Diabetic ketoacidosis
Epidemiology
Among adults, two-thirds of episodes of diabetic ketoacidosis (DKA) occur in people diagnosed with type 1 diabetes, while one third occur in those with type 2 diabetes.[9] Between 6% and 21% of adults present with DKA at the time of initial diagnosis of type 1 diabetes.[1] In people with preexisting type 2 diabetes, DKA may be triggered by conditions of physiologic stress (such as infections, trauma, or cardiovascular events) or by the use of certain drugs (e.g., sodium-glucose cotransporter-2 [SGLT2] inhibitors, and the dual SGLT1/SGLT2 inhibitor sotagliflozin). DKA has also been increasingly documented as a presenting feature of newly diagnosed type 2 diabetes; this is referred to as ketosis-prone diabetes mellitus.[9][10] Since the early 2000s, the prevalence of ketosis-prone type 2 diabetes worldwide has increased, with epidemiologic data suggesting that people of African or Hispanic origin are at greater risk.[9] Most often, individuals with ketosis-prone type 2 diabetes have obesity and a strong family history of type 2 diabetes, as well as evidence of insulin resistance.[9]
As the majority of people with DKA are hospitalized, most epidemiologic data come from hospital discharge coding.[9] From 2000 to 2009, the rate of hospitalizations for DKA in the US decreased overall, from 21.9 to 19.5 in 1000 persons with diabetes, but then increased to 30.2 in 1000 persons with diabetes in 2014.[11] In 2014, rates of hospitalization for DKA were highest among people age <45 years (44.3 in 1000 persons with diabetes) and decreased with age (5.2 in 1000 persons with diabetes ages 45-64 years; 1.6 in 1000 65-74 years; and 1.4 in 1000 ≥75 years).[11] In 2020, 8.8 in 1000 adults with diabetes in the US visited emergency departments with DKA.[12]
From 2000 to 2014, in-hospital mortality rates among people with DKA consistently decreased in the US, from 1.1% to 0.4%.[11] Mortality rates reported in low- and middle-income countries are much higher, potentially because of delayed diagnosis and treatment.[1] Data from India have shown a 30% mortality rate in those presenting with DKA, and studies from sub-Saharan Africa have reported similarly high mortality (26% to 41%).[9] Mortality increases substantially in those with comorbidities and with aging, reaching 8% to 10% in those ages 65-75 years.[9]
Risk factors
Diabetic ketoacidosis can occur in people with both type 1 and type 2 diabetes, but is much more common in those with type 1 diabetes. One US nationwide cohort study found that adjusted rates of hyperglycemic crises were 53 events per 1000 person-years among adults with type 1 diabetes, compared with 4 events per 1000 person-years among people with type 2 diabetes.[27]
Reduction in the net effective concentration of insulin leads to impaired carbohydrate, lipid, and ketone metabolism in diabetic ketoacidosis (DKA). Decreased insulin results in increased gluconeogenesis, accelerated glycogenolysis, and impaired glucose utilization by peripheral tissues.[1]
In one US study conducted in a large urban hospital, poor adherence to insulin treatment accounted for >50% of DKA admissions, particularly affecting African-Caribbean populations and underinsured people.[28] Psychological and social factors may impact on glycemic control, and low socioeconomic status is correlated with a higher risk for DKA.[29][30] Additionally, insulin pump failure (e.g., due to dislodgement, occlusion) can result in rapid DKA development.[4]
The most common precipitating factor for diabetic ketoacidosis (DKA) worldwide is infection, particularly urinary tract infection or pneumonia.[1][13] Increased counter-regulatory hormones, particularly epinephrine, as a systemic response to infection lead to insulin resistance, increased lipolysis, ketogenesis, and volume depletion, which may contribute to the development of hyperglycemic crises in patients with diabetes.[1] Coronavirus disease 2019 (COVID-19) infection has been associated with greater risk of DKA in both type 1 and type 2 ԁiabеtеs.[1] Several studies have reported DKA as the presentation of newly diagnosed type 1 diabetes during or after a COVID-19 infection.[4] The precise mechanisms for new onset diabetes in people with COVID-19 are not known.[4]
A substantial proportion of individuals hospitalized with diabetic ketoacidosis (DKA) experience recurrent episodes.[4] In US nationwide studies, up to 22% of people admitted with DKA had at least one readmission within 30 days or the same calendar year.[32] Among those readmitted within 30 days, 40.8% represented recurrent DKA episodes, with approximately 50% being readmitted within 2 weeks.[32][33] Among those readmitted within the same calendar year, 86% had 1-3 DKA readmissions and 14% had ≥4.[33] Assessment of precipitating and contributing causes of DKA admission and close follow-up within 2-4 weeks after discharge may reduce recurrent DKA.[1]
Prior history of hypoglycemic crises, suggestive of greater glycemic variability, is also a risk factor for DKA.[1] One study found severe hypoglycemia to be associated with a three- to fourfold increase in the risk of experiencing a hyperglycemic crisis.[27]
Poorly controlled diabetes is associated with an increased risk of hyperglycemic crises.[4] One study found that for patients with type 1 diabetes, risk of experiencing a hyperglycemic crisis increased when the HbA1c level exceeded 7% (53 mmol/mol).[27] The incidence risk ratio was 7.81 (95% CI 5.78 to 10.54) for HbA1c levels of ≥10% (≥86 mmol/mol) compared with HbA1c levels of 6.5% to 6.9% (48-52 mmol/mol).[27] For patients with type 2 diabetes, the risk increased continuously for all HbA1c levels above 5.6% (38 mmol/mol), and the incidence risk ratio was 7.06 (95% CI 6.26 to 7.96) for HbA1c levels of ≥10% (≥86 mmol/mol).[27]
Adverse social determinants of health are among the strongest factors associated with recurrent diabetic ketoacidosis (DKA).[1] Multiple studies have suggested that low income, area-level deprivation, housing insecurity, and lack of insurance or presence of underinsurance (in health systems where this is applicable) lead to increased risk of DKA and hyperosmolar hyperglycemic state, with approximately 40% of hyperglycemic crises occurring in lower-income and underserved populations.[1]
One nationwide US cohort study found that rates of hyperglycemic crises were significantly higher among younger adults in patients with type 1 and type 2 diabetes.[27] In 2014, rates of hospitalization for diabetic ketoacidosis in the US were highest among people age <45 years (44.3 in 1000 persons with diabetes) and decreased with age (5.2 in 1000 persons with diabetes ages 45-64 years; 1.6 in 1000 65-74 years; and 1.4 in 1000 ≥75 years).[11]
The presence of diabetic neuropathy, nephropathy, and retinopathy has been associated with a higher risk of diabetic ketoacidosis (DKA).[27] One large prospective cohort study found that reduced estimated glomerular filtration rate (eGFR <60 mL/minute/1.73 m²), even when excluding patients with end-stage renal disease, was associated with a higher risk of hospitalization for DKA (hazard ratio 1.71, 95% CI 1.26 to 2.67) compared with an eGFR >60 mL/minute/1.73 m². This association was independent of markers of glycemic control.[34]
The presence of comorbidities including cerebrovascular disease, heart failure, dementia, chronic obstructive pulmonary disease, cirrhosis, or cancer has been associated with an increased risk of diabetic ketoacidosis in patients with type 2 diabetes.[27]
Acute medical events such as stroke, with increased levels of counter-regulatory hormones and compromised access to water and insulin, may contribute to the development of hyperglycemic crises.[1]
Hormonal derangements in some endocrine glands lead to increased counter-regulatory hormones and development of diabetic ketoacidosis in patients with concomitant diabetes.[36]
Drugs that affect carbohydrate metabolism may precipitate hyperglycemic crises.[1] This may include corticosteroids, thiazide diuretics, pentamidine, sympathomimetics, and atypical antipsychotics.[15]
Cocaine use may be an independent risk factor associated with recurrent diabetic ketoacidosis (DKA).[39] Cannabis use (and associated hyperemesis syndrome) has also been associated with an increased risk of DKA in adults with type 1 diabetes.[4]
Sodium-glucose cotransporter-2 (SGLT2) inhibitors (e.g., canagliflozin, dapagliflozin, empagliflozin, ertugliflozin), used for glycemic control of type 2 diabetes (or more recently, cardiovascular event risk reduction), have been the subject of a Food and Drug Administration (FDA) warning about a risk for DKA.[40] The risk is heightened with use of an SGLT2 inhibitor in certain situations, such as during severe illness or a period of prolonged fasting, or perioperatively, and their use should be avoided in such cases.[4] The American Diabetes Association warns that the risk of DKA in people with type 1 diabetes using SGLT2 inhibitors can be 5-17 times higher than in nonusers.[4] In contrast, observational studies and randomized controlled trials have shown that DKA is uncommon in people with type 2 diabetes treated with SGLT2 inhibitors (0.6 to 4.9 events per 1000 patient-years).[41]
The dual SGLT1/SGLT2 inhibitor sotagliflozin, which has been approved to reduce the risk of hospitalization for heart failure in patients with type 2 diabetes with chronic kidney disease or high risk of/established cardiovascular disease, as well as in people with heart failure (both with and without diabetes), has also been been associated with increased rates of DKA. In clinical trials of sotagliflozin in people with type 1 diabetes, results showed improvements in hemoglobin A1c and body weight, but use was associated with an eightfold increase in DKA compared with placebo.[4][42]
Immune checkpoint inhibitor therapy for cancer (PD-1 and PD-L1 blocking antibodies such as nivolumab, pembrolizumab, and avelumab) appears to be associated with a risk for DKA and type 1 diabetes mellitus.[16][43][44][45] It has been estimated that up to 75% of people who develop immune checkpoint inhibitor-induced hyperglycemia/diabetes present with DKA.[46]
Hypercortisolism leads to insulin resistance and may occasionally precipitate diabetic ketoacidosis in patients with concomitant diabetes; it more commonly precipitates hyperosmolar hyperglycemic state.[47]
One US nationwide cohort study found that black patients with type 1 or type 2 diabetes had higher risks of hyperglycemic crises than individuals in other racial/ethnic groups.[27] This disparity persisted after adjustment for key socioeconomic, clinical, and treatment-related factors, suggesting that additional intrinsic and extrinsic factors are associated with hyperglycemic crises among black patients.[27]
Diabetic ketoacidosis (DKA) has also been increasingly documented as a presenting feature of newly diagnosed type 2 diabetes, referred to as ketosis-prone diabetes.[9][10] Epidemiologic data suggest that people of African or Hispanic origin are at greater risk.[9] Individuals with ketosis-prone type 2 diabetes often have obesity and a strong family history of type 2 diabetes, as well as evidence of insulin resistance.[9] Approximately 80% of obese black patients with DKA have type 2 diabetes, characterized by higher insulin secretion, the absence of autoimmune markers, and a lack of human leukocyte antigen (HLA) genetic association compared with lean patients with type 1 diabetes.[6]
Fasting increases the risk of dehydration, hyperglycemia, and ketoacidosis in people with diabetes to a varying degree (depending on type of diabetes and therapy used, among other things).[4] Following a very low carbohydrate or ketogenic diet in conjunction with sodium-glucose cotransporter-2 (SGLT2) inhibitor and dual SGLT1/2 inhibitor use can increase diabetic ketoacidosis risk.[4][19]
Pregnancy is a ketogenic state and there is a risk of diabetic ketoacidosis (DKA) in pregnant individuals with pre-existing diabetes (more so for those with type 1, rather than type 2, diabetes) at lower glucose levels (e.g., may present as euglycemic DKA).[4] Up to 2% of pregnancies with pregestational diabetes are complicated by DKA.[4] However, the incidence of DKA in gestational diabetes is low (<0.1%).[4]
People with type 2 diabetes and dementia are at increased risk for diabetic ketoacidosis than those without dementia.[4]
The presence of mental health conditions, such as depression, bipolar disorder, and eating disorders, has been associated with increased risk for hyperglycemic crises.[4]
Alcohol and/or substance use are risk factors for diabetic ketoacidosis (DKA).[4] Excessive alcohol intake and use of illicit drugs also increase the risk of DKA associated with the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dual SGLT1/2 inhibitors.[4][19]
Cocaine use may be an independent risk factor associated with recurrent DKA.[39] Cannabis use (and associated hyperemesis syndrome) has also been associated with an increased risk of DKA in adults with type 1 diabetes.[4]
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