What literature can you find on treating HHS or hyperglycemic hyperosmolar state?

Comment by InpharmD Researcher

Guidelines for the management of hyperosmolar hyperglycemic state (HHS) recommend structured care pathways emphasizing cautious intravenous fluid resuscitation, gradual correction of hyperosmolality and hyperglycemia, selective use of insulin, electrolyte monitoring and replacement, and treatment of precipitating causes. These recommendations are largely consensus-based, reflecting the absence of randomized trials specific to HHS. Recent primary literature consists predominantly of retrospective cohort studies and administrative database analyses evaluating clinical outcomes. Collectively, these studies describe in-hospital and long-term mortality, organ dysfunction, thromboembolic and cardiovascular events, hypoglycemia during treatment, healthcare utilization, and overlap with diabetic ketoacidosis, with adverse outcomes most frequently reported in older patients, those with significant comorbidities, infection, electrolyte disturbances, or mixed DKA–HHS presentations. Please refer to Table 1 for a summary of recent primary literature on HHS. An additional search did not identify any new evidence that would substantially change current guideline-based management or overall understanding of HHS outcomes.

Background

According to the 2026 American Diabetes Association (ADA) Standards of Care in Diabetes in the Hospital, diabetic ketoacidosis and hyperglycaemic hyperosmolar state (HHS) should be managed by administering intravenous (IV) fluids, insulin, and electrolytes, with close monitoring during treatment, ensuring a timely and bridged transition from IV to maintenance subcutaneous insulin, and identifying and treating the precipitating cause (Recommendation 16.16; Grade A). The 2026 Standards include a treatment pathway for DKA and HHS and explicitly indicate that detailed diagnostic criteria, management targets, and treatment pathway elements for hyperglycaemic crises are derived from the 2024 joint international consensus guidelines, which serve as the primary reference for condition-specific technical detail in HHS management. [1]

Per 2024 joint international consensus guidelines by ADA, European Association for the Study of Diabetes, Joint British Diabetes Societies for Inpatient Care, American Association of Clinical Endocrinology, and Diabetes Technology Society (EASD–JBDS–AACE–DTS), treatment of HHS consists of prompt IV fluid resuscitation, insulin therapy, electrolyte management, and identification and treatment of precipitating causes. Initial therapy prioritizes restoration of intravascular volume using isotonic saline or balanced crystalloids, typically 500-1000 mL per hour for the first 2–4 hours in patients without cardiac or renal compromise, with smaller boluses recommended in older adults and those with heart failure or end stage kidney disease. Glucose and osmolality correction must be gradual in HHS: plasma glucose reduction should not exceed 90-120 mg/dL/hr, serum sodium decline should not exceed 10 mmol/L in 24 hours, and serum osmolality should fall no faster than 3–8 mOsm/kg per hour to reduce the risk of neurologic complications. Fixed rate IV insulin is recommended at 0.05 units/kg/hr in HHS without significant ketoacidosis and at 0.1 units/kg/hr in mixed DKA–HHS presentations; continuation of preexisting basal insulin is advised. Potassium replacement is initiated once serum potassium falls below 5.0 mmol/L, targeting 4-5 mmol/L with frequent monitoring. Routine bicarbonate and phosphate administration are not recommended, with bicarbonate reserved for severe acidosis (pH <7.0). HHS is considered resolved when serum osmolality normalizes, hyperglycaemia is corrected, urine output is adequate, and mental status improves. [2]

The 2023 Joint British Diabetes Societies (JBDS) guideline describes HHS as a medical emergency with high mortality, occurring predominantly in adults with type 2 diabetes, but also reported in younger patients, and occasionally presenting with mixed features of DKA. HHS is defined by marked hypovolemia, serum osmolality ≥320 mOsm/kg, severe hyperglycemia ≥30 mmol/L, minimal ketonemia (≤3.0 mmol/L), and absence of significant acidosis (pH >7.3, bicarbonate ≥15 mmol/L). Management is structured around a standardized care pathway encompassing three themes (clinical assessment and monitoring, interventions, and prevention of harm) across five time-based phases spanning 0 to 72 hours, with emphasis on frequent reassessment. The primary treatment objectives are gradual correction of dehydration and hyperosmolality, avoidance of rapid osmotic shifts, and prevention of complications. Initial management prioritizes intravenous 0.9% sodium chloride to restore circulating volume, with estimated fluid deficits of approximately 100 to 220 mL/kg, adjusted for age and comorbidities. Serum osmolality should decline gradually at a target rate of approximately 3 to 8 mOsm/kg/h, with blood glucose reduced to 10 to 15 mmol/L during the first 24 hours. Insulin therapy is not initiated immediately unless significant ketonemia is present; a fixed-rate intravenous insulin infusion at 0.05 units/kg/h is recommended only once glucose and osmolality no longer decline with fluid replacement alone. Intravenous glucose (5% or 10%) is introduced once blood glucose falls below 14 mmol/L, and potassium replacement is guided by serial serum potassium measurements. Resolution of HHS is defined holistically and requires serum osmolality <300 mOsm/kg, correction of hypovolemia with urine output ≥0.5 mL/kg/h, return of cognitive status to the pre-morbid baseline, and blood glucose <15 mmol/L. The guideline notes that treatment recommendations are largely consensus-based rather than derived from randomized trials and emphasizes close monitoring to reduce risks including cerebral edema, osmotic demyelination, thrombosis, hypoglycemia, and fluid overload. [3]

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What literature can you find on treating HHS or hyperglycemic hyperosmolar state?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Table 1 for your response.

Overview of Recent Primary Literature Assessing Hyperosmolar Hyperglycemic State
Citation/Design Objective

Patients

 Methods/Intervention Main Outcomes/Conclusions

Liang 20261

Retrospective, cross-sectional analysis

 To evaluate the in-hospital outcomes of DKA and HHS among patients with type 2 diabetes who have severe kidney disease

N= 690,031

DKA (n= 4,773)

HHS (n= 2,179)

Non-DKA/HHS (n= 683,079)

Retrospective analysis of hospital discharge records from the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample (2016 to 2022). Patients were categorized into DKA, HHS, and non-DKA/HHS groups based on discharge diagnoses. Hospitalizations coded for both DKA and HHS were excluded from further comparative analysis.

Outcomes (HHS vs Non DKA-HHS):

In-hospital mortality: 60 (2.8%) vs 28,701 (4.2%); aOR 0.77 (0.60–1.00)

Acute neurological failure: 124 (5.7%) vs 29,672 (4.3%); aOR 1.51 (1.26–1.82)

Septic shock: 48 (2.2%) vs 10,008 (1.5%); aOR 1.52 (1.14–2.02)

Mechanical ventilation: 141 (6.5%) vs 31,072 (4.5%); aOR 1.43 (1.20–1.69)

PE/DVT: 22 (1.0%) vs 10,199 (1.5%); aOR 0.64 (0.42–0.98)

In-hospital mortality was higher in DKA than HHS (7.8% vs 2.8%; aOR 3.08, 95% CI 2.33–4.08). DKA patients had higher adjusted odds of acute respiratory failure (26.8% vs 19.5%; aOR 1.51, 95% CI 1.33–1.71), acute liver failure (2.0% vs 0.6%; aOR 3.13, 95% CI 1.77–5.51), sepsis (27.1% vs 12.3%; aOR 2.72, 95% CI 2.35–3.15), and need for mechanical ventilation (11.8% vs 6.5%; aOR 1.94, 95% CI 1.60–2.35). DKA was also associated with longer hospital stays and higher hospitalization costs compared with HHS.

Authors' Conclusion:

Among adults with T2D and severe kidney disease, DKA is associated with substantially higher in-hospital mortality, more frequent organ complications, longer stays, and markedly higher costs compared to hospitalizations without hyperglycemic emergencies and those for HHS. These distinctions highlight the need for prevention, early recognition, and kidney-adapted management strategies. Further research incorporating clinical and laboratory parameters is needed to refine risk stratification and to determine optimal treatment algorithms in this high-risk group.

Kew 20252

Mixed-methods observational study

 To develop and implement a standardized multicenter surveillance system for the systematic collection of data on clinical presentation, management practices, and outcomes in patients with HHS All patients (N= 218)

Patients at hospitals in the UK were included in the Digital Evaluation of Ketosis and Other Diabetes Emergencies (DEKODE)-HHS surveillance model. The model involved structured data collection on demographics, biochemistry, treatment, and outcomes of HHS care. The surveillance tool was piloted and refined before dissemination to all centers. Training sessions were delivered to ensure uniform understanding of diagnostic criteria and data definitions.

Outcomes:

Time from admission to diagnosis, hours (IQR): 1.95 (0.77–6.0)

HHS >24 hours after admission: 17 (7.8%)
 
HHS duration, hours: 48.2 (24.9–74.15)
 
Time from HHS resolution to MFFD, days: 7.13 (2.98–12.89)
 
LOS, days: 10.3 (6.03–16.98)
 
Death: 35 (16.1%)
 

Authors' Conclusion:

The DEKODE-HHS model represents the first UK multicenter surveillance initiative for HHS. It identifies variation in practice and outcome predictors while highlighting systemic barriers to guideline adherence. This model provides a scalable framework for continuous quality improvement in HHS management and may inform future updates to national guidance.

Cao 20253

Retrospective study

 To investigate the clinical characteristics, prevalence, and diagnostic parameters of this under-recognized HHS subtype

N= 174

HHS without measured hypernatremia (n= 160)

HHS with measured hypernatremia (n= 14)

Retrospective review of adult diabetic patients with HHS at a single institution from 2018 to 2024.

Outcomes:

Hypernatremia prevalence:

Measured sodium >145 mmol/L: 14/174 (8%)

Corrected sodium >145 mmol/L: 166/174 (95.4%)

Diagnostic sensitivity:

Effective serum osmolarity >300 mOsm/L: 174/174 (100%)

Total serum osmolarity >320 mOsm/L: 111/174 (63.8%)

Free water deficit

Increased with higher corrected sodium and effective osmolarity.

Median free water deficit: 1.76 L (total osm ≤320 mOsm/L) vs 3.58 L (total osm >320 mOsm/L); p< 0.001

DKA overlap:

Concurrent DKA: 114/174 (65.5%)

Absence of acidosis: 39/174 (22.4%)

LOS:

Longer with measured hypernatremia (10.6 vs 4.35 days; p= 0.009) and higher effective or total serum osmolarity.

Authors' Conclusion:

HHS with hypernatremia, defined by corrected sodium, is highly prevalent and clinically relevant, as corrected sodium better reflects the true free water deficit. HHS management should include evaluating both measured and corrected sodium, adopting effective serum osmolarity > 300 mOsm/L as a more sensitive diagnostic criterion, and reevaluating the exclusion criteria of significant ketonemia and acidosis. These refinements may enhance diagnostic accuracy and enable more personalized fluid management in HHS.

Shvarts 20254

Retrospective cohort study

 To examine clinical characteristics and the outcomes of HHS and DKA syndromes, and to characterize the factors contributing to a higher mortality rate in HHS. To contribute to the development of effective treatment strategies, with the goal of reducing HHS mortality in future research

N= 608

HHS (n= 223)

DKA (n= 385)

 Retrospective analysis of admissions for HHS and DKA in adult patients between 2015 and 2021. Clinical characteristics and outcomes of patients with HHS vs. DKA were compared. 

Outcomes (HHS vs DKA):

In-hospital mortality: 91 (41.2%) vs 18 (4.7%); p< 0.001

1-year mortality: 113 (50.7%) vs 44 (11.4%); p< 0.001

ICU admission: 0 (0.0%) vs 97 (25.2%); p< 0.001

Mechanical ventilation: 7 (3.1%) vs 23 (6.0%); p= 0.17

LOS, days (IQR): 4.0 (3.0–6.0) vs 3.0 (2.0–6.0); p= 0.07

Recurrent event at 30 days: 10 (4.7%) vs 19 (4.9%); p= 1.00

Recurrent event at 1 year: 25 (11.2%) vs 67 (17.4%); p= 0.04

In the entire cohort, age, CCI, and bedridden status were significantly associated with 1-year mortality.

In the matched cohort, DKA versus HHS was not significantly associated with in-hospital mortality, 1-year mortality, LOS, or other outcomes.

Authors' Conclusion:

Metabolic abnormalities alone do not appear to explain the worse outcomes observed in HHS compared to DKA. Our findings indicate that baseline comorbidities, age and infection trigger have more significant impact on outcomes than the patients’ metabolic status.

Alroobi 20255

Retrospective cohort study

 To assess in-hospital cardiovascular outcomes of DKA and HHS in type 2 diabetes patients with heart failure and compare both complications

N= 1,122,300

DKA (n= 5,375)

HHS (n= 4,809)

Reference group: remaining patients with T2D and heart failure who did not develop DKA or HHS

 Patients at hospitals in the United States were analyzed using the National Inpatient Sample database (2008 to 2019). The DKA and HHS groups were compared for in-hospital cardiovascular outcomes. Outcomes were adjusted for baseline characteristics and comorbidities.

Outcomes (Non DKA-HHS vs HHS):

Mortality: 132,281 (2.4%) vs 97 (2.0%); aOR 1.00 (0.81–1.24)

Acute renal failure: 1,611,069 (28.8%) vs 1,965 (40.9%); aOR 1.59 (1.49–1.70)

Cardiogenic shock: 72,942 (1.3%) vs 86 (1.8%); aOR 1.05 (0.84–1.32)

Ischemic stroke: 14,057 (0.3%) vs 16 (0.3%); aOR 1.45 (0.88–2.39)

Compared with HHS, DKA was associated with higher adjusted mortality (aOR 2.90, 95% CI 2.22–3.79) and cardiogenic shock (aOR 2.86, 95% CI 2.13–3.83). Associations persisted after propensity score matching.

Authors' Conclusion:

DKA and HHS are associated with worse cardiovascular outcomes in heart failure patients with type 2 diabetes. Further, when both conditions were compared, the mortality risk and cardiogenic shock were higher in DKA compared to HHS. Implementing tailored fluid and electrolyte management, optimizing insulin protocols, and enhancing monitoring with early intervention could be lifesaving for these high-risk patients.

Huang 20256

Population-based, retrospective observational study

 To compare the outcomes of hospitalized DKA patients with and without CVD, and to assess outcomes between DKA and HHS in diabetes patients with CVD, as well as between those who developed DKA and those who did not

Patients with diabetes and CVD:

HHS (n= 16,367)

DKA (n= 62,052)

Patients at hospitals across the United States were analyzed using data from the National Inpatient Sample database (2016 to 2022). Models were adjusted for demographic, socioeconomic, hospital-level, and clinical covariates, including age, race, admission type, insurance, income quartile, patient location, hospital characteristics, comorbidity burden, and admission year.

Outcomes (HHS vs DKA):

In-hospital mortality: 632 (3.9%) vs 4,675 (7.5%); aOR 2.30 (2.11–2.51)

Acute kidney failure:  9,853 (60.2%) vs 37,229 (60.0%); aOR 1.15 (1.10–1.19)

Sepsis: 2,843 (17.4%) vs 17,398 (28.0%); aOR 2.00 (1.91–2.09)

Septic shock: 255 (1.6%) vs 1,498 (2.4%); aOR 1.71 (1.49–1.96)

Acute respiratory failure: 3,306 (20.2%) vs 15,765 (25.4%); aOR 1.41 (1.35–1.48)

Authors' Conclusion:

This study demonstrates that CVD significantly affects the outcomes of patients admitted for DKA. Moreover, similar negative outcomes were observed when comparing DKA patients with HHS and those who developed DKA versus those who did not. These findings highlight the need for careful management of DKA in patients with CVD to optimize clinical outcomes.

Fujiya 20257

Retrospective cohort study

 To investigate the clinical characteristics and prognoses of patients with HHS at a university hospital in Japan

N= 84

Isolated HHS (n= 70)

Mixed DKA/HHS (n= 14)

Retrospective medical record review of patients hospitalized in Japan between 2018 and 2023, classified into isolated HHS and mixed DKA/HHS groups. Median age of patients with HHS was 75 years.

Outcomes (Isolated HHS vs Mixed DKA/HHS):

30-day mortality: 26.0% vs 0%

Severe altered consciousness (JCS grade 3): 32.9% vs 7.1%

Median length of stay: 21 vs 36 days

Infection as precipitating factor: 51.4% vs 50.0%

Isolated HHS with non-ketotic metabolic acidosis had higher 30-day mortality (54.6%) than isolated HHS without acidosis (20.7%).

Metabolic acidosis (non-ketotic) independently associated with 30-day mortality (age/sex-adjusted OR 8.08, 95% CI 1.63–40.2)

Authors' Conclusion:

HHS predominantly affects elderly patients and is often associated with poor diabetes management. The isolated HHS group had a worse prognosis than the mixed DKA/HHS group, and the presence of metabolic acidosis other than ketoacidosis significantly increased mortality. Regular blood glucose monitoring and appropriate diabetes medications are crucial for preventing the development of HHS.

González-Vidal 20248

Retrospective cohort study

 To investigate the long-term implications of hypoglycemia during HHS, particularly in terms of all-cause mortality

N= 170

No hypoglycemia during initial intravenous insulin therapy (n= 125)

Hypoglycemia during initial intravenous insulin therapy (n= 45)

Retrospective analysis of patients admitted for HHS at a hospital in Spain. All patients were managed according to consensus recommendations for HHS. Treatment consisted of initial intravenous insulin infusion therapy, followed by transition to a subcutaneous long-acting and short-acting insulin therapy protocol once clinically stable. Glycemic control was monitored using frequent capillary blood glucose measurements, typically 5 to 10 checks per day. Seven patients died during the intravenous insulin phase and did not transition to subcutaneous insulin.

Outcomes (No vs Yes):

Hypoglycemia during the initial intravenous insulin therapy phase

In-hospital mortality: 4 (3.2%) vs 7 (15.5%); p= 0.004

1-year mortality: 31 (28.1%) vs 19 (47.5%); p= 0.026

2-year mortality: 38 (36.9%) vs 23 (60.5%); p= 0.012

Authors' Conclusion:

Hypoglycemia during HHS is a marker of long-term mortality, especially when it occurs during the initial intravenous insulin therapy phase.

Abbreviations: aOR, adjusted odds ratio; DKA, diabetic ketoacidosis; DVT, deep vein thrombosis; CCI, Charlson Comorbidity Index; CVD, cardiovascular disease; HHS, hyperosmolar hyperglycemic state; ICU, intensive care unit; IQR, interquartile range; JCS, Japan Coma Scale; LOS, length of stay; MFFD, medically fit for discharge; PE, pulmonary embolism; T2D, type 2 diabetes.
References:
[1] Liang W, Yu H, Deng H, et al. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in type 2 diabetes patients with severe kidney disease: a 7-year retrospective analysis. Journal of Diabetes and its Complications. 2026;40(2):109253. doi:10.1016/j.jdiacomp.2025.109253
[2] Kew TM, Manta A, Sawlani JP, et al. Identifying interhospital variation in hyperosmolar hyperglycemic syndrome (HHS) care: development and outcomes of the DEKODE HHS model. BMJ Open Diabetes Res Care. 2025;13(6):e005489. Published 2025 Dec 7. doi:10.1136/bmjdrc-2025-005489
[3] Cao S, Cao S. Hyperglycemic Hypernatremic Hypertonic State: A Predominant HHS Subtype and Its Clinical and Diagnostic Features. J Clin Endocrinol Metab. Published online July 21, 2025. doi:10.1210/clinem/dgaf422
[4] Shvarts B, Golbets E, Sagy I, et al. Is Our Understanding of Hyperosmolar Hyperglycemic State Accurate?. J Emerg Med. 2025;79:531-538. doi:10.1016/j.jemermed.2025.09.016
[5] Alroobi H, Dargham S, Mahfoud Z, Jayyousi A, Al Suwaidi J, Abi Khalil C. Diabetic ketoacidosis and hyperosmolar hyperglycemic state in diabetes patients with heart failure: insight from the National inpatient sample. BMC Cardiovasc Disord. 2025;25(1):384. Published 2025 May 20. doi:10.1186/s12872-025-04832-3
[6] Huang Y, Xu Z, Deng H, et al. Outcomes following hospitalization for diabetic ketoacidosis in patients with cardiovascular disease. Endocr Connect. 2025;14(9):e250276. Published 2025 Sep 5. doi:10.1530/EC-25-0276
[7] Fujiya T, Iwafuchi K, Itasaka T, et al. Clinical features and outcomes of hyperglycemic hyperosmolar syndrome: a retrospective study at a Japanese university hospital. Diabetol Int. 2025;16(4):630-640. Published 2025 Jun 16. doi:10.1007/s13340-025-00823-z
[8] González-Vidal T, Lambert C, García AV, et al. Hypoglycemia during hyperosmolar hyperglycemic crises is associated with long-term mortality. Diabetol Metab Syndr. 2024;16(1):83. Published 2024 Apr 10. doi:10.1186/s13098-024-01329-5