INITIAL TREATMENT — Metformin is generally preferred for initial treatment of type 2 diabetes, but a SGLT2 inhibitor or GLP-1 receptor agonist may be added or substituted in patients with obesity or CV or renal comorbidities. Initial combination therapy can be considered in patients with A1C levels 1.5-2% above goal and in those with comorbidities for whom specific classes of drugs have additional benefits (e.g., CVD, CKD, HF, obesity).1

Adding a Second Drug – Most patients require multiple drugs for glycemic control. The choice of a second glucose-lowering drug is generally based on A1C levels and the presence of comorbid conditions (see Table 1). When added to metformin, another oral noninsulin drug generally lowers A1C by about 0.7-1% and a GLP-1 receptor agonist or dual GIP/GLP-1 receptor agonist generally lowers it by ≥1%.

The SGLT2 inhibitors canagliflozin and empagliflozin and the GLP-1 receptor agonists dulaglutide, liraglutide, and semaglutide have reduced the risk of MACE in patients with type 2 diabetes and established CVD. Canagliflozin, dapagliflozin, empagliflozin, and SC semaglutide have improved kidney outcomes. Liraglutide, semaglutide, and the GIP/GLP-1 receptor agonist tirzepatide can produce significant weight loss in patients with overweight/obesity. SGLT2 inhibitors have been more effective than GLP-1 receptor agonists in preventing hospitalization for HF.

METFORMIN — The biguanide metformin reduces hepatic gluconeogenesis. It may also reduce intestinal absorption of glucose and (to a lesser extent) increase peripheral glucose uptake. Metformin is generally preferred for initial treatment of type 2 diabetes, particularly in patients without CV or renal comorbidities or obesity. It generally reduces A1C by 1-1.5%, causes minimal weight loss or is weight-neutral, and does not cause hypoglycemia. In a study that included 17 systematic reviews with meta-analyses, use of metformin was associated with a lower risk of all-cause mortality and CV mortality compared to use of a sulfonylurea or insulin.2

Adverse Effects – Metformin can cause GI adverse effects (metallic taste, nausea, diarrhea, abdominal pain), vitamin B12 deficiency, and (rarely) lactic acidosis. Slow titration of the dose and taking the drug with food can minimize GI adverse effects.

Metformin is contraindicated for use in patients with an eGFR <30 mL/min/1.73 m², and starting the drug in patients with an eGFR ≤45 mL/min/1.73 m² is generally not recommended.3

SGLT2 INHIBITORS — SGLT2 inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion, reducing fasting and postprandial blood glucose levels without causing hypoglycemia. They generally reduce A1C by 0.5-0.7% in patients with adequate renal function. Added to standard treatment, canagliflozin and empagliflozin have reduced the risk of MACE in patients with type 2 diabetes and established CVD.4,5 Canagliflozin, empagliflozin, and dapagliflozin are FDA-approved to reduce the risk of hospitalization for HF and slow progression of CKD.4,6-10 In patients with CKD, empagliflozin has reduced the risk of kidney disease progression, end-stage kidney disease, and CV death for up to 12 months after it was discontinued.11 Ertugliflozin and bexagliflozin have not been shown to reduce the risk of MACE, and they are not approved by the FDA for any CV or renal indications.12,13

Adverse Effects – SGLT2 inhibitors can increase the risk of genital mycotic infection, bacterial urinary tract infection, volume depletion, acute kidney injury, and hypotension. Ketoacidosis can occur rarely. Increased risks of lower limb amputations (canagliflozin, ertugliflozin), falls, bone fractures (canagliflozin), urosepsis, pyelonephritis, and Fournier's gangrene have been reported.

INCRETIN-BASED DRUGS — GLP-1 receptor agonists potentiate glucose-dependent secretion of insulin, suppress glucagon secretion, slow gastric emptying, and promote satiety without causing hypoglycemia. They generally reduce A1C by 0.5-2%; reductions appear to be greatest with semaglutide and tirzepatide.

Dulaglutide, liraglutide, and SC and PO semaglutide have reduced the risk of MACE in adults with established CVD, but they have not been shown to reduce hospitalization for HF. SC semaglutide has slowed progression of CKD in patients with type 2 diabetes.14-22 In patients with type 2 diabetes and peripheral artery disease with intermittent claudication, SC semaglutide reduced progression of peripheral artery disease by 54% independent of baseline glycemic control and body mass index (BMI).23

Wegovy, a subcutaneously injected formulation of semaglutide, is FDA-approved for chronic weight management in patients ≥12 years old, to reduce the risk of MACE in adults with established CVD and obesity/overweight, and for treatment of noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced hepatic fibrosis in adults.24,25 Liraglutide is FDA-approved as Saxenda for chronic weight management in patients ≥12 years old.

Tirzepatide is a subcutaneously injected incretin peptide hormone with activity at GIP and GLP-1 receptors. In clinical trials in patients with type 2 diabetes, tirzepatide reduced A1C (2-2.5%) and body weight (7-13 kg) more than SC semaglutide, insulin degludec, and insulin glargine.26 A cardiovascular outcomes trial (SURPASS-CVOT) evaluating the effect of tirzepatide on MACE in patients with type 2 diabetes is expected to be published soon.27 Kidney outcomes trials with tirzepatide are ongoing.

Tirzepatide is also FDA-approved as Zepbound for chronic weight management in adults and for treatment of moderate to severe obstructive sleep apnea (OSA) in adults with obesity.28,29

Semaglutide vs Tirzepatide – In two large systematic reviews with meta-analyses in patients with type 2 diabetes, tirzepatide was more effective in reducing A1C and weight than SC semaglutide. The incidence of GI adverse events was about the same with both drugs.30,31

Adverse Effects – Incretin-based drugs commonly cause GI adverse effects (nausea, vomiting, diarrhea, constipation); slow titration of the dose can improve tolerability. Acute pancreatitis, gall bladder disease including cholelithiasis, and renal failure (possibly due to dehydration), and increases in heart rate have been reported. Hypoglycemia occurs rarely, predominantly with concurrent use of other glucose-lowering drugs. GLP-1 receptor agonists have been associated with reductions in muscle mass and nutritional deficiencies.32

GLP-1 receptor agonists have been associated with an increased risk of gastroesophageal reflux disease (GERD) and its complications, including Barrett's esophagus.33 The labels of all GLP-1 receptor agonists and tirzepatide include postmarketing reports of ileus associated with their use.34 Pulmonary aspiration has been reported rarely with use of these drugs in patients undergoing procedures requiring general anesthesia or deep sedation who had residual gastric contents despite preoperative fasting.35

In patients with type 2 diabetes, use of GLP-1 receptor agonists and tirzepatide have been associated with an increased risk of ocular complications including diabetic retinopathy, nonarteritic anterior ischemic optic neuropathy (NAION), and neovascular age-related macular degeneration (AMD).36-38

The labels of all GLP-1 receptor agonists and tirzepatide include a boxed warning about a risk of thyroid C-cell tumors (based on animal data; no corroborating human data). These drugs are contraindicated for use in patients with a personal or family history of medullary thyroid carcinoma and in those with multiple endocrine neoplasia syndrome type 2.

DPP-4 INHIBITORS — The DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, and sitagliptin potentiate glucose-dependent secretion of insulin and suppress glucagon secretion. They typically reduce A1C by 0.5-0.8%. In large randomized controlled trials in patients with type 2 diabetes who have established CVD or are at high risk for CVD, DPP-4 inhibitors have not increased or decreased the risk of MACE, hospitalization for HF, or progression of CKD.39

Adverse Effects – DPP-4 inhibitors are generally well tolerated. Joint pain and myalgia can occur. They can increase the risk of pancreatitis and hepatic dysfunction/hepatitis. Worsening of HF can occur with use of alogliptin or saxagliptin.

SULFONYLUREAS — Sulfonylureas interact with ATP-sensitive potassium channels in the beta-cell membrane to increase secretion of insulin independent of nutrient intake, which can often cause hypoglycemia. The sulfonylureas glimepiride, glipizide, and glyburide reduce A1C by 1-1.5%. Their effectiveness in reducing A1C, ease of use, and low cost led to their widespread use as second-line agents, but they can cause weight gain and hypoglycemia and have not been shown to have a beneficial effect on CV or renal outcomes.40,41 Because of its adverse effects, many expert clinicians recommend against use of glyburide.

Adverse Effects – Hypoglycemia is common with use of a sulfonylurea, especially glyburide. Weight gain can occur.

THIAZOLIDINEDIONES — Pioglitazone and rosiglitazone (not currently available in the US) increase insulin sensitivity in adipose tissue, skeletal muscle, and the liver and decrease hepatic glucose production. They reduce A1C by 1-1.5%.

Adverse Effects – Thiazolidinediones cause weight gain and fluid retention/peripheral edema. They can increase the risk of HF (use in patients with NYHA class III or IV HF is contraindicated), bone fractures, bladder cancer, and macular edema.42

MEGLITINIDES — Nateglinide and repaglinide, although structurally different from sulfonylureas, also bind to ATP-sensitive potassium channels on beta cells and increase insulin release independent of nutrient intake. Repaglinide reduces A1C more than nateglinide (1.0% vs 0.5%). Both drugs are rapidly absorbed and cleared; plasma levels of insulin peak 30-60 minutes after each dose. They have not been shown to improve CV outcomes or reduce microvascular complications, and they can cause hypoglycemia.

ALPHA-GLUCOSIDASE INHIBITORS — Acarbose and miglitol inhibit the alpha-glucosidase enzymes that line the brush border of the small intestine, interfering with hydrolysis of carbohydrates and delaying absorption of glucose and other monosaccharides. To decrease postprandial glucose concentrations, acarbose and miglitol should be taken with each meal. They are minimally effective in reducing A1C and frequently cause GI adverse effects such as bloating and flatulence.

PREGNANCY AND LACTATION — Insulin is the drug of choice for treatment of type 2 diabetes in pregnant women. Insufficient data are available on the long-term safety of other glucose-lowering drugs during pregnancy.

Insulin and metformin are generally considered safe for use while breastfeeding. Data on the use of SGLT2 inhibitors, GLP-1 receptor agonists, tirzepatide, or DPP-4 inhibitors in lactating women or their effects on the breastfed infant or milk production are limited.

Additional Content Available:
Comparison Chart: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors
Comparison Chart: GLP-1 and GIP/GLP-1 Receptor Agonists for Type 2 Diabetes

REFERENCES