Complications
Diabetic ketoacidosis (DKA) is the classical acute complication of type 1 diabetes, characterized by hyperglycemia and metabolic acidosis.
The most common precipitants are missed insulin injections or physiologic stresses such as infection or myocardial infarction.
Workup (e.g., ECG, search for infection) is indicated to detect precipitating factors.
In the setting of insulin deficiency, stress hormones including glucagon, cortisol, and catecholamines raise blood glucose levels and stimulate ketogenesis.
Hyperglycemia and ketosis cause osmotic diuresis leading to dehydration.
Symptoms tend to be due to dehydration and metabolic acidosis and include dry mouth, shortness of breath, abdominal pain, nausea, vomiting, and altered sensorium.
Blood glucose and ketone levels are high and there is an anion gap metabolic acidosis.
Treatment involves rapid hydration, insulin infusion, and correction of electrolyte imbalance. Hourly monitoring of blood glucose and 1- to 4-hourly monitoring of electrolytes is required. Insulin infusion must continue until ketosis has resolved and a subcutaneous injection of insulin has been given. Subcutaneous insulin alone has been used successfully to manage mild cases of DKA.
Closure of the anion gap will indicate correction of the ketoacidosis.
Potassium repletion is usually indicated because initially apparently normal serum potassium does not reflect true total body depletion.
Treatment with bicarbonate is not indicated except when arterial blood pH is <6.9. Serum phosphorus level is usually low, but does not require replacement unless it is <1.0 mg/dL (<0.323 mmol/L).[167]
The main complication of insulin treatment is hypoglycemia. The American Diabetes Association defines level 1 hypoglycemia as ≥54 mg/dL but <70 mg/dL (≥3.0 mmol/L but <3.9 mmol/L); level 2 hypoglycemia (clinically significant) as <54 mg/dL (<3.0 mmol/L); and level 3 hypoglycemia (severe) as any low blood glucose level leading to cognitive and/or physical impairment requiring assistance from another person for recovery.[1]
Patients with type 1 diabetes are generally sensitive to insulin.[1] Therefore, even a slightly higher dose of insulin, decreased food intake, or increased physical activity can lead to hypoglycemia.[1] Young children and older people are especially vulnerable to hypoglycemia as they are less able to recognize the symptoms and clearly communicate their needs (and older adults are more likely to have comorbidities such as chronic kidney disease (CKD) and cognitive impairment which further increase the risk), potentially necessitating less stringent goals for glucose control.[1] Other clinical risk factors for hypoglycemia include a prior episode of hypoglycemia (especially level 2 or 3 events; this is the strongest risk factor for hypoglycemia recurrence and severity), hypoglycemic unawareness (due to impaired hormonal counterregulation which often occurs in those with recurrent hypoglycemia), autonomic neuropathy, and long duration of diabetes.[1] Alcohol and exercise can cause delayed hypoglycemia, up to 24 hours after the event.[1][56] Socioeconomic and cultural factors may be relevant also, including religious fasting and food insecurity.[1] Hypoglycemia risk should be considered when choosing treatment plans and glycemic goals.[1]
If the patient is able to ingest orally, hypoglycemia can be treated with ingestion of glucose (preferred; 15 g is suitable for most people) or other glucose-containing carbohydrate.[1] Blood sugar should be tested and treatment effect apparent in 15 minutes, but if hypoglycemia persists, treatment should be repeated.[1]
If oral intake is not possible, glucagon (parenteral or intranasal administration) or intravenous dextrose is required.[1][168]
Patient caregivers and family members should be educated about the signs and symptoms of hypoglycemia and taught how to administer oral glucose or glucagon intranasally or as an intramuscular or subcutaneous injection.[1] Unless hypoglycemia is recurring, the next meal or snack should be eaten, and the next dose of basal insulin in the multiple daily injections regimen given. Basal insulin via insulin pump may be suspended until the patient has recovered.
Hypoglycemia should be asked about at every visit and all people with type 1 diabetes should be screened for possible hypoglycemia unawareness at least yearly.[1] Hypoglycemia unawareness is a significant risk factor for level 3 hypoglycemia, and if identified, the American Diabetes Association (ADA) recommends referral for an evidence-based intervention to help reestablish awareness.[1] A strict period of several weeks without hypoglycemia (which can improve counterregulation) may improve hypoglycemia awareness in some patients.[1]
Type 1 diabetes may be associated with autoimmune skin diseases such as necrobiosis lipoidica, granuloma annulare, vitiligo, and bullosis diabeticorum. In addition, there is a small risk of insulin-induced lipodystrophy (a cause of erratic insulin absorption that can lead to increased glycemic variability and unexplained hypoglycemia), allergic or irritant contact dermatitis caused by insulin pumps or CGM sensors or adhesives, and infection at site of insertion.[1][56] Skin exam should form a routine part of diabetes care, and any skin reactions addressed promptly to avoid interference with use of diabetes devices.[1][56] Lipodystrophy can be avoided by rotating injection or pump insertion sites.[1]
Retinopathy is the most common microvascular complication of diabetes and its risk is increased at all levels of glycosylated hemoglobin (HbA1c) above the nondiabetic range. The incidence is 1 in 100 person-years for a mean HbA1c value of 5.5% and 9.5 in 100 person-years for a mean HbA1c value of 10.5%.[160] There is an increased risk of development or progression of diabetic retinopathy in individuals with preexisting type 1 diabetes during pregnancy.[1]
Most patients have evidence of retinopathy 20 years after diagnosis of diabetes. Patients develop microaneurysms, exudates, hemorrhages, angiogenesis, and glaucoma.
Retinopathy may be asymptomatic at any stage, even advanced, so screening is essential to ensure prompt diagnosis and intervention that can prevent vision loss.[1] Early referral to an ophthalmologist is recommended if there is any level of diabetic macular edema, moderate or worse nonproliferative, or any proliferative, diabetic retinopathy.[1]
Primary prevention includes strict glycemic control. Progression of very mild to moderate nonproliferative retinopathy can be delayed through glycemic, blood pressure, and lipid control (and prevention of development or progression of kidney disease).[1] It should be noted that rapid reduction of HbA1c (e.g., in the context of preconception) can be associated with worsening retinopathy.[1] In advanced disease, panretinal laser photocoagulation and intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) can be administered to reduce risk of blindness.[1] Intravitreal injections of anti-VEGF are first-line treatment for center-involved macular edema with impaired vision acuity.[1]
Diabetic kidney disease is the most common cause of end-stage renal disease (ESRD) in developed countries. In patients with type 1 diabetes, the annual incidence of microalbuminuria and albuminuria is between 1.3% and 3.8%.[169] Typically, diabetic nephropathy develops after 10 years of type 1 diabetes.[1] In one cohort study, the cumulative risk of ESRD was 2.2% after 20 years and 7.0% after 30 years from the diabetes diagnosis.[170]
The pathogenesis of diabetic nephropathy involves glomerular mesangial sclerosis leading to proteinuria and progressive decline in glomerular filtration. Increased urinary albumin excretion (≥30 mg/g) is an early sign of disease and a marker of much increased cardiovascular risk.[1] Testing urinary albumin and estimated glomerular filtration rate (eGFR) should be done yearly in people who have had type 1 diabetes for 5 years or more, and may need to be repeated more frequently if they have CKD.[1] Patients should be referred to a nephrologist if they have continuously worsening renal tests, eGFR <30 mL/min/1.73 m², or rapidly progressing kidney disease, or if there is uncertainty about etiology.[1]
Glycemic control and blood pressure control with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor blocker delays onset and slows progression of kidney disease.[171][172] The ADA does not recommend use of the aforementioned drugs for primary prevention of CKD in people with normal blood pressure and kidney function.[1]
The duration and extent of hyperglycemia are the greatest risk factors for neuropathy, although other cardiovascular risk factors probably also contribute. Optimizing glucose management is recommended to prevent or delay the development of neuropathy, and treatment of other modifiable risk factors (e.g., lipids and blood pressure) may reduce disease progression in type 1 diabetes.[1]
Diabetic neuropathy refers to a group of disorders with varying presentations: peripheral neuropathy and autonomic neuropathy are two key groups.[1] It is a diagnosis of exclusion and other causes of neuropathy should be considered and investigated accordingly.[1] The most common early symptoms of diabetic peripheral neuropathy (DPN) are pain and dysesthesia, but up to 50% of DPN may be asymptomatic.[1] Annual screening (from 5 years after diagnosis) is therefore important, as missed diagnosis may result in diabetic foot ulcers and amputations.[1] The ADA recommends screening for distal symmetric polyneuropathy should include a careful history, and exam using pinprick or temperature sensation (measures of small-fiber function), vibration perception (with a 128 Hz tuning fork; lower-extremity reflexes may also be tested as another measure of large-fiber function), and 10 g monofilament pressure sensation.[1] Screening for autonomic neuropathy is also recommended at least annually (from 5 years after diagnosis).[1]
Pain from peripheral neuropathy should be treated, and there are several medications that are particularly effective and may be considered. The American Diabetes Association (ADA) recommends that gabapentinoids, serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, and sodium channel blockers can be used as initial pharmacologic treatments for neuropathic pain in diabetes, although referral to a neurologist or pain specialist should be made if pain control is not achieved within the scope of the treating physician's practice.[1] Topical capsaicin can be an alternative to oral medication where this is contraindicated or not tolerated or refused by the patient.[1] The opioids tapentadol and tramadol are probably effective against diabetic peripheral neuropathy-associated pain; however, their use is generally not recommended due to their high risk of addiction, and the ADA recommends avoidance of these.[1]
Treatment of autonomic neuropathy is challenging, and current treatments mostly focus on symptom management and improving quality of life.[1] Examples include use of compressive stockings for postural hypotension, medication or nonpharmacologic treatments for erectile dysfunction, and specialized eating plans for diabetic gastroparesis.[1]
Cardiovascular disease is the major cause of death and a major cause of morbidity for patients with diabetes.
Intensive glycemic control has been shown to decrease the incidence of macrovascular disease in type 1 diabetes.[163] During the 30-year follow-up of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, high doses of insulin were associated with a less favorable cardiometabolic risk profile (higher body mass index, pulse rate, triglycerides, lower high-density lipoprotein [HDL] cholesterol), but intensive control continued to have long-term beneficial effects on the incidence of cardiovascular disease in type 1 diabetes.[164][173]
The cardiovascular disease risk can be further decreased by modification of other cardiovascular risk factors (e.g., hypertension, dyslipidemia, and smoking), which should be assessed at least once a year in all patients.[1][174] Lifestyle and behavioral therapy are essential components of treatment.
Hypertension is a major risk factor for atherosclerotic cardiovascular disease (ASCVD), heart failure, and microvascular complications.[1] Evidence clearly shows a reduction in cardiovascular events and microvascular complications with treatment of hypertension.[1] It is often secondary to underlying nephropathy in patients with type 1 diabetes. The ADA recommends that blood pressure in nonpregnant adults should be treated to <130/80 mmHg (individualized as appropriate, such as in older adults).[1] Treatment includes an ACE inhibitor or angiotensin-II receptor blocker; most patients will require two or three drugs to reach their goal. One study found the optimal blood pressure threshold associated with minimal coronary artery disease risk in young adults with childhood onset type 1 diabetes was 120/80 mmHg.[175] The ADA does not recommend targeting <120/80 mmHg, as this is associated with adverse events.[1]
For patients of all ages with diabetes and ASCVD, high-intensity statin therapy should be added to lifestyle therapy.[1] Addition of ezetimibe or a PCSK9 inhibitor with proven benefit in this population is recommended if treatment goals are not achieved with statins.[1] For patients ages 40 to 75 years without known ASCVD, the ADA recommends moderate-intensity statin therapy in addition to lifestyle therapy as primary prevention, or in those at higher risk (including ≥1 atherosclerotic cardiovascular disease risk factor), high-intensity statin therapy to achieve specified lipid goals.[1] Younger adults with additional ASCVD risk factors and older adults (>75 years) may also be considered for statin therapy (as primary prevention) after discussing benefits and risks.[1] Individualization of statin therapy according to cardiovascular disease risk score is recommended.[176] ASCVD risk estimator Opens in new window The ADA advises that statins are contraindicated in pregnancy.[1]
Intensive lifestyle therapy and optimal glycemic control are recommended to decrease cardiovascular risk in patients with triglycerides ≥150 mg/dL (≥1.7 mmol/L) and/or HDL <40 mg/dL (<1 mmol/L) for men and <50 mg/dL (<1.3 mmol/L) for women.[1] There is no specific low-density lipoprotein (LDL) target.
Children should have a fasting lipid profile soon after diagnosis once adequate glucose control is achieved if age ≥2 years, with subsequent testing performed at age 9 to 11 years if results are within acceptable risk levels.[1] Monitoring can then be every 3 years if LDL <100 mg/dL (<2.6 mmol/L).[1] The optimal pharmacologic treatment of hyperlipidemia in children has not been clearly defined, although an initial approach to lipid lowering should include modifications to diet and increased exercise.[1] Statins are not approved for children aged <10 years.
All adult patients with diabetes and atherosclerotic cardiovascular disease should be treated with aspirin for secondary prevention (75-162 mg/day).[1] Aspirin can be considered for primary prevention for adults at increased cardiovascular risk, after a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding.[1] The ADA advises that retinopathy is not a contraindication to aspirin for cardioprotection, as it does not increase risk of retinal hemorrhage.[1] All patients should have smoking-cessation counseling and treatment as needed.[1]
Patients aged >55 years, with or without hypertension, but with cardiovascular disease, dyslipidemia, increased urinary albumin excretion, or smoking may benefit from an ACE inhibitor to reduce the risk of cardiovascular events.[177] The ADA recommends an ACE inhibitor or angiotensin II receptor antagonist (ARB) for adults of any age with established ASCVD to reduce risk of cardiovascular events and mortality (in addition to those ages ≥55 years with additional cardiovascular risk factors).[1]
Routine screening of asymptomatic patients for coronary artery disease is not recommended by the ADA, but investigations may be considered in those with atypical cardiac symptoms, signs or symptoms of associated vascular disease, or abnormal ECG.[1]
The incidence and prevalence of heart failure is increased in patients with type 1 diabetes, and is reported to be up to three times higher than in those without diabetes.[178][179] There is a two to five times higher crude incidence rate of heart failure hospitalization and mortality for those with type 1 diabetes, compared with those without diabetes, and higher prevalence of diastolic dysfunction.[180][181] One systematic review of over 12 million global participants revealed that heart failure may be even more prevalent among adults with type 1 diabetes than those with type 2 diabetes.[182] The ADA recommends screening adults with diabetes for heart failure, and using an interprofessional approach (with cardiovascular expertise) to optimize medical therapy for those with asymptomatic (stage B) heart failure (with use of an ACE inhibitor or ARB, and beta-blockers recommended) to reduce the risk of progression to symptomatic disease.[1]
Youth with type 1 diabetes have a higher risk of developing an eating disorder.[56] Disordered eating is twice as prevalent in people with type 1 diabetes than in those without diabetes.[188] The most commonly reported disordered eating behavior in people with type 1 diabetes is omission of insulin leading to glycosuria in order to lose weight. The repeated insulin omission can then lead to short-term complications such as dehydration, fatigue, and muscle breakdown, and long-term macrovascular complications.[189] The American Diabetes Association suggests screening for disordered or disrupted eating when patients present with unexplained weight loss and hyperglycemia.[1] An interprofessional approach to management of disordered eating and disrupted eating patterns is recommended due to the complexity of their comorbidity with diabetes.[1]
Foot ulceration and amputation are major causes of morbidity and mortality.[1] The cause can be multifactorial, including presence of diabetic peripheral neuropathy, peripheral arterial disease (PAD), and foot deformity.[1]
Prompt recognition of at-risk feet and preulcerative lesions is key to initiating treatment that can prevent adverse outcomes.[1] The ADA recommends that all people should have a comprehensive foot evaluation at least annually to identify risk factors, and evidence of sensory loss (or previous ulcers or amputations) should prompt foot inspection at every visit.[1] Foot exam should include evaluation for loss of protective sensation (LOPS), and for vascular disease (as well as assessment of the skin and for deformity).[1] Evidence of PAD should be further investigated and may require referral for further vascular assessment.[1] The ADA recommends that people with foot ulcers or high-risk feet should be cared for using an interprofessional approach facilitated by a podiatrist.[1]
All people with diabetes should be taught general foot care, including how to examine their feet and identify early foot problems.[1] Barriers to foot self-care (e.g., visual, cognitive or movement difficulties) should be addressed.[1] Initial treatment may include use of moisturizers for dry skin, nail-care recommendations and support, and use of pressure-relieving orthoses.[1] The use of specialized footwear is recommended by the ADA for those at high-risk of ulceration (e.g., those with LOPS, deformity, ulcers, callous formation, poor circulation, or history of amputation).[1]
If Charcot neuroarthropathy is suspected (i.e., warm, swollen, red foot with or without a history of trauma, and without open ulceration), the person should be urgently referred, nonweight-bearing on the affected limb, to a foot care specialist, as early diagnosis and treatment is key to avoid further complications that may lead to amputation.[1]
Adults with type 1 diabetes are at three times the risk of clinical depression compared with those without type 1 diabetes.[183] The prevalence of depression in diabetes is higher in women (28%) compared with men (18%).[184] One systematic review and meta-analysis found that the prevalence of depression in children with type 1 diabetes was 22.2%. This prevalence was higher among girls (29.7%) than boys (19.7%) and was higher in lower-middle-income countries (29.3%).[185]
The risk of psychologic adjustment and psychiatric disorders may also be higher in adolescents, at diagnosis, or when there is a change in disease status.[56][186][187] Recurrent DKA should prompt consideration of mental health problems (as should insulin omission or overdose, and chronically very high HbA1c).[56] Mental health problems in people with type 1 diabetes may lead to early complications and mortality.[56]
Diabetes distress is distinct from depression (though the two share some features), and refers to negative psychologic reactions related to the emotional burdens of managing diabetes.[1] It is prevalent in people with diabetes (up to 45% in some studies), and can also affect family and caregivers.[1] Diabetes distress can significantly impact self-management and adherence, and is associated with higher HbA1c levels and reduced health-related quality of life.[1][56]
Anxiety symptoms and disorders are also common in those with diabetes, and can affect self-management.[1] Up to 30% of youth with type 1 diabetes have significant anxiety symptoms (which overlap significantly with diabetes distress).[56]
Mental health problems should be regularly screened for (e.g., depression and diabetes distress at least annually) and promptly managed, with referral made to qualified behavioral health professionals or other appropriate specialist services if indicated, ideally one with diabetes experience.[1] Education and behavioral/psychologic interventions (e.g., motivational interviewing) have been shown to reduce diabetes distress.[1] Use of diabetes technology may be helpful, for example, an randomized controlled trial (RCT) showed decreased hypoglycemia-related anxiety in adults with type 1 diabetes after they were switched from intermittently scanned CGM to real-time CGM with alerts (with an added benefit of improved HbA1c).[1]
Type 1 diabetes is a risk factor for rapid cognitive decline. In one study, patients with >50 years duration of type 1 diabetes performed worse on immediate and delayed recall, and psychomotor speed, as compared with similar-age people without diabetes.[190] A 32-year follow-up of people with type 1 diabetes enrolled in the DCCT/EDIC study showed that poorer diabetes control was associated with more rapid decline of cognitive function. Exposure to higher HbA1c, more episodes of severe hypoglycemia, and elevated systolic blood pressure together accounted for 9.4 years of advanced aging.[191] Control of cardiovascular risk factors in addition to glycemia can help to reduce the risk of dementia.[1]
Decline in cognitive functioning can affect diabetes self-management (e.g., accidental skipped meals and incorrect insulin-dosing increasing risk of hypoglycemia) and make meeting treatment goals challenging.[1] Increased support with diabetes management and simplified treatment plans should be considered for those with cognitive decline/impairment, as well as increased vigilance for hypoglycemia (as there is a bidirectional association between cognitive impairment and hypoglycemia).[1]
Bone fragility is a complication of diabetes that can affect patients of different ages with different disease severity, as well as the duration and the presence of other complications.[182][192] People with type 1 diabetes have lower bone mineral density and are at a greater risk of fracture than individuals without diabetes (more than five times for hip fracture and two times for nonvertebral fractures).[193] One population-based cohort reported a 14% increase in the risk for all fracture types in childhood, and in adults with type 1 diabetes the risk was double that of healthy controls, impacting both sexes equally.[56] One systematic review and meta-analysis found that patients with diabetes have an increased risk of impaired fracture healing when compared with patients without diabetes. In addition, fracture healing in the lower extremities, short bones, and osteoporosis-unrelated fractures, is affected by diabetes.[194]
Emphasis on bone health is important from childhood (e.g., adequate calcium and vitamin D intake, smoking avoidance, regular weight-bearing exercise), and bone mineral density monitoring is recommended by the ADA for older adults (ages >65 years) and younger individuals with additional risk factors.[1][56] International Society for Pediatric and Adolescent Diabetes guidelines do not recommend regular bone densitometry in children and adolescents, though they advise that bone health assessment may be considered when there are certain additional risk factors (e.g., celiac disease or family history of early osteoporosis).[56]
Periodontal disease is almost twice as common in people with type 1 diabetes than in the general population.[195] Poor glycemic control is associated with increased risk of future tooth loss.[56] Dental caries are also associated with type 1 diabetes.[196] Regular dental checkups and good oral hygiene is recommended for prevention of dental problems.[56]
Impairment in hearing is more common in people with diabetes (with stronger associations found in younger people) and occurs across a range of frequencies.[1] A National Health and Nutrition Examination Survey (NHANES) analysis found it to be around twice as prevalent in those with diabetes after adjusting for age and other risk factors.[1] Reported risk factors in diabetes are low HDL-cholesterol, coronary heart disease, peripheral neuropathy, and general poor health.[1] A link between glucose levels and hearing loss has not consistently been demonstrated.[1]
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