Diabetes

Pharmacologic Treatment of Type 2 Diabetes

Background
A1C target
ADA Treatment Recommendations
Lifestyle Modification
Medications
Management Summary (Initiation)
Self-Monitoring of Blood Glucose (SMBG)
Hypoglycemia
Additional Notes

Background

Treatment of Type 2 Diabetes, whether new onset or persistent, requires multimodal, comprehensive management. Diabetic treatment includes lifestyle changes, weight management, and pharmacologic approaches. Newer drugs in the GLP-1 receptor agonist (GLP-1 RA) drug class have very high efficacy for both glycemic control and weight management and are now the preferred starting agents for patients with newly diagnosed diabetes. Aside from antihyperglycemic agents, patients may also require lipid-lowering and antihypertensive medications

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

A1C target (See ‘Related PCMed 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 de-intensifying 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 no longer the only preferred first-line agent for glycemic control, but given its low cost and accessibility is still often used for initial therapy
The ADA recommends starting patients on “high efficacy” diabetes medications based on ability to lower glucose and achieve glycemic control
ACP recommends adding an SGLT-2 inhibitor or GLP-1 agonist to metformin and lifestyle modifications in adults with T2DM and inadequate glycemic control
Consider combination therapy at treatment initiation to shorten time to glycemic control
Very high efficacy:
- Dulaglutide (Trulicity) | Semaglutide (Ozempic) | Tirzepatide (Mounjaro)
- Insulin
- Combination oral | Combination injectable (e.g., GLP-1 + Insulin)
High efficacy
- GLP-1 RA not listed above e.g., Exenatide (Byetta) | Liraglutide (Victoza)
- Metformin
- SGLT2-I e.g., Empagliflozin (Jardiance) | Canagliflozin (Invokana)
- Sulfonylurea
- Thiazolidinedione e.g., Pioglitazone (Actos) | Rosiglitazone (Avandia)
Encourage weight loss
- 3% to 7% weight loss improves glycemia and CV risk factors
- > 10% total body weight loss may have disease-modifying effects, including diabetes remission, and may improve long-term cardiovascular outcome
- Options for weight loss depend on patient’s BMI and co-morbid conditions: Lifestyle changes| Evidenced-based structured weight management programs | Pharmacotherapy | Metabolic surgery
- Very high efficacy pharmacotherapy diabetes medications for weight loss include: Semaglutide (Ozempic) | Tirzepatide (Mounjaro)
- These GLP-1 RA drugs should be first-line therapy for patients needing weight management and glycemic control
- High efficacy weight management drugs include: Liraglutide (Victoza) | Dulaglutide (Trulicity)
Consider early introduction of insulin
- Evidence of catabolism: Weight loss | Hypertriglyceridemia | Ketosis
- Hyperglycemic symptoms
- A1C levels >10% (86 mmol/mol) or blood glucose levels ≥300 mg/dL (16.7 mmol/L)
- As glycemic control improves, simplifying the regimen or changing to noninsulin agents is possible
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
- If there are cost-related barriers consider use of lower cost medications e.g metformin| sulfonylureas| TZDs| insulin
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 that are overweight or obese
- GLP-1 RA or dual GLP-1RA/GIP are recommended
- Once weight loss is attained continue therapy to maintain health benefits. Sudden discontinuation can lead to rebound weight gain and worsening of cardiometabolic risk factors
In patients with known atherosclerotic cardiovascular disease or high cardiovascular risk, kidney disease, or heart failure, the following are recommended
- Sodium–glucose cotransporter 2 inhibitors (SGLT2i)
- Glucagon-like peptide 1 receptor agonists with demonstrated CVD benefit
- If A1c remains above target for patients on SGLT2i considering adding GLP-1 RA or vice versa
In patients with concomitant biopsy-proven MASLD or high risk for liver fibrosis based on non-invasive tests
- Encourage weight loss via lifestyle changes and obesity pharmacotherapy
- Choose diabetes medications that assist with weight loss (such as GLP-1-RA or GIP or dual GLP-1-RA/GIP ) or decrease liver fibrosis (Pioglitazone)
Consideration of these medications in the setting of these co-morbidities is independent of HbA1C or HbA1C target

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
The ADA additionally recommends
- Diabetes self-education and support
- Take into consideration social determinants of health (e.g., Health literacy | Access to medications | Access to housing and food)
- Avoidance of therapeutic inertia (e.g., Reassess and modify therapy every 3 to 6 months)
Patients with diabetes should also be assessed for diabetic complications
- ASCVD Risk | Heart disease history | Staging/screening of CKD | Hypoglycemia risk | Retinopathy | Neuropathy | Screening for MASLD/NASH

Noninsulin Glucose-Lowering Agents

GLP1 receptor agonists (GLP-1-RA) or GIP : Dulaglutide (Trulicity) | Semaglutide (Ozempic) | Tirzepatide (Mounjaro)
- Very high to high efficacy drugs (see above) considered first-line therapy
- Preferred agent for patients needing glycemic control and assistance with weight management
- Recommended for patients with comorbid cardiovascular disease or chronic kidney disease
- ACP recommends using GLP-1 agonist to reduce risk for all-cause mortality|major adverse cardiovascular events| stroke
- Preferred to insulin when possible
- When insulin is started GLP1-RA should be continued for greater efficacy, weight and hypoglycemia benefit
- Strong A1C-lowering properties: Associated with decreased weight, lipid and BP
- Risks and adverse events include: Pancreatitis | Thyroid cancer (in rodent models) | Ileus | GI side effects
Biguanides
- Metformin is a high efficacy medication that is generally affordable and accessible
- 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 (e.g., bloating| abdominal discomfort| 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
Sodium-glucose cotransporter 2 inhibitors (SGLT2i): Ertugliflozin | Dapagliflozin | Canagliflozin | Empagliflozin
- Intermediate to high efficacy
- Glucosuric effect: Associated with decreased A1C, weight, and systolic BP
- Recommended for patients with concomitant CKD or cardiovascular disease
- ACP recommends using an SGLT-2 inhibitor to reduce the risk for all-cause mortality| major adverse cardiovascular events| progression of CKD | hospitalization due to CHF
- Risks and adverse events include: DKA (rare) |Genital mycotic infections | Necrotizing fasciitis of the perineum
Dipeptidyl peptidase 4 inhibitors (DPP4i): Alogliptin | Saxagliptin | Linagliptin | Sitagliptin
- Inhibit DPP4 and increase GLP1 and other incretin hormones | Modestly lower A1C | Intermediate potency | low risk of hypoglycemia
- Combination pills available with metformin, SGLT2 inhibitors, and a TZD
- Weight neutral; does not assist with weight management
- Do not add DDP-4 to GLP-1 RA or GIP/GLP-1 RA combination medication due to lack of additional glucose lowering than that of GLP-1 RA alone
- Note: ACP does NOT recommend adding a (DPP-4) inhibitor to metformin and lifestyle modifications in adults with T2DM and inadequate glycemic control
Thiazolidinediones (TZDs): Pioglitazone | Rosiglitazone
- Directly reduce insulin resistance | High efficacy 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
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

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
- Rapid acting formulations are preferable to regular human insulin
- 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
Monitor for signs of overbasalization e.g. significant bedtime-to-morning or postprandial-to-preprandial glucose differential | A1C not at target despite normal fasting glucose, etc

Management Summary (Initiation)

Recent onset T2D and A1C <9.0%
- Monotherapy (with a very high efficacy drug (GLP-1 RA) or metformin and lifestyle changes
A1C ≥9.0%
- Symptomatic (polyuria, polydipsia, or polyphagia): May need to initiate insulin to control glucose toxicity symptoms
- Asymptomatic: Consider starting combination therapy with two drugs picked based on efficacy and comorbid conditions (e.g., Obesity | CKD | CVD)

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 recommendation to use in adults on any insulin therapy
- Consider using for patients on non-insulin glucose lowering therapy
- Strong correlation between “time in range” (TIR) and HbA1c (70% TIR equates to HbA1c ~7%)
- Should be considered in patients who remains above their A1c target to identify therapeutic gaps and tailor therapy
- Educate patients on substances that can interfere with glucose readings
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 | Continuous glucose monitoring devices
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 <70
- 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)
- Educate family members or caregivers on how to administer

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 are 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 to avoid therapeutic inertia
- 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)
- Early referral to nephrology for worsening albuminuria even in setting of stable creatinine
Patients with diabetes are at high risk for complicated infectious illnesses and routine vaccinations and annual dental visits should be encouraged