diabetes mellitus type 2 (insulin-resistant)

Introduction

also see diabetes in the elderly

Etiology

• insulin resistance
  • decreased numbers of insulin receptors
  • post-receptor mechanism
• impaired beta-cell function
  • loss of 1st phase of insulin secretion
• mutations (rare)
  • insulin
  • insulin receptor
  • glucokinase
• risk factors (see risk factors for diabetes mellitus type 2)
  • age > 45 years
  • obese individuals
  • western culture diet
    • gut microbiome may play a role
    • red meat consumption
  • lack of exercise
  • previous gestational diabetes
  • impaired glucose tolerance
  • higher fasting plasma glucose within the normal range is a risk factor for young men
  • black, hispanic or native American ethnicity
  • habitual sleep duration of < 6 hours/night
    • irregular sleep patterns
  • hypertension
    • ACE inhibitors & ARBs lower risk of diabetes
    • diuretics & beta-blockers increase risk of diabetes
  • dyslipidemia - use of statins
  • smoking (see CARDIA study)
  • increased weight gain relative to height during an infant's first 3 months of life
  • sedentary lifestyle, including watching TV
  • systemic absorption of topical glucocorticoids
  • systemic absorption of inhaled glucocorticoids
  • polycystic ovary syndrome

Epidemiology

• common in developed nations
• sugar availability in a country is related to the prevalence of diabetes
• prevalence of diabetes in U.S. adults has more than doubled since 1976 (from 4.7% to 11.2%); 12-14%
  • prevalence is higher among Blacks, Hispanics, & Asians (> 20%) than among whites (11%)
  • in men, the rise is not explained entirely by increasing obesity
  • incidence of type 2 diabetes increased from 9.0 to 12.5 cases per 100,000 youths; largest increases in racial & ethnic minority groups
• > 25% of patients with diabetes have not been diagnosed
• decrease in overall mortality 1998-2014 lower in patients with type 2 diabetes than in control population
• men at greater risk of complications diabetes complications than women

Pathology

• disease often present for 5-10 years prior to diagnosis
  • retinopathy, neuropathy & nephropathy are commonly seen at clinical presentation
• overnutrition results in insulin resistance & metabolic syndrome through increases sympathetic nervous system activity
• non-enzymatic glycosylation of proteins (formation of AGE pigments)
• abnormalities in neutrophil function
  • defective chemotaxis
  • impairment of neutrophil phagocytosis
• endothelial dysfunction associated with insulin-resistance
• insulin resistance correlates with & may be caused by RBP4
• effects of glucagon-like peptide may be attenuated
• glucagon NOT supressed in post-prandial state
• adipokines resistin & adiponectin may play a role
  • in mice, raising circulating levels of adiponectin protects against insulin resistance & glucose intolerance

Genetics

• stronger genetic susceptibility than type 1 diabetes
• 25% probability of having affected parent or sibling
• may be associated with mutation in the peroxisome proliferator receptor-gamma (PPAR-gamma)
• associated with defects in MAPK8IP1
• susceptibility to diabetes mellitus type 2: PPP1R3A, MCF2L2, TCF7L2
• susceptbility to microvascular complications:
  • polymorphism(s) in EPO, SOD2
• loss of function of SLC30A8, (Zn+2 transporter) diminishes risk of type 2 diabetes
  • SLC30A8 variant Trp-325 is a risk factor that confers susceptibility to diabetes mellitus type-2
• other implicated genes INPPL1, CAPN10, MT-ND1, SLC22A2, AKT2, TGM2, HNF1B, ADRB3, INSR, GCGR, ABCC8, GLUT4, UCP1, BTC, KCNJ11, PDX1

Clinical manifestations

• symptoms insidious in onset
• polyuria
• polydipsia, polyphagia
• fatigue
• chronic cutaneous infections
• yeast vaginitis
• blurred vision
• diabetic retinopathy:
  • often present at the time of diagnosis
  • retinal microaneurysms
  • dot-blot hemorrhages
  • macular edema
• peripheral neuropathy
  • classic stocking-glove pattern
    • paresthesias, especially of feet
  • cranial nerve III palsy
• most patients are obese (> 120% of ideal body weight)

Laboratory

• diagnosis:
  • 8 hr fasting plasma glucose > 126 mg/dL on 2 separate occasions
  • HgbA1c of >= 6.5%
  • plasma glucose > 200 mg/dL 2 hr after 75 ng oral glucose tolerance test
  • random plasma glucose > 200 mg/dL with symptoms of hyperglycemia
• glucose tolerance test if glucose 120-140 mg/dL
• urinalysis
  • glycosuria: occurs when serum glucose exceeds renal threshold, about 175 mg/dL; renal threshold may be as high as 250-300 mg/dL in diabetics
  • proteinuria: albumin normally 10% of urine protein normal: < 100 mg or protein excreted in urine per day
  • albumin/creatinine ratio at diagnosis & annually thereafter
  • urinary free cortisol to rule out Cushing's syndrome in newly diagnosed patients
• glycated hemoglobin
  • hemoglobin A1c (also see glycemic control) targets:
    • < 7.0% if mild or no microvascular complications & life expectancy > 10 years
    • 7%-8.5% if microvascular or macrovascular complications, comorbid conditions, or life expectancy of 5-10 years
    • 8%-9% if advanced microvascular or macrovascular complications, severe comorbid conditions, difficulties with self-management, or life expectancy < 5 years
  • total glycated hemoglobin
  • measure every 6 months if treatment at goal
    • every 3 months if treatment is being adjusted to optimize glycemic control
• C-peptide in serum is measurable
  • repeat C-peptide in serum if initially low prior to switching to oral hypoglycemic (metformin) in newly diagnosed patients initially managed with insulin
• serology:
  • failure of oral hypoglycemics in recently diagnosed type 2 diabetes
    • misdiagosed type 1 diabetes
  • glutamate decarboxylase 65 antibody in serum
  • ICA1 autoantibody
• basic metabolic panel for serum glucose, serum creatinine (eGFR)
• fasting lipid panel at diagnosis & annually in adults 40-75 years of age
• blood glucose monitoring not recommended for type-2 diabetes not treated with insulin unless monitoring facilitates lowering of hemoglobin A1c
• see ARUP consult

Diagnostic procedures

• funduscopy to assess diabetic retinopathy at diagnosis & yearly thereafter* (see diabetic retinopathy)

10 g monofilament exam, 128 Hz tuning fork & ankle reflexes

• at diagnosis, annually thereafter
• routine screening for coronary artery disease in asymptomatic patients with diabetes mellitus does not reduce mortality
• routine myocardial perfusion screening of no benefit
• cardiac stress testing every 2 years if known CAD
• consider ankle-brachial index if > 50 years of age

* within 5 years if < 30 years of age

Radiology

• coronary computed tomography angiography of no benefit in calibrating intensity of preventive therapy in patients with diabetes mellitus

Complications

• also see diabetes mellitus complication
• increased mortality
  • especially when diagnosed at a younger age
  • 3-fold increase in mortality from pneumonia & influenza
  • cancer may exceed cardiovascular disease as a leading cause of death in adults with type 2 diabetes
    • mortality from colorectal cancer, pancreatic cancer, liver cancer, & endometrial cancer may contribute
  • increased risk of cardiac arrest with drugs that prolong QT interval, especially fluoroquinolones, mocrolides & antipsychotics
• increase in fatal myocardial infarction (MI) in diabetics
  • two-fold increase in diabetic men
  • three-fold increase in diabetic women
  • manifestations of angina & MI are often atypical
  • incidence of silent myocardial infarction is high
  • if well controlled diabetes mellitus & well-controlled hypertension, coronary artery disease & MI are the major risks
• increased incidence of peripheral vascular disease & ischemic stroke
• hyperlipidemia
• diabetic nephropathy
  • GLP-1 agonists & SGLT-2 inhibitors diminish risk of hyperkalemia in patients taking ACE-inhibitors or ARBs
• diabetic retinopathy
• diabetic polyneuropathy - diabetic foot
• gastroparesis
  • gastric emptying generally accelerated in diabetes
  • gastroparesis may be associated with small intestine bacterial overgrowth
• cognitive impairment
  • may be increased incidence of dementia
    • contributions from ischemia & hypoglycemia
    • hypoglycemia increases risk of cognitive impairment
    • cognitive impairment increases risk of hypoglycemia
  • hyperglycemia increases risk of cognitive impairment
    • advanced glycosylation end products may damage neurons & vascular endothelium
  • increased risk of cognitive impairment in patients with diabetes mellitus at midlife
    • largely due to impairments in processing speed & executive function, processes generally associated with white matter tracts & subcortical gray matter affected by cerebrovascular disease
  • diabetes mellitus type 2 for >10 years doubles risk of dementia at age 70
  • dulaglutide may attenuate cognitive decline in diabetics with additional cardiovascular risk factors
• may increase risk of acute pancreatitis
• at any given T-score or FRAX score, risk of fracture is increased relative to non-diabetic patients
• erectile dysfunction in men & diminished sexual satisfaction in women
• rheumatological complications
  • Dupuytren contracture
  • adhesive capsulitis of the shoulder
  • diabetic amyotrophy
  • carpal tunnel syndrome
  • diffuse idiopathic skeletal hyperostosis (DISH)
  • gout is common
• acanthosis nigricans
• hypoglycemia
  • especially with insulin, especially in the elderly
    • emergency department visits common
      • subsequent hospitalization common
• hyperglycemic hyperosmolar coma more common than diabetic ketoacidosis
• diagnosis prior to age 40 associated with more lifetime hospitalizations & a high burden of mental health hospitalizations
• weight gain
  • in patients receiving metformin, daily liraglutide associated with lowest risk of weight gain & glimepiride the highest

• disease interaction(s) of diabetes mellitus with food insecurity
• disease interaction(s) of diabetes mellitus type-2 with steatosis (NAFLD, MASLD)
• disease interaction of diabetes mellitus type-2 with Alzheimer's disease & related dementias
• disease interaction of diabetes mellitus type-2 with familial nephrolithiasis
• disease interaction of diabetes mellitus type-2 with familial hypercholesterolemia
• disease interaction(s) of diabetes mellitus type 2 with smoking
• disease interaction(s) of diabetes mellitus type 2 with myocardial infarction
• disease interaction(s) of diabetes mellitus type 2 with heart failure
• disease interaction(s) of diabetes mellitus type 2 with cardiovascular disease
• disease interaction(s) of obesity with diabetes mellitus type 2
• disease interaction(s) of multiple sclerosis with type-2 diabetes
• disease interaction(s) of gout with diabetes mellitus type-2
• disease interaction(s) of diabetes mellitus with alcohol abuse
• disease interaction(s) of erectile dysfunction (ED) with diabetes mellitus type-2

Differential diagnosis

• mature onset diabetes of the young (MODY)
  • young adult with lean body type
  • strong family history of diabetes

Management

new-onset diabetes mellitus type 2

• insulin for most patients with type 2 diabetes who present initially with blood glucose >= 300 mg/dL
  • insulin for 2-3 weeks if HgbA1c > 8.5% prior to switching to oral hypoglycemic(s)
• 5 mg saxagliptin plus 2000 mg metformin (oral) for patients with blood glucose 300-450 mg/dL, without ketoacidosis or symptoms of hyperosmolality
• screen for diabetic retinopathy at the time of diagnosis
• assess glycemic control every 3 months until target reached, then subsequently every 6 months

goals of glycemic control

• glycemic targets & glucose-lowering treatments should be tailored to the individual patient
  • self monitoring of blood glucose for patients using mulitple daily injections of insulin or continuous cutaneous insulin infusion
  • postprandial blood glucose for patients with at-goal preprandial blood glucose but hemoglobin A1c not at goal
  • overnight blood glucose to detect hypoglycemia or dawn phenomenon
  • individualized glycemic control may reduce healthcare costs
    • cost savings mostly from lower medication costs
  • quality of life marginally better with individualized glycemic control
  • early intensive glycemic control lowers 20 year mortality
  • avoidance of hypoglycemia top priority
• goal of hemoglobin A1c
  • Hgb A1c goal of 7%-8% for most patients
    • lower targets do not reduce mortality or CV events but do increase risk of hypoglycemia
    • American Diabetes Association (ADA)
      • < 7% healthy young adults
      • < 7.5% healthy older adults
      • older adults with with multiple chronic illnesses - < 8% complex/intermediate - < 8.5% very complex/poor health categories
      • no specific target for frail elderly with limited life expectancy
    • American Geriatrics Society
      • target HbA1c goal between 7.5% & 8% for older adults
      • higher target between 8% & 9% for those with multiple comorbidities, poor health, & limited life expectancy.
  • Hgb A1c goal of <= 7.0% not evidence-based
    • may not diminish risk of retinopathy & nephropathy, neuropathy
    • may not diminish risk of cardiovascular disease
    • harm from hypoglycemia may outweigh benefit
    • tight glycemic control (blood glucose 80-110 mg/dL) is not associated with improved outcomes & may increase mortality
    • see glycemic control
  • Hgb A1c goal <= 6.5% may increase mortality
  • U-shaped mortality curve with respect to hemoglobin A1c; HbA1c of 6.4% & HbA1c of 10.6% with significantly higher mortality rates than HbA1c of 7.5%
  • dependent elderly with HbA1c of 8-9% have better functional outcomes at 2 years than elderly with HbA1c of 7-8%
  • see ACCORD trial, ADVANCE trial, UKPD study, VADT trial
• tight glycemic control may do more harm than benefit;
  • increases risk of severe hypoglycemia
    • poor outcomes with hypoglycemia, including death, heart disease, falls, & dementia
  • intensive glucose control reduces non-fatal myocardial infarction, but not 5-year mortality
  • tight glycemic control may diminish cardiovascular events in diabetics with few comorbidities, but not those with substantial comorbidities
  • tight glycemic control may prevent or delay progression of diabetic retinopathy
  • benefits of tight glycemic control persist after treatment ends only if HgbA1c remains low
• pharmaceutical therapy (see pharmaceutical agents below)
  • metformin is the initial drug of choice
    • unless comorbidity predisposing to lactic acidosis (alcohol abuse)
    • dual therapy should be considered for asymptomatic patients with HbA1c >=9%
      • sulfonylurea recommended add on in low resource settings (WHO)
      • insulin recommended if metformin + sulfonylurea inadequate (WHO)
      • liraglutide recommended as add on in obese patient
  • insulin may be advisable for symptomatic patients or those with HbA1c of >=10% or greater or blood glucose of >= 300 mg/dL
• unless using multiple daily insulin injections, patients should avoid self testing of blood glucose
  • goal of preprandial glucose 70-130 mg/dL
    • may increase risk of severe hypoglycemia
  • goal of 1-2 hour postprandial glucose < 180 mg/dL
• patients with severe hyperglycemia well enough to go home do not benefit from more intensive glycemic control

diet

• most important management strategy in type 2 diabetes
• calorie restriction
• for many patients, diet control is more optimism than science
• Mediterranean diet
  • improves glycemic control in new onset type-2 diabetes b)reduces cardiovascular complications in patients with type-2 diabetes, including those with 'TT' variant of the TCF7L2 gene (high-risk polymorphism)
• legumes may improve glycemic control
• increased consumption of vegetables, whole grains, & soluble & insoluble fiber
• plant-based diet associated with improvement in insulin sensitivity glycemic control
• polyunsaturated fats lower mortality (RR=0.7)
  • animal fats increase mortality (RR=1.2)
• weight-loss intervention in primary care may lead to remission
• low glycemic index diet of no benefit in reducing cardiovascular risk
• coffee & green tea may reduce mortality; effects may be additive
• intensive lifestyle intervention in obese patients including diet & exercise achieving 10% reduction in body weight within one year should result in reduced use of prescription diabetes medications

regular exercise

• at least 150 minutes of physical activity every week
• combination of aerobic exercise & resistance training better than either alone
• no more than 2 consecutive days without activity
• exercise capacity is associated with increased survival
• 2-3 days/week of flexibility or balance training, such as tai chi or yoga for older adults with diabetes
• cycling lowers mortality by 25%
• exercise may be less important than diet
• take a break from prolonged sitting every 30 minutes
  • limit sitting to < 90 minutes a stretch
  • breaking up prolonged sitting with standing or walking may improve glycemic control
• precautions
  • check fasting glucose prior to vigorous exercise
  • rapidly absorbed carbohydrate prior to extended exercise if glucose is low
  • avoid exercise within 4 h of regular insulin
  • avoid jogging/ running if neuropathy or peripheral vascular disease is present
  • avoid resistance training if retinopathy is present due to risk of ocular hemorrhage

pharmaceutical agents - hypoglycemic agents

• indications:
  • when diet, exercise, & weight loss fail to improve hyperglycemia
• use oral combination therapy early
  • do not push monotherapy to maximum dose before adding second agent
  • no combination therapy is recommended over another
  • allowing patient to choose 2nd or 3rd line agent may be associated with better outcomes than choosing for the patient
• metformin (Glucophage)
  • initial drug of choice
    • unless comorbidity predisposing to lactic acidosis (alcohol abuse)
  • start 500 mg PO BID or 850 mg PO TID
  • optimal dose: 1000 mg BID
  • may be used in combination with orlistat
  • useful for overweight patients
  • do not use if eGFR < 30 ml/min/1.73 m2
    • do not start if eGFR < 45 ml/min/1.73 m2
    • formerly do not use if serum creatinine >= 1.5 mg/dL
  • 10% lower risk of cancer relative to sulfonylurea
  • better cardiovascular outcomes relative to glipizide
    • even in patients with stage 3 renal failure
  • dose-dependent reduction in risk of dementia
    • higher daily dose & cumulative dose with greater risk reduction
    • discontinuing metformin is associated with an increased risk of dementia
  • lower 5 year mortality than sulfonylurea even with GFR as low as 30 mL/min/1.73 m2 (absolute risk reduction 12/1000 patient years or less, > for lower GFR)
  • choice of add on when metformin alone is insufficient
    • not clear
    • dual therapy should be considered for asymptomatic patients with HbA1c >=9%
    • American College of Physicans (ACP) recommends adding an SGLT-2 inhibitor or a GLP-1 agonist to metformin
      • add an SGLT-2 inhibitor to reduce risk for all-cause mortality, major cardiovascular events, chronic kidney disease & hospitalization due to congestive heart failure
      • add aGLP-1 agonist to reduce the risk for all-cause mortality, major cardiovascular events & stroke
    • ACP recommends not adding a DPP-4 inhibitor to metformin
    • American Diabetes Association recommends add on agent with proven cardiovascular benefit in patients with cardiovascular disease
      • liraglutide (Victoza), empagliflozin (Jardiance) or other SGLT2 inhibitor may be acceptable for overweight patients
      • flozins increase risk of yeast infection
    • semaglutide improves HgbA1c more than canagliflozin 1.5 vs 1.0% or empagliflozin as add on to metformin
      • semaglutide also associated with more weight loss (5.3 vs 4.2 kg)
      • no dosage adjustment for renal failure with once weekly glutide
      • hypoglycemic agent of choice (if not insulin) in patients with CKD4
    • lorcaserin (Belviq) may be useful in overweight patients
    • add on sulfonylurea
      • superior to replacing metformin with sulfonylurea
      • recommended by WHO in low resource settings
      • associated with weight gain
    • insulin may be advisable for symptomatic patients or those with HbA1c of >=10% or blood glucose of >= 300 mg/dL
    • addition of insulin results in 44% increase in all-cause mortality relative to addition of sulfonylurea
    • insulin, GLP-1 receptor agonists, sulfonylureas, & DPP-4 inhibitors as add ons to metformin with similar outcomes
  • patients started on 1st-line hypoglycemic agents other than metformin are more likely to require additional treatment
• sulfonylureas should be relegated to 3rd line agents
  • avoid in patients with alcohol abuse due to risk of hypoglycemia
  • recommended add on to metformin if metformin alone inadequate in low resouce settings (WHO)
    • addition of sulfonylurea to metformin associated with 44% lower mortality than addition of insulin
    • associated with weight gain
  • glipizide (Glucatrol) preferred sulfonyurea in the elderly
    • sulfonylureas should be avoided in elderly
  • associated with greater cardiovascular risk than metformin
  • for type-2 diabetes not controlled by metformin + a sulfonylurea, no add-on drug has an obvious advantage over another
  • metformin & SGLT2 inhibitors associated with a reduced risk of all-cause mortality compared with sulfonylureas
• acarbose (Precose)
  • inhibits alpha glucosidase
  • safer add-on to metformin than sulfonylurea
• thiazolidinediones (glitazones)
  • may be used as 1st line agents
  • may diminish progression of atherosclerosis relative to sulfonylureas
  • avoid in patients with heart failure, CAD, or bladder cancer
  • avoid in patients with osteopenia or osteoporosis
    • bone loss & increased risk of bone fracture (lumbar spine & hip)
    • effects greater in women than in men
    • see pharmaceutical agents that cause bone loss
  • incidence of cardiovascular events, cardiovascular mortality, heart failure, bladder cancer, or fracture similar for pioglitazone vs sufonylurea as add on therapy to metformin
  • pioglitazone associated with reduced risk of dementia vs non-use (RR=0.84)
    • risk of dementia reduction greater among patients with a history of ischemic heart disease or stroke before diabetes onset (RR=0.46)
• gliptins (DPP-4 inhibitors):
  • sitagliptin, saxagliptin, vildagliptin
  • linagliptin (Tradjenta) in the elderly with renal insufficiency
  • gliptin as add on therapy to metformin superior to sulfonylurea
    • 2% lower mortality, 1% lower risk of stroke
    • no difference in risk of MI or hospitalization for heart failure
  • add on to SGLT-2 inhibitor (flozin) but not incretin mimetic (GLP-1 agonist)
  • gliptins may lower regional beta-amyloid burden in temporal lobes & parietal lobes & slow measures of cognitive decline more than other hypoglycemics
  • sitagliptin hypoglycemic agent of choice in patient with alcohol abuse
    • see disease interactions
• when combined with metformin, gliptins & glitazones are associated with lower risk cardiovascular disease, heart failure & all-cause mortality
• glitazars introduced in 2005
• repaglinide & nateglinide (avoid in elderly & with alcohol abuse)
• incretin mimetics (GLP-1 agonists)
  • indicated for established cardiovascular disease or high risk, kidney disease
  • beneficial for reduced ejection fraction or chronic kidney disease
    • recommendation without regard to HgbA1c or HgbA1c target
  • exenatide (Byetta) may also promote weight reduction
    • weekly exenatide does not diminish cardiovascular risk
  • incretin mimetics liraglutide & dulaglutide may reduce cardiovascular mortality & all-cause mortality in high-risk patients
  • may be use in combination with metformin, sulfonylurea or insulin
  • GLP-1 agonist + insulin superior
  • linked with renal failure in elderly
  • GLP-1 agonist preferred over insulin if injectable needed
  • semaglutide may diminish HgbA1c as add on to metformin > dulaglutide by 0.4% & > sitagliptin by 0.3-0.5%
  • dulaglutide may attenuate cognitive decline (14%) in diabetics with additional cardiovascular risk factors
  • no dosage adjustment for renal failure with weekly glutide
• SGLT-2 inhibitors (flozins)
  • starting flozin before metformin not indicated
  • flozins may be more effective as 2nd line treatment than sulfonylureas or DPP-4 inhibitors
  • indicated for established cardiovascular disease or high risk
  • beneficial for reduced ejection fraction or chronic kidney disease
    • recommendation without regard to HgbA1c or HgbA1c target
  • may be beneficial for foot ulcers & risk for foot amputation
  • canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
  • option as monotherapy when metformin, sulfonylurea, & pioglitazone contraindicated
  • a gliptin would otherwise be prescribed [NICE]
  • canagliflozin may reduce risk of hospitalization for heart failure relative to DPP-4 inhibitors, sulfonyureas, or GLP-1-receptor agonists
  • flozins lowest in cardiovascular mortality < GLP-1 agonists < DPP-4 inhibitors (no mention of metformin)
  • adding incretin mimetic (GLP-1 agonist to SGLT-2 inhibitor (flozin) improves glycemic control in poorly controlled type 2 diabetes
  • useful in patients where weight loss or minimizing weight gain is important
  • SGLT-2 inhibitors slow progression of diabetic nephropathy
  • SGLT-2 inhibitors with marginal outcome advantage vs GLP-1 agonists
• insulin
  • long-acting insulin for symptomatic patients, HbA1c of >=10%, or blood glucose >= 300 mg/dL
    • convert later to oral hypoglycemic (if feasible)
    • taper insulin for episodes of hypoglycemia
    • for elderly with multiple comorbidities, relax glycemic control
      • once daily long-acting insulin regardless of HgbA1c
  • evening dose of NPH, glargine or degludec added to oral hypoglycemic agent(s)
    • stop sulfonylureas & meglitinides when starting insulin
    • start 10 units QHS
    • target morning glucose < 150 mg/dL 80-120 mg/dL
    • premeal blood glucose target 80-130 mg/dL
    • glargine may be associated with less hypoglycemia than NPH
      • especially in elderly
    • degludec may be associated with less hypglycemia than glargine (RR=0.70)
    • continuing metformin in patients who require insulin is associated with better glycemic control, but not all-cause or cardiovascular mortality
    • if hypoglycemia with morning blood glucose < 70 mg/dL, decrease evening insulin by 4 units or 10% which ever is greater
  • addition of glargine or rosiglitazone to combination therapy of metformin plus sulfonylurea of similar initial efficacy
  • insulin glargine given early in the course of DM2 does not diminish risk of cardiovascular events
  • avoid insulin if possible in non-hospitalized elderly & in patients with alcohol abuse
  • insulin plus metformin associated with higher mortality than sulfonylurea plus metformin (mean age = 60 years; mean HgbA1c = 8.1%)
  • insulin pump associated with lower HgbA1c than multiple daily insulin injections
    • if patient is non-compliant with multiple daily insulin infections, medical compliance is unlikely to increase with an insulin pump
  • addition of weekly GLP-1 receptor agonist to evening glargine or degludec results in lower hemoglobin A1c & body weight & less hypoglcemia than addition of prandial insulin lispro
    • addition of liraglutide to insulin in patients with long-standing type 2 diabetes improves glycemic control
    • addition of weekly tirzepatide to evening glargine in patients with inadequately controlled type 2 diabetes lowerb hemoglobin A1c & body weight & rusults in less hypoglcemia than addition of prandial insulin lispro
    • degludec/liraglutide may afford better glycemic control than glargine
  • glutide or flozin with basal long-acting insulin with comparable glycemic control & less hypoglycemia than basal long-acting insulin + premeal insulin
  • may be able to discontinue insulin in ketosis-prone type-2 diabetics presenting with diabetic ketoacidosis
  • pramlintide may reduce insulin requirements
  • if insulin requirement > 200 units/day, switch to concentrated form of insulin, U-500 regular insulin (most insulins provided at 100 units/mL (U-100)
  • insulin icodec once weekly insulin investigational (not yet FDA-approved)
• rimonabant (Acomplia) may be of benefit
• bromocriptine (Cycloset) FDA-approved 2009
• cinnamon probably of no benefit
• salsalate lowers plasma glucose & Hgb A1C (0.37%) but increases LDL cholesterol, body weight & urine albumin
• sodium phenylbutyrate improves peripheral insulin sensitivity & glucose oxidation
• comparison of 1st line agents
  • if high cardiovascular risk, SGLT2 inhibitor or GLP-1 receptor agonist to reduce CV risk (ACC)
  • metformin monotherapy associated with lesser cardiovascular mortality than sulfonylurea monotherapy
  • most oral hypoglycemics have similar effects on HbA1c; however, DPP-4 inhibitors are not as effective as metformin or sulfonylureas
  • SGLT-2 inhibitors lower weight more than metformin, which lowers weight more than DPP-4 inhibitors
    • consider SGLT2 inhibitor for patient with diabetic nephropathy & stage G3 chronic renal failure
  • sulfonylureas associated with risk for severe hypoglycemia, metformin & incretin mimetics with GI side effects, & SGLT-2 inhibitors with genital mycoses
  • flozins lowest in cardiovascular mortality < GLP-1 agonists < DPP-4 inhibitors (no mention of metformin)
  • incretin mimetics may attenuate progression of albuminuria & lower risks of cardiovascular events

control of risk factors (also see diabetes mellitus complication)

• diabetic nephropathy
  • ACE inhibitor or ARB
  • dapagliflozin attenuates progression of diabetic nephropathy
  • neither Vitamin D or omega-3 fatty acid supplementation or both preserve renal function
  • semaglutide reduces risk of renal complications & cardiovascular mortality in patients with diabetic nephropathy
• dyslipidemia
  • goals somewhat controversial
    • LDL cholesterol < 70 mg/dL; < 55 mg/dL high risk
    • HDL cholesterol > 40 mg/dL (men); > 50 mg/dL (women)
    • serum triglycerides < 150 mg/dL is unfounded
      • no benefit of fibrate (see ACCORD trial, Field study)
    • fenofibrate lowers serum urate & lowers risk for gout
    • ethyl icosapentate (Vascepa) may be considered if LDL cholesterol is controlled with statin
    • atorvastatin, rosuvastatin & simvastatin best statins for lowering non-HDL cholesterol in patients with diabetes mellitus
  • AHA/ACC guidelines recommend moderate dose statin for adults 40-75 years ASCVD calculated cardiovascular risk < 7.5%
    • even if cholesterol levels are at target
    • moderate-dose statin: (atorvastatin 10-20 mg daily, rosuvastatin 5-10 mg daily, simvastatin 20-40 mg daily, pravastatin 40-80 mg daily)
  • USPSTF recommends moderate-high dose statin for adults 40-75 years of age without cardiovascular disease & at least one additional risk factor & ASCVD calculated cardiovascular risk of >= 10%
  • high-intensity statin therapy (atorvastatin, rosuvastatin)
    • known cardiovascular disease (secondary prevention)
    • AHA/ACC guidelines recommend moderate dose statin for adults 40-75 years ASCVD calculated cardiovascular risk >= 7.5%
    • LDL cholesterol > 190 mg/dL
    • 10 year history of type 2 diabetes & diabetes complication
    • ezetimibe 1st add on to high-intensity statin
    • PCSK9 inhibitor recommended if on maximum statin & ezetimibe therapy & LDL-cholesterol > 130 mg/dL
  • former & other recommendations
    • statin treatment based on individual risk rather than LDL cholesterol
    • moderate-dose statin if 10-year cardiovascular risk is >= 7.5%
      • formerly high-dose statin recommended
    • other statins for patients >= 40 years of age with 10 year risk of cardiovascular event < 7.5%
  • see use of HMG CoA reductase inhibitors (statins) ...
• cardiovascular disease
  • control of dyslipidemia (see above)
  • diet & exercise (see above)
  • aspirin 81 mg QD (75-162 mg)
    • recommended for men > 50 & women > 60 years with at least one cardiovascular risk factor without contraindications
    • men or women 50-59 years of age with cardiovascular risk >= 10% regardless of diabetes mellitus (USPSTF)
    • optional for elderly diabetics without risk factors
    • recommended for younger patients at high risk
    • may not diminish cardiovascular risk
    • aspirin reduces risk of serious vascular events (RR=0.88) but increases risk of major bleeding (RR=1.3)
  • beta-blockers may mask symptoms of hypoglycemia
    • beta-blockers not associated with increased mortality when used in combination with intensive glycemic control
    • beta-blockers may increase mortality in patients with diabetes mellitus
  • telmisartan & valsartan may reduce cardiovascular risk (15%), but other ARBs may not
  • GLP-1 receptor agonists (incretin mimetics) liraglutide & dulaglutide may reduce cardiovascular mortality & all-cause mortality in high-risk patients
  • American College of Cardiology & American College of Physicians recommend SGLT2 inhibitors & GLP-1 receptor agonists for diabetics with cardiovascular disease
    • dapagliflozin associated with reduced heart failure hospitalization
  • no significant difference in mortality or major cardiovascular events between:
    • patients undergoing revascularization & those undergoing medical therapy
    • strategies of insulin sensitization (mostly metformin &/or thiazolidinedione) vs insulin provision
    • pioglitazone vs sulfonylurea as add on therapy to metformin
  • no benefit of omega-3 fatty acids
    • fish oil supplementation & higher plasma n-3 PUFA levels, especially DHA, associated with lower risks of macrovascular complications & microvascular complications in patients with type 2 diabetes
  • no advantage of intensive lifestyle intervention over usual diabetes care in reducing cardiovascular risks in overweight diabetics
  • smoking cessation may adversely affect glycemic control
  • patients can achieve cardiovascular risk similar to non-diabetics through control of HbgA1c, hypertension, albuminuria, smoking, & dyslipidemia (elevated LDL cholesterol)
  • CABG associated with improved outcomes in diabetics undergoing revascularization
• obesity
  • weight reduction
    • weight-loss intervention in primary care may lead to type 2 diabetes remission
    • overweight boys who achieve a healthy BMI no longer at increased risk for type 2 diabetes as adults
    • lorcaserin (Belviq) may promote weight loss & slow progression to type 2 diabetes & promote remission of type 2 diabetes
    • liraglutide is appropriate add on to metformin in obese patients
  • heavier patients do not live longer
  • bariatric surgery (see bariatric surgery)
    • indications
      • BMI >= 40
      • BMI >= 35 with poor glycemic control
      • BMI thresholds for Asians should be reduced by 2.5 kg/m2
    • improves glycemic control in obese patients
    • lowers hemoglobin A1c at 7 years (mean 1.4%) & 12 years (mean 1.1%) 274]
    • outperforms medical therapy in obese patients
      • reduces risk of microvascular complications by 50% & macrovascular complications by 30%
    • 70% of patients in remission at 2 years; 30% at 15 years
    • better glycemic control than intensive medical therapy in obese patients, even after 5 years
    • may improve health in patients with a BMI of >= 35 who have an obesity-related condition
    • risk vs benefit in non-morbidly obese patients uncertain
    • reduces risk of type 2 diabetes (RR-0.2)
    • increases likelihood of discontinuing diabetes meds
    • gastric bypass is superior to gastric banding or sleeve gastrectomy for remission of type 2 diabetes & metabolic benefits
• hypertension (also see hypertension & diabetes)
  • ACE inhibitor or ARB if albuminuria &/or hypertension 1st line
    • ACE inhibitors reduce proteinuria (diabetic nephropathy)
    • ACE inhibitors of no benefit for microalbuminuria
  • use of ACE inhibitors or ARBs not recommended for patients with normal blood pressure & urine albumin/creatinine < 30 mg/g & eGFR > 60 mL/min/1.73 m2
  • angiotensin II receptor antagonists do NOT reduce proteinuria (see diabetic nephropathy)
  • thiazide diuretics recommended as 1st line agents
    • synergistic effect when used with ACE inhibitor or ARB
    • avoid in patients with history of gout
    • caution: may worsen glycemic control
  • dihydropyridine calcium channel blocker
  • carvedilol
    • less tendency to cause hyperglycemia & dyslipidemia than other beta blockers
    • may reduce risk of microalbuminuria
  • target BP of < 130/80 (2023 ADA, ACC, AHA) is the current guideline
    • previously not supported by data
    • prior target BP > 140/90 (2018 ADA)
    • stricter guidelines < 120/70 mmg Hg not widely accepted
    • < 135/80 mm Hg (American College of Physicians)
      • guideline withdrawn in 2009
    • no benefit to target systolic blood pressure lower than 2018 ADA standard therapy (< 140 mm Hg) see ACCORD trial
      • target BP of < 130/80 (2023 ADA)
    • INVEST trial results similar to ACCORD trial
    • systolic blood pressure < 120 mm Hg associated with lower risk for cardiovascular events & cardiovascular mortality but elevated risk for heart failure & all-cause mortality
    • see hypertension & diabetes
  • mortality, cardiovascular events & renal failure similar with ACE inhibitors, ARBs, calcium-channel blockers, thiazide diuretics, & beta-blockers
• diabetic retinopathy
  • comprehensive eye examination at the time of diagnosis
  • annual funduscopic examination
• obstructive sleep anea - CPAP may improve glycemic control (see nasal CPAP)
• pain from inflammatory disorders (osteoarthritis etc)
  • salsalate is an anti-inflammatory agent that lowers HgbA1c
• periodontal disease
  • treatment of periodontal disease may improve glycemic control
• alcohol abuse
  • avoid medications that increase risk of lactic acidosis (metformin) or hypoglycemia (sulfonylurea, insulin, repaglinide) patients
• vaccinations:
  • hepatitis B vaccine
    • diabetics age 19-59 years ASAP after diagnosis
    • diabetics age >= 60 years optional

exacerbations/episodes of hyperglycemia

• rule out infection, especially urinary tract infection in the elderly

episodes of illness/hospitalization

• many hospitalized patients can be managed with insulin sliding scale alone
  • use of insulin sliding scale alone not recommended
• therapy must be individualized
  • stress from acute illness can cause hyperglycemia
  • less food intake due to poor appetite or vomiting can cause hypoglycemia
• critically ill patients
  • initiate insulin infusion when plasma glucose exceeds 180-200 mg/dL
  • target plasma glucose to 140-180 mg/dL with q1-2 hour bedside blood glucose monitor
  • ICU patients target serum glucose is 140-180 mg/dL
• non-critically ill hospitalized patients who are eating
  • use basal & prandial subcutaneous insulin
    • insulin recommended if serum glucose > 180 mg/dL
    • target of 140-180 mg/dL [3
    • adequate nutritional intake: basal + prandial + correction insulin
    • poor nutritional intake or NPO: basal + correction insulin
    • other agents in hospital setting do not have proven record of safety
    • basal & prandial subcutaneous insulin + insulin sliding scale with thresholds of > 140 vs 260 mg/dL did not differ in hypoglycemia, severe hyperglycemia, or % of blood glucose in target range of 70-180 mg/dL
• stop metformin if risk of dehydration, i.e. vomiting or diarrhea, due to concern for lactic acidosis
  • restart when vomiting &/or diarrhea have stopped & eating & drinking again
• if not eating, consider holding sulfonylurea
• do NOT stop basal (long-acting) insulin
  • may need to lower the dose of basal insulin if not eating
  • fast-acting insulin may be needed for episodes of hyperglycemia
• check blood glucose frequently

assessment of disease progression

• hemoglobin A1c every 2-3 months
• urinary albumin/creatinine ratio annually
• fasting lipid panel annually
• eye exam
  • ophthalmologic evaluation at the time of diagnosis
  • funduscopic examination every 6-12 months
• foot care
  • inspect feet for deformity, ulceration, vascular insufficiency every 6 months
  • deep tendon reflex at ankles
  • vibratory & light pressure thresholds in feet
• routine cardiac stress testing not indicated

patient education

• finger stick capillary glucose technique
  • preprandial target of 80-120 mg/dL
  • routine self glucose monitoring does not improve outcomes
• factors influencing blood sugar
• signs & symptoms of hypoglycemia
• glucagon IM if found unresponsive (friends & family)
• foot care
• wine 1 glass/day with dinner may diminish fasting blood glucose
• group sessions ineffective
• peer mentoring lowers HbA1c levels by ~1%
• 4 key times when clinicians should assess the need for patient education
  • at diagnosis
  • yearly after diagnosis
  • when complications occur (i.e. stroke, vision impairment)
  • during transitions in care (i.e., due to new living situations or insurance coverage)
• diabetes & medication education prior to hospital discharge

life style intervention

• intensive therapy has its limits (see ACCORD trial, ADVANCE trial & UKPDS data)
• effect of intensive lifestyle intervention on remission of type 2 diabetes is modest
• intensive lifestyle intervention to help patients lose weight does not lower cardiovascular risk
• lifestyle modification for prevention
  • weight reduction & exercise most effective means
• intensive lifestyle intervention to reduce cardiovascular risks in overweight people with type 2 diabetes finds no advantage over usual diabetes care
• lifestyle interventions may not benefit patients with long-standing diabetes mellitus type 2
• smoking cessation may adversely affect glycemic control
• intensive lifestyle intervention in obese patients including diet & exercise achieving 10% reduction in body weight within one year should result in reduced use of prescription diabetes medications

herbal remedies

• apple cider vinegar & fenugreek seeds are the most effective herbal agents to reduce fasting blood glucose & hemoglobin A1c
  • apple cider vinegar is the most effective
• cinnamon & curcumin (turmeric) also reduce fasting blood glucose
• ginger & saffron do not

glucose monitoring

• self-monitoring of blood glucose fails to lower HgbA1c
• capillary blood glucose of little to no benefit in patients not taking insulin
• continuous glucose monitoring
  • may benefit patients taking insulin
  • may reduce hypoglycemia in hospitalized patients taking insulin
• d-Nav Insulin Guidance System measures, records, & analyzes scheduled fingerstick blood glucose levels & uses an algorithm to recommend insulin dose adjustments directly to patients

other including autologous stem cell transplantation

• screening for diabetes mellitus in high-risk individuals
• also see fasting with diabetes mellitus
• guidelines for managing type 2 diabetes in the elderly
• functional assessment/cognitive assessment for multiple episodes of hypoglycemia in elderly who had been stable on insulin-containing regimens for years
• reprogrammed autologous stem cells transformed into insulin-producing islet cells transplanted into the liver of a man with type-2 diabetes
• endoscopic catheter ablation of duodenal mucosa with electroporation, allegedly enhances sensitivity to endogenous insulin
  • recellularization via electroporation therapy (ReCET)

Comparative biology

• injection of FGF-1 into the cerebral ventricles of mice or rats with type 2 diabetes conferred glucose control for at least 17 weeks

Notes

• multidisciplinary, intensive management improves outcomes
  • clinically relevant threshold of 0.5%
• quality measures should consider hypoglycemia
• primary care providers rarely reduce hypoglycemic treatment for older patients with diabetes, even if they achieve recommended targets
  • ~50% of 600 VA primary care providers said they would not be concerned about adverse effects of tight glucose control for an older patient at high risk for hypoglycemia and an HbA1c level of 6.5%
• nurse practitioners & physician assistants provide non-inferior primary care vs physicians
• patients frequently check their blood glucose levels multiple times daily, even when guidelines suggest otherwise
• insulin use highest & discontinuation rates lowest among patients in poorest health
  • unnecessarily aggressive management may result in more harm than benefit

More general terms

• diabetes mellitus

More specific terms

• diabetes in the elderly
• diabetes mellitus, non-insulin-dependent, 5 (NIDDM5)
• insulin-resistant diabetes mellitus with acanthosis nigricans
• leprechaunism (Donohue syndrome)
• Rabson-Mendenhall syndrome (Mendenhall syndrome)
• youth-onset type 2 diabetes; mature onset diabetes of the young (MODY)

Additional terms

• blood pressure & hypertension in diabetes
• diabetes mellitus complication
• diabetics who become pregnant
• dietary therapy for diabetes mellitus
• fasting with diabetes mellitus
• glycemic control
• hyperglycemia
• hypoglycemic agent
• insulin resistance
• risk factors for coronary artery disease in patients with diabetes mellitus type-2
• risk factors for diabetes mellitus type 2 & risk factor reduction
• screening for diabetes mellitus
• use of HMG CoA reductase inhibitors (statins) in patients with diabetes mellitus

Patient information

diabetes mellitus, type-2 patient information

Database

• OMIM: https://mirror.omim.org/entry/125851
• OMIM: https://mirror.omim.org/entry/125853
• OMIM: https://mirror.omim.org/entry/138190
• OMIM: https://mirror.omim.org/entry/147670
• OMIM: https://mirror.omim.org/entry/138079
• OMIM: https://mirror.omim.org/entry/176730