1. Introduction
More than 30 million people in the United States and a staggering 422 million people worldwide have diabetes mellitus [1,2]. Over 90% of these individuals have type 2 diabetes (T2DM) [1]. Guidelines for the management of T2DM are in agreement to initiate lifestyle changes and metformin as first-line therapies for glucose control [3]. Due to continuing and progressive insulin deficiency, individuals are unable to reach glycemic targets on metformin as sole pharmacologic therapy for a prolonged duration. A consensus on the optimal add-on therapy after exhausting metformin monotherapy remains elusive. Factors such as cost, efficacy, effects on weight, hypoglycemia risk, and other adverse effects are important in the decision of which therapy to add to metformin for maintaining glycemic control. Practitioners largely remained focused on the surrogate end point of blood glucose control for decreasing the tissue complications of T2DM. However, emerging data is challenging the paradigm that glucose reduction via any means is equivalent in reducing long-term diabetes-related complications. Since the US Food and Drug administration (FDA) issued guidance for industry in establishing cardiovascular safety of new drugs developed to treat diabetes, the impetus to do large-scale cardiovascular outcome trials has led to better data on not only risk, but potential benefit of new drugs. Drugs in the classes of glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown reduction not only in blood glucose but, importantly, also in blood pressure, weight, nephropathy, hypoglycemia risk, and cardiovascular end points. Both of these classes have shown considerable promise in clinical trials, but what factors will persuade clinicians to choose one class over the other?
2. GLP-1 receptor agonists and their effects on cardiovascular and renal outcomes
Since the discovery of GLP-1 in the early 1970s, culminating in the approval of exenatide as the first GLP-1 receptor agonist approved for clinical use in 2005 [4], this class of drug has been an effective choice in managing T2DM. GLP-1 receptor agonists stimulate glucose-dependent pancreatic insulin secretion while inhibiting glucagon secretion, slowing gastric emptying, and promoting satiety. The combination of these varied mechanisms of action lead to blood glucose lowering and weight loss.
Several trials have been completed and many are ongoing to evaluate the effects of GLP-1 receptor agonists on cardiovascular and renal end points. Liraglutide was shown, over a mean follow-up of 3.8 years, in a trial of 9340 patients with T2DM and high cardiovascular risk to significantly reduce the composite major adverse cardiovascular event outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE-3) by 13% compared to placebo [5]. In fact, death from cardiovascular causes and all-cause mortality were significantly reduced by 22% and 15%, respectively. A nonsignificant reduction in myocardial infarction, nonfatal stroke, and heart failure hospitalization was also seen in patients treated with liraglutide. In a prespecified evaluation of secondary renal outcomes (composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease), liraglutide treatment led to lower rates of diabetic kidney disease compared to placebo (HR: 0.78 [0.67–0.92]) [6]. Semaglutide, the newest approved GLP-1 receptor agonist, also resulted in a decrease in the composite MACE-3 outcome by 26% [7], when it was compared to placebo in 3297 patients with T2DM and either established cardiovascular disease, chronic kidney disease, or both. Nonfatal myocardial infarction and nonfatal stroke were also seen less frequently in the semaglutide group by 26% and 39%, respectively. Death from cardiovascular causes did not differ in patients on semaglutide vs. placebo. New or worsening nephropathy rates were lower, but interestingly retinopathy complication rates were higher in those patients treated with semaglutide.
However, not all GLP-1 receptor agonists have shown a definitive cardiovascular benefit. In 14,752 patients (73.1% with previous cardiovascular disease) followed for a median of 3.2 years, extended-release exenatide treatment resulted in a 9% nonsignificant (p = 0.06) reduction in the primary composite MACE-3 end point when compared to placebo [8]. This trial did suffer from a significant rate of exenatide discontinuation, with only 57% of patients on exenatide remaining on therapy for the duration of the study. Lixisenatide, another GLP-1 receptor agonist, given to individuals with T2DM who had a recent acute coronary event (myocardial infarction or unstable angina hospitalization in previous 180 days) did not alter the rate of major cardiovascular events in a trial of 6068 patients [9]. Adverse effects with GLP-1 receptor agonists were mainly gastrointestinal in all the trials.
Several meta-analyses have been done to evaluate the effects of GLP-1 receptor agonists on cardiovascular and microvascular outcomes. Older analyses done prior to the recent large cardiovascular outcome trials did not show either cardiovascular benefit or harm with the use of GLP-1 receptor agonists. However, more recent meta-analyses including large cardiovascular outcome trials of GLP-1 receptor agonists did show a significant 11–12% reduction in all-cause mortality, with a significant 10% relative risk reduction in one analysis, but only a nonsignificant reduction in MACE-3 outcomes in the other [10,11].
3. SGLT2 inhibitors effects on cardiovascular and renal outcomes
SGLT2 inhibitors are more recent additions to the market of medications used to treat T2DM. The novel insulin-independent mechanism of action by partly inhibiting renal glucose reabsorption make SGLT2 inhibitors an ideal complementary therapy to patients with T2DM without increasing risk of hypoglycemia. These drugs lead to glucose lowering, improvements in blood pressure, and weight loss, suggesting their potential to have positive effects in reducing cardiovascular outcomes.
Two large cardiovascular outcome trials have been completed to date with SGLT2 inhibitors, with several more trials nearing completion in the next few years. In 7020 patients with DM and at high cardiovascular risk treated with either empagliflozin 10 mg/day, 25/day, or placebo, pooled results of empagliflozin users showed a significant 14% reduction in the composite MACE-3 end point over a median 3.1 year period of observation [12]. There was also shown to be a significant 38% relative risk reduction in death from cardiovascular causes, 35% relative risk reduction in hospitalization for heart failure, and 32% relative risk reduction in all-cause mortality. Empagliflozin users experienced a significant 39% reduction in incident or worsening nephropathy, and a significant 55% relative risk reduction in initiation of renal-replacement therapy, as well [13]. In a similar large outcome trial of 10,142 patients with DM and high cardiovascular risk receiving either canagliflozin or placebo (65.6% of whom had previous cardiovascular disease), canagliflozin users showed a significant 14% reduction in the composite MACE-3 end point [14]. Improvements in progression of albuminuria, and the composite outcome of 40% reduction in estimated glomerular filtration rate, need for renal-replacement therapy, and death from renal causes were also observed in canagliflozin-treated patients. However, no significant difference was shown in all-cause mortality or death from cardiovascular cause. The main adverse effects in both trials were genitourinary infections. Also, in canagliflozin-treated patients, there was a higher rate of lower limb amputation.
A recent meta-analysis of 351,476 patients treated with SGLT2 inhibitors included in the cardiovascular outcomes analysis demonstrated a significant reduction in all-cause mortality (HR: 0.67 [0.54–0.84]), cardiovascular mortality (HR: 0.77 [0.60–0.98]), hospitalization for heart failure (HR: 0.62 [0.55–0.69]), and progression of albuminuria (HR: 0.68 [0.58–0.81]) [15]. Another meta-analysis of oral anti-diabetic agents showed SGLT2 inhibitors had significantly lower rates of all-cause mortality and cardiovascular mortality when compared with placebo, sulfonylureas, thiazolidinediones, and dipeptidyl-peptidase 4 inhibitors, with a trend toward improved outcomes in comparison with metformin [16].
4. Conclusion
Worldwide the prevalence of diabetes has reached epidemic proportions, and over 90% of individuals with diabetes have T2DM. Guidelines recommend treatment with metformin and lifestyle changes, but optimal add-on therapy to metformin is still debated. Both GLP-1 receptor agonists and SGLT2 inhibitors improve hemoglobin A1c, reduce body weight, and modestly lower blood pressure. Large cardiovascular outcomes trials with GLP-1 receptor agonists and SGLT2 inhibitors have demonstrated improvements in cardiovascular end points, and in some cases nephropathy and all-cause mortality.
5. Expert opinion
Both GLP-1 receptor agonists and SGLT2 inhibitors improve hemoglobin A1c (−1 to −1.5% with GLP-1 agonists and −0.5 to −1% with SGLT2 inhibitors), reduce body weight (−1 to −3 kg, GLP-1 agonists with greater weight reduction in general), and can modestly lower blood pressure (−1 to −4 mmHg, SGLT2 inhibitors having greater improvement in blood pressure) (Table 1). For now, GLP-1 receptor agonists are injectable (semaglutide is in clinical trials to investigate oral administration) and some are given once weekly, whereas SGLT2 inhibitors are daily oral agents. Both classes of agents are anti-hyperglycemic and thus convey trivial or no hypoglycemic risk per se. Neither class is approved for use in type 1 diabetes (T1DM). Although, still under debate, use of SGLT2 may increase the risk of diabetic ketoacidosis in T2DM, and if used ‘off label’ in combination with insulin for patients with T1DM. For many patients a logical personalized approach will help in the decision of which class to consider as add-on therapy to metformin. In patients with heart failure, SGLT2 inhibitors have stronger data to indicate a benefit, while patients with a significant reduction in glomerular filtration rate may find more benefit with a GLP-1 receptor agonist. There are differences in adverse effects and warnings within each class. GLP-1 agonists have more gastrointestinal side effects and need for precaution in patients with pancreatitis, retinopathy, or medullary thyroid cancer, while SGLT2 inhibitors would not be recommended in patients predisposed to genitourinary infections, fracture, or limb amputation. The FDA and the European Medicines Agency have issued a number of warnings regarding potential adverse events with both GLP-1 agonists and SGLT2 inhibitors. Randomized clinical trials cited above and real-world observational studies [17–19] have shown significant reductions in cardiovascular end points and mortality with both GLP-1 agonists and SGLT2 inhibitors.
Table 1. Summary of outcome trials for GLP1 receptor agonists and SGLT2 inhibitors.
It should be noted that it may be difficult to compare results across trials. Often there are greater reductions in hemoglobin A1c and blood pressure in the active arms as compared to placebo, which is demonstrated in large clinical studies involving both GLP-1 receptor agonists and SGLT2 inhibitors. This, in turn, may confound interpretation of the effects of a drug per se under investigation. Similarly, ‘head to head’ comparison studies involving the new major classes of GLP-1 agonists and SGLT2 inhibitors have not been performed. Additionally, it is becoming more clear that improvements in outcomes and adverse events may not be class effects, but rather more drug-specific. Several large outcome trials have shown that choosing either a GLP-1 receptor agonist or SGLT2 inhibitor is likely to have a stronger impact on decreasing end-organ complications than the other available classes of diabetes treatments (although, yet to be definitively tested in all drug classes). Also, it is intriguing to speculate that the combination of GLP-1 receptor agonists with SGLT2 inhibitors may offer more profound glucose lowering, decrease in body weight and blood pressure. In fact, the addition of dulaglutide treatment in patients with uncontrolled DM on stable doses of SGLT2 inhibitors with or without metformin showed a significant reduction in HbA1c of −0.665 to −0.79%, and greater weight loss, −0.5 to −1.0 kg, versus placebo [20]. Furthermore, GLP-1 receptor agonists may reduce the higher glucagon levels occurring with SGLT2 inhibition, and produce additive effects on reducing cardiovascular and microvascular outcomes. Although the mechanisms behind the cardiovascular and renal benefits remain speculative (Figure 1) [21–24], the good news is that practitioners can choose from two classes of drugs (GLP-1 receptor agonists and SGLT2 inhibitors) that show exciting promise in the management of Type 2 DM. Using an individual’s clinical profile will be the best determinant in deciding when or whether to add SGLT2 inhibitors or GLP-1 receptor agonists as a second-line therapy to metformin.
Published online:
22 May 2018![]({"type":"image","src":"/na101/home/literatum/publisher/tandf/journals/content/ieop20/2018/ieop20.v019.i08/14656566.2018.1475559/20180602/images/medium/ieop_a_1475559_f0001_oc.jpg"})
Figure 1. Putative mechanisms of cardiovascular and renal benefits with GLP-1 agonists and SGLT2 inhibitors [21–24].
| Outcomes | |
|---|---|
| GLP1 receptor agonists | |
| Liraglutide [5,6] ● 9340 patients with T2DM and high cardiovascular risk | ● 13% reduction in MACE-3 ● 22% reduction in death from cardiovascular causes ● 15% reduction in all-cause mortality ● ↓ A1c −0.4% ● ↓ body weight 2.3 kg ● ↓ −1.2 mmHg systolic blood pressure ● 22% reduction in nephropathy events |
| Semaglutide [7] ● 3297 patients with T2DM, 83% had cardiovascular disease, chronic kidney disease, or both | ● 26% reduction in MACE-3 ● 26% reduction in nonfatal myocardial infarction ● 39% reduction in nonfatal stroke ● 36% reduction in new or worsening nephropathy ● No difference in cardiovascular or all-cause death ● ↓ A1c −1.1 to −1.4% ● ↓ body weight −3.6 to −4.9 kg ● 76% increase in retinopathy events ● ↓ −3.4 to −5.4 mmHg systolic blood pressure |
| Exenatide (sustained release) [8] ● 14,752 patients with T2DM with (73.1%) or without cardiovascular disease | ● 9% non-significant reduction in MACE-3 ● No difference in death from cardiovascular causes ● ↓ A1c −0.53% ● ↓ body weight −1.27 kg ● ↓ systolic blood pressure −1.57 mmHg |
| Lixisenatide [9] ● 6068 patients with T2DM and a recent coronary event | ● No significant difference in MACE-4 ● No significant difference in death from cardiovascular causes ● ↓ A1c −0.27% ● ↓ body weight −0.7 kg ● ↓ −0.8 mmHg systolic blood pressure |
| SGLT2 inhibitors | |
| Empagliflozin [12,13] ● 7020 patients with T2DM and high cardiovascular risk | ● 14% reduction in MACE-3 ● 38% reduction in death from cardiovascular causes ● 35% reduction in hospitalization for heart failure ● 32% reduction in all-cause mortality ● 39% reduction in new or worsening nephropathy ● ↓ A1c −0.24 to −0.36% at week 204 |
| Canagliflozin [14] ● 10,142 patients with T2DM and high cardiovascular risk | ● 14% reduction in MACE-3 ● No difference in cardiovascular or all-cause death ● 33% reduction in hospitalization for heart failure ● 40% reduction in composite renal outcomes ● ↓ A1c −0.58% ● ↓ body weight −1.60 kg ● ↓ −3.93 mmHg systolic blood pressure |
T2DM: type 2 diabetes; MACE-3: death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke; MACE-4: hospitalization for unstable angina, in addition to MACE-3 end points.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.