Integrating GLP-1 RAs Into T2DM Treatment

Learning Objectives

Upon completion, participants should be able to:

• Apply current evidence regarding the use of GLP-1 RAs to treatment decisions for patients with T2DM?
• Incorporate interview techniques to guide patient-centered discussions about individuals’ concerns related to GLP-1 RA therapy to maximize treatment adherence and persistence

You can redeem CME credit for this activity here: https://link.med-iq.com/Ar34o7

Meet the Patients

Read each patient’s detailed history, then review whether they may benefit from glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy.

Meet Your Patient: Jeannette

Jeannette, a 62-year-old woman with newly diagnosed type 2 diabetes mellitus (T2DM), is starting first-line treatment. Her medical history is significant for a myocardial infarction 1 year ago. Her current medications include:

• Aspirin?81 mg daily
• Atorvastatin 40 mg daily
• Losartan 100 mg daily
• Metoprolol tartrate 100 mg twice daily

Meet Your Patient: Frank

Frank, a 49-year-old man, presents for T2DM management.

He is a busy business manager and says that lately he has had trouble finding time for self-care. He admits he likes to “let loose” sometimes, which involves drinking alcohol to excess. His medical history is significant for pancreatitis 1 year ago, but he is not sure what caused it.

His current medications include:

• Glipizide 5 mg twice daily
• Insulin glargine 30 units daily
• Metformin 1,000 mg twice daily

He explains that he wants to take fewer medications, partly because he misses medication doses sometimes as he is “just too tired” when he gets home.

Meet Your Patient: Carlos

Carlos, a 56-year-old man, was diagnosed with T2DM 5 years ago during routine screening.

During his visit, he mentions “it has always been hard to get control of my diabetes.” Some days, his morning readings are 66 mg/dL, and other days, they are greater than 180 mg/dL.

Carlos is confused as to why his readings fluctuate. He gets shaky if he misses lunch or takes a walk in the evening before dinner; he often snacks in the midafternoon and at bedtime because he is worried about getting shaky. He has gained 18 lb since his diagnosis and believes it is due to his medications.

His current medications include:

• Glipizide 10 mg twice daily
• Insulin glargine 80 units daily
• Metformin 1,000 mg twice daily
• Sitagliptin 50 mg daily

Meet Your Patient: Maggie

Maggie, a 64-year-old woman with chronic kidney disease (CKD), presents for T2DM management and lab review.

She says that she feels well and explains that she has been working hard to prevent needing dialysis because her sister recently began dialysis treatment. She shares that she “will do whatever it takes” to prevent needing dialysis herself. She has adopted a vegetarian diet and has lost 12 lb.

Her current medications include:

• Atorvastatin 80 mg daily
• Sitagliptin/metformin 50/1,000 mg twice daily
• Valsartan 160 mg daily

Answer

Jeannette, Carlos, and Maggie!

Answer Explanation

Jeannette

Jeannette has newly diagnosed T2DM. According to the American Diabetes Association (ADA) guidelines, because she has atherosclerotic cardiovascular disease (ASCVD) (previous myocardial infarction), her first-line therapy should be a GLP-1 RA or sodium-glucose cotransporter 2 (SGLT2) inhibitor with proven benefit, regardless of previous metformin use or current HbA1C. Either agent class would help her achieve glucose targets, but because her BMI is 30 kg/m^2, a GLP-1 RA with potent weight reduction is the best option.

Carlos

A 1% reduction in HbA1C is needed, but hypoglycemia is a concern. He has fluctuating fasting glucose, likely from nocturnal hypoglycemia. He also has hypoglycemia symptoms when walking. The glipizide is not helping him reach his treatment goals and is contributing to hypoglycemia; this will need to be reduced or stopped. Weight loss is also a goal, so it would be appropriate to add an SGLT2 inhibitor or a GLP-1 RA to his current metformin regimen. The dipeptidyl peptidase 4 (DPP4) inhibitor is currently dosed sub-therapeutically and will need to be stopped if a GLP-1 RA is started.

Maggie

Maggie’s primary concern is preventing advanced CKD. She is actively engaged in therapeutic lifestyle changes, and her HbA1C is in an acceptable range. Regardless of her HbA1C level, however,?an SGLT2 inhibitor should be considered because of her albuminuria. The 2025 ADA guidelines recommend an SGLT2 inhibitor for patients with albuminuric CKD. Alternatively, a GLP-1 RA with proven CKD benefit can be used. The recent FLOW trial showed primary renal composite benefit from semaglutide in patients with T2DM and CKD.

Answer Explanation

Frank

Although Frank wants to simplify his regimen, he occasionally binge drinks alcohol and has a history of pancreatitis, which makes DPP4 inhibitors and GLP-1 RAs not appropriate treatment options for him. Because of his albuminuria, an SGLT2 inhibitor would be most appropriate.???? ?

WHERE DO GLP-1 RAS FIT IN THE T2DM TREATMENT ALGORITHM?

Treatment guidelines emphasize a holistic, person-centered approach to T2DM management, which encompasses 4 care components:

• Medication for glycemic?management
• Weight management
• Cardiovascular risk factor management
• Cardiorenal protection

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GLP-1 RAs play an important role in holistic T2DM treatment paradigms due to:

• Potent and persistent HbA1C-lowering effects and associated weight loss
• Reduction in major cardiovascular events (MACE)
• Microvascular benefits of specific agents

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GLP-1 RAs are indicated as first-line treatment options for patients with T2DM:

• Who have or are at risk of ASCVD
• Without ASCVD who warrant high or very high glycemic efficacy to address their specific preferences and treatment needs
• Who need potent HbA1C reduction
• Who need to lose at least 10% of their body weight as part of their treatment goals

GLP-1 RAs with proven CVD benefit may also be considered for patients with CKD who cannot tolerate or have contraindications to treatment with an SGLT2 inhibitor

• Can be used in combination with SGLT2 inhibitors if goals are not met
• Canagliflozin, dapagliflozin, and empagliflozin (SGLT2 inhibitors) have CKD benefit

Combinations of GLP-1 RAs and SGLT2 inhibitors have shown benefits. A meta-analysis found that combination therapy is associated with a greater reduction in HbA1C, body weight, and systolic blood pressure compared with either class alone.

Another meta-analysis found that combination therapy with GLP-1 RAs and SGLT2 inhibitors decreased the incidence of cardiovascular events compared with active control/placebo (relative risk, 0.19; 95% CI, 0.04-0.96; P = .403).

In a population-based cohort study, combination therapy with a GLP-1 RA and an SGLT2 inhibitor was associated with a lower risk of MACE and serious renal events compared with either class alone.

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In May 2022, the US FDA approved the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor coagonist, tirzepatide.

Tirzepatide is indicated for patients who require highly potent medications for reducing HbA1C and weight.

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The cardiovascular and renal effects of tirzepatide are still under investigation.

• A post-hoc analysis from the SURPASS-4 trial compared tirzepatide and insulin glargine on kidney parameters in patients with T2DM who had a high CV risk or established CV disease.
• Participants who received tirzepatide had a lower occurrence of composite kidney endpoints (eGFR decline ≥ 40% from baseline, renal death, kidney failure, or new-onset macroalbuminuria) compared with those who received insulin glargine (HR, 0.58; 95% CI, 0.43-0.80]).

The Role of GLP-1 RAs in T2DM Treatment

American Diabetes Association 2025 Recommendations for Glucose-Lowering Medications in the Management of T2DM

Goal: CV and Kidney Risk Reduction (high-risk individual with T2DM)

ASCVD or indicators of high CVD risk

· GLP-1 RA or SGLT2 inhibitor with proven CVD benefit

• If HbA1C is above goal: If on a GLP-1 RA, consider adding an SGLT2 inhibitor with proven CVD benefit or vice versa; pioglitazone

Heart failure

· Current/prior symptoms and HFrEF or HFpEF (documented)

• SGLT2 inhibitor with proven HF benefits

CKD: eGFR < 60 mL/min/1.73 m^2 OR albuminuria (ACR ≥ 3.0 mg/mmol); repeat measurement to confirm CKD

· On ACE inhibitor or ARB—maximally tolerated dose

• SGLT2 inhibitor with evidence of reducing CKD progression; can be started with eGFR ≥ 20 mL/min/1.73 m^2; once initiated, continue until dialysis or transplantation
• OR GLP-1 RA with CKD benefit
• For individuals on SGLT2 inhibitor or a GLP-1 RA and HbA1C is above goal, consider incorporating the other agent

Glucose-lowering therapies: MASLD or MASH

·?Pioglitazone, GLP-1 RA, and dual GIP/GLP-1 RA have potential benefit

·?Decompensated cirrhosis: use insulin

The Role of GLP-1 RAs in T2DM Treatment American Diabetes Association 2025 Recommendations for Glucose-Lowering Medications in the Management of T2DM

Goal: Weight Management and Glycemic Goals

·?Weight management

• Very high efficacy for weight loss: semaglutide, tirzepatide
• High efficacy for weight loss: dulaglutide, liraglutide
• Intermediate efficacy for weight loss: GLP-1 RA (not listed above); SGLT2 inhibitor
• Neutral for weight loss: metformin, DPP4 inhibitor

Glycemic management: Approaches that provide efficacy to achieve goals

·?Metformin/other agents/combination therapy that provide adequate efficacy to achieve and maintain glycemic treatment goals

• Very high efficacy: dulaglutide, semaglutide, tirzepatide, insulin; combination oral; combination injectable (GLP-1 RA and insulin)
• High efficacy: GLP-1 RA (not listed above), metformin, pioglitazone, SGLT2 inhibitor, sulfonylurea
• Intermediate: DPP4 inhibitor

·?If HbA1C is above goal or barriers to care are identified:

• Refer to diabetes self-management education and support
• Consider technology to identify therapeutic gaps and tailor therapy
• Identify and address social determinants of health that impact achievement of treatment goals

DIFFERENTIATING AMONG GLP-1 RAS

All FDA-approved GLP-1 RAs have been shown to be effective in reducing HbA1C levels.

Clinically significant differences exist among individual GLP-1 RAs in:

• Duration of action ?
• Magnitude of HbA1C reduction
• Anticipated weight loss
• Frequency and severity of adverse effects?

With the exception of oral semaglutide, all other GLP-1 RAs are administered subcutaneously via pen injection devices or in fixed-dose combinations with basal insulin.

GLYCEMIC AND EXTRAGLYCEMIC EFFECTS OF GLP-1 RAS

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CV and Renal Benefits

CVD is?the leading cause of morbidity and mortality in patients with T2DM.??????

The GLP-1 RAs dulaglutide, liraglutide, and semaglutide can substantially reduce MACE.

Improved CV outcomes could be due to GLP-1 RA–related:

• Weight loss
• Improvement in blood and lipid profile
• Direct effects on heart function

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All FDA-approved GLP-1 RAs have been evaluated for CV safety in CV outcomes?studies.

• A systematic review and meta-analysis of 7 trials enrolling 56,004 patients examined rates of CV death, stroke, and all-cause mortality in patients with T2DM who were treated with GLP-1 RAs (GLP-1 RAs included lixisenatide, liraglutide, exenatide, semaglutide, dulaglutide, and albiglutide)
• Overall, summary hazard ratios were significant for reductions in:

Diabetes-related kidney disease?affects between 20% and 40% of individuals with T2DM and is an independent risk factor for hypertension, CVD, retinal disease, and premature death.

GLP-1 RAs have been shown to:??????

·?Prevent new-onset macroalbuminuria

·?Reduce urinary albumin excretion

·?Slow declines in eGFR; additionally, trials of liraglutide and subcutaneous semaglutide have shown reduced composite renal outcomes overall and in individuals with reduced eGFR?

·?Reduce the risk of major kidney disease events and death from CV causes in patients with T2DM and CKD; in the FLOW trial, semaglutide (vs placebo) reduced risk of:

• Major kidney disease events (HR, 0.76; 95% CI, 0.66-0.88)
• Composite of the onset of kidney failure (HR, 0.79; 95% CI, 0.66-0.94)
• Death from CV causes (HR, 0.71; 95% CI, 0.56-0.89)

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Trials of GLP-1 RAs have reported reduced composite renal outcomes overall and in individuals with reduced eGFR.?

·?The long-term use of dulaglutide in patients with T2DM has also been associated with reduced composite renal outcomes when compared with placebo, including:

• The first occurrence of new macroalbuminuria
• A sustained decline in eGFR of 30% or more from baseline
• Chronic renal replacement therapy (HR, 0.85; 95% CI, 0.77-0.93;?P?= .004)

·?Lastly, the systematic review and meta-analysis of 7 trials including 56,004 patients noted earlier found a significant HR for the composite renal outcome (defined as development of new-onset macroalbuminuria, decline in eGFR [or increase in creatinine], progression to end-stage renal disease, or death from renal causes) (HR, 0.83; 95% CI, 0.78-0.89)

SAFETY AND ADVERSE EFFECTS OF GLP-1 RAS

Common adverse events for GLP-1 RAs and GIP/GLP-1 receptor co-agonist (effect > 5%) include nausea, vomiting, and diarrhea.

Contraindications for GLP-1 RAs and GIP/GLP-1 receptor co-agonist include?personal or family history of medullary thyroid carcinoma.

Note:

• Use with caution in patients with a history of pancreatitis
• Pulmonary aspiration during general anesthesia or deep sedation has been reported; instruct patients to inform healthcare providers of any planned surgeries

ADDRESSING COMMON BARRIERS TO INITIATING GLP-1 RA THERAPY

Therapeutic lifestyle changes including healthy nutrition and regular physical activity should be highlighted in conversations with patients with T2DM regardless of the pharmacologic treatment provided. Diabetes self-management education and support can help patients cope with their disease, improve self-efficacy, and promote optimal diabetes health outcomes.

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Discussing GLP-1 RAs With Patients?

To develop a patient-centered treatment plan and help patients optimize adherence, clinicians should discuss patient preferences, prior treatment experiences, lifestyle issues, and clinical and personal goals and concerns.

Identifying patients’ goals is an essential initial step in treatment selection and is critical to shared decision making in T2DM management.

Adherence

Despite the availability of several effective therapeutic options, many patients with T2DM are not achieving their treatment goals. This is even frequently observed with patients taking insulin and is primarily driven by concerns about hypoglycemia and lack of dose titration. Notably, GLP-1 RAs have similar efficacy to insulin and have beneficial effects on other organ systems, but they are not associated with hypoglycemia risk. For patients who would benefit from a GLP-1 RA, several options are available: daily injection, weekly injection, and a daily pill taken 30 minutes before ingesting the first food, beverage, or other oral medication of the day.

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Medication Costs

The financial cost of medications is a significant burden for patients in the US and is often a major source of stress for patients with T2DM. Although Medicare Part D plans often cover GLP-1 RAs, out-of-pocket expenses can be high and vary depending on the individual drug. In addition to prescribing specific agents covered by patients’ private or public health insurance, clinicians can help patients address the financial burden of treatment by connecting them with discounts, rebates, and other price adjustments to help offset medication costs of GLP-1 RAs.

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Injection Fears?

Patients with T2DM who are not already using insulin may have anxiety related to the use of injectable GLP-1 RAs.?Discussing the injection process, showing patients the injection pen device, and providing training on using injection pens can be helpful. It is important to emphasize the small needle size, small-volume injection, and relatively painless administration. Clinicians should also explain that the initiation of injectable GLP-1 RAs does not mean the patient has failed to control their T2DM and that the less frequent dosing regimens may potentially be less burdensome than the patient’s current treatments.

Adverse Effects?

Side effects of GLP-1 RAs are related to their mechanism of action and include nausea, vomiting, dyspepsia, and diarrhea. Patients should be informed about the potential for gastrointestinal adverse effects before initiating therapy with GLP-1 RAs. If nausea or vomiting occurs, the GLP-1 RA dose can be reduced temporarily and increased when tolerability improves. To reduce the risk of gastrointestinal effects, patients should be advised to decrease food intake and stop eating when they feel full. Patients should also be educated on the signs and symptoms of pancreatitis.

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Treatment Complexity

Increased complexity of medication regimens is associated with poorer glycemic control in T2DM.?GLP-1 RAs address 5 of the 8 pathophysiologic issues in T2DM, and they are among the most potent treatment options. For patients who are appropriate candidates for GLP-1 RA therapy, regimens can often be simplified by removing other therapeutic agents and reducing insulin doses. Furthermore, because GLP-1 RAs are dosed once daily or once weekly, they often provide a low treatment dose burden.

Patient Expectations

Establishing clear expectations regarding reduced HbA1C levels, weight loss, and adverse effects with GLP-1 RA therapy sets patients up for success. When patients feel in control, they are more likely to adhere to therapy. Clinicians should explain that although GLP-1 RAs can result in weight loss over time, not all patients experience this effect.?It should also be emphasized that a healthy diet and physical activity remain key elements for weight loss, improved glycemic control, and improvements in CV risk factors.

Addressing Patient Concerns?

Patient Concern: I don’t like the sound of the side effects that happen with GLP-1 RAs. I feel pretty good with my current medicines.

GOOD RESPONSE:

Many of the side effects of GLP-1 RAs can be prevented with careful and mindful eating.

BETTER RESPONSE:

Patients who experience side effects despite making changes to their eating habits tend to have them for only a few weeks.

BEST RESPONSE:

If the side effects are bothersome or persistent, we can switch to a different titration schedule, a different medication within the class, or a medication in another class, if needed.

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Patient Concern: I take so many medicines, and the cost of everything really adds up. Can we make things simpler?

GOOD RESPONSE:

Cost is a common concern. We will work with you to make sure that we offer you treatments you can afford.

BETTER RESPONSE:

We can check your insurance plan and make sure we choose a medicine that is covered. There may also be rebates or discounts to help with your out-of-pocket costs.

BEST RESPONSE:

A GLP-1 RA will reduce the need for your other medications and sometimes even help with your weight and blood pressure.

You can redeem CME credit for this activity here: https://link.med-iq.com/Ar34o7

References

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