CLINICAL ACTIONS:

• Treatment of Type 2 Diabetes, whether new onset or persistent, requires multimodal, comprehensive management. Diabetic treatment includes lifestyle changes, weight management, and pharmacologic approaches. Aside from antihyperglycemic agents, patients may also require lipid-lowering and antihypertensive medications
• Initial therapy and A1C
• Lifestyle therapy plus antihyperglycemic monotherapy (preferably with metformin)

A1C target (See ‘Related ObG Topic’ below): Currently, there are different professional guideline thresholds

• ACP: Aim to achieve an HbA1c level between 7% and 8% in most patients with type 2 diabetes and consider deintensifying pharmacologic therapy in patients with type 2 diabetes who achieve HbA1c levels less than 6.5%
• ADA: Recommends <7% for the general population and to consider more stringent goals (<6.5%) for selected patients without significant hypoglycemia (e.g., long life expectancy, no CVD and treated with lifestyle or metformin only)
• AACE/ACE: ≤6.5% if target can be achieved safely

ADA Treatment Recommendations Include the Following

• Metformin is the preferred initial medication if tolerated by patient, with other agents added to metformin as needed to achieve target
  • Benefits: Low hypoglycemia risk | May help with modest weight loss | Good antihyperglycemic efficacy at doses of 1,000 to 2,000 mg/day
  • Side effects: GI intolerance (bloating, abdominal discomfort, and diarrhea)
  • Renal disease: Can be used with reduced estimated glomerular filtration rates (eGFR) ≥30 mL/min/1.73 m2
  • Vitamin B12 deficiency: Periodically test for vitamin B12 levels
• Consider early introduction of insulin
  • Catabolism: Weight loss | Hypertriglyceridemia | Ketosis
  • Hyperglycemic symptoms
  • A1C levels >10% (86 mmol/mol) or blood glucose levels ≥300 mg/dL (16.7 mmol/L)
• Dual therapy: Consider in newly diagnosed patients if A1C ≥1.5% (12.5 mmol/mol) above target
  • Initial dual therapy extends time to treatment failure (compared to sequential addition of medications)
  • High costs and tolerability issues are important barriers to the use of GLP-1 receptor agonists
• Continue metformin for as long as tolerated and not contraindicated
  • Add other agents, including insulin, to metformin
  • Glucagon-like peptide 1 receptor agonist is preferred to insulin when possible

With Comorbidities in addition to Type 2 Diabetes

• In patients with known atherosclerotic cardiovascular disease or at high risk, kidney disease, or heart failure, the following are recommended
  • Sodium–glucose cotransporter 2 inhibitors
  • Glucagon-like peptide 1 receptor agonists with demonstrated CVD benefit
• Consideration of these medications in the setting of these co-morbidities is independent of HbA1C or HbA1C target

SYNOPSIS:

Management should be individualized based on numerous factors, such as age, life expectancy, comorbid conditions, duration of diabetes, risk of hypoglycemia or adverse consequences from hypoglycemia, patient motivation, and adherence. The ADA states that

A patient-centered approach should be used to guide the choice of pharmacologic agents. Considerations include comorbidities (atherosclerotic cardiovascular disease, heart failure, chronic kidney disease), hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences.

KEY POINTS

Lifestyle Modification

• ACCE/ACE list the following as key areas for lifestyle modification
  • Nutrition: Weight management | plant-based diet
  • Physical Activity: 150 min/week exertion such as walking or stair climbing | Strength training
  • Sleep: About 6 to 8 hours/night
  • Behavioral support: Community engagement | Alcohol moderation
  • Smoking cessation: No tobacco products

Medications

Noninsulin Glucose-Lowering Agents

• Biguanides
  • Metformin is considered first line medication
  • Acceptable alternatives (described below) to metformin as initial therapy include
    • GLP1 receptor agonists | SGLT2 inhibitors | DPP4 inhibitors | TZDs | AGIs
    • SUs, and glinides may also be appropriate as monotherapy for select patients
• GLP1 receptor agonists (GLP-RA): Exenatide | Dulaglutide | Semaglutide | Liraglutide
  • Next in line to be added to metformin when dual or triple therapy indicated (same suggested hierarchy level as SGLT2i)
  • Strong A1C-lowering properties: Associated with decreased weight, lipid and BP
• Sodium-glucose cotransporter 2 inhibitors (SGLT2i): Ertugliflozin | Dapagliflozin | Canagliflozin | Empagliflozin
  • Next in line to be added to metformin when dual or triple therapy indicated (same suggested hierarchy level as GLP1-RA)
  • Glucosuric effect: Associated with decreased A1C, weight, and systolic BP
• Dipeptidyl peptidase 4 inhibitors (DPP4i): Alogliptin | Saxagliptin | Linagliptin | Sitagliptin
  • Inhibit DPP4 and increase GLP1 and other incretin hormones | Modestly lower A1C | low risk of hypoglycemia
  • Combination pills available with metformin, SGLT2 inhibitors, and a TZD
• Thiazolidinediones (TZDs): Pioglitazone | Rosiglitazone
  • Directly reduce insulin resistance | Potent A1C-lowering properties | Low risk of hypoglycemia
  • Caution recommended due to associated risk factors: Weight gain | Increased bone fracture risk in postmenopausal females and elderly males | Elevated risk for chronic edema or heart failure
• Alpha-glucosidase inhibitors (AGIs): Acarbose | Miglitol
  • Modest A1C-lowering effects | Low hypoglycemia risk
  • Limited use in the US
• Insulin-secretagogues
  • Sulfonylureas (SUs): Glimepiride | Glipizide | Glyburide
    • Relatively potent A1C-lowering effects
    • Effects may not last | May increase weight | Risk for hypoglycemia and CVD
  • Glinides: Nateglinide | Repaglinide
    • Shorter half-life than SUs, with lower A1C-lowering effects but also lower risk of prolonged hypoglycemia
• Other medications
  • Bromocriptine | Colsevelam (bile acid sequestrant)

Note: While the ACE/ACCE algorithm (see below in ‘Learn More – Primary Sources) places GLP-RA and SGLT2i drugs as next in line to combine with metformin, the ADA states

If the A1C target is not achieved after approximately 3 months, metformin can be combined with any one of the preferred six treatment options: sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, GLP-1 RA, or basal insulin; the choice of which agent to add is based on drug-specific effects and patient factors

Insulin

• Most potent antihyperglycemic agent
• Considerations prior to use
  • Patient motivation | CVD, comorbidities and complications | Age | Risk for Hypoglycemia | Overall health |Cost considerations
• Basal analogs: Glargine | Detemir | Degludec
  • Flat serum insulin concentration for 24 hours or longer
• Human Neutral protamine Hagedorn (NPH) insulin
  • More likely to cause hypoglycemia than basal analogs
• Addition of human NPH or long-acting insulin analogs to oral agents is “well-established approach that is effective for many patients” (ADA)
• Rapid acting Insulin: Glulisine | Lispro | Aspart | Inhaled insulin (preferable to regular human)
  • May be necessary at mealtime if glycemia uncontrolled despite combination of oral medications and insulin/GLP1-RA
• Premixed insulins combining longer and shorter action insulin available but less flexible and greater risk of hypoglycemia

Management Summary (Initiation)

• Recent onset T2D and A1C
• Monotherapy (preferably metformin)

A1C >7.5% (whether newly diagnosed or not)

• If not already taking antihyperglycemic agents start on metformin plus another agent

A1C >9.0%

• Symptomatic (polyuria, polydipsia, or polyphagia): Will likely need insulin
• Asymptomatic: Start with 2 or 3 non-insulin medications

Note: Link to detailed ACE/ACCE Glycemic Control algorithm available in ‘Learn More – Primary Sources’ below)

Self-Monitoring of Blood Glucose (SMBG)

• Recommended for patients on intensive insulin therapy (basal plus prandial insulin)
  • Check prior to meals/snacks, prior to exercise, and at bedtime
  • Once-daily fasting glucose in patient on basal insulin only
  • Limited benefit for patients on oral therapy only
• Continuous glucose monitoring (CGM) devices are emerging as a complement to SMBG
  • Strong correlation between “time in range” (TIR) and HbA1c (70% TIR equates to HbA1c ~7%)
• Patients not on insulin
  • Routine glucose monitoring likely limited in clinical value
  • For some, may provide insight regarding exercise, diet and medication management

Hypoglycemia

• Risk for antihyperglycemic agents, especially insulin
• Some classes have lower risk for hypoglycemia
  • Metformin | GLP1 receptor agonists | SGLT2 inhibitors | DPP4 inhibitors | TZDs
  • However, hypoglycemia can still occur in combination with an insulin secretagogue or exogenous insulin
• Screen patients for evidence of hypoglycemia unawareness
  • Young children with type I diabetes and elderly are particularly vulnerable
  • Interventions include: Medication or diet adjustments | Patient education | Individualized glycemic goals
• Educate patients regarding symptoms
  • Tremors or feeling shaky | Nervous or anxious | Sweating, chills and clamminess | Irritability | Confusion | Tachycardia | Lightheaded or dizziness | Pallor | Drowsy or weakness | Blurred/impaired vision | Tingling or numbness in the lips, tongue, or cheeks | Headaches | Lack of coordination | Seizures (severe)
• “15-15 Rule”: Raise glucose to >70 mg/dL with 15 grams carbohydrate intake and check glucose at 15 minutes | Repeat if glucose still
• Glucose tablets or gel tube | 4 ounces (1/2 cup) of juice or regular (non-diet) soda | 1 tablespoon of sugar, honey, or corn syrup | Hard candies, jellybeans, or gumdrops (based on labelling)

Severe hypoglycemia (patient cannot treat herself or unconscious): Glucagon

• Available by injection (buttock, arm or thigh) or nasal powder (does not require inhalation)

Additional Notes

• GLP1-RA is preferable to insulin for those patients who may require an injectable medication
• Patients who require a 3rd medication and who have A1C >8.0% and/or long-standing disease: Less likely to reach their target A1C with a third oral antihyperglycemic agent
  • While adding GLP1-RA may initially work, many patients will still require insulin
• Reevaluate medications regularly
  • Every 3 to 6 months
  • Adjust as needed based on new patient factors
  • Yearly visits (or more frequent depending on clinical findings) to ophthalmologist and podiatrist
• Important to prevent complications and slow CVD / renal disease
  • Manage risk factors for atherosclerosis (e.g., BP, cholesterol, smoking, obesity)

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Learn More – Primary Sources

FDA List of Approved Diabetes Medications

AACE/ACE Comprehensive Type 2 Diabetes Management Algorithm

ADA Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022

Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians

CDC-Recognized Lifestyle Change Program

ADA Healthcare Professional Resources

Related ObG Topics: