Steven Grinspoon is an American physician and a Professor of Medicine at Harvard Medical School, Chief of the Massachusetts General Hospital (MGH), and Metabolism Unit and Director of the Nutrition and Obesity Research Center at Harvard. In addition, he is the MGH Endowed Chair in Neuroendocrinology and Metabolism. His work investigates the neuroendocrine regulation of body composition and the physiological consequences of fat distribution on cardiovascular disease and inflammation.[1] In 2015, he became the Principal Investigator of the NIH-funded Nutrition Obesity Research Center at Harvard.[2]
Grinspoon’s primary research focus has been to investigate the effects of augmenting endogenous GH pulsatility on visceral fat in lipodystrophic patients with abdominal fat accumulation and nonalcoholic fatty liver disease. This work was initiated by an observation of reduced GH secretion in HIV patients with lipodystrophy. Subsequent studies examined the mechanisms and demonstrated reduced area under the curve per peak, but maintenance of the GH pulse generator in such patients. Reasoning that augmentation of GH pulsatility might reduce visceral fat, because of its potent effects to oxidize adipose tissue, Grinspoon led a series of studies culminating in a NEJM paper demonstrating that Tesamorelin, a GHRH1-44 secretagogue, reduced visceral fat by 20% and reduced triglyceride, while improving adiponectin.[6] This work led to FDA approval of Tesamorelin as the only such approved drug for HIV lipodystrophy and first in class molecule. Subsequent studies, published in JAMA and Lancet HIV, demonstrated that Tesamorelin reduced hepatic steatosis as well, the first drug to demonstrate a significant effect among patients with HIV lipodystrophy.[7][8][9] Subsequent work demonstrated significant effects to stimulate hepatic oxidative pathways and reduce inflammatory pathways in gene set enrichment studies.[10] Grinspoon was granted a US Patent entitled “GHRH or Analogues thereof for the Use in Treatment of Hepatic Disease” for this work.[11] Tesamorelin was also investigated in generalized obesity and showed significant effects to reduce cIMT, inflammatory markers, lipids and visceral adiposity.[12]
A second and related focus of Grinspoon’s work has been to investigate the mechanisms and strategies for CVD in HIV. In this regard, he led an AHA sponsored State of the Science Symposium on CVD in HIV. The conclusions from this conference called for a better understanding and treatment strategies of CVD in HIV. This work began with epidemiologic studies demonstrating increased myocardial infarction rates in HIV patients in the JCEM.[2] This data was followed by a series of mechanistic studies demonstrating increased prevalence of plaque, particularly noncalcified, lipid rich, plaque. Grinspoon used FDG PET to demonstrate for the first time significant arterial inflammation in asymptomatic low traditional risk HIV patients, compared to Framingham risk matched control subjects, as well as non HIV patients with known CVD, published in JAMA.[13] Of note, increased arterial inflammation was most significantly associated with increased markers of immune activation. He also recently proposed the first use of tilmanocept as a CD206 specific imaging agent for arterial inflammation, with success in HIV published in JID.[14] This work was followed by studies in HIV patients in which he phenotyped the morphological characteristics of coronary plaque in HIV patients, demonstrating an increased prevalence of high risk plaque with low attenuation and positive remodeling, more vulnerable to rupture.[15] His studies suggested that treatment with a statin might uniquely target both traditional risk factors including low-density lipoprotein (LDL) but also increased immune activation indices driving atypical noncalcified high risk plaque in this population. This work culminated in a recent paper in Lancet HIV, in which he showed for the first time that a statin can significantly reduce high risk plaque volume as well as improve the high-risk morphological features in coronary lesions in HIV.[16] In recognition of this work, he has led the REPRIEVE trial, a global primary prevention study performed in 12 countries, since 2013 and gave the plenary lecture at CROI 2015 on this topic.[17][18] The REPRIEVE trial was recently closed early by its Data Safety Monitoring Board for a robust efficacy signal, demonstrating that a statin strategy reduced major adverse cardiovascular event (primary heart attacks, strokes, and cardiovascular death) by 35% over 5 years, compared to placebo. This trial was recently published in the New England Journal of Medicine and the data presented by Grinspoon at the International AIDS Society 2023 meeting in Brisbane and featured in news articles and podcasts.[19][20][21][22][23]
Grinspoon has worked to understand the mechanism, and treatment strategies for metabolic dysregulation in HIV, and was among the first to assess metformin and rosiglitazone to reverse insulin resistance and increase adipogenesis in this population. He also recognized reduced DICER as a factor that may contribute to dysfunctional adipose tissue in HIV.[6][7][8]
Grinspoon, Steven K. (April 2003). "Weight loss and wasting in patients infected with human immunodeficiency virus.” Clinical Infectious Diseases36 (69-78).[26]
Grinspoon, Steven K. (19 June 2008). “Initiative to Decrease Cardiovascular Risk and Increase Quality of Care for Patients Living With HIV/AIDS”.Circulation (journal)18[27]
Grinspoon, Steven K. ;Lake, Jordan, Stanley, Takara; Apovian, Caroline; Brown, Todd. (15 May 2017). “Practical Review of Recognition and Management of Obesity and Lipohypertrophy in Human Immunodeficiency Virus Infection”. Clinical Infectious Diseases64 (1422–1429).[28]
Grinspoon, Steven K; Brown, Todd T. (2020) Williams Textbook of Endocrinology:”Endocrinology of HIV/AIDS”. Elsevier.[29]
Grinspoon, Steven K; Stlanley, Takara L. (January 2022) Oxford Textbook of Endocrinology and Diabetes: “Abnormalities in HIV Infection”. Oxford University Press.[30]
Grinspoon, Steven K; Zanni, Markella V.; Fitchenbaum, Carl J. (July 23, 2023) New England Journal of Medicine: “Pitavastatin to Prevent Cardiovascular Disease in HIV Infection”. Massachusetts Medical Society.[31]
^Fourman LT, Billingsley JM, Agyapong G, Ho Sui SJ, Feldpausch MN, Purdy J, Zheng I, Pan CS, Corey KE, Torriani M, Kleiner DE, Hadigan CM, Stanley TL, Chung RT, Grinspoon SK. Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD. JCI Insight. 2020 Aug 20;5(16):e140134. doi:10.1172/jci.insight.140134 PMID 32701508; PMCID: PMC7455119.
^US 10946073, Grinspoon, Steven K., "GHRH or analogues thereof for use in treatment of hepatic disease", published 2021-03-16, assigned to Massachusetts General Hospital
^Makimura H, Feldpausch MN, Rope AM, Hemphill LC, Torriani M, Lee H, Grinspoon SK. Metabolic effects of a growth hormone-releasing factor in obese subjects with reduced growth hormone secretion: a randomized controlled trial. J Clin Endocrinol Metab. 2012 Dec;97(12):4769-79. doi:10.1210/jc.2012-2794 Epub 2012 Sep 26. PMID 23015655; PMCID: PMC3513535.
^Grinspoon, Steven K.; Brown, Todd T. (2020). Williams Textbook of Endocrinology:”Endocrinology of HIV/AIDS”. Elsevier. ISBN978-0-323-55596-8.
^Grinspoon, Steven K.; Stanley, Takara L. (January 2022). Oxford Textbook of Endocrinology and Diabetes (3 ed.). Oxford University Press. p. 1715–1724. ISBN9780191840739.
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