, and a body mass index greater than 30 kg/m².

The rationale for looking at glycemic control separately was that statins had been shown to increase the risk for diabetes and it was unknown whether or not the newly available PCSK9 inhibitors would have a similar effect, particularly if used in combination with statins. So while the first analysis aimed to see if evolocumab was able to lower lipids in diabetic patients as well as it does in nondiabetic patients, the second looked to see if it could do so without causing problems with glycemic control.

Mean changes in LDL-C from baseline to the end of extension studies showed a similar benefit of evolocumab in patients with type 2 diabetes and those at high or low risk for diabetes (–56%, –54%, and –49%, respectively) which was greater than that seen in patients who received only standard of care (+3%, +5%, and +7%, respectively).

“One year of treatment with evolocumab showed no measurable effect, and I think that’s the key, no measurable effect on glycemic parameters including new onset diabetes versus standard of care alone,” Dr. Sattar reported.

Median change in fasting plasma glucose from baseline to the end of open-label follow-up in patients on evolocumab in addition to standard of care was no different from that in patients who received standard of care alone. Likewise, mean HbA_1c changes were marginal, at +0.16% and +0.23% in patients with diabetes, +0.05& and +0.06% in patients at high, and +0.06% and +0.07% in patients at low diabetes risk.

Overall, post baseline rates of new onset diabetes were there same (4%) in patients treated with evolocumab and in those who received standard of care alone. In patients with normal glucose levels at baseline (fasting plasma glucose less than 100 mg/dL) rates were 2% in both groups, and 7% and 8% in those who had impaired fasting glucose (100-125 mg/dL) at baseline.

“Overall the results are encouraging that these [PCSK9 inhibitors] may not cause dysglycemia-like statins do,” Dr. Sattar said.

During the discussion, it was noted that statins were used in the standard of care group, but the number of patients using statins at the start of the open studies was so small that it is unlikely to have biased the results seen and will be addressed when the paper is drafted for publication, he said.

The Food and Drug Administration recently approved evolocumab (Repatha) for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.

Amgen sponsored the OSLER studies. Dr Sattar reported financial relationships with Amgen, Merck, and Sanofi.

STOCKHOLM – Evolocumab, used in addition to the standard of care, lowered low-density lipoprotein cholesterol (LDL-C) and improved other lipid parameters in people with type 2 diabetes just as effectively as it did in those without, with no apparent detrimental effects on glycemic control, judging from findings from two open-label extension studies.

According to analysis of 1-year data derived from two multicenter, open-label extension studies of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, the mean percentage change from baseline in LDL-C with evolocumab was –56.4% in subjects with and –52.2% in subjects without type 2 diabetes. By comparison, there were 3.4% and 6% increases in LDL-C in diabetic and nondiabetic individuals who received standard of care alone.

Similar changes from baseline in non–high-density lipoprotein cholesterol were seen, with –46.4% and –43.9% decreases and 4.3% and 5.6% rises in the diabetic and nondiabetic groups who were or were not treated with evolocumab in addition to standard of care. Triglycerides were also reduced with evolocumab (–13% in diabetic and –7.8% in nondiabetics) vs. the standard of care (1.6% and 3.0% increases, respectively). And, reductions in lipoprotein (a) were observed with evolocumab (–27.5% and –25.1) but not with standard of care alone.

These effects were comparable among a variety of subgroups of patients with type 2 diabetes, said the presenting study investigator Dr. Naveed Sattar, at the annual meeting of the European Association for the Study of Diabetes. The reductions were “comparable among type 2 diabetes subgroups stratified by gender, statin intensity, insulin use, presence or absence of CVD, hemoglobin A_1c, and eGFR [epidermal growth factor receptor], with some caveats for HbA_1c and eGFR as the numbers were rather small,” he said.

Dr. Sattar, who is professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, said of this analysis: “I think based on these results, evolocumab, basically the PCSK9 inhibitors, has promising efficacy in patients with type 2 diabetes.”

The lipid analysis was based on data from the OSLER-1 and OSLER-2 studies, which altogether recruited 4,802 (75%) of subjects from the phase II and three studies conducted with evolocumab. Participants in these extension trials were randomized to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly in addition to standard of care vs. standard of care alone. There were 852 individuals with type 2 diabetes and 3,950 without diabetes at enrollment into these extension studies.

Glycemic control was looked at in a separate analysis of data from these two studies, with the patients without diabetes at enrollment being categorized into those at high risk (n = 2,432) and those at low risk (n = 1,518) of developing diabetes using standard criteria for the metabolic syndrome, impaired fasting plasma glucose, HbA_1c higher than 6%, and a body mass index greater than 30 kg/m².

The rationale for looking at glycemic control separately was that statins had been shown to increase the risk for diabetes and it was unknown whether or not the newly available PCSK9 inhibitors would have a similar effect, particularly if used in combination with statins. So while the first analysis aimed to see if evolocumab was able to lower lipids in diabetic patients as well as it does in nondiabetic patients, the second looked to see if it could do so without causing problems with glycemic control.

Mean changes in LDL-C from baseline to the end of extension studies showed a similar benefit of evolocumab in patients with type 2 diabetes and those at high or low risk for diabetes (–56%, –54%, and –49%, respectively) which was greater than that seen in patients who received only standard of care (+3%, +5%, and +7%, respectively).

“One year of treatment with evolocumab showed no measurable effect, and I think that’s the key, no measurable effect on glycemic parameters including new onset diabetes versus standard of care alone,” Dr. Sattar reported.

Median change in fasting plasma glucose from baseline to the end of open-label follow-up in patients on evolocumab in addition to standard of care was no different from that in patients who received standard of care alone. Likewise, mean HbA_1c changes were marginal, at +0.16% and +0.23% in patients with diabetes, +0.05& and +0.06% in patients at high, and +0.06% and +0.07% in patients at low diabetes risk.

Overall, post baseline rates of new onset diabetes were there same (4%) in patients treated with evolocumab and in those who received standard of care alone. In patients with normal glucose levels at baseline (fasting plasma glucose less than 100 mg/dL) rates were 2% in both groups, and 7% and 8% in those who had impaired fasting glucose (100-125 mg/dL) at baseline.

“Overall the results are encouraging that these [PCSK9 inhibitors] may not cause dysglycemia-like statins do,” Dr. Sattar said.

During the discussion, it was noted that statins were used in the standard of care group, but the number of patients using statins at the start of the open studies was so small that it is unlikely to have biased the results seen and will be addressed when the paper is drafted for publication, he said.

The Food and Drug Administration recently approved evolocumab (Repatha) for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.

Amgen sponsored the OSLER studies. Dr Sattar reported financial relationships with Amgen, Merck, and Sanofi.

STOCKHOLM – Evolocumab, used in addition to the standard of care, lowered low-density lipoprotein cholesterol (LDL-C) and improved other lipid parameters in people with type 2 diabetes just as effectively as it did in those without, with no apparent detrimental effects on glycemic control, judging from findings from two open-label extension studies.

According to analysis of 1-year data derived from two multicenter, open-label extension studies of the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, the mean percentage change from baseline in LDL-C with evolocumab was –56.4% in subjects with and –52.2% in subjects without type 2 diabetes. By comparison, there were 3.4% and 6% increases in LDL-C in diabetic and nondiabetic individuals who received standard of care alone.

Similar changes from baseline in non–high-density lipoprotein cholesterol were seen, with –46.4% and –43.9% decreases and 4.3% and 5.6% rises in the diabetic and nondiabetic groups who were or were not treated with evolocumab in addition to standard of care. Triglycerides were also reduced with evolocumab (–13% in diabetic and –7.8% in nondiabetics) vs. the standard of care (1.6% and 3.0% increases, respectively). And, reductions in lipoprotein (a) were observed with evolocumab (–27.5% and –25.1) but not with standard of care alone.

These effects were comparable among a variety of subgroups of patients with type 2 diabetes, said the presenting study investigator Dr. Naveed Sattar, at the annual meeting of the European Association for the Study of Diabetes. The reductions were “comparable among type 2 diabetes subgroups stratified by gender, statin intensity, insulin use, presence or absence of CVD, hemoglobin A_1c, and eGFR [epidermal growth factor receptor], with some caveats for HbA_1c and eGFR as the numbers were rather small,” he said.

Dr. Sattar, who is professor of metabolic medicine at the Institute of Cardiovascular and Medical Sciences, University of Glasgow, said of this analysis: “I think based on these results, evolocumab, basically the PCSK9 inhibitors, has promising efficacy in patients with type 2 diabetes.”

The lipid analysis was based on data from the OSLER-1 and OSLER-2 studies, which altogether recruited 4,802 (75%) of subjects from the phase II and three studies conducted with evolocumab. Participants in these extension trials were randomized to receive subcutaneous evolocumab 140 mg every 2 weeks or 420 mg monthly in addition to standard of care vs. standard of care alone. There were 852 individuals with type 2 diabetes and 3,950 without diabetes at enrollment into these extension studies.

Glycemic control was looked at in a separate analysis of data from these two studies, with the patients without diabetes at enrollment being categorized into those at high risk (n = 2,432) and those at low risk (n = 1,518) of developing diabetes using standard criteria for the metabolic syndrome, impaired fasting plasma glucose, HbA_1c higher than 6%, and a body mass index greater than 30 kg/m².

The rationale for looking at glycemic control separately was that statins had been shown to increase the risk for diabetes and it was unknown whether or not the newly available PCSK9 inhibitors would have a similar effect, particularly if used in combination with statins. So while the first analysis aimed to see if evolocumab was able to lower lipids in diabetic patients as well as it does in nondiabetic patients, the second looked to see if it could do so without causing problems with glycemic control.

Mean changes in LDL-C from baseline to the end of extension studies showed a similar benefit of evolocumab in patients with type 2 diabetes and those at high or low risk for diabetes (–56%, –54%, and –49%, respectively) which was greater than that seen in patients who received only standard of care (+3%, +5%, and +7%, respectively).

“One year of treatment with evolocumab showed no measurable effect, and I think that’s the key, no measurable effect on glycemic parameters including new onset diabetes versus standard of care alone,” Dr. Sattar reported.

Median change in fasting plasma glucose from baseline to the end of open-label follow-up in patients on evolocumab in addition to standard of care was no different from that in patients who received standard of care alone. Likewise, mean HbA_1c changes were marginal, at +0.16% and +0.23% in patients with diabetes, +0.05& and +0.06% in patients at high, and +0.06% and +0.07% in patients at low diabetes risk.

Overall, post baseline rates of new onset diabetes were there same (4%) in patients treated with evolocumab and in those who received standard of care alone. In patients with normal glucose levels at baseline (fasting plasma glucose less than 100 mg/dL) rates were 2% in both groups, and 7% and 8% in those who had impaired fasting glucose (100-125 mg/dL) at baseline.

“Overall the results are encouraging that these [PCSK9 inhibitors] may not cause dysglycemia-like statins do,” Dr. Sattar said.

During the discussion, it was noted that statins were used in the standard of care group, but the number of patients using statins at the start of the open studies was so small that it is unlikely to have biased the results seen and will be addressed when the paper is drafted for publication, he said.

The Food and Drug Administration recently approved evolocumab (Repatha) for use in addition to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.

Amgen sponsored the OSLER studies. Dr Sattar reported financial relationships with Amgen, Merck, and Sanofi.