Overview of Recent Primary Literature Assessing Hyperosmolar Hyperglycemic State

Patients

Liang 2026¹

Retrospective, cross-sectional analysis

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

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)

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

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

N= 608

HHS (n= 223)

DKA (n= 385)

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

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

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

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

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

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.