Pumps, Pipes, and Filters: SGLT2 Inhibitors for Most Type 2 Diabetes?

November 23, 2018

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors should be considered for use in most patients with type 2 diabetes regardless of presence of atherosclerotic cardiovascular disease or history of heart failure, according to the authors of a new meta-analysis of the three major cardiovascular outcomes trials with these drugs.

The meta-analysis was conducted by a group led by Thomas A. Zelniker, MD, of Brigham and Women's Hospital, Boston, Massachusetts.

It includes data from the EMPA-REG OUTCOME trial with empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), the CANVAS program with canagliflozin (Invokana, Janssen), and the DECLARE-TIMI 58 trial with dapagliflozin (Farxiga/Forxiga, AstraZeneca), with a total of 34,322 patients (60.2% with established atherosclerotic cardiovascular disease), 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalizations for heart failure events, and 766 renal composite outcomes.

The meta-analysis was published online on November 10 in The Lancet.

Results show that across the three trials, SGLT2 inhibitors reduced major adverse cardiovascular events by 11% (hazard ratio [HR], 0.89; 95% CI, 0.83 - 0.96), with benefit only seen in patients with atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80 - 0.93) and not in those without (HR, 1.00; 95% CI, 0.87 - 1.16). 

But the SGLT2 inhibitors also reduced the risk of cardiovascular death or hospitalization for heart failure by 23% (HR, 0.77; 95% CI, 0.71 - 0.84), with a similar benefit in patients with and without atherosclerotic cardiovascular disease, and with and without a history of heart failure.

The drugs also reduced the risk of renal disease progression by 45% (HR, 0.55; 95% CI, 0.48 - 0.64), with a similar benefit in those with and without atherosclerotic cardiovascular disease.

The magnitude of benefit of SGLT2 inhibitors varied with baseline renal function, with greater reductions in hospitalizations for heart failure and lesser reductions in progression of renal disease in patients with more severe kidney disease at baseline.

"These data suggest that SGLT2 inhibitors should be considered in patients with type 2 diabetes regardless of presence of atherosclerotic cardiovascular disease or history of heart failure, given that SGLT2 inhibitors safely reduce HbA1c and reduce the risk of hospitalization for heart failure and progression of renal disease across a broad spectrum of patients with type 2 diabetes," the authors conclude.

And, they stress, "Reductions in major adverse cardiovascular events can also be expected in patients with established atherosclerotic cardiovascular disease."

In an accompanying editorial, Subodh Verma, MD, of St Michael's Hospital, Toronto, Ontario, Canada, and colleagues, say the meta-analysis "provides compelling evidence that SGLT2 inhibitors should now be considered as first-line therapy after metformin in most people with type 2 diabetes, irrespective of whether or not they have established atherosclerotic vascular disease, chronic kidney disease, or heart failure."

The editorialists suggest that separation of primary versus secondary prevention may not be appropriate in patients with diabetes.

Totality of Data Makes Several Patterns Clear, Helps Elucidate Mechanism

"The totality of these data now makes several patterns clear," say Zelniker and colleagues in their article.

"First, SGLT2 inhibitors have their greatest and most consistent effect on reducing the relative risk of hospitalization for heart failure (31%) and of progression of renal disease (45%)."

"Their effect on the composite atherosclerotic outcome of myocardial infarction, stroke, or cardiovascular death (major adverse cardiac events), originally a safety outcome stemming from regulatory guidance, was more modest but still significant, with an 11% reduction in relative risk."

"Second, for particular outcomes the clinical effects of SGLT2 inhibitors depend on the patient population in which they are used."

"The reduction in major adverse cardiac events was apparent only in patients with established atherosclerotic cardiovascular disease, whereas no effect was observed in patients without atherosclerotic cardiovascular disease."

Conversely, "the reduction in hospitalization for heart failure was robust and of similar magnitude regardless of the presence of established atherosclerotic cardiovascular disease or a history of heart failure. The reduction in progression of renal disease was also equally robust in patients with and without atherosclerotic cardiovascular disease."

Zelniker and colleagues also say these latest data help elucidate the mechanism of action of these drugs.

"Our data suggest that the renoprotective effects of SGLT2 inhibitors coupled with the natriuresis they induce might largely explain the reduction in hospitalization for heart failure."

Patients with lower estimated glomerular filtration rate (eGFR) at baseline are at an increased risk of hospitalization for heart failure, they explain.

"Therefore, renoprotection and natriuresis induced by SGLT2 inhibitors could be of particular benefit in this susceptible population."

Reductions in both the progression of kidney disease and hospitalization for heart failure and their attendant interventions and downstream complications might then reduce the risk of both cardiovascular and all-cause death, they theorize.

However, "the beneficial effect on myocardial infarction remains a topic of active investigation."

"By and Large" Results Were Consistent Across Three Trials

They further note that "by and large" the results were consistent between the three different trials of SGLT2 inhibitors.

However, in patients with atherosclerotic cardiovascular disease, the effect of empagliflozin on cardiovascular death was more pronounced than that of canagliflozin or dapagliflozin, and an increased risk of amputations and fractures was only seen with canagliflozin.

"Although it is theoretically possible that drug-specific differences in effects exist within this class, other possibilities should be considered," they write, adding that "multiple differences were found in the patient characteristics in each trial that might explain the observed variations with regard to cardiovascular death, and subgroup analyses by one variable might not fully capture other important differences."

On the safety of these drugs, the authors state: "Overall, SGLT2 inhibitors are well tolerated and generally safe drugs, although patients have an increased risk of mycotic genital infections, which are usually easily managed and uncommonly recur."

SGLT2 inhibitors do appear to increase the risk of diabetic ketoacidosis, but the rates were very low and risk can be reduced with proper patient education and vigilance.

"Also, initial concerns about safety signals for stroke were not supported in the present meta-analysis. An increased risk of amputation and fracture was seen only in one trial."

Numbers Needed to Treat, Call for Cost-Effectiveness Studies

In their editorial, Verma and colleagues say the separation of primary versus secondary prevention may not be appropriate in type 2 diabetes because this distinction "is entirely based on atherosclerotic risk and not risk of hospitalization for heart failure or renal disease."

And this meta-analysis indicates that, irrespective of atherosclerotic vascular disease, declining renal function is strongly associated with hospitalization for heart failure and renal disease progression, "outcomes uniquely sensitive to SGLT2 inhibitor therapy," they emphasize.

"We therefore propose that whereas the nomenclature of primary versus secondary prevention is appropriate for atherosclerotic outcomes, it is likely to be inappropriate for a person with type 2 diabetes who is at risk of hospitalization for heart failure and renal disease."

They note that the latest American Diabetes Association/European Association for the Study of Diabetes joint position statement has prioritized the use of SGLT2 inhibitors in people with atherosclerotic vascular disease, heart failure, or chronic kidney disease.

But they propose that these drugs should be considered in an even broader population of people with type 2 diabetes and multiple risk factors, which they say is supported by the current meta-analysis.

The editorialists calculate that from the available analyses, the absolute risk reductions over 5 years are estimated to be about 0.8% for hospitalization for heart failure and about 1.4% for renal disease progression in patients with multiple risk factors, which would yield numbers needed to treat of 124 to prevent one hospitalization for heart failure and 73 to prevent one episode of renal disease progression over 5 years.

"Some might argue that the economic effect of preventing hospitalization for heart failure and transition to end-stage renal disease is much greater than preventing a nonfatal myocardial infarction or stroke, and formal cost-effectiveness analyses in this regard will be instructive," they conclude.

Zelniker reports research grants to his institution from AstraZeneca and grants from Bristol-Myers Squibb during the conduct of the study. Verma has received research support and honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Janssen, Merck, and Novo Nordisk. Disclosures for the other authors are listed with the article.

Lancet. Published online November 10, 2018. Abstract, Editorial

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