Article

To the Editor:

A 72-year-old man presented with symptomatic anemia and nonpalpable purpura of the legs, abdomen, and arms of 2 weeks’ duration (Figure 1). There were no associated perifollicular papules. Physical examination of the hair and gingiva were normal.

The patient’s medical history was notable for a poorly differentiated pancreatic adenocarcinoma (pT3N1M0) resected 7 months prior using a Whipple operation (pancreaticoduodenectomy). Adjuvant therapy consisted of 5 cycles of intravenous gemcitabine and paclitaxel. Treatment was discontinued 1 month prior due to progressive weight loss and the presence of new liver metastases on computed tomography. There was no recent history of corticosteroid, antiplatelet, or anticoagulant use. The patient had no known history of trauma at the affected sites.

The patient’s laboratory workup revealed the following results: hemoglobin, 5.5 g/dL (reference range, 13–18 g/dL); platelets, 128×10⁹/L (reference range, 150–400×10⁹/L); total white blood cell count (24.0×10⁹/L [reference range, 4.0–11.0×10⁹/L]), consisting of neutrophils (2.4×10⁹/L [reference range, 2.0–7.5×10⁹/L]), lymphocytes (3.1×10⁹/L [reference range, 1.5–4.0×10⁹/L]), and monocytes (18.5×10⁹/L [reference range, 0.2–0.8×10⁹/L]). Fibrinogen, activated partial thromboplastin time, and prothrombin time were within reference range. Results of a bone marrow biopsy showed 64% blasts. The lactate dehydrogenase level was 286 U/L (reference range, 135–220 U/L) and CA-19-9 antigen was 238 U/mL (reference range, 0–39 U/mL).

Results from a skin punch biopsy from the right leg showed a normal epidermis and papillary dermis. The reticular dermis was expanded by a diffuse cellular infiltrate with dermal edema and separation of collagen bundles (Figure 2), which consisted of small cells with irregular, cleaved, and notched nuclei, containing a variable amount of eosinophilic cytoplasm. Mitotic figures were present (Figure 3). There was no evidence of vasculitis, and Congo red stain for amyloid was negative. These atypical cells were positive for the leukocyte common antigen, favoring a hematopoietic infiltrate (Figure 4). Other positive markers included CD4 (associated with helper T cells, and mature and immature monocytes), CD68 (a monocyte/macrophage marker), and CD56 (associated with natural killer cells, myeloma, acute myeloid leukemia [AML], and neuroendocrine tumors). The cells were negative for CD3 (T-cell lineage–specific antigen), CD5 (marker of T cells and a subset of IgM-secreting B cells), CD34 (early hematopoietic marker), and CD20 (B-cell marker). Other negative myeloid markers included myeloperoxidase, CD117, and CD138. These findings suggested leukemic cell recruitment at the site of a reactive infiltrate. The patient completed 2 cycles of intravenous azacitidine with little response and subsequently opted for palliative measures.

Nonpalpable purpura has a broad differential diagnosis including primary and secondary thrombocytopenia; coagulopathies, including vitamin K deficiency, specific clotting factor deficiencies, and amyloid-related purpura; genetic or acquired collagen disorders, including vitamin C deficiency; and eruptions induced by drugs and herbal remedies.

Leukemia cutis is a relatively rare cause of purpura and is defined as cutaneous infiltration by neoplastic leucocytes.¹ It most commonly is associated with AML and complicates approximately 5% to 15%of all adult cases.² Cutaneous involvement occurs predominantly in monocytic variants; acute myelomonocytic leukemia and acute monocytic leukemia may arise in up to 50% of these cases.³ The clinical presentation may vary from papules, nodules, and plaques to rarer manifestations including purpura. A leukemic infiltrate often is associated with sites of inflammation, such as infection or ulceration,⁴ though there was no reported history of any known triggering events in our patient. Lesions usually involve the legs, followed by the arms, back, chest, scalp, and face.⁴ One-third of cases coincide with systemic symptoms, and approximately 10% precede bone marrow or peripheral blood involvement, referred to as aleukemic leukemia. The remainder of cases arise following an established diagnosis of systemic leukemia.⁵ Leukemia cutis is considered a marker of poor prognosis in AML,^4,6 requiring treatment for the underlying systemic disease. Our case also was complicated by a concurrent pancreatic malignancy and relatively advanced age, which limited the feasibility of further treatment.

To the Editor:

A 72-year-old man presented with symptomatic anemia and nonpalpable purpura of the legs, abdomen, and arms of 2 weeks’ duration (Figure 1). There were no associated perifollicular papules. Physical examination of the hair and gingiva were normal.

The patient’s medical history was notable for a poorly differentiated pancreatic adenocarcinoma (pT3N1M0) resected 7 months prior using a Whipple operation (pancreaticoduodenectomy). Adjuvant therapy consisted of 5 cycles of intravenous gemcitabine and paclitaxel. Treatment was discontinued 1 month prior due to progressive weight loss and the presence of new liver metastases on computed tomography. There was no recent history of corticosteroid, antiplatelet, or anticoagulant use. The patient had no known history of trauma at the affected sites.

The patient’s laboratory workup revealed the following results: hemoglobin, 5.5 g/dL (reference range, 13–18 g/dL); platelets, 128×10⁹/L (reference range, 150–400×10⁹/L); total white blood cell count (24.0×10⁹/L [reference range, 4.0–11.0×10⁹/L]), consisting of neutrophils (2.4×10⁹/L [reference range, 2.0–7.5×10⁹/L]), lymphocytes (3.1×10⁹/L [reference range, 1.5–4.0×10⁹/L]), and monocytes (18.5×10⁹/L [reference range, 0.2–0.8×10⁹/L]). Fibrinogen, activated partial thromboplastin time, and prothrombin time were within reference range. Results of a bone marrow biopsy showed 64% blasts. The lactate dehydrogenase level was 286 U/L (reference range, 135–220 U/L) and CA-19-9 antigen was 238 U/mL (reference range, 0–39 U/mL).

Results from a skin punch biopsy from the right leg showed a normal epidermis and papillary dermis. The reticular dermis was expanded by a diffuse cellular infiltrate with dermal edema and separation of collagen bundles (Figure 2), which consisted of small cells with irregular, cleaved, and notched nuclei, containing a variable amount of eosinophilic cytoplasm. Mitotic figures were present (Figure 3). There was no evidence of vasculitis, and Congo red stain for amyloid was negative. These atypical cells were positive for the leukocyte common antigen, favoring a hematopoietic infiltrate (Figure 4). Other positive markers included CD4 (associated with helper T cells, and mature and immature monocytes), CD68 (a monocyte/macrophage marker), and CD56 (associated with natural killer cells, myeloma, acute myeloid leukemia [AML], and neuroendocrine tumors). The cells were negative for CD3 (T-cell lineage–specific antigen), CD5 (marker of T cells and a subset of IgM-secreting B cells), CD34 (early hematopoietic marker), and CD20 (B-cell marker). Other negative myeloid markers included myeloperoxidase, CD117, and CD138. These findings suggested leukemic cell recruitment at the site of a reactive infiltrate. The patient completed 2 cycles of intravenous azacitidine with little response and subsequently opted for palliative measures.

Nonpalpable purpura has a broad differential diagnosis including primary and secondary thrombocytopenia; coagulopathies, including vitamin K deficiency, specific clotting factor deficiencies, and amyloid-related purpura; genetic or acquired collagen disorders, including vitamin C deficiency; and eruptions induced by drugs and herbal remedies.

Leukemia cutis is a relatively rare cause of purpura and is defined as cutaneous infiltration by neoplastic leucocytes.¹ It most commonly is associated with AML and complicates approximately 5% to 15%of all adult cases.² Cutaneous involvement occurs predominantly in monocytic variants; acute myelomonocytic leukemia and acute monocytic leukemia may arise in up to 50% of these cases.³ The clinical presentation may vary from papules, nodules, and plaques to rarer manifestations including purpura. A leukemic infiltrate often is associated with sites of inflammation, such as infection or ulceration,⁴ though there was no reported history of any known triggering events in our patient. Lesions usually involve the legs, followed by the arms, back, chest, scalp, and face.⁴ One-third of cases coincide with systemic symptoms, and approximately 10% precede bone marrow or peripheral blood involvement, referred to as aleukemic leukemia. The remainder of cases arise following an established diagnosis of systemic leukemia.⁵ Leukemia cutis is considered a marker of poor prognosis in AML,^4,6 requiring treatment for the underlying systemic disease. Our case also was complicated by a concurrent pancreatic malignancy and relatively advanced age, which limited the feasibility of further treatment.

To the Editor:

A 72-year-old man presented with symptomatic anemia and nonpalpable purpura of the legs, abdomen, and arms of 2 weeks’ duration (Figure 1). There were no associated perifollicular papules. Physical examination of the hair and gingiva were normal.

The patient’s medical history was notable for a poorly differentiated pancreatic adenocarcinoma (pT3N1M0) resected 7 months prior using a Whipple operation (pancreaticoduodenectomy). Adjuvant therapy consisted of 5 cycles of intravenous gemcitabine and paclitaxel. Treatment was discontinued 1 month prior due to progressive weight loss and the presence of new liver metastases on computed tomography. There was no recent history of corticosteroid, antiplatelet, or anticoagulant use. The patient had no known history of trauma at the affected sites.

The patient’s laboratory workup revealed the following results: hemoglobin, 5.5 g/dL (reference range, 13–18 g/dL); platelets, 128×10⁹/L (reference range, 150–400×10⁹/L); total white blood cell count (24.0×10⁹/L [reference range, 4.0–11.0×10⁹/L]), consisting of neutrophils (2.4×10⁹/L [reference range, 2.0–7.5×10⁹/L]), lymphocytes (3.1×10⁹/L [reference range, 1.5–4.0×10⁹/L]), and monocytes (18.5×10⁹/L [reference range, 0.2–0.8×10⁹/L]). Fibrinogen, activated partial thromboplastin time, and prothrombin time were within reference range. Results of a bone marrow biopsy showed 64% blasts. The lactate dehydrogenase level was 286 U/L (reference range, 135–220 U/L) and CA-19-9 antigen was 238 U/mL (reference range, 0–39 U/mL).

Results from a skin punch biopsy from the right leg showed a normal epidermis and papillary dermis. The reticular dermis was expanded by a diffuse cellular infiltrate with dermal edema and separation of collagen bundles (Figure 2), which consisted of small cells with irregular, cleaved, and notched nuclei, containing a variable amount of eosinophilic cytoplasm. Mitotic figures were present (Figure 3). There was no evidence of vasculitis, and Congo red stain for amyloid was negative. These atypical cells were positive for the leukocyte common antigen, favoring a hematopoietic infiltrate (Figure 4). Other positive markers included CD4 (associated with helper T cells, and mature and immature monocytes), CD68 (a monocyte/macrophage marker), and CD56 (associated with natural killer cells, myeloma, acute myeloid leukemia [AML], and neuroendocrine tumors). The cells were negative for CD3 (T-cell lineage–specific antigen), CD5 (marker of T cells and a subset of IgM-secreting B cells), CD34 (early hematopoietic marker), and CD20 (B-cell marker). Other negative myeloid markers included myeloperoxidase, CD117, and CD138. These findings suggested leukemic cell recruitment at the site of a reactive infiltrate. The patient completed 2 cycles of intravenous azacitidine with little response and subsequently opted for palliative measures.

Nonpalpable purpura has a broad differential diagnosis including primary and secondary thrombocytopenia; coagulopathies, including vitamin K deficiency, specific clotting factor deficiencies, and amyloid-related purpura; genetic or acquired collagen disorders, including vitamin C deficiency; and eruptions induced by drugs and herbal remedies.

Leukemia cutis is a relatively rare cause of purpura and is defined as cutaneous infiltration by neoplastic leucocytes.¹ It most commonly is associated with AML and complicates approximately 5% to 15%of all adult cases.² Cutaneous involvement occurs predominantly in monocytic variants; acute myelomonocytic leukemia and acute monocytic leukemia may arise in up to 50% of these cases.³ The clinical presentation may vary from papules, nodules, and plaques to rarer manifestations including purpura. A leukemic infiltrate often is associated with sites of inflammation, such as infection or ulceration,⁴ though there was no reported history of any known triggering events in our patient. Lesions usually involve the legs, followed by the arms, back, chest, scalp, and face.⁴ One-third of cases coincide with systemic symptoms, and approximately 10% precede bone marrow or peripheral blood involvement, referred to as aleukemic leukemia. The remainder of cases arise following an established diagnosis of systemic leukemia.⁵ Leukemia cutis is considered a marker of poor prognosis in AML,^4,6 requiring treatment for the underlying systemic disease. Our case also was complicated by a concurrent pancreatic malignancy and relatively advanced age, which limited the feasibility of further treatment.

The patient is probably experiencing migraine without aura. Migraines are a complex disorder characterized by recurrent episodes of headache, most often unilateral. These attacks are associated with symptoms related to the central nervous system. Approximately 15% of patients with migraine experience aura (temporary visual, sensory, speech, or other motor disturbances). More research is needed to determine whether migraine with and without aura are potentially different diagnostic entities.

Classic migraine is a clinical diagnosis. When patients experience migraine symptoms routinely, however, it is important to consider whether these signs and symptoms can be accounted for by another diagnosis. Neuroimaging and, less commonly, lumbar puncture may be indicated in some presentations; red flags that call for additional workup are captured in the acronym SNOOP: systemic symptoms, neurologic symptoms, onset is acute, older patients, and previous history. In addition, classic migraine should be distinguished from common headaches as well as rare subtypes of migraine. For instance, hemiplegic migraine typically presents with temporary unilateral hemiparesis, sometimes accompanied by speech disturbance, and may be inherited (familial hemiplegic migraine). Basilar migraine is another rare subtype of migraine that manifests with signs of vertebrobasilar insufficiency. Attacks of chronic paroxysmal hemicrania are unilateral (just as migraines can be in about half of all cases); they are marked by their high intensity but short duration, and are accompanied by same-side facial autonomic symptoms (eg, tearing, congestion). Such patients' history and presentation do not fulfill criteria put forth by the American Headache Society (AHS) for chronic migraine, which specify having headaches 15 or more days per month for more than 3 months, and in which on at least 8 days per month those attacks are consistent with migraine or are relieved by a triptan or ergot derivative.

Migraine management must be personalized for each patient and is often associated with a marked trial-and-error period. Migraine without aura and migraine with aura are treated via similar approaches. AHS guidelines include several medications that may be effective in mitigating migraines, including both migraine-specific agents (ergotamine, ergotamine derivatives, and lasmiditan), and nonspecific agents (NSAIDs, combination analgesics, intravenous magnesium, isometheptene-containing compounds, and antiemetics). Triptans represent first-line acute treatment for migraine, but the FDA has approved five acute migraine treatments in total: celecoxib, lasmiditan, remote electrical neuromodulation (REN), rimegepant, and ubrogepant. For moderate or severe attacks, migraine-specific agents are recommended: beyond triptans, dihydroergotamine (DHE), small-molecule calcitonin gene-related peptide receptor antagonists (gepants), and selective serotonin (5-HT1F) receptor agonists (ditans). Patients should limit medication use to an average of two headache days per week, and those who do not find relief within these parameters are candidates for preventive migraine treatment.

Angeliki Vgontzas, MD, Instructor, Department of Neurology, Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women's Hospital/Brigham and Women's Faulkner Hospital, Boston, Massachusetts.

Angeliki Vgontzas, MD, has disclosed no relevant financial relationships.

The patient is probably experiencing migraine without aura. Migraines are a complex disorder characterized by recurrent episodes of headache, most often unilateral. These attacks are associated with symptoms related to the central nervous system. Approximately 15% of patients with migraine experience aura (temporary visual, sensory, speech, or other motor disturbances). More research is needed to determine whether migraine with and without aura are potentially different diagnostic entities.

Classic migraine is a clinical diagnosis. When patients experience migraine symptoms routinely, however, it is important to consider whether these signs and symptoms can be accounted for by another diagnosis. Neuroimaging and, less commonly, lumbar puncture may be indicated in some presentations; red flags that call for additional workup are captured in the acronym SNOOP: systemic symptoms, neurologic symptoms, onset is acute, older patients, and previous history. In addition, classic migraine should be distinguished from common headaches as well as rare subtypes of migraine. For instance, hemiplegic migraine typically presents with temporary unilateral hemiparesis, sometimes accompanied by speech disturbance, and may be inherited (familial hemiplegic migraine). Basilar migraine is another rare subtype of migraine that manifests with signs of vertebrobasilar insufficiency. Attacks of chronic paroxysmal hemicrania are unilateral (just as migraines can be in about half of all cases); they are marked by their high intensity but short duration, and are accompanied by same-side facial autonomic symptoms (eg, tearing, congestion). Such patients' history and presentation do not fulfill criteria put forth by the American Headache Society (AHS) for chronic migraine, which specify having headaches 15 or more days per month for more than 3 months, and in which on at least 8 days per month those attacks are consistent with migraine or are relieved by a triptan or ergot derivative.

Migraine management must be personalized for each patient and is often associated with a marked trial-and-error period. Migraine without aura and migraine with aura are treated via similar approaches. AHS guidelines include several medications that may be effective in mitigating migraines, including both migraine-specific agents (ergotamine, ergotamine derivatives, and lasmiditan), and nonspecific agents (NSAIDs, combination analgesics, intravenous magnesium, isometheptene-containing compounds, and antiemetics). Triptans represent first-line acute treatment for migraine, but the FDA has approved five acute migraine treatments in total: celecoxib, lasmiditan, remote electrical neuromodulation (REN), rimegepant, and ubrogepant. For moderate or severe attacks, migraine-specific agents are recommended: beyond triptans, dihydroergotamine (DHE), small-molecule calcitonin gene-related peptide receptor antagonists (gepants), and selective serotonin (5-HT1F) receptor agonists (ditans). Patients should limit medication use to an average of two headache days per week, and those who do not find relief within these parameters are candidates for preventive migraine treatment.

Angeliki Vgontzas, MD, Instructor, Department of Neurology, Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women's Hospital/Brigham and Women's Faulkner Hospital, Boston, Massachusetts.

Angeliki Vgontzas, MD, has disclosed no relevant financial relationships.

The patient is probably experiencing migraine without aura. Migraines are a complex disorder characterized by recurrent episodes of headache, most often unilateral. These attacks are associated with symptoms related to the central nervous system. Approximately 15% of patients with migraine experience aura (temporary visual, sensory, speech, or other motor disturbances). More research is needed to determine whether migraine with and without aura are potentially different diagnostic entities.

Classic migraine is a clinical diagnosis. When patients experience migraine symptoms routinely, however, it is important to consider whether these signs and symptoms can be accounted for by another diagnosis. Neuroimaging and, less commonly, lumbar puncture may be indicated in some presentations; red flags that call for additional workup are captured in the acronym SNOOP: systemic symptoms, neurologic symptoms, onset is acute, older patients, and previous history. In addition, classic migraine should be distinguished from common headaches as well as rare subtypes of migraine. For instance, hemiplegic migraine typically presents with temporary unilateral hemiparesis, sometimes accompanied by speech disturbance, and may be inherited (familial hemiplegic migraine). Basilar migraine is another rare subtype of migraine that manifests with signs of vertebrobasilar insufficiency. Attacks of chronic paroxysmal hemicrania are unilateral (just as migraines can be in about half of all cases); they are marked by their high intensity but short duration, and are accompanied by same-side facial autonomic symptoms (eg, tearing, congestion). Such patients' history and presentation do not fulfill criteria put forth by the American Headache Society (AHS) for chronic migraine, which specify having headaches 15 or more days per month for more than 3 months, and in which on at least 8 days per month those attacks are consistent with migraine or are relieved by a triptan or ergot derivative.

Migraine management must be personalized for each patient and is often associated with a marked trial-and-error period. Migraine without aura and migraine with aura are treated via similar approaches. AHS guidelines include several medications that may be effective in mitigating migraines, including both migraine-specific agents (ergotamine, ergotamine derivatives, and lasmiditan), and nonspecific agents (NSAIDs, combination analgesics, intravenous magnesium, isometheptene-containing compounds, and antiemetics). Triptans represent first-line acute treatment for migraine, but the FDA has approved five acute migraine treatments in total: celecoxib, lasmiditan, remote electrical neuromodulation (REN), rimegepant, and ubrogepant. For moderate or severe attacks, migraine-specific agents are recommended: beyond triptans, dihydroergotamine (DHE), small-molecule calcitonin gene-related peptide receptor antagonists (gepants), and selective serotonin (5-HT1F) receptor agonists (ditans). Patients should limit medication use to an average of two headache days per week, and those who do not find relief within these parameters are candidates for preventive migraine treatment.

Angeliki Vgontzas, MD, Instructor, Department of Neurology, Harvard Medical School; Associate Neurologist, Department of Neurology, Brigham and Women's Hospital/Brigham and Women's Faulkner Hospital, Boston, Massachusetts.

Angeliki Vgontzas, MD, has disclosed no relevant financial relationships.

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Ronald Goldenberg, MD, completed his residency in Internal Medicine in 1987 at the University of Toronto, and his fellowship in Endocrinology & Metabolism in 1989 at the University of Toronto.  Dr. Goldenberg is a past chair of the Ontario Medical Association Section on Endocrinology & Metabolism and a previous President of the Toronto Diabetes Association. Dr. Goldenberg has been an investigator in a wide array of clinical trials in the areas of diabetes, hypertension, obesity, and dyslipidemia. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia and thyroid disorders. He has been actively involved in Continuing Medical Education for the last 3 decades, with a strong focus on translating evidence-based medicine into practical patient care.

As a consultant endocrinologist with an area of interest that includes clinical care of diabetes, can you briefly tell us what the top 5 studies of 2021 were that are most likely to influence diabetes or obesity practice?

Dr. Goldenberg: 2021 was a banner year for clinicians managing diabetes and or obesity. There were many key trials that were published and or presented. In my mind, the most important ones that will really influence practice include the STEP program of semaglutide 2.4 mg once weekly in the management of overweight or obesity. There is the FIGARO-DKD and FIDELITY analysis of finerenone in patients with type 2 diabetes and chronic kidney disease. Other top studies include the SURPASS trials of a novel dual incretin agonist called tirzepatide, the EMPEROR-Preserved trial with empagliflozin and a pooled analysis of empagliflozin in both HFrEF and HFpEF trials, and the AMPLITUDE-O trial, which is a cardiovascular outcome trial with an exendin-based GLP-1 receptor agonist known as efpeglenatide.

2021 was definitely a landmark year in diabetes. Let's start with the STEP program with semaglutide 2.4. What were the important findings in these studies?

Dr. Goldenberg: STEP is the Phase III program for 2.4 milligrams once weekly in the management of overweight or obesity. The STEP program studies that have been published and/or presented in 2021 include four Phase IIIa trials STEP 1 through STEP 4, as well as three Phase IIIb trials, STEP 5, 6, and 8. They're all rather similar, as they each enrolled patients with overweight and/or obesity. Patients were up-titrated to semaglutide 2.4 milligrams once weekly, and the top-line summary across all of these trials is that patients randomized to semaglutide 2.4 mg once weekly lost 15% to 17% of their body weight amongst those that did not have diabetes, which is really a tremendous amount of weight loss for an anti-obesity drug. And even those with type 2 diabetes lost almost 10% of their body weight, which is pretty impressive given that patients with type 2 diabetes are often somewhat refractory to weight loss.

There was a high percentage of body weight loss across these trials, as roughly 86 to 90% of patients without diabetes achieved at least a 5% body weight loss and even in those with diabetes, almost 70% achieved a 5% loss in their body weight. As far as overall safety, the safety profile of semaglutide 2.4 mg once weekly was generally similar to the GLP-1 receptor agonist class. The most common side effects were gastrointestinal. Nausea occurred anywhere from 20% to 58% of patients, but it was generally transient. Very few people withdrew because of gastrointestinal side effects.

 I think the key thing for clinicians to know about the STEP program is that it's the results of these trials that led to the FDA approving semaglutide 2.4 mg once weekly as a new agent for the management of overweight and/or obesity.

You mentioned FIGARO-DKD and FIDELITY with Finerenone. Can you talk more about the relevance of this data and summarize the key findings?

Dr. Goldenberg: Finerenone is a new selective non-steroidal mineralocorticoid receptor antagonist that interacts with the mineralocorticoid receptor in a different way compared to traditional steroidal mineralocorticoid receptor agonists.  We know from pre-clinical data that this agent targets inflammation and fibrosis in both the kidney and the heart. The finerenone Phase III program focused on patients with type 2 diabetes and chronic kidney disease. In 2021, they published the FIGARO-DKD trial. This enrolled almost 7,500 patients with type 2 diabetes and an eGFR of 25 ml/min or more along with albuminuria.

The key result of this trial is the primary outcome of CV death non-fatal MI, non-fatal stroke, or hospitalization for heart failure was reduced by 13%. The number needed to treat after 3 ½ years was 47. The primary outcome was mainly driven by a reduction for hospitalization for heart failure. Key secondary outcomes included composite kidney outcomes, one of which was defined by a sustained eGFR reduction of 40% or more along with end-stage kidney disease or renal death. This did not quite reach statistical significance, but a more stringent outcome that included a reduction in eGFR of at least 57% or more was in fact reduced by 23%.

End-stage kidney disease was reduced by 36% in the FIGARO-DKD trial. Finerenone was well tolerated. Hyperkalemia occurred in 10.8% of patients on finerenone and 5.3% on placebo but it was quite unusual to have to stop finerenone because of hyperkalemia. Building on FIGARO-DKD in 2021 was a prespecified meta-analysis of two large Phase III trials, the FIGARO-DKD trial and also the previously published FIDELIO-DKD trial and in this pooled analysis the composite cardiovascular outcome was reduced by 14%. The benefit on cardiovascular events was independent of the baseline eGFR or urine albumin to creatinine ratio, as well as independent of the use of SGLT2 inhibitors or GLP-1 receptor agonists.

There was also a 23% reduction in a composite kidney outcome that used a sustained 57% reduction in eGFR as part of that outcome and essentially each component of the composite kidney outcome was reduced,  including kidney failure, end-stage kidney disease, eGFR of less than 15 ml/min in addition to a  ≥57% decrease in eGFR. And this kidney outcome showed a benefit irrespective of the use of SGLT2 inhibitor at baseline although the number of patients taking an SGLT2 inhibitor in this analysis was relatively small. So overall, the results of finerenone in 2021 support the use of this agent in patients with type 2 diabetes and chronic kidney disease to improve both cardiovascular and kidney outcomes.

Thank you for this insight. Regarding the SURPASS trials with tirzepatide, what is tirzepatide and what was its impact on glycemia and weight?

Dr. Goldenberg. My pleasure. Tirzepatide is a unique dual GIP/GLP-1 receptor agonist that has been formulated to be given as a once weekly injection. In 2021, we heard the first results from the Phase III program including SURPASS-1 through SURPASS-5. In these trials, patients were randomized to tirzepatide 5 mg, 10 mg, or 15 mg, and often compared to placebo or an active comparator. Across the SURPASS trials, the A1C reduction from baseline was between 1.9% to 2.6%. Up to 97% of patients on tirzepatide achieved a HbA1c of less than 7%, and up to 62% achieve a normal HbA1c of less than 5.7%.

In addition to these rather robust glycemic outcomes, there was excellent weight loss in the SURPASS program with the weight reduction ranging from 6 to 13 kg from baseline. Interestingly, in the SURPASS studies, tirzepatide showed superiority to semaglutide 1 mg and also superiority to titrated basal insulin. As far as safety, the side effect profile was similar to all GLP-1 receptor agonists with transient nausea being the most common side effect. Overall, tirzepatide will definitely add to our ability to treat our patients with type 2 diabetes with an incretin agent, and when this agent gets approved, hopefully, it will provide robust glycemic lowering and weight loss.

The fourth key study you mentioned is the EMPEROR-Preserved along with the EMPEROR-Pooled with the empagliflozin. What did they find in this analysis?

Dr. Goldenberg: The EMPEROR-Preserved was the first completed large randomized clinical trial of an SGLT2 inhibitor in patients with heart failure with preserved ejection fraction. They enrolled almost 6,000 patients with HFpEF with or without type 2 diabetes and they were randomized to empagliflozin 10 mg or placebo. The primary outcome of cardiovascular death or hospitalization for heart failure was reduced by 21% with empagliflozin and the number needed to treat was 31. This primary outcome was largely driven by a reduction in hospitalization for heart failure. The primary outcome showed consistent benefit across 15 prespecified subgroups, including those with or without type 2 diabetes, and including a spectrum of baseline left ventricular ejection fractions from 40% to 50% to greater than 60%.

There were also some key secondary endpoints:  total hospitalization for heart failure was reduced by 27% and empagliflozin also slowed the decline of eGFR over time in the EMPEROR-Preserved trial. The agent was well tolerated. There was a slight signal for more hypotension and genital mycotic infections, but otherwise really no concerning adverse effects.

Building on the EMPEROR-Preserved trial was a prespecified pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved,  the two large outcome trials with empagliflozin in heart failure patients. The prespecified primary outcome of this analysis was a major renal outcome which included a GFR reduction of ≥40%, renal replacement therapy or sustained eGFR <10-15 ml/min. While in EMPEROR-Reduced there was a significant 49% reduction in this composite renal outcome, in EMPEROR-Preserved there was no significant reduction. Because of the heterogeneity across these two trials, it was not statistically valid to pool these two results for the composite renal outcome. However, what they found in EMPEROR-Pooled is that if you use a more robust renal outcome including at least a 50% decline in eGFR, then there seems to be a trend that varies depending on baseline left ventricular ejection fraction, suggesting a benefit on the renal outcome if your baseline left ventricular function ranges from 40% to 60%, but lack of benefit with a baseline left ventricular ejection fraction of over 60%. The top line summary of this data is that for the first time we have robust evidence that an SGLT2 inhibitor, in this case empagliflozin 10 mg, can provide a cardiovascular benefit in patients with HFpEF, in addition to the known benefit in HFrEF patients.

Finally, there's the AMPLITUDE-O with efpeglenatide, an international randomized controlled trial conducted at approximately 344 sites in 28 countries. What are the key learnings and messages for this specific study?

Dr. Goldenberg: Efpeglenatide is an exendin-4-based GLP-1 receptor agonist that is given once weekly and the AMPLITUDE-O trial is the cardiovascular outcome trial with efpeglenatide done in patients with type 2 diabetes and either cardiovascular disease or chronic kidney disease plus at least one cardiovascular risk factor. It was an important trial because prior to this cardiovascular outcome trial studies of exendin-4-based GLP-1 receptor agonist have been neutral. However, the AMPLITUDE-O study showed for the first-time superiority with an exendin-4-based GLP-1 receptor agonist. In this case, efpeglenatide 4 or 6 milligrams versus placebo was associated with a 27% reduction in the primary outcome of CV death, non-fatal MI or non-fatal stroke.

Importantly, there was a consistent benefit with efpeglenatide across a spectrum of prespecified subgroups,  the most important one being those that entered the trial on a background SGLT2 inhibitor, which represented about 15% of the patients. They derived the same overall benefit as those not taking an SGLT2 inhibitor. It is important to appreciate that this is probably the most robust data we have for showing a cardiovascular benefit of adding a GLP-1 receptor agonist to an SGLT2 inhibitor in high risk patients with type 2 diabetes. AMPLITUDE-O also adds to the already appreciated knowledge of the cardiovascular benefit of GLP-1 receptor agonists and builds on this story by showing that you can get a cardiovascular benefit with an exendin-4-based GLP-1 receptor agonist and you can get a benefit as an add on to SGLT2 inhibitors.

Ronald Goldenberg, MD, completed his residency in Internal Medicine in 1987 at the University of Toronto, and his fellowship in Endocrinology & Metabolism in 1989 at the University of Toronto.  Dr. Goldenberg is a past chair of the Ontario Medical Association Section on Endocrinology & Metabolism and a previous President of the Toronto Diabetes Association. Dr. Goldenberg has been an investigator in a wide array of clinical trials in the areas of diabetes, hypertension, obesity, and dyslipidemia. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia and thyroid disorders. He has been actively involved in Continuing Medical Education for the last 3 decades, with a strong focus on translating evidence-based medicine into practical patient care.

As a consultant endocrinologist with an area of interest that includes clinical care of diabetes, can you briefly tell us what the top 5 studies of 2021 were that are most likely to influence diabetes or obesity practice?

Dr. Goldenberg: 2021 was a banner year for clinicians managing diabetes and or obesity. There were many key trials that were published and or presented. In my mind, the most important ones that will really influence practice include the STEP program of semaglutide 2.4 mg once weekly in the management of overweight or obesity. There is the FIGARO-DKD and FIDELITY analysis of finerenone in patients with type 2 diabetes and chronic kidney disease. Other top studies include the SURPASS trials of a novel dual incretin agonist called tirzepatide, the EMPEROR-Preserved trial with empagliflozin and a pooled analysis of empagliflozin in both HFrEF and HFpEF trials, and the AMPLITUDE-O trial, which is a cardiovascular outcome trial with an exendin-based GLP-1 receptor agonist known as efpeglenatide.

2021 was definitely a landmark year in diabetes. Let's start with the STEP program with semaglutide 2.4. What were the important findings in these studies?

Dr. Goldenberg: STEP is the Phase III program for 2.4 milligrams once weekly in the management of overweight or obesity. The STEP program studies that have been published and/or presented in 2021 include four Phase IIIa trials STEP 1 through STEP 4, as well as three Phase IIIb trials, STEP 5, 6, and 8. They're all rather similar, as they each enrolled patients with overweight and/or obesity. Patients were up-titrated to semaglutide 2.4 milligrams once weekly, and the top-line summary across all of these trials is that patients randomized to semaglutide 2.4 mg once weekly lost 15% to 17% of their body weight amongst those that did not have diabetes, which is really a tremendous amount of weight loss for an anti-obesity drug. And even those with type 2 diabetes lost almost 10% of their body weight, which is pretty impressive given that patients with type 2 diabetes are often somewhat refractory to weight loss.

There was a high percentage of body weight loss across these trials, as roughly 86 to 90% of patients without diabetes achieved at least a 5% body weight loss and even in those with diabetes, almost 70% achieved a 5% loss in their body weight. As far as overall safety, the safety profile of semaglutide 2.4 mg once weekly was generally similar to the GLP-1 receptor agonist class. The most common side effects were gastrointestinal. Nausea occurred anywhere from 20% to 58% of patients, but it was generally transient. Very few people withdrew because of gastrointestinal side effects.

 I think the key thing for clinicians to know about the STEP program is that it's the results of these trials that led to the FDA approving semaglutide 2.4 mg once weekly as a new agent for the management of overweight and/or obesity.

You mentioned FIGARO-DKD and FIDELITY with Finerenone. Can you talk more about the relevance of this data and summarize the key findings?

Dr. Goldenberg: Finerenone is a new selective non-steroidal mineralocorticoid receptor antagonist that interacts with the mineralocorticoid receptor in a different way compared to traditional steroidal mineralocorticoid receptor agonists.  We know from pre-clinical data that this agent targets inflammation and fibrosis in both the kidney and the heart. The finerenone Phase III program focused on patients with type 2 diabetes and chronic kidney disease. In 2021, they published the FIGARO-DKD trial. This enrolled almost 7,500 patients with type 2 diabetes and an eGFR of 25 ml/min or more along with albuminuria.

The key result of this trial is the primary outcome of CV death non-fatal MI, non-fatal stroke, or hospitalization for heart failure was reduced by 13%. The number needed to treat after 3 ½ years was 47. The primary outcome was mainly driven by a reduction for hospitalization for heart failure. Key secondary outcomes included composite kidney outcomes, one of which was defined by a sustained eGFR reduction of 40% or more along with end-stage kidney disease or renal death. This did not quite reach statistical significance, but a more stringent outcome that included a reduction in eGFR of at least 57% or more was in fact reduced by 23%.

End-stage kidney disease was reduced by 36% in the FIGARO-DKD trial. Finerenone was well tolerated. Hyperkalemia occurred in 10.8% of patients on finerenone and 5.3% on placebo but it was quite unusual to have to stop finerenone because of hyperkalemia. Building on FIGARO-DKD in 2021 was a prespecified meta-analysis of two large Phase III trials, the FIGARO-DKD trial and also the previously published FIDELIO-DKD trial and in this pooled analysis the composite cardiovascular outcome was reduced by 14%. The benefit on cardiovascular events was independent of the baseline eGFR or urine albumin to creatinine ratio, as well as independent of the use of SGLT2 inhibitors or GLP-1 receptor agonists.

There was also a 23% reduction in a composite kidney outcome that used a sustained 57% reduction in eGFR as part of that outcome and essentially each component of the composite kidney outcome was reduced,  including kidney failure, end-stage kidney disease, eGFR of less than 15 ml/min in addition to a  ≥57% decrease in eGFR. And this kidney outcome showed a benefit irrespective of the use of SGLT2 inhibitor at baseline although the number of patients taking an SGLT2 inhibitor in this analysis was relatively small. So overall, the results of finerenone in 2021 support the use of this agent in patients with type 2 diabetes and chronic kidney disease to improve both cardiovascular and kidney outcomes.

Thank you for this insight. Regarding the SURPASS trials with tirzepatide, what is tirzepatide and what was its impact on glycemia and weight?

Dr. Goldenberg. My pleasure. Tirzepatide is a unique dual GIP/GLP-1 receptor agonist that has been formulated to be given as a once weekly injection. In 2021, we heard the first results from the Phase III program including SURPASS-1 through SURPASS-5. In these trials, patients were randomized to tirzepatide 5 mg, 10 mg, or 15 mg, and often compared to placebo or an active comparator. Across the SURPASS trials, the A1C reduction from baseline was between 1.9% to 2.6%. Up to 97% of patients on tirzepatide achieved a HbA1c of less than 7%, and up to 62% achieve a normal HbA1c of less than 5.7%.

In addition to these rather robust glycemic outcomes, there was excellent weight loss in the SURPASS program with the weight reduction ranging from 6 to 13 kg from baseline. Interestingly, in the SURPASS studies, tirzepatide showed superiority to semaglutide 1 mg and also superiority to titrated basal insulin. As far as safety, the side effect profile was similar to all GLP-1 receptor agonists with transient nausea being the most common side effect. Overall, tirzepatide will definitely add to our ability to treat our patients with type 2 diabetes with an incretin agent, and when this agent gets approved, hopefully, it will provide robust glycemic lowering and weight loss.

The fourth key study you mentioned is the EMPEROR-Preserved along with the EMPEROR-Pooled with the empagliflozin. What did they find in this analysis?

Dr. Goldenberg: The EMPEROR-Preserved was the first completed large randomized clinical trial of an SGLT2 inhibitor in patients with heart failure with preserved ejection fraction. They enrolled almost 6,000 patients with HFpEF with or without type 2 diabetes and they were randomized to empagliflozin 10 mg or placebo. The primary outcome of cardiovascular death or hospitalization for heart failure was reduced by 21% with empagliflozin and the number needed to treat was 31. This primary outcome was largely driven by a reduction in hospitalization for heart failure. The primary outcome showed consistent benefit across 15 prespecified subgroups, including those with or without type 2 diabetes, and including a spectrum of baseline left ventricular ejection fractions from 40% to 50% to greater than 60%.

There were also some key secondary endpoints:  total hospitalization for heart failure was reduced by 27% and empagliflozin also slowed the decline of eGFR over time in the EMPEROR-Preserved trial. The agent was well tolerated. There was a slight signal for more hypotension and genital mycotic infections, but otherwise really no concerning adverse effects.

Building on the EMPEROR-Preserved trial was a prespecified pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved,  the two large outcome trials with empagliflozin in heart failure patients. The prespecified primary outcome of this analysis was a major renal outcome which included a GFR reduction of ≥40%, renal replacement therapy or sustained eGFR <10-15 ml/min. While in EMPEROR-Reduced there was a significant 49% reduction in this composite renal outcome, in EMPEROR-Preserved there was no significant reduction. Because of the heterogeneity across these two trials, it was not statistically valid to pool these two results for the composite renal outcome. However, what they found in EMPEROR-Pooled is that if you use a more robust renal outcome including at least a 50% decline in eGFR, then there seems to be a trend that varies depending on baseline left ventricular ejection fraction, suggesting a benefit on the renal outcome if your baseline left ventricular function ranges from 40% to 60%, but lack of benefit with a baseline left ventricular ejection fraction of over 60%. The top line summary of this data is that for the first time we have robust evidence that an SGLT2 inhibitor, in this case empagliflozin 10 mg, can provide a cardiovascular benefit in patients with HFpEF, in addition to the known benefit in HFrEF patients.

Finally, there's the AMPLITUDE-O with efpeglenatide, an international randomized controlled trial conducted at approximately 344 sites in 28 countries. What are the key learnings and messages for this specific study?

Dr. Goldenberg: Efpeglenatide is an exendin-4-based GLP-1 receptor agonist that is given once weekly and the AMPLITUDE-O trial is the cardiovascular outcome trial with efpeglenatide done in patients with type 2 diabetes and either cardiovascular disease or chronic kidney disease plus at least one cardiovascular risk factor. It was an important trial because prior to this cardiovascular outcome trial studies of exendin-4-based GLP-1 receptor agonist have been neutral. However, the AMPLITUDE-O study showed for the first-time superiority with an exendin-4-based GLP-1 receptor agonist. In this case, efpeglenatide 4 or 6 milligrams versus placebo was associated with a 27% reduction in the primary outcome of CV death, non-fatal MI or non-fatal stroke.

Importantly, there was a consistent benefit with efpeglenatide across a spectrum of prespecified subgroups,  the most important one being those that entered the trial on a background SGLT2 inhibitor, which represented about 15% of the patients. They derived the same overall benefit as those not taking an SGLT2 inhibitor. It is important to appreciate that this is probably the most robust data we have for showing a cardiovascular benefit of adding a GLP-1 receptor agonist to an SGLT2 inhibitor in high risk patients with type 2 diabetes. AMPLITUDE-O also adds to the already appreciated knowledge of the cardiovascular benefit of GLP-1 receptor agonists and builds on this story by showing that you can get a cardiovascular benefit with an exendin-4-based GLP-1 receptor agonist and you can get a benefit as an add on to SGLT2 inhibitors.

Ronald Goldenberg, MD, completed his residency in Internal Medicine in 1987 at the University of Toronto, and his fellowship in Endocrinology & Metabolism in 1989 at the University of Toronto.  Dr. Goldenberg is a past chair of the Ontario Medical Association Section on Endocrinology & Metabolism and a previous President of the Toronto Diabetes Association. Dr. Goldenberg has been an investigator in a wide array of clinical trials in the areas of diabetes, hypertension, obesity, and dyslipidemia. His major areas of interest include clinical care of diabetes, obesity, dyslipidemia and thyroid disorders. He has been actively involved in Continuing Medical Education for the last 3 decades, with a strong focus on translating evidence-based medicine into practical patient care.

As a consultant endocrinologist with an area of interest that includes clinical care of diabetes, can you briefly tell us what the top 5 studies of 2021 were that are most likely to influence diabetes or obesity practice?

Dr. Goldenberg: 2021 was a banner year for clinicians managing diabetes and or obesity. There were many key trials that were published and or presented. In my mind, the most important ones that will really influence practice include the STEP program of semaglutide 2.4 mg once weekly in the management of overweight or obesity. There is the FIGARO-DKD and FIDELITY analysis of finerenone in patients with type 2 diabetes and chronic kidney disease. Other top studies include the SURPASS trials of a novel dual incretin agonist called tirzepatide, the EMPEROR-Preserved trial with empagliflozin and a pooled analysis of empagliflozin in both HFrEF and HFpEF trials, and the AMPLITUDE-O trial, which is a cardiovascular outcome trial with an exendin-based GLP-1 receptor agonist known as efpeglenatide.

2021 was definitely a landmark year in diabetes. Let's start with the STEP program with semaglutide 2.4. What were the important findings in these studies?

Dr. Goldenberg: STEP is the Phase III program for 2.4 milligrams once weekly in the management of overweight or obesity. The STEP program studies that have been published and/or presented in 2021 include four Phase IIIa trials STEP 1 through STEP 4, as well as three Phase IIIb trials, STEP 5, 6, and 8. They're all rather similar, as they each enrolled patients with overweight and/or obesity. Patients were up-titrated to semaglutide 2.4 milligrams once weekly, and the top-line summary across all of these trials is that patients randomized to semaglutide 2.4 mg once weekly lost 15% to 17% of their body weight amongst those that did not have diabetes, which is really a tremendous amount of weight loss for an anti-obesity drug. And even those with type 2 diabetes lost almost 10% of their body weight, which is pretty impressive given that patients with type 2 diabetes are often somewhat refractory to weight loss.

There was a high percentage of body weight loss across these trials, as roughly 86 to 90% of patients without diabetes achieved at least a 5% body weight loss and even in those with diabetes, almost 70% achieved a 5% loss in their body weight. As far as overall safety, the safety profile of semaglutide 2.4 mg once weekly was generally similar to the GLP-1 receptor agonist class. The most common side effects were gastrointestinal. Nausea occurred anywhere from 20% to 58% of patients, but it was generally transient. Very few people withdrew because of gastrointestinal side effects.

 I think the key thing for clinicians to know about the STEP program is that it's the results of these trials that led to the FDA approving semaglutide 2.4 mg once weekly as a new agent for the management of overweight and/or obesity.

You mentioned FIGARO-DKD and FIDELITY with Finerenone. Can you talk more about the relevance of this data and summarize the key findings?

Dr. Goldenberg: Finerenone is a new selective non-steroidal mineralocorticoid receptor antagonist that interacts with the mineralocorticoid receptor in a different way compared to traditional steroidal mineralocorticoid receptor agonists.  We know from pre-clinical data that this agent targets inflammation and fibrosis in both the kidney and the heart. The finerenone Phase III program focused on patients with type 2 diabetes and chronic kidney disease. In 2021, they published the FIGARO-DKD trial. This enrolled almost 7,500 patients with type 2 diabetes and an eGFR of 25 ml/min or more along with albuminuria.

The key result of this trial is the primary outcome of CV death non-fatal MI, non-fatal stroke, or hospitalization for heart failure was reduced by 13%. The number needed to treat after 3 ½ years was 47. The primary outcome was mainly driven by a reduction for hospitalization for heart failure. Key secondary outcomes included composite kidney outcomes, one of which was defined by a sustained eGFR reduction of 40% or more along with end-stage kidney disease or renal death. This did not quite reach statistical significance, but a more stringent outcome that included a reduction in eGFR of at least 57% or more was in fact reduced by 23%.

End-stage kidney disease was reduced by 36% in the FIGARO-DKD trial. Finerenone was well tolerated. Hyperkalemia occurred in 10.8% of patients on finerenone and 5.3% on placebo but it was quite unusual to have to stop finerenone because of hyperkalemia. Building on FIGARO-DKD in 2021 was a prespecified meta-analysis of two large Phase III trials, the FIGARO-DKD trial and also the previously published FIDELIO-DKD trial and in this pooled analysis the composite cardiovascular outcome was reduced by 14%. The benefit on cardiovascular events was independent of the baseline eGFR or urine albumin to creatinine ratio, as well as independent of the use of SGLT2 inhibitors or GLP-1 receptor agonists.

There was also a 23% reduction in a composite kidney outcome that used a sustained 57% reduction in eGFR as part of that outcome and essentially each component of the composite kidney outcome was reduced,  including kidney failure, end-stage kidney disease, eGFR of less than 15 ml/min in addition to a  ≥57% decrease in eGFR. And this kidney outcome showed a benefit irrespective of the use of SGLT2 inhibitor at baseline although the number of patients taking an SGLT2 inhibitor in this analysis was relatively small. So overall, the results of finerenone in 2021 support the use of this agent in patients with type 2 diabetes and chronic kidney disease to improve both cardiovascular and kidney outcomes.

Thank you for this insight. Regarding the SURPASS trials with tirzepatide, what is tirzepatide and what was its impact on glycemia and weight?

Dr. Goldenberg. My pleasure. Tirzepatide is a unique dual GIP/GLP-1 receptor agonist that has been formulated to be given as a once weekly injection. In 2021, we heard the first results from the Phase III program including SURPASS-1 through SURPASS-5. In these trials, patients were randomized to tirzepatide 5 mg, 10 mg, or 15 mg, and often compared to placebo or an active comparator. Across the SURPASS trials, the A1C reduction from baseline was between 1.9% to 2.6%. Up to 97% of patients on tirzepatide achieved a HbA1c of less than 7%, and up to 62% achieve a normal HbA1c of less than 5.7%.

In addition to these rather robust glycemic outcomes, there was excellent weight loss in the SURPASS program with the weight reduction ranging from 6 to 13 kg from baseline. Interestingly, in the SURPASS studies, tirzepatide showed superiority to semaglutide 1 mg and also superiority to titrated basal insulin. As far as safety, the side effect profile was similar to all GLP-1 receptor agonists with transient nausea being the most common side effect. Overall, tirzepatide will definitely add to our ability to treat our patients with type 2 diabetes with an incretin agent, and when this agent gets approved, hopefully, it will provide robust glycemic lowering and weight loss.

The fourth key study you mentioned is the EMPEROR-Preserved along with the EMPEROR-Pooled with the empagliflozin. What did they find in this analysis?

Dr. Goldenberg: The EMPEROR-Preserved was the first completed large randomized clinical trial of an SGLT2 inhibitor in patients with heart failure with preserved ejection fraction. They enrolled almost 6,000 patients with HFpEF with or without type 2 diabetes and they were randomized to empagliflozin 10 mg or placebo. The primary outcome of cardiovascular death or hospitalization for heart failure was reduced by 21% with empagliflozin and the number needed to treat was 31. This primary outcome was largely driven by a reduction in hospitalization for heart failure. The primary outcome showed consistent benefit across 15 prespecified subgroups, including those with or without type 2 diabetes, and including a spectrum of baseline left ventricular ejection fractions from 40% to 50% to greater than 60%.

There were also some key secondary endpoints:  total hospitalization for heart failure was reduced by 27% and empagliflozin also slowed the decline of eGFR over time in the EMPEROR-Preserved trial. The agent was well tolerated. There was a slight signal for more hypotension and genital mycotic infections, but otherwise really no concerning adverse effects.

Building on the EMPEROR-Preserved trial was a prespecified pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved,  the two large outcome trials with empagliflozin in heart failure patients. The prespecified primary outcome of this analysis was a major renal outcome which included a GFR reduction of ≥40%, renal replacement therapy or sustained eGFR <10-15 ml/min. While in EMPEROR-Reduced there was a significant 49% reduction in this composite renal outcome, in EMPEROR-Preserved there was no significant reduction. Because of the heterogeneity across these two trials, it was not statistically valid to pool these two results for the composite renal outcome. However, what they found in EMPEROR-Pooled is that if you use a more robust renal outcome including at least a 50% decline in eGFR, then there seems to be a trend that varies depending on baseline left ventricular ejection fraction, suggesting a benefit on the renal outcome if your baseline left ventricular function ranges from 40% to 60%, but lack of benefit with a baseline left ventricular ejection fraction of over 60%. The top line summary of this data is that for the first time we have robust evidence that an SGLT2 inhibitor, in this case empagliflozin 10 mg, can provide a cardiovascular benefit in patients with HFpEF, in addition to the known benefit in HFrEF patients.

Finally, there's the AMPLITUDE-O with efpeglenatide, an international randomized controlled trial conducted at approximately 344 sites in 28 countries. What are the key learnings and messages for this specific study?

Dr. Goldenberg: Efpeglenatide is an exendin-4-based GLP-1 receptor agonist that is given once weekly and the AMPLITUDE-O trial is the cardiovascular outcome trial with efpeglenatide done in patients with type 2 diabetes and either cardiovascular disease or chronic kidney disease plus at least one cardiovascular risk factor. It was an important trial because prior to this cardiovascular outcome trial studies of exendin-4-based GLP-1 receptor agonist have been neutral. However, the AMPLITUDE-O study showed for the first-time superiority with an exendin-4-based GLP-1 receptor agonist. In this case, efpeglenatide 4 or 6 milligrams versus placebo was associated with a 27% reduction in the primary outcome of CV death, non-fatal MI or non-fatal stroke.

Importantly, there was a consistent benefit with efpeglenatide across a spectrum of prespecified subgroups,  the most important one being those that entered the trial on a background SGLT2 inhibitor, which represented about 15% of the patients. They derived the same overall benefit as those not taking an SGLT2 inhibitor. It is important to appreciate that this is probably the most robust data we have for showing a cardiovascular benefit of adding a GLP-1 receptor agonist to an SGLT2 inhibitor in high risk patients with type 2 diabetes. AMPLITUDE-O also adds to the already appreciated knowledge of the cardiovascular benefit of GLP-1 receptor agonists and builds on this story by showing that you can get a cardiovascular benefit with an exendin-4-based GLP-1 receptor agonist and you can get a benefit as an add on to SGLT2 inhibitors.

Key clinical point: Despite reducing cellular inflammation and improving clinical outcome for joint involvement, adalimumab, a tumor necrosis factor (TNF) inhibitor, did not affect the levels of interleukin (IL)-17 cytokines and its receptors in the skin and synovium of patients with psoriatic arthritis (PsA).

Major finding: At baseline, the skin of patients with PsA vs. healthy donors (HD) showed significantly lower levels of IL-17A (P = .017) and its receptor IL-17RA (P = .007), but higher levels of IL-17F (P = .0002) and its receptor IL-17RC (P = .024). After 4 weeks of treatment, patients recieving adalimumab and placebo showed similar levels of IL-17A, IL-17F, and IL-17RC.

Study details: Findings are from a double-blind, single-center study including 24 patients with PsA and mild psoriatic skin lesions who were randomly assigned to adalimumab or placebo.

Disclosures: This study was funded by the Innovative Medicines Initiatives European Union. The authors declared no conflicts of interest.

Source: Bolt JW et al. Biomedicines. 2022;10(2):324 (Jan 29). Doi: 10.3390/biomedicines10020324.

Key clinical point: Despite reducing cellular inflammation and improving clinical outcome for joint involvement, adalimumab, a tumor necrosis factor (TNF) inhibitor, did not affect the levels of interleukin (IL)-17 cytokines and its receptors in the skin and synovium of patients with psoriatic arthritis (PsA).

Major finding: At baseline, the skin of patients with PsA vs. healthy donors (HD) showed significantly lower levels of IL-17A (P = .017) and its receptor IL-17RA (P = .007), but higher levels of IL-17F (P = .0002) and its receptor IL-17RC (P = .024). After 4 weeks of treatment, patients recieving adalimumab and placebo showed similar levels of IL-17A, IL-17F, and IL-17RC.

Study details: Findings are from a double-blind, single-center study including 24 patients with PsA and mild psoriatic skin lesions who were randomly assigned to adalimumab or placebo.

Disclosures: This study was funded by the Innovative Medicines Initiatives European Union. The authors declared no conflicts of interest.

Source: Bolt JW et al. Biomedicines. 2022;10(2):324 (Jan 29). Doi: 10.3390/biomedicines10020324.

Key clinical point: Despite reducing cellular inflammation and improving clinical outcome for joint involvement, adalimumab, a tumor necrosis factor (TNF) inhibitor, did not affect the levels of interleukin (IL)-17 cytokines and its receptors in the skin and synovium of patients with psoriatic arthritis (PsA).

Major finding: At baseline, the skin of patients with PsA vs. healthy donors (HD) showed significantly lower levels of IL-17A (P = .017) and its receptor IL-17RA (P = .007), but higher levels of IL-17F (P = .0002) and its receptor IL-17RC (P = .024). After 4 weeks of treatment, patients recieving adalimumab and placebo showed similar levels of IL-17A, IL-17F, and IL-17RC.

Study details: Findings are from a double-blind, single-center study including 24 patients with PsA and mild psoriatic skin lesions who were randomly assigned to adalimumab or placebo.

Disclosures: This study was funded by the Innovative Medicines Initiatives European Union. The authors declared no conflicts of interest.

Source: Bolt JW et al. Biomedicines. 2022;10(2):324 (Jan 29). Doi: 10.3390/biomedicines10020324.

Key clinical point: The disease burden of psoriatic arthritis (PsA) was higher in women vs. men even after 1 year of standard-of-care treatment.

Major finding: Women vs. men reported a significantly longer duration of symptoms, higher tender joint count (both P < .05) and enthesitis at baseline (P < .05), and higher disease activity, higher levels of pain, and a lower functional capacity even after 1 year of follow-up (all P < .05). Minimal disease activity was predominantly present among men vs. women at baseline (18% vs. 10%; P < .05) and at 1 year of follow-up (59% vs. 37%, P < .00).

Study details: This prospective cohort study included 307 men and 313 women newly diagnosed with PsA from the Dutch south-west Early Psoriatic Arthritis Registry (DEPAR), who were followed up for 1 year.

Disclosures: No source of funding was reported for the study. The DEPAR cohort received funding from the Dutch Government, Pfizer, and other sources. The authors declared no conflicts of interest.

Source: Passia E et al. Arthritis Res Ther. 2022;24:22 (Jan 11). Doi: 10.1186/s13075-021-02680-y.

Key clinical point: The disease burden of psoriatic arthritis (PsA) was higher in women vs. men even after 1 year of standard-of-care treatment.

Major finding: Women vs. men reported a significantly longer duration of symptoms, higher tender joint count (both P < .05) and enthesitis at baseline (P < .05), and higher disease activity, higher levels of pain, and a lower functional capacity even after 1 year of follow-up (all P < .05). Minimal disease activity was predominantly present among men vs. women at baseline (18% vs. 10%; P < .05) and at 1 year of follow-up (59% vs. 37%, P < .00).

Study details: This prospective cohort study included 307 men and 313 women newly diagnosed with PsA from the Dutch south-west Early Psoriatic Arthritis Registry (DEPAR), who were followed up for 1 year.

Disclosures: No source of funding was reported for the study. The DEPAR cohort received funding from the Dutch Government, Pfizer, and other sources. The authors declared no conflicts of interest.

Source: Passia E et al. Arthritis Res Ther. 2022;24:22 (Jan 11). Doi: 10.1186/s13075-021-02680-y.

Key clinical point: The disease burden of psoriatic arthritis (PsA) was higher in women vs. men even after 1 year of standard-of-care treatment.

Major finding: Women vs. men reported a significantly longer duration of symptoms, higher tender joint count (both P < .05) and enthesitis at baseline (P < .05), and higher disease activity, higher levels of pain, and a lower functional capacity even after 1 year of follow-up (all P < .05). Minimal disease activity was predominantly present among men vs. women at baseline (18% vs. 10%; P < .05) and at 1 year of follow-up (59% vs. 37%, P < .00).

Study details: This prospective cohort study included 307 men and 313 women newly diagnosed with PsA from the Dutch south-west Early Psoriatic Arthritis Registry (DEPAR), who were followed up for 1 year.

Disclosures: No source of funding was reported for the study. The DEPAR cohort received funding from the Dutch Government, Pfizer, and other sources. The authors declared no conflicts of interest.

Source: Passia E et al. Arthritis Res Ther. 2022;24:22 (Jan 11). Doi: 10.1186/s13075-021-02680-y.

Key clinical point: Patients with psoriatic arthritis (PsA) have high anxiety levels before initiating biologics, which decreased within 6 months thereafter and was tied with better patient outcomes.

Major finding: Overall, 64% of patients had high anxiety levels before initiating biologics, with the proportion of patients with high anxiety levels and mean anxiety scores decreasing significantly within 6 months of initiating biologics (both P < .001). A change in anxiety score correlated positively with a change in pain score, patient global assessment score, Bath Ankylosing Spondylitis Disease Activity Index, Health Assessment Questionnaire-Disability Index score, Disease Activity Score-28, and PsA Impact of Disease score (all P < .05).

Study details: Findings are from an analysis of 147 patients with PsA who initiated  biologic agents and had an anxiety score assessed at both baseline and first visit within 6 months.

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

Source: Ayan G et al. Clin Rheumatol. 2022 (Jan 27). Doi: 10.1007/s10067-021-06012-y.

Key clinical point: Patients with psoriatic arthritis (PsA) have high anxiety levels before initiating biologics, which decreased within 6 months thereafter and was tied with better patient outcomes.

Major finding: Overall, 64% of patients had high anxiety levels before initiating biologics, with the proportion of patients with high anxiety levels and mean anxiety scores decreasing significantly within 6 months of initiating biologics (both P < .001). A change in anxiety score correlated positively with a change in pain score, patient global assessment score, Bath Ankylosing Spondylitis Disease Activity Index, Health Assessment Questionnaire-Disability Index score, Disease Activity Score-28, and PsA Impact of Disease score (all P < .05).

Study details: Findings are from an analysis of 147 patients with PsA who initiated  biologic agents and had an anxiety score assessed at both baseline and first visit within 6 months.

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

Source: Ayan G et al. Clin Rheumatol. 2022 (Jan 27). Doi: 10.1007/s10067-021-06012-y.

Key clinical point: Patients with psoriatic arthritis (PsA) have high anxiety levels before initiating biologics, which decreased within 6 months thereafter and was tied with better patient outcomes.

Major finding: Overall, 64% of patients had high anxiety levels before initiating biologics, with the proportion of patients with high anxiety levels and mean anxiety scores decreasing significantly within 6 months of initiating biologics (both P < .001). A change in anxiety score correlated positively with a change in pain score, patient global assessment score, Bath Ankylosing Spondylitis Disease Activity Index, Health Assessment Questionnaire-Disability Index score, Disease Activity Score-28, and PsA Impact of Disease score (all P < .05).

Study details: Findings are from an analysis of 147 patients with PsA who initiated  biologic agents and had an anxiety score assessed at both baseline and first visit within 6 months.

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

Source: Ayan G et al. Clin Rheumatol. 2022 (Jan 27). Doi: 10.1007/s10067-021-06012-y.

Key clinical point: Minimal important change (MIC) of the Psoriatic Arthritis Disease Activity Score (PASDAS) could help physicians understand patients' perspectives of disease activity and provide an additional tool for the treatment of psoriatic arthritis (PsA).

Major finding: The overall MIC of the PASDAS was 0.67 (95% CI 0.55-0.79) and results for improvement and deterioration were 0.65 (95% CI 0.46-0.83) and 0.71 (95% CI 0.49-0.93), respectively.

Study details: Findings are from a retrospective cohort study that evaluated routine practice data of 408 patients with PsA.

Disclosures: This work was supported by the Regional Junior Researcher Grant from the Sint Maartenskliniek, Nijmegen, and the Radboudumc, Nijmegen, the Netherlands. The authors declared no conflicts of interest.

Source: Mulder MLM et al. Rheumatology (Oxford). 2022 (Jan 13). Doi: 10.1093/rheumatology/keac025.

Key clinical point: Minimal important change (MIC) of the Psoriatic Arthritis Disease Activity Score (PASDAS) could help physicians understand patients' perspectives of disease activity and provide an additional tool for the treatment of psoriatic arthritis (PsA).

Major finding: The overall MIC of the PASDAS was 0.67 (95% CI 0.55-0.79) and results for improvement and deterioration were 0.65 (95% CI 0.46-0.83) and 0.71 (95% CI 0.49-0.93), respectively.

Study details: Findings are from a retrospective cohort study that evaluated routine practice data of 408 patients with PsA.

Disclosures: This work was supported by the Regional Junior Researcher Grant from the Sint Maartenskliniek, Nijmegen, and the Radboudumc, Nijmegen, the Netherlands. The authors declared no conflicts of interest.

Source: Mulder MLM et al. Rheumatology (Oxford). 2022 (Jan 13). Doi: 10.1093/rheumatology/keac025.

Key clinical point: Minimal important change (MIC) of the Psoriatic Arthritis Disease Activity Score (PASDAS) could help physicians understand patients' perspectives of disease activity and provide an additional tool for the treatment of psoriatic arthritis (PsA).

Major finding: The overall MIC of the PASDAS was 0.67 (95% CI 0.55-0.79) and results for improvement and deterioration were 0.65 (95% CI 0.46-0.83) and 0.71 (95% CI 0.49-0.93), respectively.

Study details: Findings are from a retrospective cohort study that evaluated routine practice data of 408 patients with PsA.

Disclosures: This work was supported by the Regional Junior Researcher Grant from the Sint Maartenskliniek, Nijmegen, and the Radboudumc, Nijmegen, the Netherlands. The authors declared no conflicts of interest.

Source: Mulder MLM et al. Rheumatology (Oxford). 2022 (Jan 13). Doi: 10.1093/rheumatology/keac025.

Key clinical point: Entheseal power Doppler (PD) signal, entheseal bone erosions, and gray scale (GS) joint synovitis were indicative of severe psoriatic arthritis (PsA) in terms of ultrasound (US)-detected joint bone erosion.

Major finding: At least 1 joint bone erosion was found in 45.2% of patients and was associated with PD signal at enthesis (odds ratio [OR] 1.74; P < .01), entheseal bone erosions (OR 3.17; P = .01), and GS synovitis (OR 2.59; P = .02).

Study details: Findings are from a cross-sectional study including 104 patients with PsA.

Disclosures: This study did not receive any specific funding. E Filippucci and W Grassi declared receiving speaker fees from various sources.

Source: Smerilli G et al. J Rheumatol. 2022 (Feb 1). Doi: 10.3899/jrheum.210974.

Key clinical point: Entheseal power Doppler (PD) signal, entheseal bone erosions, and gray scale (GS) joint synovitis were indicative of severe psoriatic arthritis (PsA) in terms of ultrasound (US)-detected joint bone erosion.

Major finding: At least 1 joint bone erosion was found in 45.2% of patients and was associated with PD signal at enthesis (odds ratio [OR] 1.74; P < .01), entheseal bone erosions (OR 3.17; P = .01), and GS synovitis (OR 2.59; P = .02).

Study details: Findings are from a cross-sectional study including 104 patients with PsA.

Disclosures: This study did not receive any specific funding. E Filippucci and W Grassi declared receiving speaker fees from various sources.

Source: Smerilli G et al. J Rheumatol. 2022 (Feb 1). Doi: 10.3899/jrheum.210974.

Key clinical point: Entheseal power Doppler (PD) signal, entheseal bone erosions, and gray scale (GS) joint synovitis were indicative of severe psoriatic arthritis (PsA) in terms of ultrasound (US)-detected joint bone erosion.

Major finding: At least 1 joint bone erosion was found in 45.2% of patients and was associated with PD signal at enthesis (odds ratio [OR] 1.74; P < .01), entheseal bone erosions (OR 3.17; P = .01), and GS synovitis (OR 2.59; P = .02).

Study details: Findings are from a cross-sectional study including 104 patients with PsA.

Disclosures: This study did not receive any specific funding. E Filippucci and W Grassi declared receiving speaker fees from various sources.

Source: Smerilli G et al. J Rheumatol. 2022 (Feb 1). Doi: 10.3899/jrheum.210974.

Key clinical point: Patients with psoriatic arthritis (PsA) receiving tofacitinib experienced a shorter time to initial clinically meaningful response than those who switched from placebo to tofacitinib.

Major finding: Median time to the initial Health Assessment Questionnaire-Disability Index score response was shorter in patients receiving 5 mg tofacitinib (29-30 days) and 10 mg tofacitinib (53.5 days) than in those switching from placebo to 5 mg tofacitinib (162 days) or 10 mg tofacitinib (112 days; P < .01). The initial Functional Assessment of Chronic Illness Therapy-Fatigue total score response was achieved faster with 5 mg tofacitinib vs. other treatment groups.

Study details: Findings are from a post hoc analysis of 2 phase 3 trials (OPAL BROADEN and OPAL BEYOND) including 816 patients with PsA randomly assigned to 5 mg tofacitinib, 10 mg tofacitinib, 40 mg adalimumab, or placebo switching to 5 or 10 mg tofacitinib at month 3.

Disclosures: This study was funded by Pfizer. The authors declared receiving research grants, consulting fees, and honoraria from Pfizer and other sources. Four authors declared being employees and stockholders of Pfizer.

Source: Gladman DD et al. Arthritis Res Ther. 2022;24:40 (Feb 9). Doi: 10.1186/s13075-022-02721-0.

Key clinical point: Patients with psoriatic arthritis (PsA) receiving tofacitinib experienced a shorter time to initial clinically meaningful response than those who switched from placebo to tofacitinib.

Major finding: Median time to the initial Health Assessment Questionnaire-Disability Index score response was shorter in patients receiving 5 mg tofacitinib (29-30 days) and 10 mg tofacitinib (53.5 days) than in those switching from placebo to 5 mg tofacitinib (162 days) or 10 mg tofacitinib (112 days; P < .01). The initial Functional Assessment of Chronic Illness Therapy-Fatigue total score response was achieved faster with 5 mg tofacitinib vs. other treatment groups.

Study details: Findings are from a post hoc analysis of 2 phase 3 trials (OPAL BROADEN and OPAL BEYOND) including 816 patients with PsA randomly assigned to 5 mg tofacitinib, 10 mg tofacitinib, 40 mg adalimumab, or placebo switching to 5 or 10 mg tofacitinib at month 3.

Disclosures: This study was funded by Pfizer. The authors declared receiving research grants, consulting fees, and honoraria from Pfizer and other sources. Four authors declared being employees and stockholders of Pfizer.

Source: Gladman DD et al. Arthritis Res Ther. 2022;24:40 (Feb 9). Doi: 10.1186/s13075-022-02721-0.

Key clinical point: Patients with psoriatic arthritis (PsA) receiving tofacitinib experienced a shorter time to initial clinically meaningful response than those who switched from placebo to tofacitinib.

Major finding: Median time to the initial Health Assessment Questionnaire-Disability Index score response was shorter in patients receiving 5 mg tofacitinib (29-30 days) and 10 mg tofacitinib (53.5 days) than in those switching from placebo to 5 mg tofacitinib (162 days) or 10 mg tofacitinib (112 days; P < .01). The initial Functional Assessment of Chronic Illness Therapy-Fatigue total score response was achieved faster with 5 mg tofacitinib vs. other treatment groups.

Study details: Findings are from a post hoc analysis of 2 phase 3 trials (OPAL BROADEN and OPAL BEYOND) including 816 patients with PsA randomly assigned to 5 mg tofacitinib, 10 mg tofacitinib, 40 mg adalimumab, or placebo switching to 5 or 10 mg tofacitinib at month 3.

Disclosures: This study was funded by Pfizer. The authors declared receiving research grants, consulting fees, and honoraria from Pfizer and other sources. Four authors declared being employees and stockholders of Pfizer.

Source: Gladman DD et al. Arthritis Res Ther. 2022;24:40 (Feb 9). Doi: 10.1186/s13075-022-02721-0.