Type 1 diabetes mellitus - BMJ · 1/21/2020 · Type 1 diabetes mellitus is a metabolic disorder...

Type 1 diabetesmellitus

The right clinical information, right where it's needed

Last updated: Jan 21, 2020

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 4

Etiology 4

Pathophysiology 4

Classification 5

Prevention 6

Screening 6

Diagnosis 7

Case history 7

Step-by-step diagnostic approach 7

Risk factors 8

History & examination factors 9

Diagnostic tests 10

Differential diagnosis 11

Diagnostic criteria 12

Treatment 13

Step-by-step treatment approach 13

Treatment details overview 18

Treatment options 19

Emerging 26

Follow up 28

Recommendations 28

Complications 30

Prognosis 33

Guidelines 34

Diagnostic guidelines 34

Treatment guidelines 35

Online resources 36

References 37

Disclaimer 48

Summary

◊ Type 1 diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to absoluteinsulin deficiency.

◊ Patients most often present with a few days or weeks of polyuria, polydipsia, weight loss, andweakness.

◊ Some patients may present with diabetic ketoacidosis.

◊ Intensive glycemic control has been shown to decrease the incidence of microvascular andmacrovascular complications.

◊ Microvascular complications include retinopathy, nephropathy, and neuropathy.

◊ Macrovascular complications include coronary artery, cerebrovascular, and peripheral vasculardisease.

Type 1 diabetes mellitus BasicsBA

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DefinitionType 1 diabetes mellitus is a metabolic disorder characterized by hyperglycemia due to absolute insulindeficiency. The condition develops due to destruction of pancreatic beta cells, mostly by immune-mediatedmechanisms. In some patients there may be no evidence of autoimmune destruction of pancreatic beta cells;this is called idiopathic type 1 diabetes.

EpidemiologyType 1 diabetes accounts for about 5% to 10% of all patients with diabetes. It is the most commonlydiagnosed diabetes of youth (under 20 years of age) and causes ≥85% of all diabetes cases in this agegroup worldwide.[3] It is estimated that 1,106,500 people aged 0-19 years have type 1 diabetes worldwide,with 132,600 newly diagnosed cases each year.[4]

In the US from 2011-2012, more than 17,900 people aged under 20 years were newly diagnosed with type1 diabetes annually (annual rate for new cases about 21 in 100,000).[5] In a study of adults diagnosed withdiabetes in the US in 2016 and 2017, type 1 diabetes accounted for 5.6% of cases.[6]

There is significant geographic variation in the incidence of type 1 diabetes. It is more common in Europeansand less common in Asians. Thus, a child in Finland is 40 times more likely to develop type 1 diabetesthan a child in Japan and almost 100 times more likely to get the disease than a child in the Zunyi region ofChina.[7] Worldwide, the incidence of type 1 diabetes is increasing by 3% every year, although the reasonsfor this are unclear.[8] [9] [10] [11] One report showed a more rapid increase in nonwhite racial and ethnicgroups.[12]

Type 1 diabetes can present at any age, with the highest incidence observed in children aged 10-14years.[3] It affects males and females equally.[3]

EtiologyCertain human leukocyte antigen (HLA)-DR/DQ gene polymorphisms, particularly HLA-DR and HLA-DQalleles, increase susceptibility to, or provide protection from, the disease.[13] [14] In susceptible individuals,environmental factors may trigger the immune-mediated destruction of pancreatic beta cells. Although thegeographic variation in disease prevalence and increasing worldwide incidence of type 1 diabetes argue fora major environmental contribution to pathogenesis, the specific factors involved remain unknown. Amongviruses, the strongest associations have been found with human enteroviruses.[15] [16] [17] Among dietaryfactors, supplementation with vitamin D may be protective.[18] [19] Further research is required to determinethe effect of cow's milk, early introduction of cereals, or maternal vitamin D ingestion on type 1 diabetesrisk.[20] [21] [22] Celiac disease shares the HLA-DQ2 genotype with type 1 diabetes, and is more commonamong those with type 1 diabetes.[23] [24] The incidence of type 1 diabetes may also be higher among thosewith celiac disease, although a causal relationship is not suggested.[25]

PathophysiologyType 1 diabetes usually develops as a result of autoimmune pancreatic beta-cell destruction in geneticallysusceptible individuals. Up to 90% of patients will have autoantibodies to at least one of three antigens:glutamic acid decarboxylase; insulin; and a tyrosine-phosphatase-like molecule, islet autoantigen-2

4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 21, 2020.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is

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Type 1 diabetes mellitus Basics

(IA-2).[26] Over 25% of individuals without one of these or islet cytoplasmic autoantibodies will have positiveantibodies to ZnT8, a pancreatic beta-cell-specific zinc transporter.[27] In addition, 10% of adults who havebeen classified as having type 2 diabetes may have circulating islet cell antibodies or antibodies to glutamicacid decarboxylase, indicating autoimmune destruction of beta cells.[28]

Beta-cell destruction proceeds subclinically for months to years as insulitis (inflammation of the beta cell).When 80% to 90% of beta cells have been destroyed, hyperglycemia develops. Insulin resistance has no rolein the pathophysiology of type 1 diabetes. However, with increasing prevalence of obesity, some patients withtype 1 diabetes may be insulin resistant in addition to being insulin deficient.

Patients with insulin deficiency are unable to utilize glucose in peripheral muscle and adipose tissues.This stimulates the secretion of counter-regulatory hormones such as glucagon, epinephrine, cortisol, andgrowth hormone. These counter-regulatory hormones, especially glucagon, promote gluconeogenesis,glycogenolysis, and ketogenesis in the liver. As a result, patients present with hyperglycemia and anion gapmetabolic acidosis.

Long-term hyperglycemia leads to vascular complications due to a combination of factors that includeglycosylation of proteins in tissue and serum, production of sorbitol, and free radical damage. Microvascularcomplications include retinopathy, neuropathy, and nephropathy. Macrovascular complications includecardiovascular, cerebrovascular, and peripheral vascular disease. Hyperglycemia is known to induceoxidative stress and inflammation. Oxidative stress can cause endothelial dysfunction by neutralizing nitricoxide. Dysfunctional endothelium allows entry of low-density lipoprotein into the vessel wall, which induces aslow inflammatory process and leads to atheroma formation.[29]

ClassificationTypes of type 1 diabetesAutoimmune or classical

• Characterized by absolute insulin deficiency and the presence of antibodies to pancreatic beta cells.

Idiopathic

• Uncommon form that is characterized by absence of antibodies.

• Increased likelihood in patients of African or Asian ancestry and has a strong genetic component.

Presentation of idiopathic type 1 diabetes does not differ from that of autoimmune type 1 diabetes.

The American Diabetes Association has produced a staging system for type 1 diabetes based on clinicalfeatures and the presence of autoantibodies. The persistent presence of two or more autoantibodies is analmost certain predictor of clinical hyperglycemia and diabetes, and the rate of progression is dependenton the age at first detection of antibody, the number of antibodies, the antibody specificity, and the antibodytiter.[1] Glucose and glycosylated hemoglobin (HbA1c) levels rise well before the clinical onset of diabetes,making early diagnosis possible. This staging can serve as a framework for future research and screening.

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This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Jan 21, 2020.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is


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ScreeningRoutine screening is not recommended for type 1 diabetes due to a low population prevalence. Screeningfor antibodies that confer high risk is also not recommended because animal and human studies have notconfirmed the utility of treatment (e.g., with nicotinamide; or oral, parenteral, or nasal insulin) to prevent ordelay type 1 diabetes in high-risk individuals. Screening for related antibodies is only recommended in thecontext of a clinical research study.[42]




Type 1 diabetes mellitus Diagnosis

Case historyCase history #1A 12-year-old white girl is brought to the emergency department by her parents due to 12 hours of rapidlyworsening nausea, vomiting, abdominal pain, and lethargy. Over the last week she has felt excessivelythirsty and has been urinating a lot. Physical examination reveals a lean, dehydrated girl with deep rapidrespirations, tachycardia, and no response to verbal commands.

Other presentationsThe rate of beta-cell destruction varies in type 1 diabetes. In some patients, there may be a slowdestruction leading to gradual onset of symptoms that is clinically indistinguishable from type 2 diabetes.When the initial presentation of type 1 diabetes occurs in adulthood, some refer to it as latent autoimmunediabetes in adults (LADA). It is useful to distinguish LADA from type 2 diabetes, because patients withLADA usually require insulin therapy. Features that suggest the presence of LADA rather than type 2diabetes include two or more of the following: age of onset less than 50 years, acute symptoms, bodymass index less than 25 kg/m², and personal or family history of autoimmune disease.[2]

Step-by-step diagnostic approachClinical presentationType 1 diabetes presents with polyuria, polydipsia, weight loss, generalized weakness, and blurredvision. Some patients present with diabetic ketoacidosis, the acute complication of type 1 diabetes.These patients have symptoms of dehydration and acidosis such as nausea, vomiting, abdominal pain,tachypnea, tachycardia, and lethargy. Rarely, a patient is diagnosed with type 1 diabetes during routineblood tests. The condition is diagnosed long before its chronic complications have developed.

DiagnosisDiagnosis can be made on the basis of any of the following:[1]

1. In a symptomatic patient, random plasma glucose of >200 mg/dL (>11 mmol/L)2. Fasting plasma glucose >126 mg/dL (>6.9 mmol/L)3. Plasma glucose ≥200 mg/dL (≥11 mmol/L) 2 hours after 75 g oral glucose4. Glycosylated hemoglobin (HbA1c) ≥6.5% (≥48 mmol/mol).

In an asymptomatic patient, results should be confirmed by repeating the test (from the same sample orin two separate test samples).[1] In symptomatic patients, measurement of plasma glucose if sufficient todiagnose diabetes.[1] Diabetes is the overall diagnostic term applied to people satisfying these criteria,with type 1 and type 2 being further subclasses based on clinical and/or laboratory criteria.[34]

The diagnosis of type 1 diabetes is often obvious from the clinical presentation, but can be confirmedthrough additional testing. Low C-peptide levels and presence of one or more autoimmune markersare consistent with a diagnosis of type 1 diabetes.[35] Autoimmune markers include autoantibodies to

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glutamic acid decarboxylase (GAD), insulin, islet cells, islet antigens (IA2 and IA2-beta), and the zinctransporter ZnT8.

Elevated plasma or urine ketones in the presence of hyperglycemia suggests type 1 diabetes, but isoccasionally seen at presentation in a patient with type 2 diabetes. As an example, when an obeseteenager with a positive family history of type 2 diabetes is found to have high plasma glucose levels onroutine blood tests, the diagnosis of type 1 versus type 2 diabetes may not be clear. If C-peptide levels arevery low or undetectable relative to the plasma glucose and anti-GAD antibodies are positive in such apatient, a diagnosis of type 1 diabetes can be made.

It is also important to consider monogenic diabetes in the differential for type of diabetes, sincethis accounts for up to 4% of pediatric diabetes and insulin treatment is inappropriate in thesecases.[35] Suspicion should be higher in antibody-negative, ketone-negative pediatric diabetes witha family history of diabetes in multiple generations.[1] The two main forms of monogenic diabetes arematurity-onset diabetes of the young (MODY) and neonatal diabetes. Genetic testing is definitive and canbe used to counsel the patient and family members.

[VIDEO: Venepuncture and phlebotomy: animated demonstration ]

Risk factorsStronggeographic region• Human leukocyte antigen (HLA) risk profile for type 1 diabetes is widening over time, which may reflect

increased environmental influence on susceptible genotypes.[32]• Geographic variation ranges from 1/100,000 in regions of China to 38/100,000 in Finland.[7] Regional

variation suggests different contributing risk exposures.[10]

Weakgenetic predisposition• In one study, concordance for type 1 diabetes was 27.3% in monozygotic twins and 3.8% in dizygotic

twins.[30]• HLA on chromosome 6 thought to contribute to half of the familial basis.[31]• DR4-DQ8 and DR3-DQ2 present in 90% of children with type 1 diabetes; considered susceptibility

genes.[31]• DR15-DQ6 considered protective.[31]• Insulin gene on chromosome 11 thought to be second most important susceptibility gene, contributing

10% of genetic susceptibility.[31]• Several other loci associated with type 1 diabetes under study.[31]

infectious agents• Strongest evidence to date is for human enteroviruses.[15] [16] [17]



http://bestpractice.bmj.com/procedural-videos/en-us/e6907c5c-b46a-4086-a762-d5857b761fb4



dietary factors• Among dietary factors, supplementation with vitamin D may be protective.[18] [19] Further research

is required to determine the effect of cow's milk, early introduction of cereals, or maternal vitamin Dingestion on type 1 diabetes risk.[20] [21] [22] There is no consensus about the effect of breast-feedingon risk for type 1 diabetes.[33]

History & examination factorsKey diagnostic factorspolyuria (common)• Getting up at night to urinate is typical.

polydipsia (common)• Getting up at night to drink water is typical.

Other diagnostic factorsyoung age (common)• Usually presents in childhood or adolescence. Typical age 5 to 15 years.• Average age varies in different studies. Incidence increasing in children <5 years old.[36]

weight loss (common)• Weight loss occurs at onset.

blurred vision (common)• Occurs with high or fluctuating blood sugar levels.

nausea and vomiting (common)• Suggest diabetic ketoacidosis.

abdominal pain (common)• Suggests diabetic ketoacidosis.

tachypnea (common)• Suggests diabetic ketoacidosis.

lethargy (common)• Suggests diabetic ketoacidosis.

coma (uncommon)• Suggests diabetic ketoacidosis.

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Diagnostic tests1st test to order

Test Resultrandom plasma glucose

• Confirms diagnosis in the presence of symptoms of polyuria,polydipsia, and unexplained weight loss.[1]

≥200 mg/dL (≥11 mmol/L)

fasting plasma glucose• Fasting is defined as no caloric intake for at least 8 hours.

≥126 mg/dL (≥6.9 mmol/L)

2-hour plasma glucose• Plasma glucose is measured 2 hours after 75 g oral glucose load.

≥200 mg/dL (≥11 mmol/L)

plasma or urine ketones• In the presence of hyperglycemia suggest type 1 diabetes.

medium or high quantity

HbA1c• Reflects degree of hyperglycemia over the preceding 3 months.

≥6.5% (≥48 mmol/L)

Other tests to consider

Test Resultfasting C-peptide

• C-peptide is a byproduct formed when proinsulin is processed toinsulin. Therefore, its levels reflect insulin production. Half life of C-peptide is 3 to 4 times longer than that of insulin.

• Low or undetectable C-peptide level indicates absence of insulinsecretion from pancreatic beta cells.

low or undetectable

autoimmune markers• These include autoantibodies to glutamic acid decarboxylase, insulin,

islet cells, islet antigens (IA2 and IA2-beta), and the zinc transporterZnT8.

• Presence indicates autoimmune beta-cell destruction.

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Differential diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Monogenic diabetes:maturity onset diabetes ofthe young

• Maturity-onset diabetesof the young (MODY) isthe most common form ofmonogenic diabetes andaffects 1% to 2% of peoplewith diabetes.[37]

• MODY is caused bymutation of a single gene(i.e., monogenic). It hasautosomal dominantinheritance and shouldbe suspected in cases ofdiabetes in nonobese, youngpatients (adolescence oryoung adult) with familyhistory of diabetes intwo or more successivegenerations.[38]

• Presents with nonketotic,noninsulin-dependentdiabetes that respondsto oral glucose loweringdrugs.[39]

• C-peptide present.• Autoantibodies absent.• Genetic testing in patients

with high index of suspicionidentifies mutations mostcommonly in genesencoding glucokinase andtranscription factors.[39]

Neonatal diabetes • Diabetes diagnosed under 6months of age.[1]

• Usually isolated diabetesin an autosomal dominantpattern of inheritance.

• Some monogenic causesare characterized bya variety of syndromicfeatures.[40]

• Genetic testing with majorityof mutations in the genesencoding the adenosinetriphosphate-sensitivepotassium channel and theinsulin gene.[40]

Latent autoimmunediabetes in adults (LADA)

• Typical age of onsetof diabetes is over 30years old. Patients areusually nonobese andrespond initially to lifestylemodifications and oralagents. Production ofinsulin gradually decreases(between 6 months and 5years), such that treatmentwith insulin is required.[41]

• LADA is considered a subsetof type 1 diabetes; however,patients with LADA arefrequently misclassified ashaving type 2 diabetes.

• Low to normal initial C-peptide level.

• Can be positive for atleast 1 of the 4 antibodiescommonly found in type 1diabetic patients.[41]

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Condition Differentiating signs /symptoms

Differentiating tests

Type 2 diabetes • Typically, signs of insulinresistance (such asacanthosis nigricans) shouldbe sought and in theirabsence clinical suspicion oftype 1 diabetes is greater.

• Signs of more marked insulindeficiency (for example,glycemic lability as well assusceptibility to ketosis) raisesuspicion of type 1 diabetes.

• Older age and slowonset, obesity, a strongfamily history, absenceof ketoacidosis, andinitial response to oralantihyperglycemic drugs aretypical of type 2 diabetes.

• C-peptide present.• Autoantibodies absent.• Testing for C-peptide and

autoantibodies usually notrequired.

Diagnostic criteriaAmerican Diabetes Association: criteria for diagnosis of diabetes[1]In the absence of unequivocal hyperglycemia, any of the tests should be confirmed by repeat testing onthe same sample or on two separate test samples. Screening tests are generally most applicable to type 2diabetes.

• Random plasma glucose level ≥200 mg/dL (≥11 mmol/L) in the presence of symptoms ofhyperglycemia; OR

• Fasting plasma glucose ≥126 mg/dL (≥6.9 mmol/L); OR• Plasma glucose level ≥200 mg/dL (≥11 mmol/L) 2 hours after a 75 g oral glucose load; OR• HbA1c ≥6.5% (≥48 mmol/L).




Type 1 diabetes mellitus Treatment

Step-by-step treatment approachFor updates on diagnosis and management of coexisting conditions during the pandemic, see our topic"Management of coexisting conditions in the context of COVID-19".

In the short term, insulin is life-saving because it prevents diabetic ketoacidosis, a potentially life-threateningcondition. The long-term goal of insulin treatment is the prevention of chronic complications by maintainingblood glucose levels as close to normal as possible. Generally, glycosylated hemoglobin (HbA1c) goalsdetermine the aggressiveness of therapy, which is in turn individualized. The American Diabetes Association(ADA) recommends a target HbA1c goal of <7% for adult patients and many children.[1] [35] [47] Lessstringent goals may be appropriate for very young children, older adults, people with a history of severehypoglycemia, and those with limited life expectancies, advanced microvascular or macrovascularcomplications, or comorbid conditions.[1]

Good glycemic control in type 1 diabetes requires attention to diet, exercise, and insulin therapy. Allthree components should be coordinated for ideal control. Self-monitoring of blood glucose (SMBG) isa core component of good glycemic control. Patients on multiple injections daily should consider SMBGbefore meals, occasionally after meals and at bedtime, and before exercising to assess presence andadequate treatment of hypoglycemia, and before any task during which hypoglycemia could have particularlydangerous consequences.[1] Some patients will need to check their blood glucose 6-10 times daily.

As continuous glucose monitoring (CGM) technology continues to improve, the indications for its useare likely to expand.[48] Evidence supports use of CGM for improved glucose control in adults andchildren.[49] [50] [51] Appropriate use of CGM is when it is targeted at people with type 1 diabetes whohave hypoglycemic unawareness, frequent hypoglycemia, or continued poor control during intensified insulintherapy, and at those who are willing to use CGM frequently.[1] [52] The limiting factor for tight glycemiccontrol in type 1 diabetes is hypoglycemia. Well-controlled blood pressure and lipids and avoidance ofsmoking are essential components of cardiovascular risk reduction.

Including technology-based methods, along with individual and group settings, are recommended for thedelivery of effective diabetes self-management education and support.[1] This approach can be used foradults,[53] as well as children and adolescents.[54]

Diet and exerciseThere is no standardized dietary advice that is suitable for all individuals with diabetes.[1] Individualizednutrition advice should be based on personal and cultural preferences, health literacy and numeracy,access to healthful food choices, and willingness and ability to make behavioral changes. It should alsoaddress barriers to change. All patients with diabetes should receive individualized medical nutritiontherapy, preferably provided by a registered dietitian who is experienced in providing this type of therapyto diabetes patients.[55] Carbohydrate counting or consistent carbohydrate intake with respect to time andamount may improve glycemic control. Rapid-acting insulins may make timing of meals less crucial thanin the past, but regular meals are still important.

Adults with diabetes are recommended to engage in 150 minutes/week of moderate-intensity aerobicexercise (to 50% to 70% of max heart rate) spread over at least 3 days per week, with no more than 2consecutive days without exercise.[1] Children and adolescents with diabetes should aim for 60 minutesof moderate- to vigorous-intensity aerobic activity daily and vigorous muscle-strengthening and bone-strengthening activities at least 3 days per week.[35] Patients with type 1 diabetes can safely exercise

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and manage their glucose levels.[35] [56] Pre-exercise carbohydrate intake and insulin doses can beeffectively modified to avoid hypoglycemia during exercise and sports.[57] [58] Hypoglycemia can occurup to 24 hours after exercise and may require reducing insulin dosage on days of planned exercise. Acarbohydrate snack should be given at the start of exercise if the blood sugar is <100 mg/dL (<5.6 mmol/L).

Clinical judgment should be used in determining whether to screen asymptomatic individuals for coronaryartery disease prior to recommending an exercise program.[1]

The following should be assessed prior to starting an exercise program: age; physical condition; bloodpressure; and presence or absence of autonomic neuropathy or peripheral neuropathy, preproliferative orproliferative retinopathy, or macular edema. Vigorous exercise may be contraindicated with proliferative orsevere preproliferative diabetic retinopathy. Nonweight-bearing exercise may be advisable in patients withsevere peripheral neuropathy.

Prolonged sitting should be interrupted every 30 minutes with short bouts of physical activity.[1]

Initiating insulinIntensive therapy with insulin should be started as soon as possible after diagnosis.[59] Unlike olderregimens that used nonphysiologic insulin dosing, intensive therapy aims to mimic physiologic insulinrelease by combining basal insulin with bolus dosing at mealtimes. Both continuous infusion with aninsulin pump and a regimen of multiple daily injections (MDI) can provide intensive therapy.[60]

The choice between pump and MDI is based on patient interest and self-management skills, as well asphysician preference, as outcomes are generally similar.[61] The insulin pump uses regular or rapid-acting insulin, and provides a basal rate of insulin and delivers mealtime bolus dosing. However, thepatient or parent must still measure blood glucose frequently in order to adjust the pump to deliver theappropriate amount of insulin. Insulin pumps may reduce hypoglycemia, especially when combinedwith continuous glucose monitoring systems (CGMS) and threshold suspend features,[62] and improveHbA1c, while providing greater flexibility.[63] [64] [65] Use of a pump requires a motivated patient withstrong family support (for children) and access to practitioners trained in pump therapy.[66]

Using a combination of long- (insulins glargine, detemir, or degludec) or intermediate-acting (NPH) insulinfor basal dosing, and rapid- (insulins lispro, aspart, or glulisine) or short- (regular-) acting insulin for bolusdosing, MDI regimens can be designed based on physician and patient preference and modified basedon finger-stick data. There is no consensus as to whether insulin analogs are superior to conventionalinsulins for glycemic control or reductions in complications.[67] [68]

In the past, many patients were managed with twice-daily injections of a mixture of rapid-acting andintermediate-acting insulin. This regimen may be used if patients are unable to comply with MDI, but it isno longer a first-line recommendation for management because of its lack of flexibility.

Designing a regimenAn initial total daily dose of insulin in adults can be 0.2 to 0.4 units/kg/day. In children, an initial daily dosewill be 0.5 to 1.0 units/kg/day, and during puberty the requirements may increase to as much as 1.5 units/kg/day. Often, when first started on insulin, patients with type 1 diabetes will experience a honeymoonperiod, during which they may require only 10 or 15 units/day. One half of the total dose is given as basalinsulin and one half as bolus dosing.[1] The bolus dosing is divided and given before meals. Patientsneed to self-monitor their blood glucose levels. The insulin doses can be adjusted every 2-3 days to





maintain target blood glucose. To achieve an HbA1c <7% (<53 mmol/mol), the pre-meal blood glucosegoal is 80-130 mg/dL (4.4 to 7.2 mmol/L) and the postmeal blood glucose goal (1-2 hours after startingthe meal) is <180 mg/dL (10.0 mmol/L).

The simplest approach to covering mealtime insulin requirements is to suggest a range of doses, suchas 4 units for a small meal, 6 units for a medium-sized meal, and 8 units for a larger meal. For greaterflexibility of carbohydrate content of meals, pre-meal insulin can be calculated based on the estimatedamount of carbohydrate in the meal and the patient's individual insulin-to-carbohydrate ratio. A simplebeginning approach is to use 1 unit of mealtime insulin for every 15 g of carbohydrate in the meal.Patients can use the carbohydrate content per serving listed on food packaging to assess the number ofgrams in their anticipated meal, but carbohydrate counting is best learned with the help of a nutritionist.Using a food diary and 2-hour postprandial blood glucose measurements, the insulin-to-carbohydrateratio can be adjusted.

A correction dose may be added to the bolus insulin based on the pre-meal blood glucose level.Correction dosing may be calculated as follows when the patient's total daily dose of insulin (TDD) andfood intake is stable: 1800/TDD = the predicted point drop in blood glucose per unit of rapid acting insulin.For example, if the TDD is 40 units of insulin, 1800/40 = 45 point drop per unit of insulin.

Example of correction dosing based on pre-meal glucose and above calculation:

• 45-90 mg/dL (2.2 to 4.9 mmol/L): subtract 1 unit from mealtime insulin• 91-135 mg/dL (5.0 to 7.4 mmol/L): add 0 units of correction insulin• 136-180 mg/dL (7.5 to 9.9 mmol/L): add 1 unit of correction insulin• 181-225 mg/dL (9.9 to 12.4 mmol/L): add 2 units of correction insulin• 226-270 mg/dL (12.4 to 14.5 mmol/L): add 3 units of correction insulin• 271-315 mg/dL (14.5 to 17.3 mmol/L): add 4 units of correction insulin• 316-360 mg/dL (17.4 to 19.8 mmol/L): add 5 units of correction insulin• 361-405 mg/dL (19.8 to 22.3 mmol/L): add 6 units of correction insulin• >405 mg/dL (>22.3 mmol/L): add 7 units of correction insulin; call healthcare provider.

The number used to calculate the correction dose may be as low as 1500 or as high as 2200. There areno specific guidelines to determine this number. In general, a lower number should be used for obese,insulin-resistant patients, and a higher number should be used for lean, insulin-sensitive patients.

This correction dose can be added to the patient's mealtime insulin requirement (whether based ongeneral meal size or carbohydrate counting) and given as the total bolus dose.

Pump therapy utilizes a similar concept as basal and bolus dosing and does not require multiple injectionsof insulin. However, patients still need to monitor their blood glucose from 4-7 times daily. There is someevidence that insulin pump therapy may be associated with improved glycemic control and lower risk ofhypoglycemia,[69] including in children, adolescents, and young adults.[70] Because of the monitoringand dose adjustment required, patients selected for pump therapy must be skilled in diabetes self-management and able to manage and troubleshoot the various pump components.[71]

The insulin pump uses a subcutaneous insulin injection port. The port is changed every 3 days and mayreduce anxiety and help achieve better glycemic control in selected patients.[72] [73]

CGMS measure subcutaneous interstitial fluid glucose every 5 minutes. CGMS may be indicated inselected patients with widely fluctuating glucose levels or hypoglycemia unawareness. A 3-day glucose

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monitoring system using a CGMS may help the physician adjust insulin doses. Real-time CGMS, worn bya patient on a regular basis, may help improve glycemic control.[74] [75] [76] [77] The glucose sensorsused in CGMS are not reliable at lower ranges of glucose, and thus do not eliminate the need for fingersticks. Development of these systems is ongoing.[48]

CGMS are also less accurate than traditional capillary blood glucose monitoring methods. However,they provide information on glucose trends, provide alarms to alert patients to impending hypo- orhyperglycemia, and reduce episodes of hypoglycemia.[62] [78] Insulin pumps with glucose sensorsintegrated into the same unit are called sensor-augmented insulin pumps. Functionality between sensorand pump has been integrated in one available device: a "closed loop" system. The insulin deliverycan be determined automatically based on sensed glucose levels. These integrated devices use acomputerized control algorithm to create the closed loop insulin delivery system, which functions as anartificial pancreas.[35] [79] In clinical trials, such systems have been shown to reduce the risk of nocturnalhypoglycemia and to improve glucose control, including in children.[49] [80] [81] Some models come withsmartphone apps that can be used to monitor glucose and insulin dosing. Use of sensors and sensor-augmented pumps is increasing and is increasingly reimbursed by insurance providers.

Hypoglycemia is the most common and potentially most serious side effect of insulin therapy, as it canlead to decreased quality of life, confusion, seizures, and coma. Episodes of hypoglycemia should besought at each visit, and efforts made to determine contributing factors, and the ability of the patient torecognize and treat it appropriately.

Goal not metIf glycemic control is not adequate as measured by the HbA1c or by episodes of hypoglycemia, thepatient's nutrition, exercise, and insulin regimen must be re-examined. Children and adolescents mayhave erratic eating patterns or snack frequently. Consultation with a nutritionist is an invaluable part of thetreatment approach, as patients can learn how to count carbohydrates and adjust their pr-emeal insulinto allow for flexibility in meal content and activity. Consistent hyperglycemia may require an increase inbasal insulin. Preprandial and postprandial hyperglycemia may be due to inadequate insulin coverage forthe most recent meal, and may be addressed by considering carbohydrate content of meals, the patient'sassessment of their carbohydrate intake, and subsequent pre-meal insulin dosing. If a patient is gettingregular insulin, replacing it with rapid-acting insulin may reduce postprandial glucose excursions.

Other conditions contributing to unstable diabetes and that co-exist most commonly with diabetes includeceliac disease, thyroid disease, Addison disease, and psychosocial distress. Celiac disease, thyroiddisease, and psychosocial distress should be screened for at diagnosis and on a regular basis, whileincreased clinical suspicion should prompt screening for Addison disease and pernicious anemia.

Episodes of hypoglycemia occur with different frequency among patients. Patients should check a 3 a.m.blood glucose if there is concern about risk of nocturnal hypoglycemia. Nocturnal hypoglycemia mayresult in rebound hyperglycemia in the morning. The dose of basal insulin should be decreased to preventnocturnal hypoglycemia. A bedtime snack is not an effective way of decreasing the risk of nocturnalhypoglycemia.[82] Alcohol may cause acute hypoglycemia, but both alcohol and exercise can causedelayed hypoglycemia (by up to 24 hours).





Noninsulin treatmentsPramlintide is indicated as adjunctive treatment in patients with postprandial hyperglycemia that cannotbe controlled with pre-meal insulin alone. For example, it may be useful in a patient with high postprandialglucose, but who develops late hypoglycemia when pre-meal insulin is increased.

The therapy of people with type 1 diabetes also involves regular eye examinations, foot care, treatment ofdyslipidemia, and blood pressure control.

Adults with type 1 diabetes are at three times the risk of clinical depression compared with those withouttype 1 diabetes.[83] The prevalence of depression in diabetes is higher in women (28%) compared withmen (18%).[84] The risk may also be higher in adolescents, at diagnosis, or when there is a change indisease status.[85] Psychosocial screening and support can help to ameliorate distress and improve theindividual’s and family's capacity for self-care.

PregnancyInfants of women with diabetes are at high risk of major congenital malformations and miscarriage.[86]Preconception diabetes care reduces this risk.[87] Preconception counseling should, therefore, beincorporated in the routine diabetes clinic visit for all women of childbearing potential. Women with type1 diabetes should use an effective method of contraception until they plan pregnancy. The AmericanDiabetes Association (ADA) recommends that HbA1c should be <6.5% (<48 mmol/mol) before conceptionif this can be achieved without hypoglycemia.[1] Women should also be evaluated before pregnancy forretinopathy, nephropathy, neuropathy, and possible cardiovascular disease, which may worsen during orcomplicate pregnancy.

In addition to the complications noted above, infants of mothers with hyperglycemic diabetes are atrisk of macrosomia and neonatal distress. Preeclampsia is also more common in diabetic pregnancies.Euglycemia or near-euglycemia reduces the risk of complications. During pregnancy, women shouldbe cared for by a multidisciplinary team, including a nutritionist, a nurse educator, an endocrinologist,and an obstetrician. All pregnant women require a dilated eye exam soon before or early in pregnancy.Women with diabetes have an increased risk of having infants with neural tube defects, compared withthe general population,[88] and should take a folic acid supplement prior to and during pregnancy. Statins,angiotensin-converting enzyme inhibitors, and angiotensin-II receptor blockers should be discontinuedpreconception. Intensive insulin treatment with MDI or insulin pump should be started. Commonly usedinsulins during pregnancy include NPH, detemir, regular, lispro, and aspart.[89] Use of CGM duringpregnancy may help in improving glycemic control and neonatal outcomes.[90]

There are no large randomized trials supporting the safety of insulin glargine in pregnant patientswith diabetes. However, insulin glargine has been safely used in many patients during pregnancy. Itcan be considered second-line to NPH or insulin detemir for basal insulin dosing during pregnancybecause there are fewer long-term safety monitoring data. There are few data comparing outcomes forcontinuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant womenwith diabetes.[91] However, one randomized controlled trial reports better glycemic outcomes with use ofmultiple daily injection therapy versus insulin pump therapy.[92] ADA guidelines recommend the followingblood glucose targets in pregnant women with pre-existing type 1 diabetes (the same as for gestationaldiabetes): <95 mg/dL (<5.3 mmol/L) fasting, and either <140 mg/dL (<7.8 mmol/L) 1 hour postprandiallyor <120 mg/dL (<6.7 mmol/L) 2 hours postprandially, with HbA1c goal individualized <6% (<42 mmol/mol)or up to <7% (<53 mmol/mol) as necessary to prevent hypoglycemia.[1]

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The ADA recommends that all pregnant women with preexisting type 1 diabetes should consider dailylow-dose aspirin starting at the end of the first trimester in order to reduce the risk of preeclampsia.[1]

Ongoing comprehensive medical evaluationIncludes assessment of diabetic complications, a psychosocial assessment, and management ofcomorbid conditions (e.g., autoimmune diseases).[1]

Treatment details overviewPlease note that formulations/routes and doses may differ between drug names and brands, drugformularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

Ongoing ( summary )nonpregnant

1st basal-bolus insulin

adjunct pre-meal insulin correction dose

adjunct amylin analog

2nd fixed-dose insulin

pregnant


plus low-dose aspirin



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Treatment optionsPlease note that formulations/routes and doses may differ between drug names and brands, drugformularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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Ongoingnonpregnant


Primary options

» insulin glargine: injected subcutaneouslyonce daily-or-» insulin NPH: injected subcutaneously twicedaily-or-» insulin detemir: injected subcutaneouslytwice daily-or-» insulin degludec: injected subcutaneouslyonce daily

--AND--» insulin regular: injected subcutaneously twoto three times daily-or-» insulin lispro: injected subcutaneously pre-meal-or-» insulin aspart: injected subcutaneously pre-meal-or-» insulin glulisine: injected subcutaneouslypre-meal

OR

» pump: uses regular insulin or insulins lispro,aspart, or glulisine

» An initial total daily dose of insulin in adultscan be 0.2 to 0.4 units/kg/day. In children aninitial daily dose will be 0.5 to 1.0 units/kg/day, and during puberty the requirements mayincrease to as much as 1.5 units/kg/day. Often,when first started on insulin, patients with type1 diabetes will experience a honeymoon period,during which they may require only 10 or 15units/day. One half of the total dose is given asbasal insulin and one half as bolus dosing. Thebolus dosing is divided and given before meals.Patients need to self-monitor their blood glucoselevels. The insulin doses can be adjusted every2-3 days to maintain pre-meal and postmealtargets.[1]

» The simplest approach to covering mealtimeinsulin requirements is to suggest a range ofdoses, such as 4 units for a small meal, 6 unitsfor a medium-sized meal, and 8 units for a largermeal. For greater flexibility of carbohydratecontent of meals, pre-meal insulin can be





Ongoingcalculated based on the estimated amountof carbohydrate in the meal and the patient'sindividual insulin-to-carbohydrate ratio. Asimple beginning approach is to use one unit ofmealtime insulin for every 15 g of carbohydratein the meal. Patients can use the carbohydratecontent per serving listed on food packaging toassess the number of grams in their anticipatedmeal, but carbohydrate counting is best learnedwith the help of a nutritionist. Using a fooddiary and 2-hour postprandial blood glucosemeasurements, the insulin-to-carbohydrate ratiocan be adjusted.

» Reasonable to begin therapy with 2-4insulin injections daily to cover basal insulinrequirements and to cover mealtime insulinneeds. Intermediate- or long-acting insulins tocover basal, and short- or rapid-acting to covermealtime needs, should be used.

» Regular and NPH insulins are less expensivethan the insulin analogs. Regular insulin is givenabout 30 minutes prior to the meal, while rapid-acting insulins (lispro, aspart, or glulisine) canbe injected 15 minutes before to shortly after ameal. In children with erratic eating habits, rapid-acting insulins can be given just after the meal.NPH and insulin detemir are injected twice dailywhile insulin glargine can be injected once daily.The regimen should be individualized to obtainthe best possible glycemic control.

» A correction dose may be incorporated into theinsulin doses based on pre-meal glucose levels.

» Patients with interest and good self-management skills may prefer to use an insulinpump.

adjunct pre-meal insulin correction dose

Treatment recommended for SOME patients inselected patient group

» A correction dose may be added to the bolusinsulin based on the pre-meal blood glucoselevel. Correction dosing may be calculated asfollows when the patient's total daily dose ofinsulin (TDD) and food intake is stable: 1800/TDD = the predicted point drop in blood glucoseper unit of rapid acting insulin. For example, ifthe TDD is 40 units of insulin, 1800/40 = 45 pointdrop per unit of insulin.

» Example of correction dosing based on pre-meal glucose and above calculation:

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Ongoing» 45-90 mg/dL (2.2 to 4.9 mmol/L): subtract 1unit from mealtime insulin

» 91-135 mg/dL (5.0 to 7.4 mmol/L): add 0 unitsof correction insulin

» 136-180 mg/dL (7.5 to 9.9 mmol/L): add 1 unitof correction insulin

» 181-225 mg/dL (9.9 to 12.4 mmol/L): add 2units of correction insulin





» >405 mg/dL (>22.3 mmol/L): add 7 units ofcorrection insulin; call healthcare provider.

» The number used to calculate the correctiondose may be as low as 1500 or as high as 2200.There are no specific guidelines to determinethis number. In general, a lower number shouldbe used for obese, insulin-resistant patients, anda higher number should be used for lean, insulin-sensitive patients.

» This correction dose can be added to thepatient's mealtime insulin requirement (whetherbased on general meal size or carbohydratecounting) and given as the total bolus dose.

adjunct amylin analog

Treatment recommended for SOME patients inselected patient group

Primary options

» pramlintide: 15-60 microgramssubcutaneously before each meal

» Synthetic analog of human amylin, a proteinthat is co-secreted with insulin by pancreaticbeta cells. It reduces postprandial glucoseincreases by prolonging gastric emptying time,reducing postprandial glucagon secretion, andreducing food intake through centrally mediatedappetite suppression.[93]

» May be given as an injection before each mealto get more stable glycemic control. However,





Ongoinginsulin treatment must continue in addition topramlintide.

» At initiation the current pre-meal insulin doseshould be reduced by about 50% to avoidhypoglycemia, and then titrated up.

» Indicated as adjunctive treatment in patientswith postprandial hyperglycemia that cannotbe controlled with pre-meal insulin alone. Forexample, it may be useful in a patient withhigh postprandial glucose, but who developslate hypoglycemia when pre-meal insulin isincreased.

» Should not be used in a patient withgastroparesis. The most common side effect isnausea, occurring in 28% to 48% of patients.[93]

2nd fixed-dose insulin

Primary options

» insulin NPH/insulin regular: (50/50, 70/30)injected subcutaneously twice daily

OR

» insulin aspart protamine/insulin aspart:(70/30) injected subcutaneously twice daily

OR

» insulin lispro protamine/insulin lispro:(50/50, 75/25) injected subcutaneously twicedaily

OR

» insulin degludec/insulin aspart: (70/30)injected subcutaneously once or twice daily

» Fixed-dose insulin is used when patients arealready doing well on a fixed-dose regimen; orcannot manage 3-4 insulin injections daily; orhave trouble mixing insulin.

pregnant


Primary options

» insulin NPH: injected subcutaneously twicedaily-or-» insulin detemir: injected subcutaneouslytwice daily

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Ongoing--AND--

» insulin regular: injected subcutaneously twoto three times daily-or-» insulin lispro: injected subcutaneously pre-meal-or-» insulin aspart: injected subcutaneously pre-meal

Secondary options

» insulin glargine: injected subcutaneouslyonce daily

--AND--» insulin regular: injected subcutaneously twoto three times daily-or-» insulin lispro: injected subcutaneously pre-meal-or-» insulin aspart: injected subcutaneously pre-meal

OR

» pump: uses regular insulin or insulins lisproor aspart

» Blood sugar goals, if able to be achievedwithout significant hypoglycemia, are fasting<90 mg/dL (<5 mmol/L), 1-hour postprandial<130-140 mg/dL (<7.2 to 7.8 mmol/L), and 2-hour postprandial <120 mg/dL (<6.7 mmol/L).If these targets result in hypoglycemia, lessstringent targets are appropriate.[1]

» HbA1c should be <6.5% (<48 mmol/mol)before conception, if it can be achieved withouthypoglycemia.[1] HbA1c in pregnancy can bemonitored monthly.[1]

» Patients should monitor their blood glucosefrom 4-7 times per day and the pattern should beexamined every few weeks early in pregnancyso that nutrition content and timing, exercisepatterns, and the insulin doses can be modifiedto achieve optimal control.

» Insulin requirements generally increase earlyin pregnancy, then decrease from about 8-16weeks before rising throughout the rest of thepregnancy.

» Commonly used insulins during pregnancyinclude NPH, detemir, regular, lispro, andaspart.[89] Use of CGM during pregnancy may





Ongoinghelp in improving glycemic control and neonataloutcomes.[90] There are no large randomizedtrials supporting the safety of insulin glargine inpregnant patients with diabetes. However, insulinglargine has been safely used in many patientsduring pregnancy. It can be considered second-line to NPH or insulin detemir for basal insulindosing during pregnancy because there arefewer long-term safety monitoring data. Thereare few data comparing outcomes for continuoussubcutaneous insulin infusion versus multipledaily injections of insulin for pregnant womenwith diabetes.[91]

plus low-dose aspirin

Treatment recommended for ALL patients inselected patient group

Primary options

» aspirin: 60-125 mg orally once daily, usualdose 81 mg/day

» The American Diabetes Associationrecommends that all pregnant women withpre-existing type 1 diabetes should considerdaily low-dose aspirin starting at the end of thefirst trimester in order to reduce the risk of pre-eclampsia.[1]

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EmergingImmunotherapyType 1 diabetes is an autoimmune disease modulated by cytotoxic T cells. Several agents have beenstudied for treatment of new-onset disease. Nonantigen-specific systemic immunotherapies, including T-cell suppressors (cyclosporine), antiproliferative agents (methotrexate, azathioprine), and antithymocyteglobulin have shown a strong tendency to adverse effects. Although cyclosporine use did reduce insulinrequirements in the short term, it was associated with nephrotoxicity, and the effect on beta cells waned withtreatment cessation. Antigen-specific vaccination with recombinant glutamic acid decarboxylase was shownto increase stimulated C-peptide in patients treated within 3 months of diagnosis.[94] Trials are under way toinvestigate treatment of type 1 diabetes with dendritic cells, mesenchymal stem cells, cord blood transfusion,and immunomodulators currently approved for use in other diseases, such as granulocyte colony stimulatingfactor or tumor necrosis factor-alpha inhibitors.[95]

TepilizumabOne clinical trial of the anti-CD3 monoclonal antibody, teplizumab, in patients with new-onset diabetesshows that the decline in beta-cell function (measured by C-peptide) is slowed and insulin requirements forglycemic control are reduced.[96] [97] In one study of patients who did not have diabetes, but who were athigh-risk (≥2 type 1 diabetes auto-antibodies and dysglycemia), teplizumab delayed progression to clinicaldisease.[98] The Food and Drug Administration has granted teplizumab breakthrough therapy designationfor the prevention or delay of clinical type 1 diabetes in at-risk individuals, which may expedite the reviewprocess for approval of this drug.

Islet cell transplantationIslet cells prepared from a donor pancreas are injected into the portal vein. The cells seed in the liver andproduce insulin. Patients who undergo this procedure require immunosuppressive therapy afterwards. Thereis some initial success with this procedure but the long-term results remain disappointing. Even in the bestcenters, less than 50% of patients are free of insulin requirement at 1 year and only 10% at 5 years.[99] [100]The American Diabetes Association (ADA) recommends that this procedure be performed only within thecontext of a controlled research study at this time.

Inhaled insulinIn June 2014, the FDA approved a rapid-acting inhaled insulin. It can be administered before meals andshould be used in combination with long-acting insulin. It can cause bronchospasm in patients with asthmaand chronic obstructive pulmonary disease, and should not be used if these conditions are present. Themost common side effects in a 24-week safety and efficacy trial were hypoglycemia, cough, and throatinfection. Long-term safety data are lacking.[101] Moreover, it is available only in fixed doses of 4 or 8 units.Therefore, dose adjustments can be made only in multiples of 4 which may present difficulty in fine-tuningthe dose in patients with type 1 diabetes. More experience is needed before inhaled insulin is routinelyprescribed in type 1 diabetes.

Islet cell regenerationStudies done in mouse models show that from the onset of insulinitis, there is a mass of beta cells withinan inflammatory milieu that may be recoverable and serve as a future source of functioning beta cells.[102]Several trials are under way to investigate mono- and combination therapies to arrest inflammation andpossibly allow beta-cell regeneration.

Insulin sensitizersA systematic review suggested that use of metformin in type 1 diabetes reduced insulin requirements butnot HbA1c levels after 1 year of follow-up.[103] Further research is indicated to better delineate the potentialindications and benefits of this treatment in type 1 diabetes.[104] [105]





Sodium-glucose co-transporter 2 inhibitorsSodium-glucose co-transporter 2 (SGLT2) inhibitors are oral medications that reduce glucose in an insulin-independent manner, by inhibiting SGLT2 in the proximal renal tubule and blocking glucose reabsorption.They are associated with modest weight loss and blood pressure reduction. SGLT2 inhibitors are approvedfor use in individuals with type 2 diabetes. Several reports have highlighted the risk of euglycemic diabeticketoacidosis in both type 2 and type 1 diabetes.[106] [107] Studies are ongoing to assess safety and efficacyof this class of medications in type 1 diabetes.[1] [108] [109] The European Medicines Agency's Committeefor Medicinal Products for Human Use (CHMP) has approved the selective SGLT2 inhibitor dapagliflozinfor use in patients with type 1 diabetes mellitus and a body mass index ≥27 kg/m² as an adjunct to insulin,when insulin alone does not provide adequate glycemic control despite optimal insulin therapy.[110] [111][112] In March 2019, the CHMP recommended that sotagliflozin, a dual inhibitor of SGLT1 and SGLT2, alsobe approved for the same indication.[106] [113] [114] [115] [116] However, the Food and Drug Administration(FDA) rejected approval of sotagliflozin for type 1 diabetes in March 2019. Patients must fulfill requirementsto minimize the increased risk of diabetic ketoacidosis with both of these drugs.

Glucagon-like peptide-1 (GLP-1) agonistsGLP-1 is a gut peptide that increases insulin secretion and decreases glucagon secretion in a glucose-dependent manner. In patients with type 2 diabetes, GLP-1 receptor agonists increase levels of GLP-1 andlead to more glucose-dependent insulin secretion, less glucagon secretion, delayed gastric emptying, andincreased satiety. The specific advantage of GLP-1 agonists is weight loss, which may be desirable in somepatients with type 1 diabetes.[117] The GLP-agonist liraglutide added to insulin improved glucose control inclinical trials with type 1 diabetes, but also increased the risk of both hypoglycemia and hyperglycemia withketosis. Therefore, GLP-1 agonists should not routinely be used in type 1 diabetes.

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Type 1 diabetes mellitus Follow upFO

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RecommendationsMonitoring

• Glycosylated hemoglobin (HbA1c) should be checked twice yearly in patients who are meetingtreatment goal of <7.5% for patients aged under 18 years with type 1 diabetes and <7% for adultpatients. It is recommended to check HbA1c every 3 months in patients whose therapy is beingmodified or who are not meeting the goal. In very old or very young patients and in those with ahistory of severe hypoglycemia or limited lifespan, the HbA1c goal can be less stringent.[1] [47]

• Check blood pressure at each visit and treat to a goal of <140/90 mmHg.[1] In older adults, treatingto <130/70 mmHg is not recommended.

• For patients who are not on statins, it is recommended to check a screening lipid profile (totalcholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, andtriglycerides) in adults with diabetes at the time of first diagnosis, at initial medical evaluation, andthen every 5 years thereafter if aged under 40 years (annually may be indicated in some cases).Lifestyle modification should be recommended to all patients with diabetes to improve lipid profile.For patients with atherosclerotic cardiovascular disease, a high-intensity statin should be added tolifestyle therapy. For patients aged 40-75 years without additional atherosclerotic cardiovasculardisease risk factors, the American Diabetes Association (ADA) recommends adding a moderate-intensity statin. For patients aged 40-75 years with additional atherosclerotic cardiovasculardisease risk factors, the ADA recommends adding a high-intensity statin. Once a patient is takinga statin, LDL cholesterol levels should be assessed 4-12 weeks after initiation of statin therapy,after any change in dose, and on an individual basis (e.g., to monitor adherence and efficacy). Ifa patient is adherent to statin therapy but not responding, clinical judgment is recommended todetermine the need for and timing of lipid panels.[1]

• In the US, initial screening for retinopathy by an ophthalmologist is recommended within 5 yearsof initial diagnosis of diabetes, and every 2 years after that if no evidence of retinopathy. In thepresence of abnormal findings, more frequent follow-up may be indicated (e.g., annually).[1]Recommendations differ in other countries; for example, in the UK, screening for retinopathy isoffered at the time of diagnosis and annually to all patients over the age of 12 years.[139] [140]Local guidance should be consulted.

• Yearly screening for increased urinary albumin excretion and serum creatinine to estimateglomerular filtration rate should be done in all patients who have had type 1 diabetes for 5 years ormore.[1]

• Screen yearly for distal symmetric polyneuropathy using pinprick sensation, temperature andvibration perception (with 128 Hz tuning fork), and 10 g monofilament pressure sensation at thedistal plantar aspect of both great toes and ankle reflexes.

• Symptoms of autonomic neuropathy can be assessed through history (exercise intolerance,constipation, diarrhea, gastroparesis, bladder or sexual dysfunction, hypoglycemic autonomicfailure), and physical exam (resting tachycardia, orthostatic hypotension).[1]

• Yearly dental exams are indicated in patients with and without teeth, to control periodontal disease,which both contributes to and exacerbates hyperglycemia.

• Vaccines should be provided in accordance with age-specific guidelines for the general population,including those for influenza and pneumococcal pneumonia. Hepatitis B vaccine should beprovided for unvaccinated adults with diabetes aged 19-59 years, and should be considered forunvaccinated adults with diabetes aged ≥60 years.[1]

• Patients with autoimmune diabetes are more likely to have thyroid disease, celiac disease, anddepression.[47] Physicians should have a low threshold for screening for these conditions.

Patient instructions• The physician should advise the patient and/or caregivers that it is important to eat a healthy diet

and regular meals. Referral to a nutritionist or a dietitian can be helpful in planning a diet.• Patients should be advised on exercise. They should build up exercise slowly. If the weather is very

hot or cold, they could walk at an indoor track or mall. Patients may need to take less insulin or eat




Type 1 diabetes mellitus Follow up

a snack before exercise. They should also be advised to check their blood glucose before and afterexercising. Any patients with peripheral neuropathy would be wise to perform low-impact exercisessuch as swimming, bicycling, or arm exercises.

• The physician should help the patient plan how often to check blood glucose. The most likely timeswould be before each meal and at bedtime. Patients may also check 2 hours after meals and whenexercising.

• Patients should usually have a HbA1c performed every 3 months.• Patients should be advised that hypoglycemia may occur if they skip a meal, take too much insulin,

exercise, or become ill. Alcohol and exercise can cause delayed hypoglycemia that may appeareven up to 24 hours later. Symptoms should be described including feeling very hungry, nervous,shaky, sweaty, dizzy, or confused. In order to raise the blood glucose, patients can take glucosetablets or gels, or drink milk or juice, depending on how low the blood sugar falls. Patients shouldsee their physician for adjustment of medication should hypoglycemia occur. A glucagon kit shouldbe prescribed for emergencies in the case of severe hypoglycemia or when the patient is unableto drink or eat. Family members and coworkers should be instructed on how to administer this. Forchildren, school and camp staff and caretakers should be educated on how to deal with low bloodsugar.

• The American Diabetes Association (ADA) defines level 1 hypoglycemia as ≥54 mg/dL but <70mg/dL (≥3.0 mmol/L but <3.9 mmol/L), requiring treatment with fast-acting carbohydrate and doseadjustment of glucose-lowering therapy. Level 2 hypoglycemia (clinically significant) is defined as<54 mg/dL (<3.0 mmol/L). Level 3 hypoglycemia (severe) is defined as any low blood glucose levelleading to cognitive impairment requiring assistance from another person for recovery.[1]

• Patients should discuss their insulin requirement with their physician prior to skipping any meals(e.g., for a medical test).

• Patients should also be educated on the symptoms of hyperglycemia, including blurred vision,thirst, frequent urination, or tiredness, and should see their physician immediately if these occur.Patients should also seek medical attention if they develop a fever, cough, dysuria, or woundson the feet. If patients are sick or if they note a fingerstick >250 mg/dL (>13.9 mmol/L) on twosuccessive pre-meal checks, they should check their urine ketones and call their physician if theketones are positive.

• If patients smoke, they should be strongly advised to quit, and offered appropriate treatments asneeded.

• Physicians should check patients' cholesterol and blood pressure, and assess for neuropathy atoffice visits.

• Patients should be up to date with their vaccination schedule.• Patients should be encouraged to discuss any feelings of depression with their physicians so that

appropriate treatment can be offered.• Children can take part in all activities at home or school. Staff members at school or camp should

assist with a child's needs, including checking blood sugars, taking insulin as needed, eatingregular meals, and treating any low blood sugars.

• Further information is available at the ADA website. [American Diabetes Association]

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Complications

Complications Timeframe Likelihooddiabetic ketoacidosis (DKA) short term high

DKA is the classical acute complication of type 1 diabetes, characterized by hyperglycemia and metabolicacidosis.

The most common precipitants are missed insulin injections or physiologic stresses such as infection ormyocardial 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 raiseblood 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 ofbreath, 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. Hourlymonitoring of blood glucose and 1- to 4-hourly monitoring of electrolytes is required. Insulin infusion mustcontinue until ketosis has resolved and a subcutaneous injection of insulin has been given.

Closure of the anion gap will indicate correction of the ketoacidosis.

Potassium repletion is usually indicated because initially apparently normal serum potassium does notreflect true total body depletion.

Treatment with bicarbonate is not indicated except when arterial blood pH is <6.9. Serum phosphorus levelis usually low, but does not require replacement unless it is <1.0 mg/dL (0.323 mmol/L).[128]

hypoglycemia short term high

The main complication of insulin treatment is hypoglycemia. The American Diabetes Association defineslevel 1 hypoglycemia as ≥54 mg/dL but <70 mg/dL (≥3.0 mmol/L but <3.9 mmol/L), requiring treatmentwith fast-acting carbohydrate and dose adjustment of glucose-lowering therapy. Level 2 hypoglycemia(clinically significant) is defined as <54 mg/dL (<3.0 mmol/L). Level 3 hypoglycemia (severe) is defined asany low blood glucose level leading to cognitive impairment requiring assistance from another person forrecovery.[1]

Patients with type 1 diabetes are generally sensitive to insulin.

Therefore, even a slightly higher dose of insulin, decreased food intake, or increased physical activitycan lead to hypoglycemia. Children <6 to 7 years old may not be aware of hypoglycemia, necessitatingless stringent goals for glucose control.[1] Other risk factors for hypoglycemia include a prior episode ofhypoglycemia, hypoglycemic unawareness, autonomic neuropathy, and long duration of diabetes. Alcoholand exercise can cause delayed hypoglycemia, up to 24 hours after the event.





Complications Timeframe LikelihoodIf the patient is able to ingest orally, hypoglycemia can be treated with 4 ounces of fruit juice or sweetenedfluids or glucose tablets (15-20 g of carbohydrate).[1] Blood sugar should be tested and treatment effectapparent in 15 minutes.

If oral intake is not possible, glucagon (parenteral or intranasal administration) or intravenous dextrose isrequired.

Patient caregivers and family members of patients with type 1 diabetes should be educated about thesigns and symptoms of hypoglycemia and taught how to administer oral glucose or glucagon intranasallyor as an intramuscular or subcutaneous injection . Unless hypoglycemia is recurring, the next meal orsnack should be eaten and the next dose of basal insulin should be given.

Episodes of hypoglycemia and the possibility of hypoglycemia unawareness should be assessed at eachvisit. A strict period of several weeks without hypoglycemia may improve hypoglycemic awareness in somepatients.

retinopathy long term high

Retinopathy is the most common microvascular complication of diabetes and its risk is increased atall levels of glycosylated hemoglobin (HbA1c) above the nondiabetic range. The incidence is 1 in 100person-years for a mean HbA1c value of 5.5% and 9.5 in 100 person-years for a mean HbA1c value of10.5%.[121] There is an increased risk of retinopathy in women with pre-existing type 1 diabetes duringpregnancy.[1]

Twenty years after diagnosis, most patients have evidence of retinopathy. Patients developmicroaneurysms, exudates, hemorrhages, angiogenesis, and glaucoma.

Retinopathy is usually asymptomatic until its late stages, so screening is essential.

Primary prevention includes strict glycemic control. Progression of very mild to moderate nonproliferativeretinopathy can be delayed through glycemic, blood pressure, and lipid control.[1] In advanced disease,photocoagulation and vitrectomy can be done to prevent blindness.[1] Intravitreal injections of antivascularendothelial growth factors are given for center-involved macular edema.[1]

diabetic kidney disease long term high

Diabetic kidney disease is the most common cause of end-stage renal disease (ESRD) in developedcountries. In patients with type 1 diabetes, the annual incidence of microalbuminuria and albuminuria isbetween 1.3% and 3.8%.[129] In one cohort study, the cumulative risk of ESRD was 2.2% after 20 yearsand 7.0% after 30 years from the diabetes diagnosis.[130]

The pathogenesis of diabetic nephropathy involves glomerular mesangial sclerosis leading to proteinuriaand progressive decline in glomerular filtration. Increased urinary albumin excretion (>30 mg/day) is theearliest sign of disease and a marker of much increased cardiovascular risk. Test yearly in people whohave had type 1 diabetes for 5 years or more.[1]

Glycemic control and blood pressure control with an ACE inhibitor or angiotensin-II receptor blocker delaysonset and slows progression of disease.[131] [132]

peripheral or autonomic neuropathy long term high

More than 50% of patients will develop neuropathy.[133]

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Complications Timeframe LikelihoodStrict glycemic control prevents onset and delays progression of diabetic neuropathy, which manifestsmost commonly as distal symmetric polyneuropathy affecting sensory axons.

The duration and extent of hyperglycemia are the greatest risk factors, although other cardiovascular riskfactors probably also contribute.

The other most common types of neuropathy include mononeuropathy, mononeuritis multiplex,polyradiculopathies, and autonomic neuropathy.

Once distal symmetric polyneuropathy is diagnosed, simple inspection should be performed at 3-to 6-month intervals, and referral for podiatric care and special footwear should be made. There areseveral medications that are particularly effective and may be considered. In the US, Food and DrugAdministration-approved medications for diabetic neuropathic pain include pregabalin, duloxetine, andtapentadol. Other treatments that are not approved for this indication may also be helpful, includingtricyclic antidepressants, anticonvulsants, a 5-hydroxytryptamine and norepinephrine uptake inhibitor, orcapsaicin cream.[1]

For autonomic neuropathy, current treatments for this complication are mostly inadequate. However,symptom management can be considered: for example, compressive stockings for posturalhypotension.[1]

cardiovascular disease long term high

Cardiovascular disease is the major cause of death and a major cause of morbidity for patients withdiabetes.

Intensive glycemic control has been shown to decrease the incidence of macrovascular disease in type 1diabetes.[124] During the 30-year follow-up of the Diabetes Control and Complications Trial/Epidemiologyof Diabetes Interventions and Complications (DCCT/EDIC) study, high doses of insulin were associatedwith a less favorable cardiometabolic risk profile (higher body mass index, pulse rate, triglycerides, lowerhigh-density lipoprotein [HDL] cholesterol), but intensive control continued to have long-term beneficialeffects on the incidence of cardiovascular disease in type 1 diabetes.[125] [134]

The cardiovascular disease risk can be further decreased by modification of other cardiovascular riskfactors.[135] Lifestyle and behavioral therapy are essential components of treatment.

Hypertension is often secondary to underlying nephropathy in patients with type 1 diabetes. Bloodpressure should be treated to <140/80 mm Hg with an ACE inhibitor or angiotensin-II receptor blocker;most patients will require two or three drugs to reach goal. Intensifying antihypertensive therapy to bloodpressure targets <140/90 was associated with a lower risk of coronary artery disease in one study.[136]

For patients of all ages with diabetes and overt cardiovascular disease, high-intensity statin therapy shouldbe added to lifestyle therapy. For patients without known cardiovascular disease, individualization ofstatin therapy according to their cardiovascular disease risk score is recommended.[137] [ASCVD riskestimator]

Intensive lifestyle therapy and optimal glycemic control are recommended to decrease cardiovascular riskin patients with triglycerides ≥150 mg/dL (≥1.7 mmol/L) and/or HDL <40 mg/dL (<1 mmol/L) (<50 mg/dL[<1.3 mmol/L] among women).[1] There is no specific low-density lipoprotein (LDL) target.

Children should have a fasting lipid profile once adequate glucose control is achieved if age ≥2 years, withsubsequent testing performed at age 9-11 years.[1] Monitoring can 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 clearlydefined, although an initial approach to lipid lowering should include modifications to diet and increasedexercise. Statins are not approved for children aged <10 years.[1]



http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/




Complications Timeframe LikelihoodAll adult patients with diabetes and cardiovascular disease should be treated with aspirin for secondaryprevention (75-162 mg/day). Aspirin can be considered for primary prevention for men and women atincreased cardiovascular risk, after a comprehensive discussion with the patient on the benefits versusthe comparable increased risk of bleeding.[1] All patients should have smoking-cessation counseling andtreatment as needed.

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 ofcardiovascular events.[138]

No evidence-based guidelines exist for screening asymptomatic patients for coronary heart disease.[1]

Prognosis

Untreated type 1 diabetes is a fatal condition due to diabetic ketoacidosis. Poorly controlled type 1 diabetesis a risk factor for chronic complications such as blindness, renal failure, foot amputations, and heart attacks.Intensive glycemic control has been shown to decrease the incidence of microvascular and macrovasculardisease in type 1 diabetes,[120] [121] [122] [123] [124] and the decreased incidence of macrovasculardisease has been shown to persist for up to 30 years.[125] Even a few years of intensive glucose controltranslate to reduced rates of microvascular and macrovascular complications 10 years later.[121] [126] TheAmerican Diabetes Association recommends maintaining glycosylated hemoglobin (HbA1c) <7% to preventcomplications in most nonpregnant adults with type 1 diabetes, with less stringent goals in children andadolescents.[1]

Overall, cardiovascular disease is the major cause of death and a major cause of morbidity for patients withdiabetes. One analysis of patients with type 1 diabetes diagnosed before the age of 15 years found that theleading cause of death before the age of 30 years was acute complications of diabetes. After the age of 30years cardiovascular disease was predominant, although death attributable to acute complications was stillimportant in this age group.[127]

With careful planning and adequate treatment, most women with type 1 diabetes can have successfulpregnancies.

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Type 1 diabetes mellitus GuidelinesG

UID

ELIN

ES

Diagnostic guidelines

International

Standards of medical care in diabetes - 2020 [1]Published by: American Diabetes Association Last published: 2020

Classification of diabetes mellitus [43]Published by: World Health Organization Last published: 2019

Type 1 diabetes [44]Published by: Centers for Disease Control and Prevention Last published: 2019

Clinical practice guidelines for the prevention and management of diabetesin Canada [45]Published by: Diabetes Canada Last published: 2018

ISPAD clinical practice consensus guidelines 2018 [46]Published by: International Society for Paediatric and AdolescentDiabetes (ISPAD)

Last published: 2018



https://professional.diabetes.org/content-page/practice-guidelines-resources

https://www.who.int/publications-detail/classification-of-diabetes-mellitus

https://www.cdc.gov/diabetes/basics/index.html

https://www.diabetes.ca/health-care-providers/clinical-practice-guidelines?Categories=&SearchText=&Page=1


https://www.ispad.org/page/ISPADGuidelines2018


Type 1 diabetes mellitus Guidelines

Treatment guidelines

International

Standards of medical care in diabetes - 2020 [1]Published by: American Diabetes Association Last published: 2020

Type 1 diabetes [44]Published by: Centers for Disease Control and Prevention Last published: 2019

Clinical practice guidelines for the prevention and management of diabetesin Canada [45]Published by: Diabetes Canada Last published: 2018

Diabetes technology: continuous subcutaneous insulin infusion therapy andcontinuous glucose monitoring in adults [118]Published by: The Endocrine Society Last published: 2016

Clinical practice guidelines for developing a diabetes mellituscomprehensive care plan [119]Published by: American Association of Clinical Endocrinologists,American College of Endocrinology


ISPAD clinical practice consensus guidelines 2018 [46]Published by: International Society for Paediatric and AdolescentDiabetes (ISPAD)


GU

IDELIN

ES



35

https://professional.diabetes.org/content-page/practice-guidelines-resources

https://www.cdc.gov/diabetes/basics/



https://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-guidelines

https://www.endocrine.org/guidelines-and-clinical-practice/clinical-practice-guidelines

https://www.aace.com/publications/guidelines

https://www.aace.com/publications/guidelines



Type 1 diabetes mellitus Online resourcesO

NLI

NE

RES

OU

RCES

Online resources

1. ASCVD risk estimator (external link)

2. American Diabetes Association (external link)




http://www.diabetes.org/


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• Ly TT, Nicholas JA, Retterath A, et al. Effect of sensor-augmented insulin pump therapy andautomated insulin suspension vs standard insulin pump therapy on hypoglycemia in patients with type1 diabetes: a randomized clinical trial. JAMA. 2013 Sep 25;310(12):1240-7. Full text Abstract

• Nathan DM, Genuth S, Lachin J; The Diabetes Control and Complications Trial Research Group.The effect of intensive treatment of diabetes on the development and progression of long-termcomplications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. Fulltext Abstract

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Contributors:

// Authors:

Rajesh K. Garg, MDProfessor of MedicineUniversity of Miami, Miller School of Medicine, Miami, FLDISCLOSURES: RKG is an author of a number of references cited in this topic.

Varsha Vimalananda, MD, MPHAssistant ProfessorSection of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University School ofMedicine, Boston, Core Investigator, Center for Healthcare Organization and Implementation Research,Edith Nourse Rogers Memorial VA Medical Center, Bedford, MADISCLOSURES: VV declares that she has no competing interests.

// Peer Reviewers:

Zachary Bloomgarden, MDClinical ProfessorMedicine/Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NYDISCLOSURES: ZB declares that he has no competing interests.

Alicia Jenkins, MB, BS, MD, FRACP, FRCPAssociate ProfessorDepartment of Medicine, University of Melbourne, Melbourne, Australia, Professor, Harold Hamm OklahomaDiabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OKDISCLOSURES: AJ has been a (non-salaried) co-investigator on multi-center clinical trials supported byNovo, Eli Lilly, Sanofi-Aventis, and Medtronic. She does not hold any stocks or shares in these companies.She has received a speaker's honorarium from Novo.

Type 1 diabetes mellitus - BMJ · 1/21/2020 · Type 1 diabetes mellitus is a metabolic disorder...

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