Cardiorenal effects of therapies for type 2 diabetes and obesity

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are established glucose-lowering and weight-lowering agents used in the management of type 2 diabetes mellitus and obesity. Several recent clinical trials have provided evidence that these agents can decrease the risk of, and slow progression of, cardiovascular and renal diseases independently of their glucose-lowering and weight-lowering effects. In clinical trials and ‘real-world’ observational studies in people with and without diabetes, SGLT2 inhibitors have offered protection against heart failure and chronic kidney disease, while GLP-1 receptor agonists have been associated with reductions in atherosclerotic cardiovascular events and albuminuria. Based on this evidence, SGLT2 inhibitors and GLP-1 receptor agonists can now be considered for use beyond diabetes and obesity as new treatment options in the management of cardiorenal disease.

Introduction

Recent updates to guidelines for the management of type 2 diabetes (T2DM) have emphasised the importance of addressing cardiorenal risk and weight control, in conjunction with blood glucose regulation.^1–4 All guidelines remain committed to lifestyle interventions (diet, physical activity and behavioural changes) as foundational therapy to be introduced at diagnosis, optimised and continued life-long. However, the progressive nature of T2DM typically requires the addition and dose-escalation of one or more blood glucose-lowering agents to achieve and maintain adequate glycaemic control.⁵ Several of the newer glucose-lowering agents have shown sufficient weight-reducing potency that they have been adopted for the treatment of obesity in people without diabetes.^6,7 Also, some of these agents have shown cardioprotective and renoprotective effects that are independent of their glucose-lowering and weight-lowering effects.⁸ This narrative account summarises key evidence concerning the cardiorenal effects of glucose-lowering therapies, and notes opportunities for their use in people with and without T2DM or obesity.

Type 2 diabetes

Many different combinations of genetic and environmental factors conspire to impair insulin sensitivity (i.e. cause insulin resistance) and disrupt insulin secretion by pancreatic beta-cells, giving rise to the hyperglycaemia of T2DM (figure 1).⁹ Obesity and chronic low-grade inflammation aggravate insulin resistance during the prodromal (prediabetes) period, and the hyperinsulinaemia that initially compensates for insulin resistance exerts damaging sequelae on the vasculature and stress on pancreatic beta-cell function. The glucotoxic effects of persistent hyperglycaemia underpin the characteristic microvascular (chronic kidney disease [CKD] and retinopathies) and neuropathic complications of T2DM, while the broader metabolic disturbances (especially dyslipidaemia) plus insulin resistance contribute to the cardiovascular (CV) risk.¹⁰ The CV risk, in turn, adds to the renal risk, and vice versa.¹¹ Accordingly, preference is now given to treatment strategies for T2DM that can directly address the cardiorenal risk, alongside the control of blood glucose and body weight.

The main glucose-lowering agents that offer cardiorenal protective properties with weight restraint/loss are metformin, sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists (table 1).¹² Other glucose-lowering agents continue to receive extensive and effective use in the management of T2DM, notably dipeptidyl-peptidase-4 (DPP4) inhibitors, pioglitazone and sulfonylureas, but these agents are more often used as second-line and third-line glucose-lowering therapies as they offer lesser or uncertain CV benefits (figure 2 and supplementary table 1).

Metformin

Metformin is the most commonly used first-line glucose-lowering agent for people with T2DM.¹³ This agent is usually continued throughout the clinical course of T2DM, unless renal function falls below an estimated glomerular filtration rate (eGFR) of 30 ml/min/1.73 m². Metformin counters insulin resistance and lowers blood glucose without precipitating overt hypoglycaemia, and can assist modest weight reduction and lowering of CV risk. As a long-established antidiabetic therapy (dating from 1957) with a respected safety profile, metformin has not been subjected to the recent large CV outcome trials (CVOTs) that have assessed major adverse cardiac events (MACE: CV deaths, non-fatal myocardial infarction [MI] and stroke) for more recently approved antidiabetic medications. However, extensive long-term use of metformin has provided substantial evidence to support its established use as a first-line therapy.¹⁴ It is also noted that the majority of patients with T2DM in the CVOTs were taking the newer agent as an add-on to metformin therapy.

Key evidence regarding metformin emerged in the United Kingdom Prospective Diabetes Study (UKPDS). This was a prospective randomised trial that found relative risk reductions in MI (by 39%), diabetes-related deaths (by 42%) and all-cause mortality (by 36%) after 10 years of treatment with metformin in overweight and obese newly diagnosed T2DM.¹⁵ These reductions were largely retained after 10 years of post-trial follow-up (by 33%, 30% and 27%, respectively, for MI, diabetes deaths and all-cause mortality).¹⁶ Other long-term prospective trials in T2DM have also noted fewer major CV events with metformin, and many long-term observational studies have corroborated these findings.¹⁷ For example, two meta-analyses of 16 and 40 observational studies found metformin reduced all-cause mortality by 56% and 33%, respectively.^18,19 Two meta-analyses of nine and 11 observational studies involving T2DM patients with heart failure found that metformin was associated with reduced all-cause mortality by 20% and 22%, respectively.^20,21

The CV effects of metformin appear to be largely independent of glycaemic and weight control. They have been attributed to modest improvements in endothelial-mediated vascular reactivity and decreased atherogenesis linked to reduced insulin resistance and an improved lipid profile.¹⁷ Regarding atherogenesis, metformin has been reported to reduce chronic inflammation, decrease endothelial production of attractant and adhesion molecules, reduce monocyte infiltration and foam cell formation, reduce oxidative stress and reduce hyperinsulinaemia.¹⁷ Additional, and often overlooked, effects of metformin include reduced hypercoagulation and improved thrombolysis associated with decreased platelet aggregation, altered fibrin polymerisation and reduced plasminogen-activator inhibitor-1 (PAI-1).^22,23 Metformin has little effect on blood pressure beyond small reductions consistent with decreases in adiposity, and its impact on CV events has typically taken several years to emerge in the various studies. Also, it is reminded that metformin should not be continued in severe hypoxaemic disease.

The renal effects of metformin are often misrepresented. Metformin is eliminated unchanged in the urine, so use of metformin requires adequate renal function to prevent drug accumulation, which carries the risk (albeit rare) of lactic acidosis.¹⁴ Although metformin should be discontinued if renal function is severely impaired (eGFR <30 ml/min/1.73 m²), metformin does not harm the kidney and has been reported to reduce the risk or progression of kidney damage in diabetes.^24,25 Metformin is best taken just before main meals with gradual dose titration to avoid/minimise gastrointestinal side effects, and it is noted that metformin has been reported to offer potential benefits against some cancers, age-related cognitive decline and certain infections.²⁶

SGLT2 inhibitors

Since their introduction in 2012, SGLT2 inhibitors have become established blood glucose-lowering and body weight-lowering agents in the management of T2DM.^12,27 They act as competitive inhibitors of SGLT2 in the proximal renal tubules, reducing glucose reabsorption from the renal filtrate and lowering blood glucose through increased glucosuria. The caloric deficit of the glucosuria (typically 60–100 g/day) enables the weight loss, while reductions in glucotoxicity and adiposity reduce insulin resistance and insulin concentrations. SGLT2 inhibitors do not cause overt hypoglycaemia because another sodium-glucose cotransporter (SGLT1) in the proximal tubules can reabsorb all of the glucose that remains in the filtrate at low glucose concentrations.

In addition to these metabolic effects, SGLT2 inhibitors afford cardiorenal protective benefits (figure 2).^28–30 In a meta-analysis of large prospective CVOTs in T2DM patients, about two-thirds of whom had a history of atherosclerotic CV disease (ASCVD) (supplementary table 2), SGLT2 inhibitors reduced the risk of MACE by 10%, CV death by 15% and hospitalisation for heart failure (hHF) by 32%.³⁰ While the reductions in MACE and CV death were statistically significant for those with ASCVD (11% and 17%, respectively), the numerical reductions in these events did not achieve statistical significance for those without ASCVD (6% and 5%, respectively). However, the reduction in hHF was highly significant for those with and without ASCVD (30% and 37%, respectively) and was evident within a few weeks of SGLT2 inhibitor initiation in individuals with a history of HF (supplementary table 3). Other analyses have confirmed these findings and reported all-cause mortality to be reduced by 13%.³¹ As noted above, the vast majority of patients in these trials were already taking metformin, but subanalyses indicate similar reductions in hHF occurred among those not taking metformin.³² Also, reductions in hHF were evident across a range of ejection fractions (HFrEF, HFmrEF, HFpEF) and in chronic kidney disease (CKD), and did not correlate with the extent of glucose-lowering or weight-lowering.³³ This prompted further studies with two SGLT2 inhibitors (empagliflozin and dapagliflozin), which found reductions in hHF and CV death (by ~10–30%) in individuals without diabetes, and these agents now have broadened indications to include treatment of symptomatic chronic HF. Ongoing studies are assessing how the effects on HF are affected by ASCVD.^29,34–36

The improved HF prognosis with use of SGLT2 inhibitors is ascribed, in part, to their antihypertensive action, which is associated with volume contraction due to the osmotic diuresis induced by the glucosuria. It is also suggested that the caloric deficit of glucosuria, which is compensated by mobilisation of fatty acids from adipose tissue, can improve myocardial energetics through increased supply of fatty acids and ketones.^37,38 Direct effects of SGLT2 inhibitors on myocardial function, and reductions in inflammation and oxidative stress are further proposed mechanisms that reduce CV risk.^37,38

A particularly advantageous feature of SGLT2 inhibitors is their protective effects against CKD.^30,39 The onset and progression of CKD, as indicated by the decline in eGFR, is hastened in T2DM, but slowed during use of a SGLT2 inhibitor. This is typically accompanied by a reduction in albuminuria, and there are reports of reductions in some markers of kidney injury, renal inflammation and tubulointerstitial fibrosis.⁴⁰ The nephro-protective effect of SGLT2 inhibitors has been noted at all stages of renal impairment and has prevented progression to end stage renal failure (supplementary table 4). For example, the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) study in T2DM patients with an eGFR 30–90 ml/min/1.73 m² and a urinary albumin–creatinine ratio (UACR) of 300–5000 mg/g, prospectively compared the SGLT2 inhibitor canagliflozin with placebo. Canagliflozin slowed the annual decline in eGFR by 1.5 ml/min/1.73 m² (4.7 vs. 3.2 ml/min/1.73 m² in the placebo and canagliflozin groups, respectively) and reduced UACR by ~30% (~900 vs. ~600 mg/g in the placebo and canagliflozin groups, respectively).⁴¹ Other studies have noted similar effects on renal function in people with and without diabetes,^30,42,43 and various SGLT2 inhibitors are now approved to treat CKD in nondiabetic patients.

The nephro-protective effect of SGLT2 inhibitors is mostly attributed to increased tubuloglomerular feedback, in which SGLT2 inhibition in the proximal tubule increases sodium passage along the nephron. Raised tubular sodium activates cells of the macula densa to promote the formation of adenosine, which diffuses locally and constricts adjacent afferent glomerular arterioles. The resulting decrease in intraglomerular pressure reduces hyperfiltration-mediated glomerular damage.^44,45 Other effects of SGLT2 inhibitors on renal haemodynamics and energy substrate utilisation by the kidney have also been suggested.

For practical purposes, it is noted that eGFR will quickly fall by about 5 ml/min/1.73 m² on initiation of a SGLT2 inhibitor, then level out and often gradually return over three to six months. Thus, although some SGLT2 inhibitors are approved to specifically treat CKD, their initiation is not recommended at an eGFR <20–25 ml/min/1.73 m². It is useful to remind patients about possible urinary infections and to maintain adequate fluid intake.^30,39

GLP-1 receptor agonists

GLP-1 receptor agonists (introduced in 2005) mimic the incretin effect, in which blood glucose concentrations are lowered by potentiating nutrient-induced insulin secretion.⁴⁶ These agents also suppress glucagon secretion when glucose concentrations are raised, but not at low glucose concentrations, thus avoiding overt hypoglycaemia. Additionally, GLP-1 receptor agonists delay gastric emptying and exert a centrally mediated satiety effect, thereby facilitating weight loss.^12,27 As peptide molecules, GLP-1 receptor agonists are expensive and administered by subcutaneous injection (although semaglutide is also available as an oral formulation), making them generally preferred as second-line or third-line agents for overweight/obese T2DM patients. Several members of the class exert particularly potent weight-loss effects, and high-dose formulations of these agents (liraglutide and semaglutide) and a related incretin-based peptide (tirzepatide) have received indications specifically to treat obesity.^47,48

CVOTs conducted with GLP-1 receptor agonists in individuals with T2DM have produced numerical reductions in MACE, which have achieved statistical significance with some agents (figure 2 and supplementary table 5). Also, various components of MACE have been significantly reduced in these trials, but without a consistent pattern. In a meta-analysis of eight CVOTs, GLP-1 receptor agonists reduced the risk of MACE by 14%, CV death by 13%, all-cause mortality by 12% and hHF by 11%.⁴⁹ Similar findings have been reported with other analyses that have included randomised and ‘real-world’ observational studies, and several studies have indicated significant reductions in non-fatal stroke and MI.^50–52 The reductions in MACE and CV death achieved with GLP-1 receptor agonists in T2DM patients have been marginally greater among those with (rather than without) established CV disease, and appear to be largely independent of concurrent treatment with metformin or the extent of glucose-lowering and weight-lowering.⁵¹ Indeed, reductions in MACE have been observed during the use of GLP-1 receptor agonists in overweight/obese people without T2DM.^48,53,54

Receptors for GLP-1 are expressed by cardiomyocytes and endothelium, and GLP-1 receptor agonists have consistently reduced blood pressure in clinical trials. This has been attributed to a modest vasodilatory effect due, in part, to increased endothelial nitric oxide production, reduced angiotensin II production and, possibly, increased natriuresis.⁵⁵ While this evidently helps to reduce atherogenesis, improves coronary perfusion and the myocardial microcirculation, GLP-1 receptor agonists may also act directly on myocardial cells to enhance nutrient metabolism and reduce oxidative stress.⁵⁶

Assessment of renal function during the CVOTs, and other studies with GLP-1 receptor agonists, have consistently identified reductions in the onset and progression of albuminuria (supplementary table 6). Significant reductions in micro- and macro-albuminuria (typically UACR less than and more than 300 mg/g, respectively) have also been recorded in most of the studies with each of the various agents.^51,57,58 For example, a meta-analysis of 27 studies found an overall 16% reduction in albuminuria in patients with T2DM, and efficacy was seen across the spectrum of CKD down to eGFR 15 ml/min/1.73 m².⁵⁷ Although undoubtedly assisted by improved control of blood glucose and body weight, the renal effects of GLP-1 receptor agonists were not closely correlated with the extent of glucose-lowering and weight-lowering, and appeared to be largely independent of the concurrent use of other glucose-lowering agents (except insulin). However, reductions in albuminuria were generally greater in individuals with a higher baseline systolic blood pressure (>130 mmHg), and it is these individuals who typically achieve a greater reduction of blood pressure during GLP-1 receptor agonist therapy. However, no association with any particular type of concurrent antihypertensive therapy was observed. Various composite measures of renal function, including changes in eGFR, progression to end-stage renal disease and cardiorenal mortality, have been reported in trials with GLP-1 receptor agonists. These have not shown consistent benefits, although some studies have noted a reduced rate of decline in eGFR.^51,59 In the recently reported FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial, administration of semaglutide (1 mg weekly for 3.4 years) to T2DM patients with CKD (eGFR 25–75 ml/min/1.73 m² and UACR >100 mg/g) reduced a renal composite of kidney failure (dialysis, transplantation or eGFR <15 ml/min/1.73 m²) or >50% decrease in eGFR or renal/CV death by 24%, and showed a reduced rate of decline in eGFR by 1.16 ml/min/1.73 m².⁵⁹

While the renal benefits of GLP-1 receptor agonists are primarily ascribed to reduced blood pressure and accompanying control of glycaemia and weight, it is noted that GLP-1 receptors are expressed by cells in the glomerulus and cortical segments of the renal tubules, and direct effects to reduce local inflammation, renal hypoxia and fibrosis have been suggested.⁶⁰ In routine practice, once-weekly subcutaneously injected GLP-1 receptor agonists are now used more commonly than daily injections, and the dose is escalated slowly (as per product label) to minimise gastrointestinal side effects. Also, caution or discontinuation should be considered at eGFR 15–30 ml/min/1.73 m², depending on the agent used.

Other glucose-lowering agents

The recently approved incretin-based dual agonist peptide, tirzepatide, activates receptors for GLP-1 and for glucose-dependent insulinotropic polypeptide (GIP), and has shown greater glucose-lowering and weight-lowering effects than current agonists of GLP-1 receptors alone.⁶¹ Initial evidence indicates that this dual agonist exerts similar or greater cardiorenal protective properties compared with agonists of GLP-1 receptors alone.^48,62,63 Other dual receptor agonists for GIP/GLP-1 and glucagon/GLP-1 are advanced in development, as well as triple receptor agonists for GIP/GLP-1/glucagon and a combination of a GLP-1 receptor agonist with an amylin analogue.⁴⁸ While the metabolic and cardiorenal effects of GLP-1 receptor agonists and SGLT2 inhibitors are well studied in combination with metformin, recent evidence suggests that the combination of a GLP-1 receptor agonist with a SGLT2 inhibitor can achieve greater decreases in blood glucose, body weight and blood pressure, with lower risk of MACE or serious renal events, than either alone.^64–67

In current practice, there is still considerable reliance on other established glucose-lowering therapies in the management of T2DM, notably DPP4 inhibitors, sulfonylureas and pioglitazone.⁵ Many studies have affirmed the glucose-lowering efficacy of DPP4 inhibitors without causing overt hypoglycaemia, and often with some weight loss. DPP4 inhibitors have a good safety profile, but they have not shown significant cardiorenal benefits independently of glucose and weight control.¹² Sulfonylureas are widely used in more severely hyperglycaemic individuals: they offer strong glucose-lowering efficacy for individuals who retain adequate beta-cell function. However, they are prone to cause weight gain and carry the risk of hypoglycaemia, and evidence for independent cardiorenal benefit remains inconclusive. Beyond its glucose-lowering effect, pioglitazone has been shown to improve the blood lipid profile, counter atherogenesis and reduce risk of stroke. However, weight gain, oedema, potential risk or aggravation of HF and other putative long-term safety concerns have limited usage.^5,12

Impact on guidelines

As noted above, all guidelines for the management of T2DM emphasise the importance of lifestyle (diet, physical activity and behavioural changes) as foundational therapy, and present iterations of these guidelines have taken note of the cardiorenal effects of SGLT2 inhibitors and GLP-1 receptor agonists. Whereas metformin remains a preferred first-line pharmacotherapy for individuals without cardiorenal disease (‘glucocentric approach’), SGLT2 inhibitors and GLP-1 receptor agonists are now included as potential first-line pharmacotherapy for individuals who present with established cardiorenal disease or who are considered to be at particularly high risk (‘cardiorenal approach’) (figure 3).^1–4 GLP-1 receptor agonists have shown greater benefits against ASCVD than SGLT2 inhibitors, whereas SGLT2 inhibitors have shown greater benefits against HF and CKD: thus, current guidelines are favouring early use of GLP-1 receptor agonists for patients with (or at particularly high risk of) ASCVD, while preference for early use of a SGLT2 inhibitor is given to patients with HF and/or CKD.^1–4 Combination of two or more differently acting glucose-lowering agents is commonly required as T2DM progresses, and insulin may be required as part of combination therapy for severely hyperglycaemic and symptomatic patients. Avoidance of medication-induced hypoglycaemia and attention to weight control are important considerations throughout. Now that some glucose-lowering agents are indicated for use beyond the control of blood glucose and body weight, they provide new opportunities for use in the management of cardiovascular and renal disease in nondiabetic individuals.^68–70 Moreover, expert groups have recently proposed interdisciplinary clinical recommendations that include SGLT2 inhibitors and GLP-1 receptor agonists within prevention and treatment strategies against a broad spectrum of conditions, including obesity, metabolic syndrome, prediabetes, diabetes, hypertension, ASCVD, CKD, and HF.^71,72

Conclusion

Over the past two decades, the initial pharmacological management of hyperglycaemia in T2DM has been focused mostly on metformin, as it lowers blood glucose without causing overt hypoglycaemia, without weight gain and with long-term benefits to reduce cardiovascular events and mortality. SGLT2 inhibitors and GLP-1 receptor agonists are also now established glucose-lowering agents that avoid overt hypoglycaemia, and these agents offer the advantage of weight reduction plus protection against a range of cardiovascular and renal comorbidities and complications, including ASCVD, HF and CKD. Recent studies have shown that the cardiorenal effects of SGLT2 inhibitors and GLP-1 receptor agonists are substantially independent of their glucose-lowering and weight-lowering properties, and are evident in people without diabetes. Thus, SGLT2 inhibitors and GLP-1 receptor agonists present new therapeutic opportunities for cardiologists and nephrologists beyond diabetes and obesity.

Key messages

• Sodium-glucose cotransporter type 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are glucose-lowering and weight-lowering agents used in the management of type 2 diabetes mellitus and obesity
• SGLT2 inhibitors can also offer protection against the onset and progression of heart failure and chronic kidney disease in people with and without diabetes
• GLP-1 receptor agonists have been reported to reduce atherosclerotic cardiovascular events and albuminuria in people with and without diabetes
• SGLT2 inhibitors and GLP-1 receptor agonists may be considered for use beyond diabetes and obesity as treatment options in the management of cardiorenal disease

Conflicts of interest

None.

Funding

None.

Editors’ note

Supplementary tables are available online.

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