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Diabetes Mellitus Type 2, Initial Treatment

Summary
Basic Information
Treatment
Special Considerations
Follow-up
Author Affiliations

Sep.23.2024

Diabetes Mellitus Type 2, Initial Treatment

Summary

Key Points

Type 2 diabetes mellitus is a chronic condition characterized by target-organ insulin resistance and relative insulin deficiency causing hyperglycemia, and is associated with micro- and macrovascular complications
Treatment of type 2 diabetes mellitus requires an individualized patient-centered approach
Initial management of type 2 diabetes mellitus includes comprehensive diabetes self-management education, lifestyle modifications, including weight loss efforts, and usually metformin as a first line agent unless contraindicated
Choice of additional therapeutic agent differs between patients depending on several factors, including:
- Comorbidities
- Cardiovascular benefit
- Cost
- Desired reduction in A1C
3 glucose-lowing drug classes (SGLT-2 inhibitors, glucagon-like peptide-1 receptor agonists, and thiazolidinediones [specifically, pioglitazone]) have been shown to reduce major atherosclerotic cardiovascular events in high-risk patients with established cardiovascular disease
Optimize glycemic goals as appropriate to the individual’s risk for hypoglycemia, presence of diabetes complications, and life expectancy

Alarm Signs and Symptoms

Signs and symptoms of severe hyperglycemia, DKA, or hyperosmolar hyperglycemic state
- Polyuria, polydipsia, or unintentional/unexplained weight loss
- Altered mental status
- Inability to tolerate oral intake due to nausea/vomiting
Signs and symptoms of hypoglycemia
- Palpitations
- Tremor
- Sweating
- Disordered speech
- Altered mental status (confusion, reduced responsiveness, coma)
- Seizures

Basic Information

Terminology

Type 2 diabetes mellitus is a condition causing hyperglycemia related to a progressive loss of pancreatic β-cell insulin secretion and varying degrees of insulin resistance¹
Diagnostic criteria (at least 1 should be present):¹
- Fasting plasma glucose 126 mg/dL or higher
- 2-hour plasma glucose 200 mg/dL or higher after 75 gram glucose load during oral glucose tolerance test
- Hemoglobin A1C 6.5% or higher
- Random plasma glucose 200 mg/dL or higher and symptoms of hyperglycemia (eg, polyuria, polydipsia, fatigue)
- If there is discordance between A1C values and glucose values, fasting plasma glucose and 2-hour plasma glucose are more accurate²
Diagnostic considerations:
- In the inpatient setting, a plasma glucose level greater than 140 mg/dL should trigger an A1C measurement, if not done within the past 3 months³
- Consider the possibility of alternative forms of diabetes, particularly type 1 diabetes or latent autoimmune diabetes in adults in the absence of risk factors for type 2 diabetes or the presence of risk factors for alternative forms, as in the following circumstances:
  - Lean body habitus
  - Absence of metabolic syndrome
  - Younger age
  - Presence of autoimmune disease
  - Negative family history of diabetes mellitus
  - Recent infection with the COVID-19 virus⁴
If there is uncertainty about the designation of type 2 diabetes, consider checking fasting C-peptide level and autoantibodies (glutamic acid decarboxylase, islet antigen 2, Zn transporter 8) to rule out type 1 diabetes mellitus and latent autoimmune diabetes in adults^5,⁶
Hyperglycemic crises are metabolic emergencies encompassing DKA and hyperosmolar hyperglycemic state⁷
Hyperosmolar hyperglycemic state, and rarely DKA, can be the initial presentation of type 2 diabetes mellitus
- Hyperosmolar hyperglycemic state
  - Occurs more commonly in those with type 2 diabetes mellitus, also typically triggered by acute illness or dehydration due to impaired thirst mechanism or limited access to fluids
  - Diagnosis
    - Severe hyperglycemia: plasma glucose greater than 600 mg/dL
    - Hyperosmolarity
    - Dehydration
    - Altered mental status
  - Distinguished from DKA by the absence of metabolic acidosis
- DKA
  - Typically occurs in patients with autoimmune type 1 diabetes mellitus but can occur in those with type 2 diabetes mellitus under conditions of stress (eg, infection, trauma, surgery)
  - DKA has also been described with the use of SGLT (sodium-glucose cotransporter)-2 inhibitors, and in the absence of significantly elevated blood glucose (euglycemic DKA)
  - Diagnosis
    - Hyperglycemia: plasma glucose greater than 250 mg/dL
    - Elevated plasma and urine ketones
    - Metabolic acidosis

Treatment

Goals of Treatment

Short-term goals
- Improve glycemic control and restore normoglycemia where possible through lifestyle changes, diabetes education, and medical therapy
- Avoid hypoglycemia through blood glucose monitoring, individualized glycemic targets, patient education, and choice of medications
- If presenting with hyperglycemic crisis (typically seen in the inpatient setting) or with catabolic hyperglycemic symptoms:
  - Restore volume status through adequate fluid repletion
  - Correct electrolyte abnormalities
  - Reverse catabolic state
Long-term goals
- Reduce the risk for microvascular complications (ie, retinopathy, peripheral neuropathy, nephropathy through adequate glycemic control)⁸
- Control of cardiovascular risk factors (eg, high cholesterol, obesity, hypertension)
- Weight reduction and weight loss maintenance

Glycemic Targets

Hemoglobin A1C
- Provides an average of blood glucose levels over the previous 2 to 3 months⁹
- Level correlates with the risk for development of microvascular as well as macrovascular complications
- Can be used as a measure of glycemic control with some caveats:
  - A1C is an average of plasma glucose levels over the past 3 months and as such is not an accurate reflection of glycemic variability
  - A1C may lead to inaccurate results in patients with conditions affecting RBC turnover
    - A1C varies across different ethnic backgrounds at any given degree of hyperglycemia
  - Individualize target A1C based on patient’s age, life expectancy, comorbidities, duration of illness, and hypoglycemic risk¹⁰
  - A hemoglobin A1C target of 7% or less is appropriate for most nonpregnant adults⁹
  - A lower hemoglobin A1C of 6.5% or less can be targeted if it can be achieved safely without increased risk for hypoglycemia or medication adverse effects⁹
  - Less stringent hemoglobin A1C goals, up to 7.5% to 8.5%,^9,¹⁰ are acceptable in older adults with multiple comorbidities, patients with limited life expectancy, or those with increased risk for hypoglycemia and/or hypoglycemia unawareness
Time in and below range targets
- Time in range refers to the percentage of readings and time spent within glucose targets and measured by a continuous glucose monitor
- The standardized glucose target is 70 to 180 mg/dL¹¹
- Time in range provides more data than A1C level about blood glucose excursions and hypoglycemic events and is not subject to the limitations of A1C measurement in certain people, such as those with a hemoglobinopathy¹²
- Time in range targets^11,¹²
  - At least 70% for most patients, which correlates with an A1C of less than 7%
  - At least 50% for patients at high risk for hypoglycemia or limited life expectancy
- Additional goals are to reduce glycemic variability (% coefficient of variation or standard deviation) target of 36% or less, and to minimize time below range or hypoglycemia (glucose levels less than 70 mg/dL) to less than 4% and time in severe hypoglycemia (less than 54 mg/dL, defined as level 2 hypoglycemia) to less than 1%^9,¹¹
- Multiple studies have demonstrated a correlation between time in range and reduction in microvascular complications, cardiovascular disease, and mortality^11,¹³

Approach to Treatment

Lifestyle modifications are the cornerstone of type 2 diabetes mellitus treatment irrespective of what other form of therapy is required
- A 3-month trial of therapeutic lifestyle changes alone, with strong focus on weight loss, is reasonable for those with mildly abnormal hemoglobin A1C who are highly motivated
- Engaging in lifestyle changes may be enough to maintain blood glucose within the target range if A1C is close to goal, although this is typically temporary and eventually pharmacotherapy becomes necessary as the disease naturally progresses
- Weight loss, regardless how achieved, has been shown to improve and even reverse hyperglycemia, reduce the need for conventional diabetes medications, and improve associated comorbidities including:
  - Hypertension
  - Albuminuria
  - Metabolic dysfunction-associated fatty liver disease
  - Sleep apnea
  - Dyslipidemia
Medical therapy is most often indicated alongside lifestyle changes at the time of diagnosis of type 2 diabetes mellitus (hemoglobin A1C of 6.5%)
- First line pharmacotherapy for most patients with type 2 diabetes is monotherapy with metformin¹⁰ with some exceptions:
  - Use a glucagonlike peptide-1 receptor agonist in the presence of ASCVD (atherosclerotic cardiovascular disease) or risk factors of ASVCD
  - Use a sodium-glucose transport protein 2 inhibitors (in the setting of chronic heart failure or chronic kidney disease
- If dual therapy is necessary, then 1 of several medications listed in Table 1 can be added to metformin, considering associated comorbidities and prioritizing cardiovascular outcomes¹⁴ (Figure 1)
- Glycemic lowering ability and durability can vary among different classes of medications to treat type 2 diabetes
  - A recent randomized controlled trial comparing the effectiveness of glucose-lowering medications for use in conjunction with metformin to maintain target glycated hemoglobin levels in type 2 diabetes found that insulin glargine and liraglutide were modestly more effective than glimepiride and sitagliptin in achieving and maintaining target hemoglobin A1C levels after a mean of 5 years¹⁵
Medications approved for the treatment of obesity can also be considered for patients with BMI 27 kg/m² or greater
- In randomized controlled trials, antiobesity medications have been shown to lower hemoglobin A1C, reduce the need for conventional diabetes medications, and improve cardiometabolic risk factors^16,^17,^18,^19,^20,²¹

Table 1. Drug Therapy: Noninsulin therapies for type 2 diabetes mellitus.
Medication	Dosing	Mechanism of action	Advantages	Side effects	Special considerations
Biguanides
Metformin	500 mg orally twice daily with meals Increase dose by 500 mg weekly up to 2550 mg/day given in divided doses	Decrease hepatic glucose production Increase muscle glucose uptake Improve insulin sensitivity	Weight-neutral or modest weight loss²² Low cost Possible CV benefits²³	GI related (eg diarrhea, nausea, indigestion) Risk of lactic acidosis (rare) Vitamin B12 deficiency	Keep lowest tolerated dose or consider trial of extended-release formulation if GI adverse effects occur Contraindicated if eGFR <30 mL/minute/1.73m²
GLP-1 RA
Exenatide (immediate-release)	5 mcg subcutaneously twice daily before the main meals of the day; at least 6 hours apart May increase to 10 mcg subcutaneously twice daily after 1 month	Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety	Intermediate to very high weight loss Greatest weight loss shown with semaglutide followed by liraglutide and dulaglutide²⁴ CV benefit with liraglutide, dulaglutide, and semaglutide^25,^26,²⁷ May slow progression of renal disease^25,^26,²⁷ Benefit in MAFLD (semaglutide)²⁸ Stroke prevention (semaglutide and dulaglutide)^26,²⁷	GI adverse effects (nausea, vomiting, constipation, or diarrhea) May increase risk of pancreatitis and cholelithiasi²⁹	Avoid if personal history of pancreatitis Contraindicated with personal or family history of medullary thyroid carcinoma Renal dose adjustments may be required Avoid with ESRD Monitor eye examination results owing to risk of worsening or progression of retinopathy²⁶
Exenatide (extended-release)	2 mg subcutaneously once weekly
Lixisenatide	10 mcg subcutaneously once daily within 1 hour before the first meal of the day for 15 days, then increase to 20 mcg subcutaneously once daily
Liraglutide	0.6 mg subcutaneously once daily for 1 week then 1.2 mg subcutaneously once daily May increase to 1.8 mg subcutaneously once daily if needed max dose 3 mg weekly in obesity
Dulaglutide	0.75 mg subcutaneously once weekly May increase to 1.5 mg subcutaneously once weekly if needed for additional glycemic control. Can further increase the dose every 4 weeks. Max dose: 4.5 mg/week
Semaglutide	Subcutaneous: 0.25 mg subcutaneously once weekly for 4 weeks, then 0.5 mg subcutaneously once weekly May further increase dose every 4 weeks. Max dose: 2 mg/week Max dose 2.4 mg weekly in obesity Oral: 3 mg orally once daily for 1 month, then 7 mg orally once daily May increase to 14 mg orally once daily after 1 month if needed
Dual GLP-1 + GIP RA
Tirzepatide	2.5 mg subcutaneously once weekly for 4 weeks, then increase to 5 mg subcutaneously once weekly May increase by 2.5 mg/week after at least 4 weeks if needed: Max: 15 mg/week	Increase glucose-dependent insulin secretion Decrease glucagon secretion Slow gastric emptying Increase satiety	Very high weight loss	GI adverse effects May increase risk of pancreatitis and cholelithiasis	No renal dose adjustment necessary Contraindicated with personal or family history of thyroid C-cell tumors Not recommended in those with a history of gastroparesis
SGLT-2 inhibitors
Canagliflozin	100 mg orally once daily May increase to 300 mg orally once daily	Increase urinary excretion of glucose	CV benefits^30,^31,³² HF benefits (in low and preserved EF)^32,³³ BP-lowering effect Intermediate weight loss Slow progression of CKD³⁴	Risk of DKA (rare) GU infections Bone fracture (canagliflozin) Risk of volume depletion	Do not exceed 100 mg orally once daily if eGFR 30-60 mL/minute/1.73m² Do not initiate if eGFR <20 mL/minute/1.73m²
Empagliflozin	10 mg orally once daily May increase to 25 mg orally once daily, if needed				Not recommended if eGFR <30 mL/minute/1.73m² Do not initiate if eGFR < 20 mL/minute/1.73m²
Dapagliflozin	5 mg orally once daily May increase to 10 mg orally once daily, if needed				Not recommended if eGFR <45 mL/minute/1.73m² Do not initiate if eGFR < 25 mL/minute/1.73m²
Ertugliflozin	5 mg orally once daily May increase to 15 mg orally once daily				Not recommended if eGFR <45 mL/minute/1.73m²
DPP-4 inhibitors
Saxagliptin	2.5 or 5 mg orally once daily	Increase glucose-dependent insulin secretion Decrease glucagon secretion	Weight-neutral Well tolerated	Joint pain	Do not exceed 2.5 mg orally once daily if eGFR <45 mL/minute/1.73m²
Sitagliptin	100 mg orally once daily				eGFR 30 to 44 mL/minute/1.73m²: 50 mg orally once daily eGFR < 30 mL /minute/1.73m²: 25 mg orally once daily
Linagliptin	5 mg orally once daily				No dose adjustment necessary for renal impairment
Alogliptin	25 mg orally once daily				CrCl 30 to <60 mL/minute: 12.5 mg orally once daily CrCl <30 mL/minute or on intermittent dialysis: 6.25 mg orally once daily
Thiazolidinediones
Pioglitazone	15 or 30 mg orally once daily May increase to 45 mg orally once daily, if needed	Increase glucose uptake in muscle and fat Decrease hepatic glucose production Improve insulin sensitivity	Benefit on MASLD²⁸ Potential CV benefit³⁵ Transient ischemic stroke prevention benefit^36,³⁷	Weight gain Edema Bone fractures	Contraindicated with HF Not recommended with renal disease due to potential fluid retention Avoid in those with bladder cancer Avoid use in individuals with osteoporosis or risk factors for osteopenia
Sulfonylureas
Glipizide	5 mg orally once daily May increase by 2.5 to 5 mg/day after several days, if needed. Max: 40 mg/day	Increase insulin secretion	Low cost	Risk of hypoglycemia, highest with glyburide³⁸ Weight gain	Divide doses more than 15 mg/day into 2 doses Renal dose adjustments required; glyburide not recommended in those with CKD
Glimepiride	1 or 2 mg orally once daily May increase by 1 or 2 mg/day every 1 to 2 weeks, if needed. Max: 8 mg/day				Start at lower doses in those with renal impairment
Glyburide	2.5 to 5 mg orally once daily May increase by 2.5 mg/day every week, if needed Max dose: 20 mg/day				Not recommended for those with renal impairment
Meglitinides
Nateglinide	120 mg orally three times a day within 30 minutes before a meal or 60 mg orally three times a day within 30 minutes before a meal for individuals near goal HbA1C	Increase insulin secretion Decrease postprandial glucose	Flexible dosing relative to meals Can be used in renal failure	Increased uric acid (for nateglinide) Hypoglycemia (less than sulfonylureas) Upper respiratory infection Weight gain (less than sulfonylureas)	Use with caution in patients with ESRD
Repaglinide	0.5 mg orally before meals if A1C < 8% or 1 or 2 mg PO before meals if A1C ≥ 8% May double the dose after 1 week, if needed Max: 4 mg/dose and 16 mg/day	Increase insulin secretion Decrease postprandial glucose			No dose adjustment necessary if CrCl > 40 mL/minute Reduce starting dose to 0.5 mg if CrCl 20-39 mL/minute
Alpha-glucosidase inhibitors
Acarbose	25 mg orally three times a day at meals May double dose every 4 to 8 weeks, if needed for additional glycemic control Max dose: 100 mg orally three times a day	Delay carbohydrate digestion and absorption from intestine	Low risk of adverse events Decrease postprandial glucose	Abdominal pain Diarrhea Flatulence Elevated serum transaminases	For weight < 60 kg: max dose 50 mg orally three times daily
Amylin analogs
Pramlintide	60 mcg subcutaneously before each major meal May increase to 120 mcg/dose , if tolerated, after at least 3 days	Decrease glucagon secretion Slow gastric emptying Increase satiety	Weight loss CV neutral	Gastrointestinal adverse effects	Potential to delay absorption of concomitantly administered oral medications; give other oral medications at least 1 hour before or 2 hours after pramlintide Contraindicated in those with confirmed gastroparesis or hypoglycemia unawareness

Choice of second line or dual therapy (after metformin and lifestyle changes) is individualized and takes into account the following:
- Baseline hemoglobin A1C¹⁰
  - If hemoglobin A1C is less than 7.5%: start with monotherapy and lifestyle changes, but may consider a trial of lifestyle changes alone for 3 months
  - If hemoglobin A1C 7.5% to 9% or higher: initiate monotherapy and lifestyle changes
  - If hemoglobin A1C greater than 9%: will likely require dual therapy in addition to lifestyle changes. May also consider adding insulin therapy if hemoglobin A1C greater than 10%
  - Insulin is the drug of choice if the patient presents with a hyperglycemic crisis or has catabolic symptoms of insulin deficiency (ie, weight loss, ketosis)
- Associated comorbidities
  - Overweight or obesity
    - Consider selecting a diabetes medication that favors weight loss like glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, or a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist³⁹
    - Avoid sulfonylureas or insulin, both of which promote weight gain
  - Atherosclerotic cardiovascular disease
    - Use a glucagon-like peptide-1 receptor agonist or sodium-glucose cotransporter-2 inhibitor with proven beneficial cardiovascular outcomes in those with established atherosclerotic cardiovascular disease or at high risk for atherosclerotic cardiovascular disease (see Tables 1 and 2)^25,^26,^27,^30,³¹
      - In randomized controlled trials, the glucagon-like peptide-1 receptor agonists liraglutide, semaglutide, and dulaglutide, and the sodium-glucose cotransporter-2 inhibitors canagliflozin, dapagliflozin, and empagliflozin have been shown to reduce 3-point major adverse cardiovascular events in patients with known history of atherosclerotic cardiovascular disease⁴⁰
        3-point major adverse cardiovascular events is a composite of nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death
      - Primary prevention studies have been less conclusive. However, there is evidence from observational studies that both drug classes (glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors) provide a modest benefit for primary prevention of cardiovascular disease, especially in those with elevated cardiovascular disease risk^40,⁴¹
  - Heart failure
    - Use a SGLT-2 inhibitor (including SGLT1/2 inhibitor) if heart failure is present. There is benefit with this class of medication in both acute and chronic heart failure with low and preserved ejection fraction^32,^33,⁴²
    - The beneficial effects of SGLT-2 inhibitors on heart failure outcomes is consistent across all drugs of this class and are independent of glycemic control⁴³
    - Empagliflozin,³⁰ canagliflozin,³¹ and dapagliflozin,^33,⁴⁴ have been shown to reduce cardiovascular mortality, as well as first and recurrent heart failure hospitalization in patients with reduced ejection fraction.³³ Similar findings were observed in a randomized controlled trial of empagliflozin compared with placebo in those with preserved ejection fraction.³² Canagliflozin and ertugliflozin also resulted in improved heart failure hospitalization in patients with type 2 diabetes mellitus when compared with placebo, although this was a secondary outcome of the randomized controlled trial^45,⁴⁶
    - Sotagliflozin is the only dual SGLT1/2 inhibitor available. It is not FDA approved for glycemia but was shown to reduce cardiovascular deaths, hospitalizations due to cardiovascular causes, and urgent visits for heart failure in patients with congestive heart failure with preserved or reduced ejection fraction when compared to placebo⁴⁷
  - Diabetic kidney disease
    - In the presence of diabetic kidney disease and albuminuria (creatinine 300 mg/g or higher), choose a sodium-glucose cotransporter-2 inhibitor over other agents if eGFR permits^45,^48,⁴⁹
    - In the presence of chronic kidney disease without albuminuria (less than 300 mg/g creatinine), use either a sodium-glucose cotransporter-2 inhibitor or a glucagon-like peptide-1 receptor agonist with proven cardiovascular benefit and that has been shown to slow renal disease progression^25,^26,²⁷
    - All sodium-glucose cotransporter-2 inhibitors, with the exception of ertugliflozin, have shown benefit on renal outcomes demonstrated by significant reduction in incidence of end-stage renal disease, a decrease in the progression of chronic kidney disease, and a reduction in death due to cardiovascular or renal causes. The studies only included patients with chronic kidney disease and albuminuria^45,^48,⁴⁹
    - Similar to their effect on heart failure outcomes, the effects of sodium-glucose cotransporter-2 inhibitors on renal outcomes are independent of glucose levels⁴³
    - Studies of glucagon-like peptide-1 receptor agonists (specifically liraglutide, dulaglutide, and semaglutide) showed an improvement in progression of nephropathy in the setting of type 2 diabetes mellitus, although the studies were not powered for that particular outcome^25,^26,²⁷
    - Consider adding finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist in patients with diabetic kidney disease and high risk for cardiovascular disease or in those who cannot tolerate sodium-glucose cotransporter-2 inhibitors to reduce the progression of chronic kidney disease⁵⁰
    - Weight loss has been shown to reduce albuminuria and reduce the progression of chronic kidney disease⁵¹
  - Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as nonalcoholic fatty liver disease (NAFLD)⁵²
    - Consider using pioglitazone, glucagon-like peptide-1 receptor agonist (high-dose semaglutide, liraglutide, or dulaglutide), or both in the presence of metabolic dysfunction-associated steatotic liver disease^28,⁵³
    - Pioglitazone (30 to 45 mg) use in MASLD is associated with reduction in cardiovascular disease, steatosis, and improvement of metabolic dysfunction–associated steatohepatitis with moderate rates of metabolic dysfunction–associated steatohepatitis resolution (approximately 50%).⁵⁴
    - Consider glucagon-like peptide-1 receptor agonist (or dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist for treatment of type 2 diabetes in patients with metabolic dysfunction–associated steatohepatitis given their cardiovascular benefit, weight loss, reduction in steatosis, and resolution of metabolic dysfunction–associated steatohepatitis (approximately 60% in the high-dose group)⁵⁵
      - Use of high-dose glucagon-like peptide-1 receptor agonists are ideal as these patients are capable of achieving weight loss that exceeds 10% of body weight, which is known to permit universal regression of steatosis, regression of fibrosis, and resolution of metabolic dysfunction–associated steatohepatitis⁵⁶
      - In 1 phase 2b randomized controlled trial of patients with metabolic dysfunction–associated steatohepatitis, daily semaglutide resulted in weight loss and higher rate of resolution of metabolic dysfunction–associated steatohepatitis and improvement in fibrosis when compared with placebo⁵⁷
      - In 1 phase2 randomized controlled trial of patients with metabolic dysfunction–associated steatohepatitis, once-weekly tirzepatide was more effective in resolving metabolic dysfunction–associated steatohepatitis without worsening of fibrosis as compared to placebo⁵⁸
  - Ischemic stroke
    - Consider using a glucagon-like peptide-1 receptor agonist^26,²⁷ or pioglitazone^36,³⁷ in the presence of earlier history of ischemic stroke or transient ischemic attack, for stroke prevention
    - In large randomized cardiovascular outcomes trials, both dulaglutide and semaglutide demonstrated significant reduction in major adverse cardiovascular events, which included nonfatal stroke^26,²⁷
    - Semaglutide additionally led to a significant reduction in nonfatal stroke as a prespecified secondary outcome of the randomized controlled trial
    - Pioglitazone was shown to be beneficial in the secondary prevention of ischemic strokes^36,³⁷
- Side effect profile/contraindications
  - Avoid medications that can cause weight gain (ie, sulfonylureas, insulin, meglitinides) in favor of those with weight-neutral or weight-losing potential whenever possible
  - When starting sodium-glucose cotransporter-2 inhibitor, scale back on blood pressure lowering medications, diuretics, or both when applicable
  - Consider risk of hypoglycemia, especially in older patients or those with jobs for whom hypoglycemic events could lead to catastrophic consequences (see Table 1)
- Patient preferences
  - Avoid glucagon-like peptide-1 receptor agonist or insulin in those who wish to avoid injectable medications
  - Use once-weekly medications, when possible, to improve adherence
- Cost and access to care/insurance coverage
Diabetes self-management education is indicated for all patients with newly diagnosed diabetes mellitus
Cardiovascular risk factor optimization
- Dyslipidemia
  - Obtain a lipid panel for all adult patients newly diagnosed with type 2 diabetes mellitus
  - Calculate 10-year cardiovascular risk using a validated tool such as the Pooled Cohort Equation⁴⁴ if patient has no known history of cardiovascular disease.⁵⁹ In adult patients with type 2 diabetes mellitus aged over 40 years, moderate-intensity statin is indicated even with a 10-year atherosclerotic cardiovascular disease risk less than 7.5%. High-intensity statin is indicated if there is history of atherosclerotic cardiovascular disease events or if the 10-year atherosclerotic cardiovascular disease risk is 7.5% or greater⁶⁰
  - Target LDL less than 70 mg/dL in those with type 2 diabetes mellitus and other cardiovascular risk factors including chronic kidney disease with albuminuria, and less than 55 mg/dL in those with established cardiovascular disease and multiple risk factors^60,⁶¹
  - If LDL goal is not achieved with lifestyle changes and statins, then adding other LDL-lowering agents may be necessary. These include cholesterol absorption inhibitors (ezetimibe), proprotein convertase subtilisin/kexin type 9 activity inhibitors (evolocumab, alirocumab and inclisiran)⁶⁰ , and bempedoic acid⁴²
  - Consider obtaining coronary artery calcium score to further risk-stratify patients with cardiovascular risk factors and borderline or intermediate 10-year Pooled Cohort Equation cardiovascular risk score⁶⁰ (5%-19.9%) if the decision about use of statin is uncertain
  - Icosapent ethyl has been shown to decrease risk for cardiovascular events and cardiovascular disease mortality in patients with hypertriglyceridemia and diabetes plus other risk factors and in patients with established cardiovascular events⁶²
- Blood pressure control
  - Individualize target blood pressure according to patient’s age and presence of other cardiovascular risk factors
  - For most patients with type 2 diabetes mellitus, a target blood pressure of less than 130/80 is appropriate¹⁰ as long as it can be achieved without risk of hypotension or other medication adverse effects

Nondrug and Supportive Care

Lifestyle modifications are a foundation of type 2 diabetes mellitus treatment, and include dietary changes, physical activity, and attention to proper sleep habits¹⁴
- These measures may be enough to maintain blood glucose within the target range if A1C is close to goal, although this is typically temporary and eventually patients will require pharmacotherapy as their disease goes through its natural progression
Body weight reduction
- Management of obesity is part of the initial therapy of type 2 diabetes mellitus, to control hyperglycemia as well as obesity-related complications that frequently co-occur with type 2 diabetes mellitus (eg, dyslipidemia, obstructive sleep apnea, hepatic steatosis¹⁴)
- Target weight loss goal of at least 5% or greater body weight is recommended for all patients with type 2 diabetes mellitus and a BMI 25 kg/m² or greater, given favorable effect of weight loss on insulin sensitivity, insulin secretion, improvement in fasting glucose, A1C, systolic and diastolic blood pressure, and lipids in proportion to the percentage of weight loss.^63,^64,⁶⁵ A higher magnitude of weight loss 10% to 15% or more of body weight is needed for remission of type 2 diabetes mellitus⁶⁶
  - In the UK Prospective Diabetes Study, the degree of weight loss needed to normalize glucose levels ranged between 16% and 35% (10-20 kg) of initial body weight and was proportional to the initial fasting glucose level, with more weight loss needed for higher fasting glucose level⁸
  - In another landmark trial, the DiRECT study, participants in the intervention group lost an average of 10 kg (approximately 10%) and almost half achieved remission from type 2 diabetes mellitus at 1 year. The degree of improvement in type 2 diabetes mellitus was related to the degree of weight loss⁶⁶
- Interventions to facilitate weight loss to achieve a 500 to 750 kcal/day energy deficit⁶⁷ include:
  - Intensive behavioral therapy with high frequency of counseling (16 or more sessions in 6 months)
  - Focus on dietary changes, physical activity, and behavioral strategies
- In the Look AHEAD (Action for Health in Diabetes) trial, participants assigned to intensive lifestyle intervention had a mean weight loss of 4.7% at 8 years and required fewer glucose-, blood pressure–, and lipid-lowering medications than those assigned to standard care. Participants who achieved greater than 10% weight loss also improved cardiovascular outcomes^68,⁶⁹
- Metabolic surgery may also be indicated but usually not used as a first line treatment
- Diet⁷⁰
  - Recommend medical nutrition therapy for all patients at the time of diagnosis with type 2 diabetes mellitus and as needed thereafter
  - Medical nutrition therapy should be provided by a registered dietician, ideally with expertise in diabetes management
  - Medical nutrition therapy has been shown to be associated with improvement in A1C levels of up to 2%⁷⁰
  - Numerous studies have failed to demonstrate superiority of 1 particular diet over another for weight loss. As such, individualize and tailor dietary guidance to patient’s preferences, cultural background, and accessibility
    - Of note, the only diet shown to prevent cardiovascular events in clinical trials in patients at high risk for cardiovascular disease is the Mediterranean diet, which consists of high amounts of olive oil, fruits, nuts, and vegetables, and moderate amounts of poultry and fish, with minimal intake of dairy products and avoidance of red and processed meats⁷¹
  - Some broad dietary guidance that is applicable to most, if not all, patients includes:
    - Avoid processed foods in favor of whole foods whenever possible
    - Focus on nonstarchy vegetables, fruits, and whole grains
    - There is some evidence that reducing carbohydrate intake (from 50%-30% of total caloric intake) leads to improvements in postprandial glucose and insulin levels even without associated weight loss⁷⁰
    - Carbohydrate quality matters as well as quantity; limit simple sugars in favor of complex carbohydrates and fiber-rich foods
    - Avoid sugar-sweetened beverages
- Exercise
  - Physical activity can have beneficial effects on diabetes control, body composition (reduced total body and visceral fat), and lipid profile even if not accompanied by weight loss⁷²
  - Adding physical activity to a nutrition program can result in more weight loss and higher incidence of diabetes remission than either alone⁷²
  - An exercise prescription should take into account the individual’s past medical history and other factors:
    - Cardiovascular disease or retinopathy
    - Baseline level of activity
    - Exercise tolerance
    - Accessibility
    - Personal preferences
  - The American Diabetes Association recommends:⁷³
    - 150 minutes or more of moderate to vigorous–intensity aerobic activity per week
    - 2 to 3 sessions of resistance training per week
    - 2 to 3 sessions per week of flexibility and balance training for older adults
    - Limit sedentary time to no more than 30 minutes at a time
Diabetes education
- Diabetes self-management education is essential for all patients, and includes specific instructions on diet, exercise, and education on glycemic targets to prevent complications
  - A critical component of type 2 diabetes mellitus management as it empowers patients and provides them with the necessary tools to make decisions related to their diabetes management on a daily basis
  - Includes instruction on how to measure and monitor blood glucose, nutrition, physical activity, medication adherence, problem solving, recognizing and treating hypoglycemia, healthy coping, and sick day management
  - Personalized to the patient’s needs, level of education, socioeconomic status, and glycemic targets
  - A meta-analysis of studies assessing the role of diabetes self-management education on glycemic control showed a mean absolute reduction in A1C of 0.57%, with better improvement seen in those with higher baseline A1C⁷⁴
- Recommended for all patients at the time of diagnosis with type 2 diabetes mellitus⁷³
- Can be delivered in the form of individual sessions or group classes but achieve best results when combined with medical nutrition therapy provided by registered dieticians⁷⁵
- In a retrospective observational study, patients who underwent diabetes self-management education and medical nutrition therapy had:⁷⁵
  - Lower A1C levels (-1.22% plus or minus 2.15% at 1 year)
  - Improved diabetes knowledge
  - Lower weight (-2.25 kg plus or minus 5.45 kg at 1 year)
  - Better lipid profile (triglycerides decreased and HDL increased at 4-6 months)
  - Lower healthcare costs
- Use of mobile phone applications for diabetes education may improve diabetes mellitus self-management and has been shown to reduce A1C⁷⁶
Smoking cessation
- Given increased risk of cardiovascular disease and microvascular complications that are already associated with type 2 diabetes mellitus but exacerbated by smoking, include counseling about smoking cessation as part of the general education at the time of diagnosis with type 2 diabetes mellitus
- Counseling should include behavioral therapy, medications, and referral to smoking cessation program as needed
Psychosocial factors
- Screen newly diagnosed patient for depression and anxiety as those can be exacerbated by the diagnosis of a chronic medical condition
- Screen older adults for cognitive impairment as it can affect their ability to manage their diabetes safely
- Evaluate the patient’s social determinants of health, as these affect the treatment plan:
  - Socioeconomic background
    - Health literacy
    - Support systems
    - Food insecurity
Sleep
- Counsel patients on sleep hygiene
  - Sleep extension to 8.5 hours was associated with weight loss due to reduced energy intake in overweight subjects⁷⁷
  - Screen for sleep disturbance and obstructive sleep apnea, especially in patients who are overweight or obese
  - Refer for sleep evaluation as needed

Drug Therapy

Metformin
- Recommend initiating metformin as initial therapy for most patients (in addition to lifestyle changes), unless contraindicated, due to the following considerations:¹⁰
  - Efficacy: average expected A1C drop is 1% to 2%⁷⁸
  - Low cost
  - Very low risk of severe adverse effects
    - Gastrointestinal adverse effects can be mitigated by slow up-titration of metformin or using the extended-release formulation
    - Avoid using metformin in the setting of acute illness due to the rare risk of lactic acidosis
    - Dose reduction is indicated for eGFR less than 45mL/minute/1.73m² and use should be avoided if eGFR is less than 30 mL/minute/1.73m²
  - Weight-neutral or mild weight loss
  - Possible beneficial effect on cardiovascular disease^23,⁷⁹
    - When compared with sulfonylureas, use of metformin results in a significant reduction in cardiovascular events, including cardiovascular mortality (hazard ratio, 0.54 with a 95% CI 0.3-0.9, P=.026).
    - A meta-analysis of 2 randomized controlled trials also reported reduction in 3-point major adverse cardiovascular events with metformin when compared with either placebo or comparator treatment^23,⁸⁰ (Table 2). It is worth mentioning that most cardiovascular outcome trials for other approved drugs were conducted on a background of metformin therapy
- Substantial track record of metformin research
- Other drug therapies and their dosing, advantages, and adverse effects are summarized in Table 1
Insulin
- For patients requiring insulin therapy:
  - Start long-acting basal insulin ideally given at bedtime at an initial dose of 10 units or 0.1 to 0.2 units/kg, which can be then titrated by approximately 2 units every 2 to 3 days until target fasting glucose is achieved¹⁴
  - Add short-acting prandial insulin before 1 or more meals in case postprandial blood glucose remains elevated despite current therapy. A starting dose of 4 units before the meal is appropriate for most patients with adequate oral intake
  - Insulin analog (or inhaled insulin) are sometimes preferred over human insulins to reduce risk of hypoglycemia
  - Prescribe glucagon, preferrable preparations that do not require reconstitution, for all individuals taking insulin

Table 2. Drug Therapy: Cardiovascular outcomes of medications used in patients with type 2 diabetes.
Name (trial)	Population	Primary CV outcome hazard ratio (95% CI)	Other CV outcome(s) hazard ratio (95% CI)	Net CV effect
Biguanides
Metformin	Meta-analysis (including UKPDS⁸⁰ and Hong 2013²⁴) T2DM⁷⁹	3-point MACE 0.52 (0.37-0.73)	All-cause mortality 0.80 (0.60-1.07)	Benefit
GLP-1 RA
Exenatide (EXSCEL)⁸¹	T2DM with (73%) or without CVD	3-point MACE 0.91 (0.83-1.0)	CV death 0.88 (0.76-1.02) MI 0.97 (0.85-1.1) Stroke 0.85 (0.7-1.03) HF hospitalization 0.94 (0.78 - 1.13)	Neutral
Lixisenatide (ELIXA)⁸²	T2DM and ACS (<180 days)	4-point MACE 1.02 (0.89-1.17)	Expanded MACE 1.02 (0.9-1.11) HF hospitalization 0.96 (0.75-1.23)	Neutral
Liraglutide (LEADER)²⁵	T2DM and CVD (81%), CKD, or HF at ≥50 years, or CV risk at ≥60 years	3-point MACE 0.87 (0.78-0.97)	Expanded MACE 0.88 (0.81-0.96) HF hospitalization 0.87 (0.73-1.05)	Benefit Reduction in 3-point MACE
Dulaglutide (REWIND)²⁷	T2DM and prior ASCVD event (32%) or risk factors for ASCVD	3-point MACE 0.88 (0.79-0.99)	Composite microvascular outcome (eye or renal) 0.87 (0.79-0.95) HF hospitalization 0.86 (0.48-1.55)	Benefit Reduction in 3-point MACE
Semaglutide (SQ) (SUSTAIN)²⁶	T2DM and CVD (60%), HF, or CKD at ≥50 years or CV risk at ≥60 years	3-point MACE 0.74 (0.58-0.95)	Expanded MACE 0.74 (0.62-0.89) HF hospitalization 1.11 (0.77-1.61)	Benefit Reduction in 3-point MACE
Oral semaglutide (PIONEER)⁸³	T2DM and CVD (age ≥50) or high CV risk (age ≥60)	3-point MACE 0.79 (0.57-1.11)	Expanded MACE or HF hospitalization 0.82 (0.61-1.10) HF hospitalization 0.86 (0.48-1.55)	Neutral
Dual GLP-1 + GIP RA
Tirzepatide⁸⁴	Meta-analysis of the 7 SURPASS trials in patients with T2DM Being tested in SURPASS-CVOT (NCT04255433)	4-point MACE 0.80 (0.57-1.11)	CV death 0.90 (0.5-1.61) All-cause death 0.80 (0.51-1.25)	Neutral, non-inferior vs pooled comparator including semaglutide dulaglutide, or basal insulin
SGLT-2 inhibitors
Canagliflozin (CANVAS)³¹	T2DM and CVD (66%) at ≥30 years or >2 CV risk factors at ≥50 years	3-point MACE 0.86 (0.75-0.97)	CV death 0.87 (0.72-1.06) All-cause mortality 0.87 (0.74-1.01) HF hospitalization 0.67 (0.52-0.87)	Benefit Reduction in 3-point MACE Reduction in HF hospitalization
Empagliflozin (EMPA-REG)³⁰	T2DM and CVD	3-point MACE 0.86 (0.74-0.99)	4-point MACE 0.89 (0.78-1.01) HF hospitalization 0.65 (0.50-0.85)	Benefit Reduction in 3-point MACE Reduction in HF hospitalization
Empagliflozin (EMPEROR-Reduced)⁸⁵	NYHA class II-IV HF and EF ≤40% with or without DM	CV death or HF hospitalization 0.75 (0.65-0.86)	Total HF hospitalizations 0.7 (0.58-0.85)
Dapagliflozin (DECLARE-TIMI)⁸⁶	T2DM and ASCVD (40%) or multiple risk factors for ASCVD	3-point MACE 0.93 (0.84-1.03) CV death or HF hospitalization 0.83 (0.73-0.95)	Death from any cause 0.93 (0.82-1.04) HF hospitalization 0.73 (0.61-0.88)	Benefit 3-point MACE outcome not significant Reduction in HF hospitalization
Dapagliflozin (DAPA-HF)⁸⁷	NYHA class II-IV HF and EF ≤40% with or without DM	Worsening HF or death from CV causes 0.74 (0.65-0.85)	CV death or HF hospitalization 0.75 (0.65-0.85)
Ertugliflozin (VERTIS CV)⁸⁵	T2DM and ASCVD	3-point MACE 0.97 (0.85-1.11)	CV death or HF hospitalization 0.88 (0.75-1.03) HF hospitalization 0.7 (0.54-0.9)	Benefit 3-point MACE outcome not significant Reduction in HF hospitalization
SGLT1/2 inhibitor
Sotagliflozin (SOLOIST-WHF)⁸⁸	T2DM and HF	CV deaths, HF hospitalizations, and urgent visits 0.67 (0.52-085)	HF hospitalizations and urgent visits 0.64 (0.49-0.83) CV deaths 0.84 (0.58-1.22)44	Benefit Reduction in HF hospitalization
DPP-4 inhibitors
Saxagliptin (SAVOR-TIMI)⁵³	T2DM and history of (78%) or at risk for CV events	3-point MACE 1.00 (0.89-1.12)	Composite of CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization, or HF 1.02 (0.94-1.11) HF hospitalization 1.27 (1.07-1.51)	Neutral Increased risk of HF hospitalization
Sitagliptin (TECOS)⁸⁹	T2DM and CV disease	4-point MACE 0.98 (0.88-1.09)	3-point MACE 0.99 (0.89-1.11) HF hospitalization 1.00 (0.83-1.2)	Neutral
Linagliptin (CARMELINA)⁹⁰	T2DM and high CV and renal risk	Time to occurrence of 3-point MACE 1.02 (0.89-1.17)	Death due to renal failure or decline in eGFR) 1.04 (0.89-1.22) HF hospitalization 0.9 (0.74-1.08)	Neutral
Alogliptin (EXAMINE)⁹¹	T2DM and MI or unstable angina	3-point MACE 0.96 (one-sided CI ≤1.16)	Extended MACE 0.95 (one-sided CI ≤1.14) HF hospitalization 1.07 (0.79-1.46)	Neutral
Thiazolidinediones
Pioglitazone	Meta-analysis Participants with CV disease⁹²	Recurrent MACE 0.74 (0.60-0.92) MI 0.77 (0.64-0.93) Stroke 0.81 (0.68-0.96)	All-cause mortality 0.94 (0.81-1.08) Risk of HF 1.33 (1.14-1.54)	Benefit Reduced risk of MACE Increased risk of HF
	PROACTIVE trial of patients with T2DM and macrovascular disease⁹³	Composite of all-cause mortality, non-fatal MI, stroke, ACS, endovascular intervention, and amputation 0.9 (0.8-1.02)	Composite of all-cause mortality, non-fatal MI, stroke 0.84 (0.72-0.98)
	IRIS – patients with prediabetes and recent TIA or stroke³⁷	Fatal or non-fatal stroke or MI 0.76 (0.62-0.93)	All-cause mortality 0.93 (0.73 to 1.17)
Sulfonylureas
Glimepiride (CAROLINA and CARMELINA trials⁹⁴	T2DM with high CV risk	3-point MACE 1.04 (0.850-1.274)	All-cause mortality 1.08 (0.88 -1.32) CV death 0.96 (0.73-1.26) Non-CV death 1.24 (0.89 - 1.73)	Neutral
Glipizide and Glyburide^95,⁹⁶	Meta-analyses including patients with T2DM	Studies with no major bias, comparator other than metfromin⁹⁵, CV events and mortality relative risk 1.06 (0.92-1.23)	Studies with bias, metformin comparator, and mortality outcome relative risk 1.53 (1.43-1.65)	Conflicting results Neutral vs. possible increased risk?
Meglitinide
Nateglinide (Navigator study)⁹⁷	Patients with IGT and CV disease or risk factors	Composite CV outcome 0.94 (0.82 - 1.09)	Extended composite CV outcomes 0.93 (0.83 -1.03)	Neutral
Alpha-glucosidase inhibitors
Acarbose (ACE trial)⁹⁸	Patient with IGT and CVD	5-point MACE 0.98 (0.86-1.11)	Composite of HF and CV death 0.89 (0.64-1.24) HF hospitalization 0.90 (0.74-1.10)	Neutral
Amylin analogs
Pramlintide⁹⁹	Poled analysis of five trials compared with placebo or insulin in patients with T2DM	4 point-MACE 1.03 (0.69-1.54)	CV disease including HF 1.00 (0.76 -1.32)	Neutral

Persistent or Recurrent Disease

Persistent hyperglycemia after at least 3 months of therapy:
- Consider weight loss interventions involving structured lifestyle interventions featuring a reduced-calorie diet, and explore other options for weight loss, such as pharmacotherapy if BMI 27 kg/m² or higher, or bariatric surgery if BMI is 35 kg/m² or higher
- Use add-on therapy based on algorithm in Figure 1
- Consider starting insulin for patients who are not meeting glycemic targets despite diet, exercise, and combination therapy to achieve optimal results
- Avoid combination of dipeptidyl peptidase-4 inhibitor with glucagon-like peptide-1 receptor agonists due to their overlapping mechanism of action
- Consider checking autoantibodies to rule out the diagnosis of type 1 diabetes mellitus in the absence of classical risk factors to type 2 diabetes mellitus

Admission Criteria

Hyperglycemic crisis, including DKA or hyperosmolar hyperglycemic state
- Altered mental status
- Dehydration
- Inability to tolerate oral intake
Severe hyperglycemia in the setting of new infection, other acute events (eg, myocardial infarction, stroke)

Special Considerations

Inpatient Initial Type 2 Diabetes Mellitus Management

Glycemic targets
- Blood glucose target for most hospitalized patients ranges from 140 to 180 mg/dL^3,¹⁰⁰
- May aim for a more strict target of 110-140 mg/dL in select critically ill patients if it can be achieved without hypoglycemia³
Management of hyperglycemia
- Insulin is the therapeutic agent of choice in the inpatient setting³
  - Start scheduled insulin if blood glucose levels remain above target. Regimens incorporating basal insulin or basal/bolus insulin regimens are superior to the use of supplemental (sliding scale) insulin alone
  - Avoid bolus or prandial insulin in the absence of basal insulin
  - Patients treated with a basal/bolus insulin regimen achieve better glycemic control and are more likely to reach blood glucose targets with lower hospital costs when compared with to sliding scale insulin alone¹⁰¹
    - A typical total daily starting dose is 0.4 to 0.5 units/kg per day (less than or equal to 0.3 units/kg in the presence of renal impairment or advanced age) divided equally into basal insulin and bolus (preprandial) doses provided patient has good oral intake⁹⁸
    - Give basal insulin once daily ideally at bedtime and titrate dose based on fasting blood glucose
    - Give short-acting insulin before meals as long as patient maintains adequate oral intake
    - Insulin requirements vary among patients; titrate based on serial glucose measurements obtained at least every 6 hours
  - Sliding scale insulin with short-acting insulin may be sufficient for patients newly diagnosed with type 2 diabetes mellitus whose blood glucose levels are close to target (less than 200 mg/dL) and for those with poor oral intake
  - Continuous IV insulin infusion is appropriate for critically ill patients,⁹⁸ especially when reaching glucose goals are otherwise difficult or unsafe and a tighter glucose control is desired; IV insulin infusion is also the treatment of choice in those presenting with hyperglycemic emergencies
- Oral therapy with dipeptidyl peptidase-4 inhibitors can be used in the inpatient setting in lieu of bolus insulin⁹⁹
  - Avoid dipeptidyl peptidase-4 inhibitors in patients with heart failure
  - If prandial blood glucose remains above goal, then discontinue the oral agent and start bolus insulin
- Other noninsulin medications are not recommended for inpatient use until safety and efficacy are established⁹⁸
- Consider adding oral therapy (metformin if appropriate) 1 to 2 days before discharge and adjusting insulin therapy as needed depending on the patient’s glycemic control and A1C and if there are no contraindications to its use¹⁰²
  - Metformin may be sufficient if A1C is close to goal
  - If insulin therapy is necessary, then dose reduction by 20% to 50%¹⁰² is prudent to avoid hypoglycemia after discharge
- Recommend inpatient Diabetes Education consult for all patients newly diagnosed with type 2 diabetes mellitus or poorly controlled diabetes
- Ensure that proper follow-up is scheduled within 1 month of discharge³

Older Adults

Glycemic targets
- Individualized depending on the patient’s functional and cognitive statuses, hypoglycemia risk, and presence of other chronic illnesses
  - A1C of 7% to 7.5% is appropriate for those who are independent and without functional or cognitive impairment or coexisting medical conditions that may lead to limited life expectancy¹⁰³
  - A more relaxed target A1C of 7.5% to 8% is appropriate for older adults with multiple comorbidities, functional or cognitive impairment, or both¹⁰³
  - If continuous glucose monitoring is used, goal time in range can be relaxed to 50% (of blood glucose readings between 70 to 180 mg/dL) in case of increased risk for hypoglycemia or limited life expectancy¹¹
This population is at increased risk for hypoglycemia, which can lead to adverse events (eg, falls, cognitive impairment, cardiac arrhythmia)
- Consider using a continuous glucose monitor in patients with increased risk for hypoglycemia, hypoglycemia unawareness, and those who live alone
- One advantage of some continuous glucose monitors is the capability to transmit data to caregivers in real time and alert them in case of hypoglycemia
Choice of pharmacotherapy
- The same general principles of treatment apply as illustrated in Figure 1 with some stipulations
  - Minimizing risk of hypoglycemia is a priority
    - Avoid using sulfonylureas and insulin if possible
  - Simplify medication regimen whenever possible given the high rate of polypharmacy in this population
  - Exercise caution when using sodium-glucose cotransporter-2 inhibitors due to increased risk of hypotension and thus falls
  - Adjust medication doses based on kidney function

Pregnant Patients

As part of preconception counseling, emphasize the need for close-to-normal glucose levels, ideally A1C less than 6.5%, to reduce the risk for congenital malformaltions¹⁰⁴
Preexisting type 2 diabetes mellitus or gestational diabetes are diagnosed during pregnancy with a fasting oral 75 g glucose tolerance test between 4 and 12 weeks of gestation¹⁰⁵
Glycemic targets and self-monitoring of blood glucose are more stringent¹⁰⁵
- Target A1C less than 6% provided no hypoglycemia
- Fasting glucose 70 to 95 mg/dL
- 1-hour postprandial 110 to 140 mg/dL
- 2-hour postprandial 100 to 120 mg/dL
- Continuous glucose monitor metrics can be used in addition to blood glucose monitoring to achieve optimal glycemic target; target glucose levels are set between 63 and 140 mg/dL with time in range goal greater than 70%¹¹
Management of hyperglycemia
- Lifestyle changes may be sufficient to achieve target blood glucose levels
- Refer to a registered dietician with particular expertise in gestational diabetes mellitus
- Insulin is the recommended/preferred medication if pharmacotherapy is needed to achieve glycemic control
- Noninsulin options
  - Both metformin and glyburide cross the placenta and are not recommended as first line agents¹⁰⁴
  - In patients with polycystic ovary syndrome who were treated with metformin, American Diabetes Association recommends discontinuation of metformin by the end of the first trimester¹⁰⁴
  - Recommendations about other agents will require further studies

Follow-up

Monitoring

Assessment of glycemic control
- A1C
  - Measure A1C every 3 months until adequate control is reached, then may reduce frequency of monitoring to every 6 months⁹
- Continuous glucose monitoring
  - Time in range correlates with A1C¹¹ and as such is an alternate measure of glycemic control
  - For example, time in range (set at 70-180 mg/dL) of 70% corresponds to an A1C of 7% and is thus an appropriate target for the majority of patients with type 2 diabetes mellitus¹¹
  - Of note, continuous glucose monitoring is typically not covered by insurance unless the patient is on multiple daily insulin injections. However, the flash glucose monitoring system is less expensive than other continuous glucose monitoring systems and may be affordable to some patients without coverage
- Self-monitoring of blood glucose
  - Routine or daily self-monitoring of blood glucose may not be necessary for those not using insulin unless there is concern for hypoglycemia (for example, patient is taking a sulfonylurea) or under circumstances where A1C may be inaccurate, such as in pregnancy or end-stage renal disease. However, self-monitoring of blood glucose may be helpful after medication changes and in the setting of acute illness, exercise, or changes in diet. Therefore, all patients should have access to self-monitoring of blood glucose
  - For patients taking insulin:
    - Self-monitor blood glucose using glucometer blood glucose once daily before breakfast for those on basal insulin at bedtime
    - Check blood glucose before meals for those on prandial insulin
    - May check blood glucose 2 hours after the meal if there is a concern for postprandial hyperglycemia and to adjust prandial insulin dose
    - Check blood glucose any time patient experiences symptoms of hypoglycemia

Complications

Microvascular complications
- Diabetic retinopathy¹⁰⁵
  - Recommend evaluation by an ophthalmologist or optometrist with a dilated eye examination at the time of diagnosis of type 2 diabetes mellitus, then annually or as needed on the basis of eye examination findings
- Peripheral neuropathy¹⁰⁵
  - Screen for peripheral neuropathy at the time of diagnosis of type 2 diabetes mellitus then at least annually
  - Perform a foot examination at diagnosis of type 2 diabetes mellitus and annually thereafter if normal
  - Evaluate distal peripheral neuropathy using 10 g monofilament and tuning fork
  - Assess for symptoms of claudication and check pedal pulses as part of the routine foot examination
  - Ensure that vitamin B12 levels are adequate for all patients on metformin
- Diabetic nephropathy¹⁰⁶
  - Screen for diabetic kidney disease by measuring creatinine, GFR, and spot urinary albumin to creatinine ratio at the time of diagnosis of type 2 diabetes mellitus and at least annually thereafter
  - Urinary albumin to creatinine ratio is a prognostic marker for renal and cardiovascular outcomes as well as a predictor of all-cause mortality and should thus be routinely monitored. A urinary albumin to creatinine ratio less than 30 mg/g is considered normal¹⁰⁶
Macrovascular complications
- Primary prevention of atherosclerotic cardiovascular disease
  - Routine screening for primary atherosclerotic cardiovascular disease in asymptomatic patients with type 2 diabetes mellitus is not currently recommended⁴²
  - Atherosclerotic cardiovascular disease risk factor calculators and coronary artery calcium score can be used to assess cardiovascular risk and thus determine the need for further therapy, such as statins or aspirin for primary prevention⁶⁰
  - Optimize glycemic control and achieve blood pressure, lipid, and BMI targets to lower atherosclerotic cardiovascular disease risk
  - Statins should be strongly considered in the absence of any contraindications in all patients with type 2 diabetes with LDL cholesterol greater than goal⁶¹
- Secondary prevention of atherosclerotic cardiovascular disease
  - Antiplatelet therapy is recommended for all patients with established atherosclerotic cardiovascular disease
  - High-intensity statin with a target LDL less than 55 mg/dL. May require additional nonstatin therapy to achieve lipid goals⁶⁰
Screen for MASLD-related fibrosis using the fibrosis-4 (FIB-4) index (derived from age, ALT, AST, and platelets)
- FIB-4 score less than 1.3 indicates low risk of having advanced fibrosis and that repeat screening in 2 to 3 years is indicated
- Patients at high (FIB greater than 2.67) or intermediate risk (FIB-4 score 1.3-2.67) should have a VCTE (vibration-controlled transient elastography) or enhanced liver fibrosis blood test for further risk stratification. Refer to a hepatologist if the liver stiffness measurement on VCTE is 8 kPA or greater or enhanced liver fibrosis is 7.7 or greater^56,^107,¹⁰⁸

Prognosis

Type 2 diabetes mellitus is a chronic condition whose prognosis in terms of micro- and macrovascular complications depends largely on glycemic control, as well as control of disease risk factors and weight loss in those with overweight or obesity^22,¹⁰⁹
Nonmodifiable risk factors that influence prognosis and mortality include age at diagnosis, such that younger patients have a more aggressive disease pattern, and ethinicity¹¹⁰
Social determinants of health can affect diabetes control and thus prognosis
Overall, the rate of all-cause mortality associated with type 2 diabetes mellitus is increased by 15% as compared with those without diabetes¹¹⁰
Atherosclerotic cardiovascular disease is a major contributor to mortality among those with type 2 diabetes mellitus and is associated with up to 3 to 4 times increased risk of death¹¹⁰

Referral

Evaluation and management of type 2 diabetes mellitus and its complications requires a multidisciplinary team approach
Refer to endocrinologist in the setting of:
- Poor glycemic control despite adequate therapy
- Use of multiple daily insulin injections to discuss insulin pump options, the need for continuous glucose monitoring, or both
- Frequent, severe, and/or nocturnal hypoglycemia
- Difficulty in optimizing cardiovascular disease risk factors
Refer to diabetes educator for diabetes support and education
Refer to obesity medicine specialist if BMI 27 kg/m² or higher to explore pharmacotherapy and to explore bariatric surgery if BMI 30 kg/m² or higher
All patients should be evaluated by an ophthalmologist with a comprehensive dilated eye examination at the time of diagnosis with type 2 diabetes mellitus
Refer to nephrologist in case of:
- Macroalbuminuria or nephrotic range proteinuria
- Uncertainty about the cause of chronic kidney disease, such as:
  - When it is present without retinopathy or other microvascular complications of type 2 diabetes mellitus
  - In case of rapid progression of albuminuria
- Acute kidney injury
- Presence of complications associated with chronic kidney disease that require specialist evaluation (eg, secondary hyperparathyroidism, anemia, electrolyte abnormalities)
- Advanced chronic kidney disease (eGFR less than 30 mL/minute/1.73m²) to discuss renal replacement therapy options, kidney transplant, or both¹¹¹
Refer to neurologist for:
- Difficult-to-control peripheral and autonomic neuropathy
- If there is concern for other causes of neuropathy, in addition to type 2 diabetes mellitus
Refer any patient with abnormal findings on foot examination to a podiatrist for monitoring and treatment

Author Affiliations

Nada Fanous, MD
Clinical Assistant Professor
Department of Internal Medicine
Division of Metabolism, Endocrinology & Diabetes
University of Michigan

Diana Barb, MD
Clinical Associate Professor
Department of Internal Medicine
Division of Endocrinology, Diabetes & Metabolism
University of Florida

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