Blood glucose control in acute stroke patients under total energy restriction with different carbohydrate intake and SGLT2 inhibitors availability: a retrospective cohort study

Hyperglycemia in acute stroke patients worsens neurological outcomes. However, effective and safe management during the acute stage has not been established. Therefore, we aimed to compare the effect of medications and nutrition therapy on blood glucose control in three cohorts with different carbohydrate content and availability of sodium-glucose cotransporter 2 inhibitors (SGLT2is) to identify the current optimal treatment for acute-stage hyperglycemia. We retrospectively studied patients with acute stroke admitted to our hospital between 2011 and 2019. We divided the study period into three periods as follows: traditional (Td, 2011–2013), transition (Ts, 2013–2014), and novel (N, 2014–2019). To evaluate glucose-lowering efficacy and safety, we included conscious patients with glycated hemoglobin A1c ≥6.5%, blood glucose levels ≥11.1 mmol/L, normal renal function at admission, oral diet and medications, and fasting blood glucose (FBG) test on day 7. We performed total energy restriction (TER) in each period with different carbohydrate contents: 60% in Td, 40% in Ts, and N. The attending physicians chose glucose-lowering medications. SGLT2is were available in the N period only. Our target FBG was <7 mmol/L by day 7. The 26, 22 and 36 patients were enrolled in the Td, Ts and N periods. The blood glucose levels significantly decreased by day 7 in all periods. The target FBG was achieved in 30.8% of Td patients, 31.8% of Ts patients, and 72.2% of N patients. The N period had the highest population of achieving the target FBG. The 40%-carbohydrate diet based on TER plus SGLT2is was the most effective way to lower blood glucose levels. The N period had the highest population of positive urine ketones. However, no symptomatic ketoacidosis occurred. A 40%-carbohydrate diet based on TER combined with SGLT2is might be a potentially effective and safe treatment for hyperglycemia in acute stroke-conscious patients.

Carbohydrate; Diabetes; Energy restriction, Hyperglycemia; SGLT2; Stroke

[1] Kruyt ND, Biessels GJ, DeVries JH, Roos YB. Hyperglycemia in acute ischemic stroke: pathophysiology and clinical management. Nature Reviews Neurology. 2010; 6: 145–155.

[2] Saxena A, Anderson CS, Wang X, Sato S, Arima H, Chan E, et al. Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: the INTERACT2 study. Stroke. 2016; 47: 682–688.

[3] Johnston KC, Bruno A, Pauls Q, Hall CE, Barrett KM, Barsan W, et al. Intensive vs standard treatment of hyperglycemia and functional outcome in patients with acute ischemic stroke: the SHINE randomized clinical trial. JAMA. 2019; 322: 326–335.

[4] Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, et al. Japanese clinical practice guideline for diabetes 2019. Diabetology International. 2020; 11: 165–223.

[5] American Diabetes Association. Facilitating behavior change and well-being to improve health outcomes: standards of medical care in Diabetes-2021. Diabetes Care. 2021; 44: S53–S72.

[6] Gray CS, Hildreth AJ, Sandercock PA, O’Connell JE, Johnston DE, Cartlidge NE, et al. Glucose-potassium-insulin infusions in the management of post-stroke hyperglycaemia: the UK glucose insulin in stroke trial (GIST-UK). The Lancet Neurology. 2007; 6: 397–406.

[7] Gerstein HC, Miller ME, Byington RP, Goff J, Bigger JT, Buse JB, et al. Effects of intensive glucose lowering in type 2 diabetes. The New England Journal of Medicine. 2008; 358: 2545–2559.

[8] ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. The New England Journal of Medicine. 2008; 358: 2560–2572.

[9] Duckworth W, Abraira C, Moritz T. Glucose control and vascular complications in veterans with type 2 diabetes. Journal of Vascular Surgery. 2009; 49: 1084.

[10] Erdmann E, Charbonnel B, Wilcox RG, Skene AM, Massi-Benedetti M, Yates J, et al. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease. Diabetes Care. 2007; 30: 2773–2778.

[11] de Jong M, van der Worp HB, van der Graaf Y, Visseren FLJ, Westerink J. Pioglitazone and the secondary prevention of cardiovascular disease. a meta-analysis of randomized-controlled trials. Cardiovascular Diabetology. 2017; 16: 134.

[12] Tang H, Shi W, Fu S, Wang T, Zhai S, Song Y, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Medicine. 2018; 7: 1070–1080.

[13] Gladstone DJ, Lindsay MP, Douketis J, Smith EE, Dowlatshahi D, Wein T, et al. Canadian stroke best practice recommendations: secondary prevention of stroke update 2020. Canadian Journal of Neurological Sciences. 2022; 49: 315–337.

[14] Buse JB, Wexler DJ, Tsapas A, Rossing P, Mingrone G, Mathieu C, et al. 2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American diabetes association (ADA) and the European association for the study of diabetes (EASD). Diabetologia. 2020; 63: 221–228.

[15] Bhattarai M, Salih M, Regmi M, Al-Akchar M, Deshpande R, Niaz Z, et al. Association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcomes in patients with type 2 diabetes and other risk factors for cardiovascular disease. JAMA Network Open. 2022; 5: e2142078.

[16] Xu B, Li S, Kang B, Zhou J. The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management. Cardiovascular Diabetology. 2022; 21: 83.

[17] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. The New England Journal of Medicine. 2015; 373: 2117–2128.

[18] Kimura G. Diuretic action of sodium-glucose cotransporter 2 inhibitors and its importance in the management of heart failure. Circulation Journal. 2016; 80: 2277–2281.

[19] Kimura G. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and stroke. Circulation Journal. 2017; 81: 898.

[20] Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016; 39: S165–S171.

[21] Accurso A, Bernstein RK, Dahlqvist A, Draznin B, Feinman RD, Fine EJ, et al. Dietary carbohydrate restriction in type 2 diabetes mellitus and metabolic syndrome: time for a critical appraisal. Nutrition & Metabolism. 2008; 5: 9.

[22] Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ, Westman EC, et al. Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition. 2015; 31: 1–13.

[23] Mori T, Yoshioka K, Tanno Y, Kasakura S. Safety and effectiveness of sodium-glucose cotransporter 2 inhibitor combined with medical nutrition therapy for hyperglycemia in acute stroke: a retrospective study. Metabolites. 2021; 12: 25.

[24] Kanazawa M, Yoshiike N, Osaka T, Numba Y, Zimmet P, Inoue S. Criteria and classification of obesity in Japan and Asia-Oceania. Asia Pacific Journal of Clinical Nutrition. 2002; 11: S732–S737.

[25] Trachtenbarg DE. Diabetic ketoacidosis. American family physician. 2005; 71: 1705–1714.

[26] Westerberg DP. Diabetic ketoacidosis: evaluation and treatment. American Family Physician. 2013; 87: 337–346.

[27] Kernan WN, Viscoli CM, Furie KL. Pioglitazone after ischemic stroke or transient ischemic attack. Journal of Vascular Surgery. 2016; 64: 260.

[28] Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin for primary and secondary prevention of cardiovascular events. Circulation. 2018; 137: 323–334.

[29] Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. The New England Journal of Medicine. 2019; 380: 347–357.

[30] Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. Journal of the American College of Cardiology. 2018; 71: 2628–2639.

[31] McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. The New England Journal of Medicine. 2019; 381: 1995–2008.

[32] Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017; 136: 249–259.

[33] American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in Diabetes-2021. Diabetes Care. 2021; 44, S125–S150.

[34] Lou Arnal LM, Campos Gutiérrez B, Cuberes Izquierdo M, Gracia García O, Turón Alcaine JM, Bielsa García S, et al. Prevalence of chronic kidney disease in patients with type 2 diabetes mellitus treated in primary care. Nefrologia. 2010; 30: 552–556. (In Spanish)

[35] Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, et al. Clinical manifestations of kidney disease among us adults with diabetes, 1988–2014. JAMA. 2016; 316: 602–610.

[36] Samukawa Y, Haneda M, Seino Y, Sasaki T, Fukatsu A, Kubo Y, et al. Pharmacokinetics and pharmacodynamics of luseogliflozin, a selective SGLT2 inhibitor, in japanese patients with type 2 diabetes with mild to severe renal impairment. Clinical Pharmacology in Drug Development. 2018; 7: 820–828.

[37] Haneda M, Seino Y, Inagaki N, Kaku K, Sasaki T, Fukatsu A, et al. Influence of renal function on the 52-week efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin in Japanese patients with type 2 diabetes mellitus. Clinical Therapeutics. 2016; 38: 66–88.e20.

[38] Zhou Z, Jardine M, Heerspink H, Neuen B, Li Q, Arnott C, et al. Effects of SGLT2 inhibitors on stroke in type 2 diabetes according to baseline kidney function. Journal of the American College of Cardiology. 2020; 75: 221.

[39] Zhou Z, Jardine MJ, Li Q, Neuen BL, Cannon CP, de Zeeuw D, et al. Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: results from the CREDENCE trial and meta-analysis. Stroke. 2021; 52: 1545–1556.

[40] Ata F, Yousaf Z, Khan AA, Razok A, Akram J, Ali EAH, et al. SGLT-2 inhibitors associated euglycemic and hyperglycemic DKA in a multicentric cohort. Scientific Reports. 2021; 11: 10293.

[41] Yamada S, Kabeya Y, Noto H. Dietary approaches for Japanese patients with diabetes: a systematic review. Nutrients. 2018; 10: 1080.