The Diabetologist: A Cardiologist’s new Best Friend? A brief look at the cardiovascular outcomes data of novel antihyperglycaemic therapies through an evolving relationship between two specialties
A Chequered Past
Diabetes and cardiovascular health have a long and intimate relationship. Cardiovascular disease is recognised as the most prevalent cause of morbidity and mortality in diabetics, with rates up to 5 times higher in diabetic women compared to the non-diabetic population (1).
The development of antihyperglycaemic therapies has long focussed on blood glucose-based measures of efficacy and has not always taken into account the effects on the cardiovascular system. One need not look too far back in time to identify therapies designed to improve diabetes related outcomes that were subsequently found, usually after marketing authorisation was granted, to engender deleterious cardiovascular consequences. Perhaps one of the most egregious examples in recent memory has been the thiazolidinedione class of drugs. In particular Rosiglitazone was shown to carry a significant risk of myocardial infarction compared to controls receiving no rosiglitazone, and a significant increase in the risk of MI, heart failure and death (2, 3). This resulted in Rosiglitazone being taken off the market in Europe.
Partly as a result of these events, the FDA mandated that all new antihyperglycaemic therapies should be evaluated for cardiovascular safety in dedicated randomised cardiovascular outcomes trials (CVOT) prior to approval. This has resulted in a plethora of studies which have largely shown neutral effects on CV outcomes (i.e. no harm).
The Acquaintance Stage
In brief, there are no placebo controlled randomised data to judge the effect of metformin on CV outcome, however data from the UKPDS study would suggest favourable effects on all-cause mortality and myocardial infarction rates (4, 5). The evidence is somewhat conflicting for sulphonylureas, with a large meta-analysis suggesting that they may be associated with increased risks of stroke and all-cause mortality (6). A more favourable option as second line therapy is now considered to be the DPP4 antagonists (sitagliptin, alogliptin, saxagliptin among others) which have a largely neutral impact on cardiovascular outcomes (7). Another addition to the antihyperglycaemic armamentarium are the GLP-1 agonists (exenatide, lixisenatide, liraglutide and semaglutide). These are injectable drugs which increase insulin secretion. They are also known as incretin mimetics and act via activation of the hormone Glucagon Like Peptide-1 receptor. Lixisenatide and exenatide have neutral effects on cardiovascular outcomes, are therefore safe, but confer no additional benefit beyond their effects related to glycaemic control and weight reduction.
The Friends Stage
The GLP-1 agonist liraglutide, on the other hand, has been tested in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (8). This study enrolled 9340 patients with type 2 diabetes (T2DM) and high cardiovascular risk (exemplified by age >50 and one or more coexisting cardiovascular disease or age >60 and one or more CV risk factors). Patients were randomised 1:1 to 1.8mg of liraglutide or placebo. The primary endpoint was a 3-point Major Adverse Cardiovascular Event (MACE) outcome (CV death, non-fatal MI, non-fatal stroke). There were also multiple pre-specified secondary outcomes including an expanded MACE (including heart failure or unstable angina related admission, and coronary revascularisation), all-cause mortality, as well as a microvascular outcome incorporating renal and retinal deterioration markers. The results were striking, and far exceeded expectations based on prior GLP-1 agonist trials. There was a significant reduction in the primary endpoint with liraglutide (HR 0.87, 95% CI=0.78 – 0.97, p=0.01 for superiority), as well as significant reductions in CV death (HR=0.78, 95% CI=0.66 – 0.93 p=0.007) and all-cause mortality (HR=0.85, 95% CI=0.74-0.97, p=0.02). Semaglutide (a longer acting once weekly GLP-1 agonist produced by the same company as liraglutide) has shown similar significant improvement in 3-point MACE (HR=0.74, p=0.02), driven largely by a reduction in non-fatal stroke (HR=0.61, p=0.04) that was not seen in LEADER (9). This trial however enrolled around 1/3 the number of patients and may therefore have been underpowered for the detection of CV death or MI signals.
The latest and most promising additions to the list of drugs available to treat diabetes are the Sodium Glucose Co-Transporter 2 inhibitors (SGLT2i). These are glycosuric agents which reduce blood glucose by preventing its tubular reabsorption resulting in a reduction in plasma glucose via urinary excretion.
The three most prominent members of the family are empagliflozin, canagliflozin and dapagliflozin. The first to report positive cardiovascular outcome data in a dedicated phase 3 CVOT was empagliflozin in the EMPA-REG OUTCOME study (10). The design of this study was similar to that of the LEADER trial. It randomised just over 7000 patients with T2DM and high cardiovascular risk to placebo, 10mg empagliflozin or 25mg empagliflozin. The primary endpoint was the same 3-point MACE outcome seen in LEADER, and there were prespecified secondary endpoints of MACE plus admission for unstable angina, heart failure admissions, and safety endpoints including renal deterioration.
Empagliflozin significantly reduced the primary endpoint (HR=0.86; 95% CI=0.74 to 0.99; P<0.001 for non-inferiority and P=0.04 for superiority), as well as heart failure hospitalisations (HR=0.65; 95% CI, 0.50 to 0.85; P=0.002), a benefit not seen in the LEADER trial. There were also significant reductions in all-cause mortality and cardiovascular mortality. Prespecified renal outcomes, reported separately to the main trial findings also revealed significant reduction in incident or worsening nephropathy (defined as progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) with a 5.1% absolute risk reduction (HR=0.61; 95% CI=0.53 to 0.70; P<0.001)(11).
Canagliflozin reported similar outcome in the CANVAS study, with a significant reduction in the primary outcome (HR=0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority), and similar beneficial effects on HF hospitalisation, and renal outcomes as those seen in EMPA-REG(12). Dapagliflozin is yet to report on its CVOT results, expected in 2019 (DECLARE trial).
Why do we feel this way?
Perhaps the most interesting difference between the LEADER and EMPA-REG trials is the timing of the separation of event curves. In LEADER, they separate well after the first year, whereas it only takes around 3 months to see the benefit from empagliflozin become apparent. The mechanism underlying the benefit with the SGLT2 inhibitors has not yet been completely elucidated, with a variety of opinions offered in the literature.
Two forms of the SGLT receptor exist - SGLT1 and SGLT2 - with the expression of the latter confined to the kidney and responsible for the reabsorption of 90% of filtered glucose in the proximal tubule. The inhibition of this receptor also reduces the reabsorption of sodium which is co-transported with glucose, and therefore also results in a natriuresis. SGLT2 inhibition therefore produces many non-hypoglycaemic effects which have been proposed as candidates for the benefits seen in clinical trials of these agents.
Haemodynamic effects which may be related to the diuretic effect of this class of drugs include blood pressure (BP) lowering. A mean drop in systolic BP (SBP), of around 4mmHg was seen in EMPA-REG and similar degree of BP lowering was demonstrated in CANVAS. We know from previous studies of antihypertensive therapies that BP reduction has beneficial effects on cardiovascular risk and development of heart failure. However, the expected benefit of BP lowering on stroke and thrombotic events seen in previous BP-lowering trials however was not readily apparent in EMPA-REG where rates of myocardial infarction and stroke were not significantly lower than in the comparator arm. This discrepancy casts some doubt on BP lowering as the sole mechanism responsible for the CV benefit of SGLT2 inhibitors.
The glycosuric and natriuretic effect of these agents also results in a diuresis and associated plasma volume contraction. This is reflected in a rise in haematocrit seen even after short term therapy which persists despite a fall after initial stimulation of erythropoietin production (13). There has been some speculation that this may account for a normalisation of plasma volume in patients who are subclinically overloaded, which may go some way toward explaining the improvement seen in heart failure hospitalisations.
Uric acid has emerged as a risk factor for cardiovascular disease. It is associated with endothelial dysfunction, increased oxidative stress, increased vascular stiffness, and has been linked to insulin resistance, hypertension, renal and cardiovascular disease (14). Clinical trials testing whether it’s therapeutic reduction engenders an improvement in hard CV outcomes are still lacking however. The ability of SGLT2 inhibitors to reduce serum uric acid levels has been suggested as a possible mechanism responsible for some of the benefit seen in the trials.
There are yet further potential mechanisms described for the benefit of SGLT2 inhibitors, such as their effect on weight loss, calorie loss through glycosuria, glucagonergic activity, and increased lipolysis. Whilst all plausible, it seems unlikely that any one of these may be responsible in isolation for the beneficial effects of these drugs on cardiovascular health (15).
Happily ever after?
The addition of SGLT2 inhibitors to the armamentarium of antihyperglycaemic medications is certainly welcome, and their beneficial effects on hard cardiovascular outcomes propels them to the top of the list of choices for second line therapy in patients with high cardiovascular risk. This means that as practicing cardiologists we should be familiar with their indications, contraindications, dosing, side effects and local availability as it will become increasingly part of our role to instigate such therapies where patients would clearly benefit from them. Time to develop a close relationship with your friendly neighbourhood diabetologist!
- Leon BM, Maddox TM. Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research. World journal of diabetes. 2015;6(13):1246-58.
- Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes'. New England Journal of Medicine. 2007;356(24):2457-71.
- Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. Jama. 2010;304(4):411-8.
- Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405-12.
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998;352(9131):854-65.
- Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: a meta-analysis of randomized clinical trials. Diabetes, Obesity and Metabolism. 2013;15(10):938-53.
- Kumar R, Kerins DM, Walther T. Cardiovascular safety of anti-diabetic drugs. European Heart Journal - Cardiovascular Pharmacotherapy. 2016;2(1):32-43.
- Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2016;375(4):311-22.
- Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine. 2016;375(19):1834-44.
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2015;373(22):2117-28.
- Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. The New England journal of medicine. 2016;375(4):323-34.
- Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England journal of medicine. 2017;377(7):644-57.
- Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes, obesity & metabolism. 2013;15(9):853-62.
- Chaudhary K, Malhotra K, Sowers J, Aroor A. Uric Acid - key ingredient in the recipe for cardiorenal metabolic syndrome. Cardiorenal medicine. 2013;3(3):208-20.
- Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016;134(10):752-72.