Artificial Sweeteners: Systematic Review with ☸️SAIMSARA



saimsara.com • Download PDF

Abstract: The aim of this paper is to systematically review and synthesize the diverse research findings on artificial sweeteners, covering their physiological effects, environmental presence, and implications for human health, to identify key themes, clinical implications, and future research directions. The review utilises 781 studies with 401682 total participants (naïve ΣN). Higher consumption of artificial sweeteners is associated with an increased risk of cardiovascular and cardiometabolic disorders, with a median reported Odds Ratio or Hazard Ratio of 1.17 (range 1.0015-1.89). These associations extend to type 2 diabetes, certain cancers, and adverse reproductive outcomes, while also highlighting widespread environmental contamination. The primary limitation affecting the certainty of these findings is the predominance of observational study designs, which preclude definitive causal inference. Clinicians should advise patients, particularly pregnant women and those with cardiometabolic risks, to exercise caution regarding artificial sweetener intake, and future research should prioritize long-term, well-controlled human randomized controlled trials to establish causality.

Review Stats
Identification of studies via EPMC (titles/abstracts) Identification Screening Included Records identified:n=1598Records excluded:n=0 Records assessed for eligibilityn=1598Records excluded:n=817 Studies included in reviewn=781 PRISMA Diagram generated by ☸️ SAIMSARA
⛛OSMA Triangle Effect-of Predictor → Outcome artificial sweeteners  →  Outcome Beneficial for patients ΣN=1866 (0%) Harmful for patients ΣN=321120 (80%) Neutral ΣN=78696 (20%) 0 ⛛OSMA Triangle generated by ☸️SAIMSARA
Show OSMA legend
Outcome-Sentiment Meta-Analysis (OSMA): (LLM-only)
Frame: Effect-of Predictor → Outcome • Source: Europe PMC
Outcome: Outcome Typical timepoints: 5-y, 60-y. Reported metrics: %, CI, p.
Common endpoints: Common endpoints: mortality, functional, complications.
Predictor: artificial sweeteners — exposure/predictor. Doses/units seen: 843.0 μg, 5.2 mg, 192 mg, 16 µg, 7.96 mg, 200 mg…. Routes seen: oral, sc. Typical comparator: control groups, control, unsweetened beverages, lactobacillus strains when….

  • 1) Beneficial for patients — Outcome with artificial sweeteners — [15], [37], [45], [55], [87], [119], [158], [165], [194], [196], [230], [231], [244], [252], [278], [282], [290], [291], [347], [393], [435], [442], [445], [466], [467], [475], [486], [518], [520], [523], [524], [533], [565], [599], [603], [630], [636], [651], [708], [718], [748] — ΣN=1866
  • 2) Harmful for patients — Outcome with artificial sweeteners — [1], [2], [4], [7], [10], [13], [14], [21], [26], [29], [31], [32], [35], [38], [40], [41], [43], [44], [49], [53], [61], [69], [72], [73], [74], [75], [78], [82], [86], [88], [92], [93], [94], [99], [100], [101], [104], [105], [106], [107], [111], [113], [115], [117], [120], [121], [124], [125], [126], [128], [136], [140], [141], [143], [147], [150], [153], [155], [168], [174], [176], [179], [182], [184], [186], [188], [192], [198], [199], [201], [204], [206], [209], [212], [215], [218], [222], [223], [224], [225], [228], [233], [239], [240], [242], [245], [246], [251], [253], [254], [255], [258], [261], [265], [267], [268], [286], [287], [295], [311], [315], [320], [323], [325], [328], [331], [332], [333], [341], [349], [351], [352], [356], [358], [360], [361], [366], [367], [369], [377], [380], [381], [384], [387], [395], [403], [409], [417], [425], [440], [446], [448], [454], [459], [460], [471], [474], [476], [478], [479], [488], [491], [495], [496], [511], [531], [539], [541], [547], [550], [564], [567], [586], [588], [606], [618], [625], [629], [634], [642], [652], [653], [659], [668], [673], [674], [682], [696], [704], [729], [731], [743], [745], [759], [767], [768], [781] — ΣN=321120
  • 3) No clear effect — Outcome with artificial sweeteners — [3], [5], [6], [8], [9], [11], [12], [16], [17], [18], [19], [20], [22], [23], [24], [25], [27], [28], [30], [33], [34], [36], [39], [42], [46], [47], [48], [50], [51], [52], [54], [56], [57], [58], [59], [60], [62], [63], [64], [65], [66], [67], [68], [70], [71], [76], [77], [79], [80], [81], [83], [84], [85], [89], [90], [91], [95], [96], [97], [98], [102], [103], [108], [109], [110], [112], [114], [116], [118], [122], [123], [127], [129], [130], [131], [132], [133], [134], [135], [137], [138], [139], [142], [144], [145], [146], [148], [149], [151], [152], [154], [156], [157], [159], [160], [161], [162], [163], [164], [166], [167], [169], [170], [171], [172], [173], [175], [177], [178], [180], [181], [183], [185], [187], [189], [190], [191], [193], [195], [197], [200], [202], [203], [205], [207], [208], [210], [211], [213], [214], [216], [217], [219], [220], [221], [226], [227], [229], [232], [234], [235], [236], [237], [238], [241], [243], [247], [248], [249], [250], [256], [257], [259], [260], [262], [263], [264], [266], [269], [270], [271], [272], [273], [274], [275], [276], [277], [279], [280], [281], [283], [284], [285], [288], [289], [292], [293], [294], [296], [297], [298], [299], [300], [301], [302], [303], [304], [305], [306], [307], [308], [309], [310], [312], [313], [314], [316], [317], [318], [319], [321], [322], [324], [326], [327], [329], [330], [334], [335], [336], [337], [338], [339], [340], [342], [343], [344], [345], [346], [348], [350], [353], [354], [355], [357], [359], [362], [363], [364], [365], [368], [370], [371], [372], [373], [374], [375], [376], [378], [379], [382], [383], [385], [386], [388], [389], [390], [391], [392], [394], [396], [397], [398], [399], [400], [401], [402], [404], [405], [406], [407], [408], [410], [411], [412], [413], [414], [415], [416], [418], [419], [420], [421], [422], [423], [424], [426], [427], [428], [429], [430], [431], [432], [433], [434], [436], [437], [438], [439], [441], [443], [444], [447], [449], [450], [451], [452], [453], [455], [456], [457], [458], [461], [462], [463], [464], [465], [468], [469], [470], [472], [473], [477], [480], [481], [482], [483], [484], [485], [487], [489], [490], [492], [493], [494], [497], [498], [499], [500], [501], [502], [503], [504], [505], [506], [507], [508], [509], [510], [512], [513], [514], [515], [516], [517], [519], [521], [522], [525], [526], [527], [528], [529], [530], [532], [534], [535], [536], [537], [538], [540], [542], [543], [544], [545], [546], [548], [549], [551], [552], [553], [554], [555], [556], [557], [558], [559], [560], [561], [562], [563], [566], [568], [569], [570], [571], [572], [573], [574], [575], [576], [577], [578], [579], [580], [581], [582], [583], [584], [585], [587], [589], [590], [591], [592], [593], [594], [595], [596], [597], [598], [600], [601], [602], [604], [605], [607], [608], [609], [610], [611], [612], [613], [614], [615], [616], [617], [619], [620], [621], [622], [623], [624], [626], [627], [628], [631], [632], [633], [635], [637], [638], [639], [640], [641], [643], [644], [645], [646], [647], [648], [649], [650], [654], [655], [656], [657], [658], [660], [661], [662], [663], [664], [665], [666], [667], [669], [670], [671], [672], [675], [676], [677], [678], [679], [680], [681], [683], [684], [685], [686], [687], [688], [689], [690], [691], [692], [693], [694], [695], [697], [698], [699], [700], [701], [702], [703], [705], [706], [707], [709], [710], [711], [712], [713], [714], [715], [716], [717], [719], [720], [721], [722], [723], [724], [725], [726], [727], [728], [730], [732], [733], [734], [735], [736], [737], [738], [739], [740], [741], [742], [744], [746], [747], [749], [750], [751], [752], [753], [754], [755], [756], [757], [758], [760], [761], [762], [763], [764], [765], [766], [769], [770], [771], [772], [773], [774], [775], [776], [777], [778], [779], [780] — ΣN=78696



1) Introduction
Artificial sweeteners (ASs), also known as non-nutritive sweeteners (NNS) or low-calorie sweeteners (LCSs), are widely consumed as sugar substitutes, driven by perceived benefits for weight management and glycemic control. However, a growing body of research increasingly challenges these assumptions, revealing complex interactions with human physiology and the environment. Recent studies explore their impact on various health outcomes, including cardiometabolic disorders, cancer, gut microbiome alterations, and neurobehavioral changes. Concurrently, the environmental persistence and widespread detection of ASs in aquatic systems highlight their emerging role as environmental contaminants. This paper synthesizes the current scientific understanding of artificial sweeteners, drawing from a comprehensive review of recent literature.

2) Aim
The aim of this paper is to systematically review and synthesize the diverse research findings on artificial sweeteners, covering their physiological effects, environmental presence, and implications for human health, to identify key themes, clinical implications, and future research directions.

3) Methods
Systematic review with multilayer AI research agent: keyword normalization, retrieval & structuring, and paper synthesis (see SAIMSARA About section for details).


4) Results
4.1 Study characteristics:
The body of research on artificial sweeteners encompasses a wide array of study designs, including numerous cohort studies (e.g., [1, 2, 4, 8, 14, 16, 21, 29, 30, 34, 36, 37, 72, 73, 87, 93, 104, 115, 118, 124, 127, 136, 215, 292, 323, 333, 336, 337, 360, 368, 371, 384, 417, 430, 438, 442, 447, 449, 450, 451, 464, 469, 472]), mixed-methods studies combining observational data with experimental or in vitro approaches (e.g., [3, 5, 7, 10, 15, 17, 26, 27, 28, 31, 32, 33, 35, 38, 39, 40, 41, 42, 43, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 88, 89, 90, 91, 92, 94, 96, 97, 98, 99, 100, 101, 102, 103, 106, 107, 108, 109, 110, 111, 112, 113, 114, 116, 117, 119, 120, 121, 122, 125, 126, 128, 129, 130, 131, 132, 133, 134, 135, 137, 138, 139, 140, 141, 142, 144, 145, 146, 147, 148, 149, 151, 152, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 172, 173, 174, 175, 177, 178, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189, 190, 192, 193, 194, 195, 196, 197, 198, 201, 202, 203, 204, 205, 206, 207, 209, 210, 211, 212, 213, 214, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 237, 238, 239, 241, 242, 243, 244, 246, 247, 248, 249, 250, 251, 253, 254, 256, 257, 258, 259, 260, 261, 262, 263, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 283, 284, 285, 288, 289, 290, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 324, 325, 326, 327, 329, 330, 331, 332, 334, 335, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 357, 358, 359, 361, 362, 365, 366, 367, 369, 370, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, 383, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 418, 419, 420, 421, 422, 423, 424, 426, 427, 428, 429, 431, 434, 435, 439, 443, 445, 446, 448, 456, 458, 460, 461, 462, 463, 465, 466, 468, 469, 471, 475, 476, 479, 482, 483, 484, 485, 487, 489, 490, 491, 492, 494, 495, 496, 497, 498, 499]), cross-sectional studies (e.g., [9, 19, 22, 44, 93, 95, 129, 139, 140, 173, 208, 245, 252, 254, 256, 309, 310, 322, 328, 401, 433, 443, 446, 484]), and randomized controlled trials (RCTs) (e.g., [16, 59, 236, 264, 364, 441, 444, 453, 467, 470, 473, 480, 486, 493, 500]). Populations range from large human cohorts (e.g., UK Biobank [29, 30, 136], NutriNet-Santé [72, 104, 124, 141, 454]), pregnant women and their offspring [4, 105, 240, 333, 381, 384, 417], and specific patient groups (e.g., PCOS [1], cancer patients [2], T2D [16, 245], IBD [47, 94, 212, 251, 258, 401]), to animal models (e.g., mice [8, 26, 43, 58, 64, 75, 88, 108, 113, 125, 128, 138, 143, 147, 150, 153, 168, 179, 184, 204, 206, 216, 217, 222, 224, 242, 246, 267, 273, 281, 282, 294, 295, 296, 299, 317, 320, 321, 325, 331, 332, 351, 358, 360, 361, 363, 366, 372, 377, 387, 389, 395, 407, 408, 409, 411, 432, 435, 436, 440, 454, 455, 457, 463, 474, 476, 478, 480, 481, 491, 493], rats [43, 64, 74, 143, 147, 175, 204, 217, 295, 307, 311, 317, 320, 321, 331, 332, 358, 361, 369, 372, 377, 395, 425, 440, 445, 494], Drosophila [6, 18, 112, 138, 294, 363]), in vitro models (e.g., Caco-2 cells [5, 186, 188, 190, 192, 495, 496], human sweet receptor [24, 79, 272, 308, 463], pancreatic islet cells [148], prostate cancer cells [45], HepG2 cells [179, 184], human microglial cells [198]), and environmental samples (e.g., water, soil, sediment, wastewater [20, 23, 25, 34, 57, 60, 63, 78, 80, 84, 85, 86, 89, 91, 96, 100, 116, 146, 151, 161, 162, 166, 167, 169, 170, 180, 181, 202, 207, 211, 214, 218, 220, 228, 229, 232, 237, 262, 266, 269, 271, 274, 276, 277, 280, 283, 289, 292, 293, 298, 301, 303, 304, 315, 316, 319, 335, 336, 337, 340, 342, 344, 350, 371, 373, 375, 378, 379, 380, 385, 386, 402, 404, 405, 410, 412, 413, 415, 416, 418, 420, 422, 427, 429, 430, 437, 438, 447, 449, 450, 472, 477, 483, 489, 492, 497, 499]). Follow-up periods vary significantly, with many studies not specifying, while others range from acute (e.g., 24-48 hours [5]) to long-term (e.g., 1 year [8], 8 years [73], 9.1 years [72], 12.6 years [30]).

4.2 Main numerical result aligned to the query:
Across multiple human cohort studies, consumption of artificial sweeteners is associated with an increased risk of cardiovascular and cardiometabolic disorders. The median reported Odds Ratio (OR) or Hazard Ratio (HR) for these outcomes is 1.17, with values ranging from 1.0015 to 1.89 [14, 21, 29, 69, 104, 115, 124]. For instance, a study in Hungary reported an OR of 1.21 for cardiovascular disease prevalence [14], while another found a HR of 1.17 for overall cardiovascular disease [104]. Similarly, a large prospective cohort study reported an HR of 1.09 for cardiovascular diseases [124]. This heterogeneity in reported effect sizes reflects variations in study populations, specific sweeteners examined, and outcome definitions.

4.3 Topic synthesis:


5) Discussion
5.1 Principal finding:
The central finding of this review is that consumption of artificial sweeteners is associated with an increased risk of cardiovascular and cardiometabolic disorders, with a median reported Odds Ratio or Hazard Ratio of 1.17 (range 1.0015-1.89) [14, 21, 29, 69, 104, 115, 124]. This suggests that despite their intended role as healthier alternatives, artificial sweeteners may contribute to adverse health outcomes.

5.2 Clinical implications:


5.3 Research implications / key gaps:


5.4 Limitations:


5.5 Future directions:


6) Conclusion
Higher consumption of artificial sweeteners is associated with an increased risk of cardiovascular and cardiometabolic disorders, with a median reported Odds Ratio or Hazard Ratio of 1.17 (range 1.0015-1.89) [14, 21, 29, 69, 104, 115, 124]. These associations extend to type 2 diabetes, certain cancers, and adverse reproductive outcomes, while also highlighting widespread environmental contamination. The primary limitation affecting the certainty of these findings is the predominance of observational study designs, which preclude definitive causal inference. Clinicians should advise patients, particularly pregnant women and those with cardiometabolic risks, to exercise caution regarding artificial sweetener intake, and future research should prioritize long-term, well-controlled human randomized controlled trials to establish causality.

References
SAIMSARA Session Index — session.json

Figure 1. Publication-year distribution of included originals
Figure 1. Publication-year distribution of included originals

Figure 2. Study-design distribution of included originals
Figure 2. Study-design distribution

Figure 3. Study-type (directionality) distribution of included originals
Figure 3. Directionality distribution

Figure 4. Main extracted research topics
Figure 4. Main extracted research topics (Results)

Figure 5. Limitations of current studies (topics)
Figure 5. Limitations of current studies (topics)

Figure 6. Future research directions (topics)
Figure 6. Future research directions (topics)