Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
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Throughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
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The book is organized in seven sections with twenty two chapters, covering a wide range of applications. Section I, caters theoretical aspects of FIS in chapter one. Section II, dealing with FIS applications to management related problems and consisting three chapters. Section III, accumulates six chapters to commemorate FIS application to mechanical and industrial engineering problems. Section IV, elaborates FIS application to image processing and cognition problems encompassing four chapters. Section V, describes FIS application to various power system engineering problem in three chapters. Section VI highlights the FIS application to system modeling and control problems and constitutes three chapters. 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1. Introduction
Metformin is derived from Galega officinalis, a natural herbal medicine. The herb was first used to relieve polyuria, a symptom of diabetes in ancient Egypt and medieval Europe [1]. Metformin is a widely used frontline drug for type 2 diabetes mellitus (T2DM). The major function of metformin is to decrease hepatic gluconeogenesis and enhance insulin sensitivity by increasing glucose uptake in muscle and adipose [2]. In addition to antidiabetes, metformin has proved to be beneficial to metabolic syndrome and nonalcoholic fatty liver disease [3, 4]. Cancer is characteristic of a metabolic disorder, inasmuch as metabolism is reprogrammed by switching oxidative phosphorylation into aerobic glycolysis, and thus, many of key molecules in these two routes are altered in their expression or posttranslational modification [5]. The incidence of cancer is higher in patients with T2DM than those without diabetes, indicating that diabetes is a risk factor of cancer [6]. Since Evan et al. reported in 2005 lower cancer incidence in patients with T2DM taking metformin than those with other antidiabetic drugs, great efforts have been made to elucidate the antitumor activity of metformin [7]. A considerable number of preclinical and clinical investigations support the beneficial effects of metformin on both prevention and treatment of various cancers. At the same time, some of mechanisms underlying metformin action on cancer cells have been unraveled, although much of them is still incomplete. Thus far, more than 300 clinical trials using metformin as a single or adjuvant agent in combination with other chemotherapies have been initiated in the treatment of various types of cancer in the world (www.clinicaltrials.gov).
2. Targets of metformin
Many functions of metformin are mediated by adenosine monophosphate-activated protein kinase (AMPK). Metformin at high doses leads to elevation of AMP, which binds to and allosterically activates AMPK, while at low doses, it engages lysosomes in the absence of AMP [8, 9]. The upstream kinases that phosphorylate AMPK α subunits at Thr172 include liver kinase B1 (LKB1), calmodulin-dependent kinase beta, and TGF-β-activated protein kinase [10, 11, 12].
AMPK plays important roles in regulating lipid and protein metabolisms by phosphorylating a series of target proteins. Thus, LKB1-AMPK pathway is critically important for metabolic adaption under stress condition, which aims to protect cells in the beginning [13]. However, persistent activation of AMPK by metformin can also cause cytostatic and even cytotoxic effects. Mounting evidence shows that metabolic syndrome and diabetes increase the risk of cancer, and correction of metabolic abnormalities alleviates cancer burdens and improves survival [14, 15, 16]. Drugs that target AMPK or downstream molecules are research focus nowadays for cancer prevention and treatment. Some of pathways downstream of AMPK essential for tumorigenesis and cancer progression are depicted in Figure 1.
Figure 1.
AMPK activation and its biological functions. AMPK is activated by increased AMP:ATP ratio induced by metabolic stress and metformin. In addition, metformin can activate AMPK through lysosomal pathway, where v-ATPase-regulator-AXIN/LKB1-AMPK complex is formed. After activation, AMPK acts on multiple molecules/pathways, including inhibition of mTORC1, lipogenesis and IGF-1 expression, and activation of p53 and FOXO3a [17, 22, 87, 88, 89]. As such, AMPK regulates cell proliferation, autophagy, and apoptosis of cancer cells.
PI3K-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway is well received as the target of AMPK. Mammalian target of rapamycin complex 1 (mTORC1) consists of mTOR, regulatory-associated protein of mTOR (Raptor), mammalian lethal with SEC13 protein 8, proline-rich AKT substrate 40 kDa, and DEP domain-containing mTOR-interacting protein [17]. Tuberous sclerosis complex 2 (TSC2) is a GTPase-activating protein that forms a complex with TSC1 to stimulate GTPase activity of Ras homolog enriched in brain (Rheb) and thus inhibits mammalian target of rapamycin complex 1 (mTORC1) activation. TSC2 is subjected to inhibition by AKT and activation by AMPK via phosphorylation at different sites. In addition, AMPK phosphorylates and inhibits Raptor, a scaffold of mTORC1. A plethora of cellular events, such as protein translation, lipogenesis, cell cycle progression, and autophagy, are regulated by the activated mTOR pathway, which are counteracted by AMPK [18]. Thus, control of mTORC1 activity is crucial for prevention and treatment of cancer.
Cancer cells always require large amount of building blocks for dividing progenitor cells. Thus, synthesis of fatty acid and cholesterol is very active [19]. Acutely, AMPK inhibits acetyl CoA carboxylase (ACC) and HMG-CoA reductase (HMGCR), which are rate-limiting enzymes for de novo synthesis of fatty acid and cholesterol, respectively [20]. In addition, AMPK activates malonyl-CoA decarboxylase (MAD) that converts malonyl-CoA to acetyl CoA. As cytosolic malonyl-CoA decreases, fatty acid synthesis is attenuated [17, 21]. AMPK also influences de novo synthesis of glycerolipid by inhibiting the rate-limiting enzyme glycerol phosphate acyltransferase (PAT) [17, 22]. Chronically, AMPK phosphorylates sterol regulatory element-binding protein-1c (SREBP-1c) and its related protein carbohydrate-response-element-binding protein (ChREBP), restricting the nuclear localization of these transcription factors, so as to inhibit transcription of target genes for lipogenesis, including those encoding ACC and fatty acid synthase (FASN) [23].
3. Clinical investigations
Decreases from 20 to 94% in cancer risk among patients with T2DM after the use of metformin have been reported since 2005 [24]. A large population study conducted by Taiwan National Health Insurance Data Survey evaluated 16,602 individuals treated with metformin or other antidiabetic drug between 2000 and 2007 and concluded a 88% reduction in the risk of various cancer types after metformin treatment [25, 26]. In line with this, numerous investigations provided supporting data that metformin reduced incidence of various cancers. For example, DeCenci et al. have found a 30% decrease in cancer incidence in patients with T2DM treated with metformin compared to those with other drugs [27, 28]. Currie et al. conducted a large cohort study with around 60,000 patients from the UK database and revealed that metformin alone decreased the incidence of colorectal and pancreatic cancer compared with insulin and sulfonylureas monotherapy after the adjustment of confound bias, but this was not seen in breast cancer (BC) and prostate cancer [29]. It is noteworthy that metformin plus insulin could alleviate the progression of cancer [hazard ratio (HR) = 0.54, 95% confidence interval (CI) 0.43–0.66] [29]. With respect to mortality, ZODIAC trial with a 10-year follow up has indicated a lower death rate of cancer among metformin users with T2DM [30]. According to Noto et al. meta-analysis, diabetic patients taking metformin showed significant reduction of incidence of multiple types of cancer [risk ratio (RR) = 0.67, 0.53–0.85], including colorectal cancer (CRC) (RR = 0.68, 0.53–0.88) and cancer mortality (RR = 0.66, 95% CI = 0.49–0.88) [31]. A study of Bowker et al. reported that metformin decreased cancer mortality in T2DM, as compared with insulin and/or sulfonylurea groups [32]. After 1-year observation, the cancer death rate of metformin, insulin, and sulfonylurea users is 3.5, 8.8, and 4.9 per 1000 patients, respectively.
Regarding tumor types, dosage of metformin, study setting, and period of intervention associated with the treatment outcomes, examples are listed in Table 1.
Diabetic patients treated with metformin ≧ 5 years had a lower incidence of cancer, compared with nonusers or short-term (<5 years treatment) metformin users
The pCR rate in 68 diabetic patients treated with metformin, 87 diabetic patients without metformin, and 2374 nondiabetic patients was 24, 8, and 16% (P = 0.02)
Reduction of cancer cell proliferation (Ki67) by 3% (P = 0.016) and increases in apoptosis by 0.49% (P = 0.004) was compared between pre- and post-surgery, despite minor change of fasting insulin level
1013 BC patients with diabetes and 4621 BC patients without diabetes were analyzed. Nondiabetic group had higher 5-year survival rate than diabetic group (82 vs. 79%, P < 0.001). In diabetic subgroup, metformin-treated group had significant higher 5-year survival rates than nonmetformin-treated group (88 vs. 73%, P< 0.001)
Metformin + chemotherapy or +hormone therapy, tamoxifen
Non-diabetic women with newly diagnosed BC (68/129) were prescribed with metformin (860 mg b.i.d.) along with chemotherapy or hormone therapy compared to nonmetformin-treated control arm over 6 or 12 months. A 3.27-fold decrease (P = 0.023, 95% CI 1.17–9.06) at the time of developing metastasis and an increase in average DFS by 2.137 (P = 0.044) in the metformin-treated group. Also, the levels of IGF-1, the ratio of IGF-1 to IGFBP-3, insulin, fasting blood glucose, HOMA-IR index notably decease, while IGFBP-3 levels significantly increase after using of metformin
A cohort study evaluated a total of 1983 women with stage ≧ 2 Her2 positive BC. Among 154/1983 diabetic patients who had already responded to previous chemotherapy. Metformin users had prolonged OS (HR = 0.52, 95% CI 0.28–0.97, P = 0.041) and reduced cancer-specific mortality of BC (HR = 0.47, 95% CI 0.24–0.90, P = 0.023), compared with nonusers
Significant benefit of RFS (n = 623 patients in two studies), OS (n = 1936 patients in five studies), and CSS (n = 535 patients in two studies) was observed in metformin-treated patients from 3094 patients with early stage CRC in nine studies, compared with that in nonmetformin using group
A significant decrease in the risk of developing colon neoplasia [RRs (95% CI) = 0.75 (0.65–0.87), Z = −3.95, P < 0.001], including the reduction of colon cancer [0.79 (0.69–0.91), Z = −3.34, P < 0.001] and colon polyps [0.58 (0.42–0.80), Z = −3.30, P < 0.001] among patients with T2DB after metformin treatment
After adjustment of cofound variates, a 30% increase in OS was demonstrated among 424/4758 patients who were diagnosed of T2DM and CRC and administrated to metformin as compared with that in other antidiabetics users
A total of 151 nondiabetic patients with CRC after polypectomy was randomized to metformin-treated arm (250 mg daily over 1 year) or placebo control arm with 1-year endoscopy reports. The incidence of total polyps and adenomas decreased in metformin-treated group by 18.5% [RR = 0.67, 95% CI (0.47–0.97), P = 0.034] and 21% [RR = 0.60, 95% CI (0.39–0.92), P = 0.16], compared with that in control group
A total of 40 women with atypical endometrial hyperplasia (AEH) or EC was assigned to receive metformin 850 mg b.i.d. over average 20 day, or no treatment before hysterectomy. Ki67 was reduced by 17.2% (95% CI 27.4–7.0, P < 0.002) in metformin-treated group
20 nondiabetic women with EC and obesity (BMI ≥ 30) were administrated with metformin 850 mg daily for 1–4 weeks before surgery. The levels of Ki67 and p-S6 were reduced between pretreatment and postsurgery by 11.75% (P = 0.008) and 51.2% (P = 0.0002), respectively. Besides, the levels of p-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-4EBP1 (P = 0.001), and ER (P = 0.0002) also decreased after surgery
17 AEH and 19 noninvasive EC patients received metformin (escalating from 750 to 2250 mg daily) after complete response treated by MPA and other drugs. Relapse rate among patients was 10%, and estimated 3-year RFS rate was 89%
Metformin significantly improved OS (HR = 0.54, 95% CI 0.30–0.97, P < 0.04) in diabetic patients with nonendometrioid EC when compared with that in nonusers with EC
A total of 102 nondiabetic patients with ALL was enrolled, 26 received metformin (850 mg t.i.d.) for 6 days during preinduction stage, and 76 were treated with traditional chemotherapy without metformin. The use of metformin prevented therapy failure and early relapse (P = 0.025) in patients bearing relative to high levels of ABCB1
Metformin users along with CRT resulted in higher pCR (34.5%) than nonmetformin cohort (4.8%, P = 0.01) and nondiabetic patients (19.6%, P = 0.05). Higher pCR rate was found to be associated with higher metformin dose (≥1500 mg/d). Post-CRT maximum SUV decreased significantly in patients taking metformin (P = 0.05)
Reduction of total CID and incidence of some gastroenterological cancers including CRC, HCC, and so on, among which the CID of esophageal cancer decreased in diabetic groups taking adjuvant metformin in comparison to non-DM groups. Metformin dosage giving rise to a significant decrease in cancer incidence was ≤500 mg/day
No statistically significant difference between metformin users and nonmetformin users for median overall survival (43.6 vs. 42.8 months, P = 0.66) or for median DFS (31.1 vs.47.0 months, P = 0.68)
A total of 44 men with castration-resistant prostate cancer was assigned to receive metformin 500 mg b.i.d. until progression. After initial metformin treatment, changes in IGF and IGBP3 and improvement of insulin sensitivity from baseline were observed but without correlation with progression. At week 4, only four patients did not have progression (95% CI, 3–22). Average PFS was 2.8 months (95% CI, 2.8–3.2) and PSA double time declined in 23 patients but not significant
Metformin 500 mg t.i.d. was prescribed to 24 men with operable prostate cancer before prostatectomy. In a per patient and per tumor analyses, Ki67 was reduced by 29.5% (P = 0.0064) and 28.6% (P = 0.0042) in comparison with the initial biopsy and postprostatectomy sections
A retrospective study examined 2901 noninvasive prostate cancer patients through radiation therapy. In 157 patients treated with metformin, PSA-RFS and DMFS were improved and the castration-resistant prostate cancer progression was alleviated
Table 1.
Examples of clinical investigations of metformin used as a neoadjuvant and adjuvant agent in cancer therapy.
3.1 The role of metformin in radiotherapy and chemotherapy
Metformin has been reported to be a useful adjuvant drug to radiotherapy or chemotherapy for different cancers, especially prostate and colon cancers [33]. The effects of metformin on overall survival (OS), relapse-free survival (RFS), and cancer-specific survival (CSS) after concurrent chemotherapy and/or radiotherapy vary on cancer types.
A previous study has shown that metformin increases radiosensitivity of luminal BC by influencing expression of thioredoxin and intracellular redox homeostasis [34]. A high level of AMPKα expression correlates with the increased radiosensitivity and better prognosis. A systemic review and meta-analysis conducted in 2018 summarized the impact of metformin on the efficacy of radiotherapy in 17 studies, including prostate cancer, head and neck cancer, rectal cancer, lung cancer, esophageal cancer, and liver cancer [35]. The study compared diabetic patients with metformin (D + M) and diabetic or nondiabetic cohort without metformin (D − M or N − M) after radiotherapy. An improved pathologic complete response (pCR), 2y-OS, and 5y-OS vary in different cancer types when analyzing D + M and D − M groups, supporting that metformin is beneficial to OS of diabetic patients while distant metastasis-free survival (DMFS) and 5-year OS were not significantly different between D + M and N − M groups. With respect to the possible mechanisms by which metformin enhances radiosensitivity, studies have indicated that p53 and AMPKα are involved [36, 37]. Despite the increased sensitivity to radiotherapy and chemotherapy, cumulative side effects and toxicity concur with the use of metformin. For example, a study has shown that combination of metformin with radiochemotherapy can lead to less tolerance to cisplatin and radiotherapy and exacerbate gastrointestinal adverse effects such as grade ≥ 3 nausea/vomiting [38].
3.2 Breast cancer
Several lines of clinical investigations have been conducted to assess the beneficial effects of metformin on BC [39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52]. Two retrospective studies revealed that long-term use of metformin (>5 years) reduced the risk of BC in T2DM women as compared with other antidiabetic drugs [39, 40]. However, Currie et al. reported that metformin use did not affect risk of breast and prostate cancer, but the reduced risk was found in colon and pancreas cancer [29].
He et al. have shown improvement of disease-free survival (DFS), DMFS, and OS in diabetic women who well-responded to previous hormone therapy and then received metformin treatment. The results demonstrated that metformin synergizes with hormone therapy [53, 54].
Metformin was used as neoadjuvant chemotherapy of BC to improve pathological conditions prior to surgery [45, 46, 47, 48]. The increased pCR in 2529 women with BC has been demonstrated in metformin-treated diabetic patients, compared to nonmetformin-treated patients with or without diabetes [45]. Another study by Niraula et al. evaluated the effect of metformin on serum biomarkers in nondiabetic BC patients before surgery [46]. The patients were treated with metformin for 2 weeks, and serum biomarkers were assessed. A notably reduction of Ki67 and elevation of apoptosis were observed in invasive tumor after the use of metformin. The significant decrease of homeostatic model assessment of insulin resistance (HOMA-IR) was also observed, while insulin and leptin displayed a modest change. However, a study showed that metformin increased phospho-AMPK (p-AMPK) and decreased p-Akt and Ki67 without induction of apoptosis, suggesting a cytostatic effect [47].
The long-term use of metformin has been shown to reduce risk of distant metastasis and mortality of BC patients with type 2 diabetes [49, 50, 51]. Furthermore, metformin use as adjuvant therapy can also improve outcomes of BC in nondiabetic patients [41, 42, 52]. For example, a single-arm phase II trial enrolled nondiabetic women with M0 stage BC. After receiving metformin of 500 mg t.i.d. for 6 months, the result showed that fasting insulin level and HOMA-IR were significantly reduced. Total cholesterol, low density lipoprotein, and leptin also similarly declined [52]. Another study focused on the optimal dose of metformin that achieves favorable effects on BC by comparing dose between 1500 and 1000 mg daily [41]. For postmenopausal women with basal testosterone levels≧0.28 ng/mL, it seemed that metformin of 1500 mg/d was better than 1000 mg/d in reduction of insulin and testosterone levels, which were associated with cancer incidence and prognosis. Combination of metformin with other chemotherapy usually generates better outcomes in nondiabetic BC patients with the higher HOMA-IR (>2.8), and HOMA-IR can be improved by metformin [42, 43, 44, 48].
In summary, studies showing beneficial effects of metformin are more than those without effects. Metformin as an adjuvant agent can suppress BC at various doses ranging from 500 to 1500 mg. The outcomes mainly include reduced risk of BC, decreases in cancer-promoting markers and metastatic events, increases in apoptotic markers, and improvement of progression-free survival (PFS) and OS.
3.3 Colon cancer
The role of metformin in preventing colon cancer has been documented in the following studies conducted in both diabetic and nondiabetic patients. A meta-analysis was carried out in 709,980 individuals with T2DM from 17 studies showing a significant decrease in the risk of colon neoplasia among metformin-treated patients compared to those without metformin, with respective reduction for either cancer or polys [55]. A randomized study enrolled a total of 26 nondiabetic individuals with aberrant crypt foci (ACF) (biomarker of CRC development) and assigned them to either receive metformin 250 mg daily for 1 month or control group [56]. Significant decreases in the average number of ACF by a 3.67-fold (P = 0.007) and in proliferating cell nuclear antigen index were discovered in metformin arm. This indicates that metformin prevents CRC by attenuating cell proliferation and ACF development.
Metformin has been used as an adjuvant agent in the treatment of CRC. First, a single-arm study has demonstrated a median PFS of 1.8 months and an OS of 7.9 months in metastatic CRC with combination of metformin (850 mg b.i.d.) and 5-fluorouracil treatment. Surprisingly, the improvement in median survival was more obvious in obese patients [57]. Second, Coyle et al. have evaluated 3092 patients with early stage of CRC [33]. It was found that the use of metformin significantly improved RFS (HR = 0.63, 95% CI 0.47–0.85), OS (0.69, 95% CI 0.58–0.83), and CSS (0.58, 95% CI 0.39–0.86) in patients with T2DM, compared with other antidiabetic drugs. Likewise, progression of CRC is also inhibited by metformin. A similar study showed prolonged OS in patients with T2DM with CRC receiving metformin, as compared with nonmetformin users (79.6 vs. 56.9 months, P = 0.048) [58]. The last randomized trial used metformin (250 mg daily) for a year in nondiabetic patients with high-risk adenoma recurrence and no colorectal polyps after polypectomy [59]. The results showed that polyps and adenomas are noticeably fewer in the metformin arm than in the control arm. The study also showed that average HOMA-IR status was significantly reduced in nonrecurrent patients by metformin, while the value remained stable in recurrent patients, indicating that insulin resistance is associated with chemoprevention outcome.
3.4 Endometrial cancer
Clinical investigations support that metformin could serve as a potential drug for protection against endometrial cancer (EC) [60, 61, 62, 63, 64, 65]. Several studies have evaluated the effects of short-term use of metformin as a neoadjuvant therapy between initial recruitment and hysterectomy surgery in nondiabetic women with EC [60, 61, 62]. The first nonrandomized trial has examined the change of Ki67 and shown a remarkable reduction after metformin use at 850 mg b.i.d. for average 20 days [60]. A significant reduction in phospho-4E-binding protein 1 (p-4EFBP1) downstream of mTOR was also observed by immunohistochemistry, while indirect serum markers of insulin resistance (fasting glucose, insulin, and HOMA-IR) and leptin only showed a decrease trend but not significant after adjusting difference. Another preoperative clinical trial was done in nondiabetic women with body mass index (BMI) ≧ 30 [61]. After taking metformin 850 mg daily for 1–4 weeks prior to surgery, Ki67, p-AMPK, p-Akt, phospho-S6 Ribosomal Protein (p-S6), and p-4EBP were significantly lower in resected specimens than in pretreatment. The reduction of p-AMPK is inconsistent with purported positive effect of metformin. This study also showed a decrease in estrogen receptor (ER) but not progesterone receptor.
According to a study evaluating the effect of metformin on EC of diabetic patients (n = 114) as compared with diabetic (n = 136) and nondiabetic (n = 735) patients without metformin from 1999 to 2009, metformin-treated group exhibits prolonged OS than nonusers before and after the adjustment of confound bias [66]. A phase II study has examined the effects of long-term metformin (2250 mg daily until recurrence) on RFS after a complete response to medroxyprogesterone acetate (MPA) in 17 individuals with atypical endometrial hyperplasia and 19 with EC [63]. The 3-year estimated RFS was 89%, and the 3-year recurrence rate showed a 4.7-fold decrease in this study compared with a previous study [64]. In contrast to short-term treatment, the other randomized factorial study does not have a significant change in PFS/OS after metformin treatment (1700 mg/d for 16 weeks and 1-year follow up) [65].
3.5 Acute lymphoid leukemia
A single study randomized to assign 102 patients with nondiabetic acute lymphoid leukemia (ALL) into a group of 26 with metformin at 850 mg t.i.d. for 10 days and the rest to the group without metformin before remission therapy [67]. Metformin displayed a beneficial effect on OS in the patients with high levels of ABCB1 expression, the gene encoding multidrug resistant protein-1. The failure rate of therapy was significantly reduced and early relapse after remission prevented by metformin, as compared with nonusers.
3.6 Oesophagal cancer
Oesophagal cancer is deadly cancer with poor prognosis, and patients usually do survive or die no longer than 30 months after chemoradiation and surgery [68]. A prospective cohort study by Taiwan National Health Insurance revealed a positive effect of metformin as an adjunct to standard chemotherapies on the cancer incidence density (CID) of gastroenterological cancers [25]. In this study, a decrease in total CID including esophageal cancer was found in diabetic groups taking adjuvant metformin in comparison to nondiabetic groups. Another study reported that metformin enhanced the efficacy of radiochemotherapy in patients with T2DM resulting in superior pCR and low postconcurrent chemoradiation (CRT) maximum SUV compared to patients with T2DM without metformin and non-DM patients [68]. Additionally, higher pCR rate was correlated with higher metformin dose (≥1500 mg/d). However, a report in 2015 demonstrated inconsistent results, in which no difference in pCR was found between metformin users and nonmetformin users [69]. Furthermore, it was shown that together with neoadjunvant chemoradiation, metformin did not improve the median OS or median DFS in diabetic patients with esophageal cancer.
3.7 Prostate cancer
The effect of metformin on prostate cancer is ambiguous. Studies of Wright and Stanford have provided a 44% decrease in the risk of prostate cancer among Caucasian men with diabetes [70]. However, investigations by others could not obtain the same conclusion on the incidence of prostate cancer in diabetic patients treated with metformin, but the mortality might be reduced [71, 72, 73]. A single-arm clinical trial has revealed a decrease in insulin-like growth factor-1 (IGF-1) and an increase in insulin-like growth factor-binding protein-3 (IGFBP-3), alongside lowering prostate-specific antigen (PSA), after giving metformin 500 mg b.i.d. over 12 weeks to patients with castration-resistant prostate cancer [74]. In a single-arm study on men with biopsy-proven localized prostate cancer, 22 patients were selected to receive metformin at 500 mg/d or b.i.d., followed by t.i.d. for 28–84 days preceding their prostatectomy. The results revealed that Ki67 index was reduced by comparing the initial biopsy with postprostatectomy sections [75]. However, the changes were not recapitulated by another study, although metformin in the prostate tissue was detected after a median of 34 days prior to prostatectomy [76]. In a retrospective study, metformin-treated diabetic individuals gained the improvement of RFS among 6863 patients after radical prostatectomy [77]. Study of Spratt et al. also demonstrated the significantly elevated PSA-RFS, DFS, and lower cancer mortality in localized prostate cancer with metformin treatment compared with that of nonusers [78].
4. Ongoing clinical trials
Previous studies of metformin use as neoadjuvant or adjuvant therapy for various types of cancer provide strong rationale of clinical trials in more vigorous settings. Thus far, more than 300 clinical trials have initiated in the world despite some are somehow either terminated or withdrawn. Table 2 lists some of them. For example, NCT02065687 is a randomized, metformin-placebo, phase II/III study that enrolls a total of 540 participants and examines the effect of adjuvant metformin together with paclitaxel and carboplatin in treatment of stages III–IV or recurrent EC. Patients receive metformin twice a day in a 5-year follow up until disease progression or undesirable adverse effects appear. According to this trial, prolonged PFS and OS will be observed after the use of metformin together with other chemotherapeutic drugs. One of the ongoing phase II trials carrying out in 151 premenopausal BC patients with BMI ≧ 25 kg/m2 evaluates treatment effect with 850 mg metformin b.i.d. vs. placebo for a year, by examining the primary outcome changes of breast density at time points of 6 and 12 months. This study spanning from March 7, 2014 to June 30, 2020 also identifies biomarkers associated with metabolic effects of metformin and attempts to find prediction factors of BC risk (NCT02028221). Also, a trial (NCT02614339) is undergoing to follow-up 3-year DFS and 5-year OS in nondiabetic patients with stage II high-risk/III CRC treated with metformin (1000 mg/day) for 48 months. This study has enrolled 593 participants and is still recruiting and expected to complete in July 2021.
(a) 408, (b) 18 years to 79 years (adult, older adult), (c) male
October 1, 2013 to August 1, 2024
Drug: metformin & placebo
Prostate cancer
Table 2.
Summary of ongoing clinical trials approved by FDA.
The trial of double-blinded 2 × 2 factorial (aspirin × metformin) design registers 160 patients with stages I–III colon cancer who undertake a completed polypectomy within recent 24 months (NCT03047837). After randomized allocation, patients will receive metformin at 850 mg b.i.d. or aspirin at 100 mg daily or two drugs together vs. placebo over 1 year. Immunohistochemistry for NF-κB, glucose metabolism, pS6K, and other biomarker will be compared pre- and postintervention (ClinicalTrials.gov Identifier: NCT03047837).
5. Cautions to be considered
5.1 Cancer type-specific effects
Whether a cancer type is sensitive to metformin depends on expression level of OCT1 in the cell membrane. Thus far, majority of previous studies have demonstrated that metformin exerts beneficial effects on different types of cancer, while some do not respond. On contrary, in some cases, for example, in glioma and leukemia cancer cells, metformin reduces cisplatin-induced apoptosis, suggesting that metformin exerts a protective effect on cytotoxic agents in some cells [79]. Hence, before going to clinical trials, preclinical tests should be undertaken to ascertain if metformin enhances the inhibitory effect of other drugs. This is feasible when PDX animal models or organoid culture techniques are available.
5.2 Genetic background of cancer
Responses of cancer cells with and without LKB1 to metformin are different. Metformin exerts cytostatic effect on cancer cells with wild-type LKB1, while it causes cytotoxicity in cells lacking LKB1. If metformin is used together with most of chemotherapeutic drugs that are cytotoxic in cancer containing wild-type LKB1, the cooperative effects might not be achieved. The reason is that more rapidly dividing cells are more sensitive to cytotoxic drugs, while cytostatic drugs slow down speed of cell growth, which might compromise the efficacy of cytotoxic chemotherapy. In this scenario, it might be a good idea to take metformin and cytotoxic drug alternately. For example, patients take a couple of cycles of cytotoxic chemotherapy and then have rest for period of time during which metformin is alternately used. The purpose is to restrain cancer in dormancy and allow the patients to restore healthy condition. In addition, Birsoy et al. have delineated that the most metformin-sensitive cells contain mutations of genes responsible for upregulation of mitochondrial oxidative phosphorylation, for example, complex I components, or glucose utilization [80]. Thus, these genes may serve as biomarkers for metformin use. Altogether, these studies point to importance of personalized medicine to determine the efficacy of metformin in cancer therapy.
5.3 Sensitivity of cancer stem cells
Cancer stem cells (CSCs) are refractory to chemotherapy, leading to the relapse of cancer. These cells metastasize to distant organs after flowing in circulation, resulting in poor prognosis. Thus, CSCs have become an important target for anticancer therapies. Hirsch et al. have reported that the CSCs derived from BC are preferentially sensitive to metformin that is used from 10 to 100 times less dosage than nonstem cancer cells [81]. This finding suggests that metformin could effectively prevent metastasis. It is especially meaningful in the case of surgically resected cancer when local metastasis in lymph nodes is cytologically tested negative, but a few CSCs may escape to circulation. At this time, metformin can be used as preventive measure.
Previous studies have demonstrated that metformin selectively targets CSCs via regulation of different pathways in various cancer types including breast, pancreatic, prostate, and colon cancer [82, 83]. For example, Zhu et al. have shown that metformin inhibits CD61high/CD49fhigh subpopulation, markers of tumor initiating cells, by inactivating epidermal growth factor receptor/ErbB2 signaling. Similarly, CD133+, aldehyde dehydrogenases 1+, and other molecules are inhibited in pancreatic and colon cancer through inhibition of the Akt/mTOR pathway [84, 85]. However, a recent study using head and neck squamous cell carcinoma has shown that metformin protects CSCs against the cisplatin-induced cell death when combining these two, which discord with previous studies [86]. Thus, it should be cautious to ascertain if metformin exerts inhibitory or protective effects on specifically originated CSCs.
6. Conclusion
Metformin is a cheap and nontoxic first-line antidiabetic medicine. It is an attractive drug that is being repurposed for multiple usages in treatment of other diseases in addition to diabetes. Metformin implements its function through AMPK-dependent and independent mechanisms. Preclinical and retrospective clinical investigations have inspired clinical trials of metformin use in various cancer therapies. It is a promising drug in neoadjuvant and adjuvant therapies. We hope these trials will come to end with positive or negative results in the next few years. In considering genetic heterogeneity of cancer, responses of different cancer types and subpopulations in the same cancer might be different. Therefore, we still have long way to go and loads of questions to be addressed.
Acknowledgments
ZL is supported by the National Natural Science Foundation of China (81572753, 31660332) and the Innovation and Entrepreneurship grant from Jiangxi Provincial Bureau of Foreign Experts, China.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"metformin, AMPK, mTORC1, diabetes, lipogenesis, cancer prevention and therapy, clinical trials",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71132.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71132.xml",downloadPdfUrl:"/chapter/pdf-download/71132",previewPdfUrl:"/chapter/pdf-preview/71132",totalDownloads:307,totalViews:0,totalCrossrefCites:1,totalDimensionsCites:2,hasAltmetrics:1,dateSubmitted:"September 23rd 2019",dateReviewed:"January 21st 2020",datePrePublished:"February 18th 2020",datePublished:null,dateFinished:null,readingETA:"0",abstract:"Metformin, the first-line antidiabetic drug, has become an attractive candidate in cancer therapy since retrospective clinical investigations reported that patients with type 2 diabetes receiving metformin had lower incidence of cancer than those with other glucose lowering drugs. In line with this, preclinical studies have demonstrated that the antitumor activity of metformin could proceed through several mechanisms. Thus far, metformin has been used in cancer prevention with reduced risk as consequence and treatment of various cancers as an adjuvant or neoadjuvant drug. Thus, existing data support the beneficial effects of metformin on many types of cancers such as reducing metastasis and mortality and improving pathological responses and survival rates. However, some reports do not support this and even show adverse effects. The discrepancy may be attributed to expression levels of its transporters or genetic background. Hence, this chapter briefly reviews information on the mechanism of metformin action and summarizes both completed and ongoing clinical trials in an attempt to evaluate the value of metformin in prevention and treatment of various cancer types.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71132",risUrl:"/chapter/ris/71132",book:{slug:"metformin"},signatures:"Yile Jiao, Xiaochen Wang and Zhijun Luo",authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Targets of metformin",level:"1"},{id:"sec_3",title:"3. Clinical investigations",level:"1"},{id:"sec_3_2",title:"3.1 The role of metformin in radiotherapy and chemotherapy",level:"2"},{id:"sec_4_2",title:"3.2 Breast cancer",level:"2"},{id:"sec_5_2",title:"3.3 Colon cancer",level:"2"},{id:"sec_6_2",title:"3.4 Endometrial cancer",level:"2"},{id:"sec_7_2",title:"3.5 Acute lymphoid leukemia",level:"2"},{id:"sec_8_2",title:"3.6 Oesophagal cancer",level:"2"},{id:"sec_9_2",title:"3.7 Prostate cancer",level:"2"},{id:"sec_11",title:"4. Ongoing clinical trials",level:"1"},{id:"sec_12",title:"5. Cautions to be considered",level:"1"},{id:"sec_12_2",title:"5.1 Cancer type-specific effects",level:"2"},{id:"sec_13_2",title:"5.2 Genetic background of cancer",level:"2"},{id:"sec_14_2",title:"5.3 Sensitivity of cancer stem cells",level:"2"},{id:"sec_16",title:"6. Conclusion",level:"1"},{id:"sec_17",title:"Acknowledgments",level:"1"},{id:"sec_20",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-1585. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28776086'},{id:"B2",body:'Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metabolism & Disposition. 2007;35(10):1956-1962. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27011019'},{id:"B3",body:'Mazza A, Fruci B, Garinis GA, Giuliano S, Malaguarnera R, Belfiore A. The role of metformin in the management of NAFLD. Experimental Diabetes Research. 2012;2012:1-13. Available from: http://www.hindawi.com/journals/jdr/2012/716404/'},{id:"B4",body:'Ghatak SB, Dhamecha PS, Bhadada SV, Panchal SJ. 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Available from: http://link.springer.com/10.1007/s12263-015-0499-6'},{id:"B86",body:'Kuo SZ, Honda CO, Li WT, Honda TK, Kim E, Altuna X, et al. Metformin results in diametrically opposed effects by targeting non-stem cancer cells but protecting cancer stem cells in head and neck squamous cell carcinoma. International Journal of Molecular Sciences. 2019;20(1):193. Available from: https://www.mdpi.com/1422-0067/20/1/193'},{id:"B87",body:'Imamura K, Ogura T, Kishimoto A, Kaminishi M, Esumi H. Cell cycle regulation via p53 phosphorylation by a 5′-AMP activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-β--ribofuranoside, in a human hepatocellular carcinoma cell line. Biochemical and Biophysical Research Communications. 2001;287(2):562-567. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0006291X0195627X'},{id:"B88",body:'Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Molecular Cell. 2005;18(3):283-293. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1097276505012207'},{id:"B89",body:'Zhou J, Huang W, Tao R, Ibaragi S, Lan F, Ido Y, et al. Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. Oncogene. 2009;28(18):1993-2002. Available from: http://www.nature.com/articles/onc200963'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Yile Jiao",address:null,affiliation:'
Queen Mary School, Nanchang University, Nanchang, China
Queen Mary School, Nanchang University, Nanchang, China
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\n
1. Introduction
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Ocular hypertension occurs when the pressure in the eye (intraocular pressure or IOP) is beyond the normal value with no signs of vision loss or damage to the optic nerve. [1] With ocular hypertension, the aqueous humor (fluid produced by the eye) is poorly drained. The buildup of fluid in the eye leads to an increase in IOP that could potentially lead to damage of the optic nerve, causing glaucoma. [2] The mean normal IOP is 15 mmHg and the mean IOP of untreated glaucoma is 18 mm Hg. [1] Ocular hypertension typically presents with no signs or symptoms, making it difficult to detect without access to an eye exam. Individuals with elevated IOP may be treated with cataract surgery and lensectomy. [2, 3] To properly address populations at risk for ocular hypertension, it is advantageous to determine how demographic variables may impact an individual’s susceptibility to blindness. Demographic variables are innate or non-changeable determinants of a disease. Addressing inequities in wealth, health, and access to medical care, as well as improved education on the benefits of early surgical intervention, can bend the curve of blindness from glaucoma. In this chapter, we use epidemiologic studies focusing specifically on Blacks to describe the prevalence and management of ocular hypertension.
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2. Prevalence of ocular hypertension in blacks
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In 2019, Black Americans made up 12.8% of US population, accounting for over 42 million people. [4] Although Blacks make up a minority of the population, many eye diseases, including ocular hypertension and glaucoma, affect a disproportionate number of Blacks, leading to higher rates of vision loss than documented in white-Americans. [5] Definitions of race and ethnicity have been ill-defined in past medical literature, with many overlaps. Therefore, the term “Blacks” in this context refers to an individual of black African descent. The population of Blacks in the Caribbean is over 21 million and in Africa is close to one billion. [6] There are also issues of decreased access to surgery in both locations. [7]
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While it has been universally accepted and documented that Blacks have higher prevalence of ocular hypertension, the degree of prevalence may differ for varying black populations. For example, the black-American and black-Caribbean populations studied in the Baltimore Eye Survey and the Barbados Eye Study, respectively, are ethnically unique. Both populations of Blacks presented with a high prevalence of ocular hypertension, but to a different degree. The prevalence of ocular hypertension in the black-Caribbean population was reported at levels nearly twice that of the black-American population. [8, 9, 10, 11] Studies have also reported a notably higher prevalence of ocular hypertension in Blacks in comparison to other racial groups (primarily white). [12, 13]
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In response to a lack of substantial ocular research with Black study participants, extensive population-based studies including the Baltimore Eye Survey [9], The Ocular Hypertension Treatment Study [2], The Barbados Eye Study [8], and the African American Eye Disease Study [13] were created to address the disproportionate prevalence of eye diseases present in Blacks. Further studies are needed to continue to build upon this body of research, particularly to look at earlier interventions of cataract surgery and trabecular bypass as an earlier intervention to prevent glaucoma.
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3. Mechanism of ocular hypertension in blacks
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Studies have shown that with age the crystalline lens increases in width. During accommodation, the iris bows posteriorly. With age there is increased contact between the posterior iris pigment epithelium and lens zonules leading to pigment liberation and obstruction of the trabecular meshwork. [14] This is often seen with heavier pigment in the trabecular meshwork inferiorly compared to superiorly on gonioscopy. [15] The increased width of the lens can also lead to pupillary block and iris obstruction of the trabecular meshwork leading to elevated intraocular pressure. This common mechanism of ocular hypertension in persons over the age of 50 is often overlooked by physicians. Current physicians and those in training must be better educated to look for this clinically and intervene promptly. Early cataract surgery and lensectomy is beneficial to remove the large lens and trabecular bypass to restore aqueous outflow via the obstructed trabecular meshwork. [14]
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4. Genetic influence on ocular hypertension
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Previous studies have shown intraocular pressure (IOP) to be highly heritable, indicating possible genetic influence on the development of ocular hypertension. [12, 16] There is additional substantial evidence suggesting that ocular hypertension leading to glaucoma may have a genetic component [17], but the specific genetic risk factors have not yet been identified. A 2012 genome wide association study conducted in 11,972 participants from The Netherlands, UK, Australia, and Canada investigated candidate genes in human ocular tissue to identify susceptibility to elevated IOP and glaucoma. [12] Elevated IOP commonly occurs in patients over the age of 50 and often presents with enlargement of the lens, narrowing of the angle, iridolenticular apposition, or pigment liberation that obstructs the trabecular meshwork. Genes regulating these ocular components were studied and the results revealed that genetic variants expressed in genes GAS7 and TMCO1 were associated with changes in IOP in the populations studied. Both revealed only marginal evidence for ocular hypertension, as GAS7 was associated with a 0.19 mmHg decrease in IOP and TMCO1 was associated with a 0.28 mmHg increase in IOP. [12] Additional findings revealed that individuals of European ancestry expressed the GAS7 variant at 0.44 frequency while those of African ancestry expressed the same variant at 0.12 frequency. [12] The lower frequency of this variant in Blacks may reflect the elevated IOP common in individuals of African descent and requires further research.
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While impressive strives have been made over the past two decades to identify genetic components of ocular diseases [18], a comprehensive understanding of the pathophysiology has frequently been limited to individuals of European and Asian ancestry, requiring an increased need for genetic research in Blacks and other understudied populations. For example, multiple genetic variants in genes associated with elevated IOP were discovered in non-Black populations and a majority do not replicate, nor have an effect, in Blacks. [19, 20, 21] In response to an increased need for the identification of genetic risk factors that underlie elevated IOP in the understudied population of Blacks, the Primary Open-Angle African American Glaucoma Genetics (POAAGG) study was created in 2014 and took place over the course of five years to address these research disparities. [22] This study identified a genetic variation known as a single nucleotide polymorphism (SNP) involved in the homeostasis of the trabecular meshwork. [23] The trabecular meshwork (TM) is located in the anterior portion of the eye and regulates the outflow of the aqueous humor into circulation. [24] If resistance increases in the TM during aqueous humor outflow, intraocular pressure may rise leading to ocular hypertension. By identifying a genetic variant that may affect the TM in Blacks, the POAAGG study has made a pertinent finding to our understanding of the role of genetics in ocular hypertension and glaucoma. As one of the first large cohort studies with over 5,000 study participants, additional analyses are needed to further validate the implications of this study.
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In addition, the progression of elevated IOP in Blacks leading to ocular hypertension is likely a combination of genetic, environmental, aging and socioeconomic factors, as well as others not mentioned. These demographic variables will continue to be explored throughout this chapter.
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4.1 Central corneal thickness in ocular hypertension
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Intraocular pressure is routinely measured in clinical practice to assess various conditions within the eye, including that of the optic nerve and visual field. [25] Goldmann applanation tonometry is the most common technique used to measure IOP, but its accuracy and use as a diagnostic tool may be impeded by the rigidity of the cornea. [25] A thicker cornea may cause an overestimate of IOP and a thinner cornea may cause an underestimate of IOP. The consensus on the necessity to correct IOP based on central corneal thickness is not yet clear. While CCT is statistically significant as a predictor of glaucoma development [2], it does not present as an independent risk factor. [26]
\n
The Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) recognized central corneal thickness as one of the most significant predictors for primary open-angle glaucoma. [2, 27] The mean central corneal thickness is about 560 μ m and the risk for developing ocular hypertension has been reported to nearly double (hazard ratio of 1.82) for every 40 μm decrease. [28] Patients with thin corneas (<555 μm) [2] may present with an underestimated IOP reading, placing the individual at potential risk if actual IOP is elevated. The primary diagnostic criteria for ocular hypertension is IOP, so any factor that hinders this measurement may lead to an errant diagnosis. Patients with ocular hypertension typically present with thicker corneas, which may lead to an overestimation of IOP, while primary open angle glaucoma patients present with thinner corneas. [29] While the influence of elevated IOP on central corneal thickness has not yet been determined, individuals whose IOPs have been reduced pharmacologically by at least 20% demonstrated no change in corneal thickness. [30]
\n
Differences in central corneal thickness were noted between black Americans and white Americans. In the OHTS, Blacks were found to have thinner central corneal thickness (555.7 μm), resulting in lower applanation readings and a miscalculated estimation of the true level of IOP. [30] The South African Eye Study [31] also measured differences in central corneal thickness and compared the findings to measurements of intraocular pressure in Blacks, mixed ethnicity peoples, and whites. The findings revealed that Blacks had the thinnest corneas and highest IOP, followed by mixed ethnicity then white individuals.
\n
These results suggest the possible need for refining the risk factor definitions when measuring central corneal thickness and IOP in varying populations. While obtaining a central corneal thickness measurements for all patients may not be necessary, patients with ocular hypertension should continue to be monitored to measure accurate IOP and determine possible susceptibility to glaucoma.
\n
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4.2 Morphological changes in the retinal nerve fiber layer in ocular hypertension
\n
Differing from glaucoma, ocular hypertension presents with a normal optic nerve and no signs of damage. Ocular hypertension is often a precursor to glaucoma as abnormally high pressures in the eye may lead to damage of the optic nerve causing vision loss or blindness. [1] Studies have indicated differences in the structure of the optic nerve between Blacks and whites. [32, 33] The optic disc area was 12% larger in Blacks compared to Whites. [32] The larger optic nerve may cause a greater strain at similar pressure levels, but it is not clear if larger optic discs affect one’s susceptibility to ocular hypertension as there are incongruous reports. [10, 34] The impact of these differences has been postulated to affect the increased susceptibility of Blacks to ocular hypertension and glaucoma.
\n
The retinal nerve fiber layer (RNFL) is primarily comprised of retinal ganglion cell axons that progressively diminish in glaucoma. As a result, the RNFL thins considerably and may present as an early manifestation of glaucoma. [35] As a precursor to glaucoma, RNFL was measured in patients with ocular hypertension and the results revealed a significant thinning of RNFL of about 15% in ocular hypertensive eyes as compared to normal eyes [36] Other studies have yet to demonstrate significant differences RNFL between normal eyes and those with ocular hypertension, possibly due to the sensitivity of the instruments used to measure and the study population. [36, 37]
\n
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5. Inequities contributing to ocular hypertension in blacks
\n
Vision loss is a pertinent public health challenge that requires the efforts of many to overcome. [38, 39] Addressing these disparities involves contending with the pervasive economic and racial inequalities that have had a disproportionate impact on Blacks, particularly in healthcare utilization. These inequities are evident in a 2020 study documenting the recency of eye examinations among black adults over the age of 55. [40] In this study, 13.4% of participants (n = 740) reported having no eye examination in the last five years and nearly 25% had not had an eye exam in the last year. [40] Concerningly, 20% of study participants with diabetes mellitus were not instructed by other healthcare providers to seek annual eye examinations.
\n
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5.1 Health and wealth inequities in blacks
\n
Systemic and social inequities have resulted in poor health outcomes in Blacks. [41] When examining wealth in the United States, there is countless evidence of extensive racial disparities. In 2016, the net worth of the average white family in the US was nearly ten times more than that of a Black family at $171,000 and $17,150 respectively. [42] These extensive differences in wealth and income reflect the consequences of years of discrimination, segregation, and inequality that mark the history of the US from its inception. The wealth gap between Blacks and whites in the US demonstrates the differences in opportunity afforded to citizens. [42] Colonialism has contributed to similar wealth disparities in the Caribbean and Africa. Differing from the circumstances in developing countries, the eye health care system in the United States is highly capable of delivering the care necessary to treat patients. [41, 43] However, much improvement is needed in the means by which education is delivered to the public and effective screening may take place.
\n
The history of medicine and health care in the United States is tainted by a myriad of forms of injustice and violence towards Blacks that includes segregation of medical facilities, unequal healthcare access, and disdainful medical experimentation. [44, 45] Today, these inequalities are especially evident in employment, housing, and wealth opportunities in medically underserved areas and populations (MUA/P). [46, 47, 48] MUA/P have been defined by the Health Resources and Services Administration as areas or populations having too few health care providers, high poverty or high elderly populations. [49] In addition, there are also social factors that have had strong implications on the health outcomes of Blacks, particularly poverty, food insecurity, and affordable housing. Low-socioeconomic status and race have been independently associated with increased vision loss placing poor Blacks at an increased risk. [47] These social factors that have often led to poor health outcomes in Blacks are rooted in racism and implicit biases that have to be recognized and changed at the personal, medical, and institutional level in order to lead to change. [50]
\n
Many studies have reported the association between visual impairment and poor quality of life, as well as physical and mental illness. [51, 52, 53] Unilateral and bilateral vision loss and blindness can impact a person’s quality of life by affecting their ability to read, walk, commute, and carry out daily activities. [54] In addition to the disparities previously mentioned, blindness can exasperate the inequities faced by Blacks in the US. Early treatment of ocular hypertension by reducing elevated IOP by 20% can reduce the risk of developing glaucoma in half [2], thereby reducing the risk of blindness. Earlier cataract surgery, clear lensectomy, and trabecular bypass may reduce it even more. Implementing measures to address ocular hypertension in Blacks can help reduce the risk of blindness and address health inequities in the medical community. In addition, public policy is needed to develop models of healthcare that make services more accessible, particularly in communities that are medically underserved.
\n
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5.2 Insurance and access to care
\n
Access to health care can impact one’s health outcomes. The utilization of healthcare may be determined by whether people know care is needed, whether obtaining care is wanted, and whether care can be accessed. [55] Access is often used to describe the ease of obtaining care, including its availability, the accommodations provided, and affordability. Health care in the United States often cannot be utilized without insurance, regardless of the presence of a healthcare provider that is geographically accessible. The public health challenge regarding ocular hypertension is that if the elevated IOP was detected earlier on, further exasperation of the condition could be slowed and potential diseases could be prevented. [56, 57] With newer surgical approaches progression can be halted with earlier cataract surgery/clear lensectomy and trabecular bypass.
\n
Successful treatments for elevated IOP have included topical medications, surgery, or laser. [58] Reducing IOP significantly may lead to a delay in progression to optic nerve damage, visual field loss, or glaucoma. [59] Several studies have reported the impact of lack of medical care on health outcomes. [60, 61] The Salisbury Eye Evaluation Study [62] was a population-based study that sought to investigate the causes of blindness and visual impairments of adults between the ages of 65 and 84. The study revealed higher levels of blindness and visual impairments in Blacks compared to whites, with 37% of the conditions classified as surgically treatable and 44% categorized as targets for low vision remediation. The study was not able to identify patients whose eye condition was amenable and chose not to undergo surgery for reasons including financial barriers, fear of the surgical procedure, or absence of functional loss. It is important to encourage all patients, particularly those with ocular hypertension, to seek continuous to monitor their condition.
\n
The Affordable Care Act (ACA) was enacted in March 2010 with its primary goals being to make affordable health insurance available to more people and to generally lower the cost of health care. [63] Better health outcomes in Blacks have been linked to increases in health insurance coverage under the ACA. [64] While uninsured rates were reduced, Black Americans remained 1.5 times more likely to be uninsured than non-Hispanic white Americans. [65] Additionally, data gained from the National Health Interview Survey conducted between 2014–2016 revealed that access and utilization of eye care is lower among racial and ethnic minorities. [66]. Increased access to health care and affordable insurance may improve the health outcomes of vulnerable populations with ocular hypertension.
\n
\n
\n
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6. Patient education for ocular hypertension
\n
Patient education is an interactive process in which learning may take place between the healthcare provider and the patient. Increased patient education of vision health may lead to an increasing trend of eye doctor visits. Previous studies have reported that those with more education are more likely to seek care from an eye care professional as opposed to those with less education [67]. As a result of ocular hypertension, many Black patients were reported to present to an ophthalmologist with more extensive damage to the optic nerve as compared to whites. [68] As a result, the disease progression in Blacks was more vulnerable to malignancy even after intervention is initiated. Safer earlier cataract surgery and trabecular bypass are important treatment options that should be offered earlier.
\n
Educating patients on ocular hypertension involves sharing the risk factors associated with the eye condition such as family history, age, medical conditions, and past eye injuries, as well prevention and treatment options. Due to the asymptomatic presentation of ocular hypertension with no signs of vision loss, it is possible that patients have not/will not seek treatment until further damage and vision loss occur. Prior recorded interactions between physicians and patients have found that providers were less likely to educate Black patients about glaucoma and were also less likely to educate patients of lower health literacy about glaucoma medications. [69] It is important for the patient’s eye health that ocular hypertension and its potential progression to glaucoma are described and apprehensible, particularly to those in populations most at risk. Through patient education of ocular hypertension, the patient may better understand their susceptibility to eye disease and can seek early treatment if necessary.
\n
\n
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7. Prevention and implementation of changes to address ocular hypertension in blacks
\n
Given the information presented in this chapter, initiation of treatment for ocular hypertension may be started earlier in Blacks with the possibility of arresting or reducing elevated IOP. The aging population of adults aged 65 and older is continuously increasing with expectation of this number to reach nearly 90 million in the US by 2050. [70] In addition, growing levels of obesity increasing the prevalence of diabetes make an increasing number of individuals at risk for vision loss in the future. As the risk factors for ocular hypertension increase, recognition of patient vulnerabilities and systemic level changes are needed to ensure that the needs of patients are properly and conveniently addressed.
\n
\n
\n
8. Conclusion
\n
This chapter has demonstrated the unique demographic and ocular characteristics that have affected Blacks in the progression of ocular hypertension. The combination of race, socioeconomic status, and access to treatment may influence the diagnosis and health outcome of individuals with ocular hypertension. Acknowledging these factors and implementing changes to promote early diagnosis and treatment, as well as addressing health and wealth disparities in high-risk populations, can lead to lower rates of glaucoma and blindness. Physician advice through patient education, as well as affordability, continuity, and frequent access to care has demonstrated a strong association with increased eye care services. [71] Diagnosis and early intervention of elevated levels of intraocular pressure and ocular hypertension may reduce the risk of glaucoma, vision loss, and blindness in future patients.
\n
\n
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"ocular hypertension, glaucoma, Blacks, cataract surgery, trabecular bypass, African-American",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75503.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75503.xml",downloadPdfUrl:"/chapter/pdf-download/75503",previewPdfUrl:"/chapter/pdf-preview/75503",totalDownloads:3,totalViews:0,totalCrossrefCites:0,dateSubmitted:"December 15th 2020",dateReviewed:"February 12th 2021",datePrePublished:"March 2nd 2021",datePublished:null,dateFinished:"March 2nd 2021",readingETA:"0",abstract:"Ocular hypertension occurs when intraocular pressure (IOP) is greater than the normal range with no evidence of vision loss or damage to the optic nerve. Individuals with ocular hypertension have an increased risk for glaucoma. The mean normal IOP is 15 mmHg and the mean IOP of untreated glaucoma is 18 mmHg. Elevated IOP commonly occurs in patients over the age of 50 and is often due to enlargement of the lens, narrowing of the angle, iridolenticular apposition, and pigment liberation that obstructs the trabecular meshwork. Cataract surgery and lensectomy can lower IOP and reduce the risk of glaucoma. The global wealth inequality of Blacks has created health inequities that have led to decreased access to surgical care contributing to higher rates of blindness from glaucoma. Greater education on the benefits of early cataract surgery and trabecular bypass for higher risk patients, as well as addressing wealth and health inequities, can help to bend the curve of blindness from glaucoma.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75503",risUrl:"/chapter/ris/75503",signatures:"Daniel Laroche and Kara Rickford",book:{id:"10343",title:"Ocular Hypertension",subtitle:null,fullTitle:"Ocular Hypertension",slug:null,publishedDate:null,bookSignature:"Prof. Michele Lanza",coverURL:"https://cdn.intechopen.com/books/images_new/10343.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"240088",title:"Prof.",name:"Michele",middleName:null,surname:"Lanza",slug:"michele-lanza",fullName:"Michele Lanza"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Prevalence of ocular hypertension in blacks",level:"1"},{id:"sec_3",title:"3. Mechanism of ocular hypertension in blacks",level:"1"},{id:"sec_4",title:"4. Genetic influence on ocular hypertension",level:"1"},{id:"sec_4_2",title:"4.1 Central corneal thickness in ocular hypertension",level:"2"},{id:"sec_5_2",title:"4.2 Morphological changes in the retinal nerve fiber layer in ocular hypertension",level:"2"},{id:"sec_7",title:"5. Inequities contributing to ocular hypertension in blacks",level:"1"},{id:"sec_7_2",title:"5.1 Health and wealth inequities in blacks",level:"2"},{id:"sec_8_2",title:"5.2 Insurance and access to care",level:"2"},{id:"sec_10",title:"6. Patient education for ocular hypertension",level:"1"},{id:"sec_11",title:"7. Prevention and implementation of changes to address ocular hypertension in blacks",level:"1"},{id:"sec_12",title:"8. Conclusion",level:"1"},{id:"sec_16",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'\nSommer, A. 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DOI: 10.1016/S0140-6736(20)32032-8.\n'},{id:"B47",body:'\nAmerican Bar Association. The Impact of Structural Racism in Employment and Wages on Minority Women’s Health [Internet] 2018. Available from: https://www.americanbar.org/groups/crsj/publications/human_rights_magazine_home/the-state-of-healthcare-in-the-united-states/minority-womens-health/ [Accessed 02-01-2021]\n'},{id:"B48",body:'\nThe Federal Reserve System. Disparities in Wealth by Race and Ethnicity in the 2019 Survey of Consumer Finances [Internet] 2020. Available from: https://www.federalreserve.gov/econres/notes/feds-notes/disparities-in-wealth-by-race-and-ethnicity-in-the-2019-survey-of-consumer-finances-20200928.htm [Accessed 02-01-2021]\n'},{id:"B49",body:'\nHealth Resources & Services Administration. MUA Find [Internet] 2021. Available from: https://data.hrsa.gov/tools/shortage-area/mua-find#:~:text=Medically%20Underserved%20Areas%2FPopulations%20are,or%20a%20high%20elderly%20population. [Accessed 02-01-2021]\n'},{id:"B50",body:'\nEnding systemic racism in medicine. Nature Medicine. 2020;26:985. DOI: 10.1038/s41591-020-0993-2\n'},{id:"B51",body:'\nKuczmarski AV, Cotugna N, Mason MA, Evans MK, Zonderman AB. Depression and Cognitive Impairment Are Associated with Low Education and Literacy Status and Smoking but Not Caffeine Consumption in Urban African Americans and White Adults. Journal of caffeine research. 2015;5(1):31-41. DOI: 10.1089/jcr.2014.0019\n'},{id:"B52",body:'\nTseng YC, Liu SH, Lou MF, Huang GS. Quality of life in older adults with sensory impairments: a systematic review. Quality of Life Research. 2018;27(8):1957-1971. DOI: 10.1007/s11136-018-1799-2.\n'},{id:"B53",body:'\nSwenor BK, Lee MJ, Varadaraj V, Whitson HE, Ramulu PY. Aging With Vision Loss: A Framework for Assessing the Impact of Visual Impairment on Older Adults. Gerontologist. 2020;60(6):989-995. DOI: 10.1093/geront/gnz117.\n'},{id:"B54",body:'\nVu HT, Keeffe JE, McCarty CA, Taylor HR. Impact of unilateral and bilateral vision loss on quality of life. British Journal of Ophthalmology. 2005;89(3):360-3. DOI: 10.1136/bjo.2004.047498.\n'},{id:"B55",body:'\nNational Academies of Sciences, Engineering, and Medicine. Health-Care Utilization as a Proxy in Disability Determination [Internet] 2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK500102/ doi: 10.17226/24969 [Accessed 02-01-2021]\n'},{id:"B56",body:'\nSommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall RM, Witt KA, Ezrine S. Racial differences in the cause-specific prevalence of blindness in east Baltimore. New England Journal of Medicine. 1991;325(20):1412-7. DOI: 10.1056/NEJM199111143252004.\n'},{id:"B57",body:'\nJohnson CA, Keltner JL, Cello KE, et al. Baseline visual field characteristics in the ocular hypertension treatment study. Ophthalmology. 2002;109(3):432-7. DOI: 10.1016/s0161-6420(01)00948-4\n'},{id:"B58",body:'\nLaroche D, Nkrumah G, Ng C. Real-world efficacy of the Hydrus microstent in Black and Afro-Latinx patients with glaucoma: a retrospective study. Therapeutic Advances in Ophthalmology 2020;12 1-9.\n'},{id:"B59",body:'\nHeijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Archives of Ophthalmology. 2002;120(10):1268-79. doi: 10.1001/archopht.120.10.1268.\n'},{id:"B60",body:'\nWashington DL. Charting the path from lack of insurance to poor health outcomes. Western Journal of Medicine. 2001;175(1):23. DOI: 10.1136/ewjm.175.1.23.\n'},{id:"B61",body:'\nInstitute of Medicine (US) Committee on the Consequences of Uninsurance. Care Without Coverage: Too Little, Too Late. Effects of Health Insurance on Health [Internet] 2002. Available from: https://www.ncbi.nlm.nih.gov/books/NBK220636/ [Accessed 02-01-2021]\n'},{id:"B62",body:'\nMuñoz B, West SK, Rubin GS, et al. Causes of blindness and visual impairment in a population of older Americans: The Salisbury Eye Evaluation Study. Archives of Ophthalmology. 2000;118(6):819-25. DOI: 10.1001/archopht.118.6.819.\n'},{id:"B63",body:'\nHealthCare.Gov. Affordable Care Act (ACA) [Internet] 2020. Available from: https://www.healthcare.gov/glossary/affordable-care-act [Accessed 02-01-2021]\n'},{id:"B64",body:'\nSommers BD, McMurtry CL, Blendon RJ, et al. Beyond Health Insurance: Remaining Disparities in US Health Care in the Post-ACA Era. Milbank Quarterly. 2017;95(1):43-69. DOI: 10.1111/1468-0009.12245.\n'},{id:"B65",body:'\nKaiser Family Foundation.Changes in Health Coverage by Race and Ethnicity since the ACA, 2010-2018 [Internet] 2020. Available from: https://www.kff.org/racial-equity-and-health-policy/issue-brief/changes-in-health-coverage-by-race-and-ethnicity-since-the-aca-2010-2018/ [Accessed 02-01-2021]\n'},{id:"B66",body:'\nVaradaraj V, Frick KD, Saaddine JB, et al. Trends in Eye Care Use and Eyeglasses Affordability: The US National Health Interview Survey, 2008-2016. JAMA Ophthalmology. 2019;137(4):391-398. DOI: 10.1001/jamaophthalmol.2018.6799.\n'},{id:"B67",body:'\nOrr P, Barrón Y, Schein OD, et al. Eye care utilization by older Americans: the SEE Project. Salisbury Eye Evaluation. Ophthalmology. 1999;106(5):904-9. DOI: 10.1016/s0161-6420(99)00508-4.\n'},{id:"B68",body:'\nGreenidge KC, Dweck M. Glaucoma in the black population: a problem of blindness. Journal of the National Medical Association. 1988;80(12):1305-9.\n'},{id:"B69",body:'\nSleath B, Blalock SJ, Carpenter DM, et al. Provider Education about Glaucoma and Glaucoma Medications during Videotaped Medical Visits. Journal of Ophthalmology. 2014;2014:238939. DOI: 10.1155/2014/238939.\n'},{id:"B70",body:'\nPopulation Reference Bureau. America’s Aging Population [Internet] 2011. Available from: https://assets.prb.org/pdf11/aging-in-america.pdf [Accessed 02-01-2021]\n'},{id:"B71",body:'\nUnzueta M, Globe D, Wu J, et al. Compliance with recommendations for follow-up care in Latinos: the Los Angeles Latino Eye Study. Ethnicity & Disease. 2004;14(2):285-91.\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Daniel Laroche",address:"dlarochemd@aol.com",affiliation:'
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The Open Access Publishing Fee (OAPF) is payable only after your full chapter, monograph or Compacts monograph is accepted for publication.
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4,000 GBP Compacts Monograph - Short Form
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An online manuscript tracking system to facilitate your work
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Assurance that your manuscript meets the highest publishing standards
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English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Permanent and unrestricted online access to your work
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Open Access Funding
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Proven world leader in Open Access book publishing with over 10 years experience
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