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Determining the Right Agent for the Right Patient with Type 2 Diabetes and Compelling Comorbidities

The Guidance for Industry, published in 2008 by the Food and Drug Administration (FDA) shifted the practice landscape for care of people with type 2 diabetes (T2D).¹ This guidance document, which was for immediate implementation, mandated all pharmaceutical companies seeking approval for new medications for the treatment of T2D to perform large-scale outcome trails to prove cardiovascular safety prior to submission of the New Drug Application. Since then, approximately two dozen kidney and cardiovascular outcome trials (CVOTs) have documented safety, and at times efficacy, of two classes of medications used in the treatment of T2D: sodium glucose cotransporter (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs). The results of these trials have both informed guidelines and influenced prescribing patterns.

A dramatic shift within the 2021 American Diabetes Association (ADA) Standards of Medical Care in Diabetes guidelines² places emphasis on pre-existing conditions of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure (HF), particularly HF with reduced ejection fraction (HFrEF), which is also echoed in the 2020 American College of Cardiology (ACC) Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients with T2D.³ Following implementation of lifestyle adjustments and first-line therapy metformin, these guidelines recommend considering the presence or absence of these compelling pre-existing conditions to inform selection of add-on glucose-lowering therapies. Individuals with evidence of ASCVD, CKD, HF, or high CV risk factors (age 55 years with coronary, carotid, or lower-extremity artery stenosis > 50%, or left ventricular hypertrophy) should receive either a SGLT2 inhibitor or GLP-1 RA with evidence of benefit through one of the aforementioned CVOTs or kidney outcome studies. If further intensification is required to meet individualized glycemic targets, initiation of an agent from the opposing class is preferred (ie, intensification to GLP-1 RA plus SGLT2 inhibitor combination therapy). Also, use of these evidence-based therapies should occur when a compelling indication presents independent of glycemic status or background therapy. Despite these guideline recommendations, questions often arise regarding choosing between these two classes in the context of compelling pre-existing conditions.

Selecting Between the SGLT2 Inhibitor and GLP-1 RA Classes

When ASCVD Predominates: No preference is given to either the SGLT2 inhibitor or the GLP-1 RA class to reduce the risk of MACE, defined as myocardial infarction (MI), cerebral vascular accident (CVA), or CV death, when ASCVD predominates. However, other considerations may guide selection. SGLT2 inhibitor trials with outcomes of demonstrated superiority of CV benefit were conducted in populations predominately with established CVD. A meta-analysis of the class showed that when stratified by secondary vs primary CV prevention, only those with pre-existing CVD gained benefit from addition of the SGLT2 inhibitor (hazard ratio [HR] 0.86; 95% confidence interval [CI] 0.8-0.93; p = 0.0002).⁴ Conversely, patients with multiple risk factors for ASCVD alone had no improved risk reduction for MACE when a SGLT2 inhibitor was added (HR 1.00; 95% CI 0.87-1.16; p = 0.98). Similarly, a meta-analysis of 7 GLP-1 RA CVOTs also showed a greater impact in patients with established CVD (HR 0.86; 95% CI 0.8-0.93) compared to the population with risk factors alone (HR 0.94; 95% CI 0.83-1.07).⁵ Although separate analysis, it appears that patients with CV risk factors may experience a greater CV benefit from adding a GLP-1 RA compared to a SGLT2 inhibitor; the risk reduction is similar when initiated in populations with established CVD. Combined, these meta-analyses suggest that no preference for the GLP-1 RA vs SGLT2 inhibitor class should be given in the context of treatment for secondary prevention of CVD.

While the overall reduction of MACE is similar between the two classes, particularly for those needing secondary prevention, the individual components of the composite MACE outcome vary. Most notable is the secondary outcome of nonfatal stroke. Although not statistically significant in each CVOT, a consistent benefit is seen among the five long-acting GLP-1 RA CVOTs, which ranges from 11% to a 39% relative risk reduction^6-10 (Table 1). In fact, the American Heart Association (AHA)/American Stroke Association (ASA) 2021 Guideline for Secondary Prevention of Ischemic Stroke further endorsed the use of GLP-1 RA in patients with established ASCVD, including ischemic stroke.¹¹ SGLT2 inhibitors do not show the same consistent benefit for this secondary outcome of stroke. Thus, a long-acting GLP-1 RA may be preferred in this context.

Another point of consideration when ASCVD predominates is the time from SGLT2 inhibitor or GLP-1 RA therapy initiation until MACE risk reduction benefit is observed. In general, SGLT2 inhibitors begin to display this benefit after 2 to 3 months of daily use,^12,13 whereas GLP1-RAs take up to 12 to 18 months^6,7,10 to demonstrate a reduction of MACE. Therefore, a patient in need of a faster onset of CV protection may benefit from initiation of a SGLT2 inhibitor. Lastly, while both classes of medications are known to facilitate weight loss, the long-acting GLP-1 RAs, predominantly semaglutide and liraglutide, are particularly efficacious for weight reduction compared to the SGLT2 inhibitors as a whole  (Table 2). Thus, initiating therapy from the GLP-1 RA class will help support weight loss, a contributor to CVD in obese patients.

When HF Predominates: Unlike when ASCVD predominates, there is clearly a greater benefit for use of the SGLT2 inhibitor class over the GLP-1 RA class when HF is the primary focus of concern. Large-scale studies evaluating the addition of a SGLT2 inhibitor to standard of care for patients with HFrEF^14,15 or HF with reduced preserved fraction (HFpEF)¹⁶ were conducted in populations both with and without T2D. Each study demonstrated an approximate 30% relative risk reduction for hospitalization for HF (hHF). Additionally, hHF was consistently an improved secondary endpoint in the CVOTs for SGLT2 inhibitors.^12,13,17,18 These studies enrolled adults with T2D but low rates of pre-existing HF (10-25%). Yet the addition of a SGLT2 inhibitor reduced the risk of hHF by approximately 30% in each study. Thus, SGLT2 inhibitors not only reduce hHF in patients with pre-existing HFrEF and HFpEF, but they also delay development of HF in those without the condition. Also, the time to benefit of hHF reduction occur early, within days, after SGLT2 inhibitor initiation. GLP-1 RAs have not demonstrated the same robust benefit on HF outcomes. As with the CVOTs for SGLT2 inhibitors, the GLP-1 RA CVOTs also reported occurrence of hHF as secondary endpoints, none of which demonstrated a statistically significant benefit. However, a meta-analysis of these trials showed a combined statistically significant benefit (HR 0.91; 95% CI 0.83-0.99; p = 0.028), albeit much smaller compared to the SGLT2 inhibitor class.⁵ It is for this reason that the ADA’s Standards of Medical Care in Diabetes recommends a SGLT2 inhibitor prior to a GLP-1 RA when HF predominates, but notes a GLP-1 RA as a worthy addition if greater glycemic control is needed.¹⁹

When CKD Predominates: As when HF predominates, the presences of CKD likewise should stimulate the preferential initiation of a SGLT2 inhibitor over a GLP-1 RA. Two large-scale kidney outcome trials evaluated the addition of a SGLT2 inhibitor to standard of care in populations with or without T2D and a past medical history of decreased estimated glomerular filtration rate (eGFR) and proteinuria.^20,21 The primary composite outcomes were generally first occurrence of any of the following: onset of end stage kidney disease (ESKD), doubling of the serum creatinine or 50% decline in eGFR, or death from kidney or cardiovascular disease. Both studies were stopped early on account of a statistically significant 30% to 39% relative risk reduction for the primary composite endpoint (Table 3). Upon further analysis, every component of the primary composite also reached statistical significance, including a notable slowing in rate of eGFR decline. Secondary kidney endpoints from several of the SGLT2 inhibitor CVOTs also suggested benefit of SGLT2 inhibition on progression of CKD.^12,13,17 Consistently, preservation of kidney function became evident after 18 months of SGLT2 inhibitor use. Secondary kidney outcomes reported with agents from the GLP-1 RA class suggest a benefit,^6,7,10,22 although primary kidney outcome data are currently lacking (Table 1).

Safety and Tolerability Considerations: Another driving force in the selection between the SGLT2 inhibitor and GLP-1 RA classes is the safety and tolerability profiles. The most bothersome side effect with SGLT2 inhibitors is the development of vulvovaginitis or balanitis mycotic infection.^23-25 Those with a history of yeast infections are at a greater risk of developing a SGLT2 inhibitor-induced event. However, most (91%) experience a single event that responds well to standard antifungal therapies. Also unique to the SGLT2 inhibitor class is the uncommon Fournier’s gangrene, a necrotizing fasciitis of the perineum and genital region.²⁶ Although rare, if it occurs emergent care is needed, including discontinuation of the SGLT2 inhibitor and initiation of broad-spectrum antibiotics. SGLT2 inhibitors can lead to volume depletion, orthostasis, and dehydration which can precipitate acute kidney failure and diabetic ketoacidosis in patients with type 1 diabetes (T1D) or advanced T2D²⁵ (Table 2). Finally, SGLT2 inhibitors should be dosed appropriately based on the patients’ eGFR.

The tolerability profile of GLP-1 RAs differs greatly from that of SGLT2 inhibitors. Their primary bothersome side effect is gastrointestinal in nature.²⁷ These include nausea, vomiting, and diarrhea, which are typically mild to moderate in intensity, occur shortly after treatment initiation or titration, but are transient with continued use. Of note, the short-acting agents, exenatide and lixisenatide, have higher rates of gastrointestinal adverse events, due to their greater impact on slowing gastric emptying. Of the long-acting GLP-1 RA, exenatide XR has the lowest rates of gastrointestinal-related symptoms (Table 2). Given this pharmacodynamic impact on gastric motility, those with a history of significant gastroparesis should avoid use of the GLP-1 RA class. Other disadvantages that may limit use include injection site reactions, exacerbated diabetic retinopathy, the potential risk of acute pancreatitis, and the black box warning regarding thyroid c-cell tumors. While some GLP-1 RA are not recommended for use in patients with a creatinine clearance (CrCl) < 30 mL/min or with ESKD,^28-30 other agents do not require specific dosage adjustments based on kidney function.³¹

Selecting an Agent Within the GLP-1 RA Class

Selecting the best GLP-1 RA for a given patient can be based on several factors, including glycemic impact, weight reduction, CV risk reduction, and kidney benefits, route and frequency of administration, and safety and tolerability profiles. Delivery devices may also influence product selection, which are addressed in more detail in Module 3.

Within Class Comparison of GLP-1 RAs: Presently, 7 GLP-1 RAs are available in the United States. Six are subcutaneous products for injection and one, semaglutide, is also available as an oral product. While daily semaglutide offers the convenience of oral administration, it must be taken each morning 30 minutes before breakfast on an empty stomach with no more than 4 oz of water.³² This method of administration is necessary to allow for drug absorption. Still, it offers a GLP-1 RA option for patients deterred by injectable therapies. The remaining 6 products are injected subcutaneously twice daily, daily, or once weekly.

GLP-1 RAs are categorized as either short-acting or long-acting, based on their half-life (Table 4). The first in class to market, exenatide, is injected twice daily within 60 minutes before the morning and evening meals and lixisenatide, although dosed only once daily, is recommended to be administered within 60 minutes before breakfast.^28,30 Due to the short half-life (2.4 h and 3 h, respectively), both of these products exhibit their glycemic impact on the post-prandial index, by lowering it between 50 mg/dL and 70 mg/dL with a minimal impact on the fasting blood glucose. Their overall A1C reduction ranges from 0.48% and 0.6% (Table 2). Thus, these products are ideal for patients desiring to blunt the post-prandial glycemic rise following a meal. Also, of note, lixisenatide is available as a fixed-dose combination with basal insulin glargine (U-100) for dual coverage of fasting and post-prandial blood glucose.³³

Like lixisenatide, liraglutide is also injected once daily, but it is considered long-acting due to its extended half-life (13 h). The remaining long-acting GLP-1 RA products (exenatide XR, dulaglutide, and semaglutide) are conveniently injected once-weekly without regards to meals. The long-acting GLP-1 RAs, which also includes oral semaglutide, provide a greater A1C decline compared to the short-acting products, which ranges from 0.88% to 1.43%, depending on the product and dose. As such, the long-acting GLP-1 RAs are preferential for patients desiring a greater A1C decline and more convenient administration (Table 2). Similar to lixisenatide, long-acting liraglutide is also available in a fixed-dose combination with basal insulin degludec (U-100), which may also prove convenient for patients desiring use of a long-acting GLP-1 RA and an ultra-long-acting basal insulin.³⁴

Comparison of GLP-1 RA by Weight Loss: Weight reduction is another noteworthy consideration that may influence GLP-1 RA product selection for a given patient. Although a class-wide effect, the impact of weight loss varies with the shorter-acting products resulting in less weight loss (0.91-1.71 kg) compared to the long-acting products (1.23-3.40 kg). This benefit is accumulated over months of continued use with a dose-dependent effect. For individuals with a compelling need for weight loss, the ADA guidelines provide a comparative ranking: semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide. Although no head-to-head study exists it appears that weekly injected semaglutide results in greater weight loss than daily oral semaglutide and long-acting GLP-1 RAs induce more weight loss than short-acting products (Table 2). Furthermore, both injected semaglutide and liraglutide are FDA-indicated specifically for weight reduction at higher doses than are used for managing T2D.^35,36

Comparison of GLP-1 RA by CV Risk Reduction: To date, all CVOTs evaluating GLP-1 RAs have demonstrated CV safety in their studied populations; however, not all have documented benefit. CV safety nor benefit of short-acting exenatide is known as it acquired market approval prior to the requirement for CVOTs.¹ The CVOTs for lixisenatide, exenatide XR, and oral semaglutide all documented safety for not increasing the risk of MACE.^8,9,37 While the CVOT for oral semaglutide (PIONEER-6) was only powered to detect noninferiority, the data were promising and suggest a potential benefit of therapy on CV outcomes. An ongoing study SOUL, powered for superiority, enrolled over 9500 participants in hopes of documenting CV benefit of the oral GLP-1 RA.³⁸ Liraglutide, dulaglutide, and injected semaglutide, however, have proven safety and efficacy in reducing the risk of MACE in patients with T2D and established CVD.^6,7,10 In fact, all three products now have expanded FDA-indications as such.^31,39,40 Furthermore, the FDA indication for dulaglutide is broader noting benefit in persons with T2D and CV risk factors alone.³¹ This indication is supported through the dulaglutide CVOT, which predominately enrolled patients with T2D requiring primary CV prevention.¹⁰ While these GLP-1 RAs have demonstrated CV risk reduction in a population requiring secondary risk reduction, dulaglutide may be the preferred choice in patients with high CV risk factors alone.^6,7,10 Table 1 provides an overview of the GLP-1 RA CVOTs. Of note, liraglutide, dulaglutide, and injected semaglutide are also the GLP-1 RAs that have demonstrated microvascular risk reduction for worsening nephropathy, which as previously mentioned was driven through a reduction in proteinuria.^6,7,10,22 Thus, one of these 3 GLP-1 RA should be selected to augment SGLT2 inhibitor use in patients with T2D and CKD.

Conclusion

The growing body of literature, since the FDA Guidance for Industry,¹ has influenced guidelines such that GLP-1 RAs or SGLT2 inhibitors are recommended for early initiation in individuals with T2D. While either pharmacologic class can be selected when ASCVD predominates, a SGLT2 inhibitor should be preferentially selected when HF or CKD is the primary concern. Still, not all SGLT2 inhibitors nor GLP-1 RAs have documented benefit to reduce the risk of these hard outcomes. Differences in A1C and body weight reductions as well as safety and tolerability considerations can guide the shared decision-making process to identify the best option for a given patient.

References

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