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Cardiovascular Protective Actions of Sodium GlucoseCotransporter 2 Inhibitors
  JOHTN
CARDIO-DIABETES
Cardiovascular Protective Actions of Sodium Glucose
Cotransporter 2 Inhibitors
Shamanna S Iyengar
Consultant
Department of Cardiology, Manipal Hospitals, BengaluruKarnataka, India
Corresponding Author: Shamanna S Iyengar, ConsultantDepartment of Cardiology, Manipal Hospitals, BengaluruKarnataka, India
e-mail: ssiyengar1945@gmail.com
 
"Current management of diabetes is characterized byopportunities, options, and obstacles."
-Dr Sanjay Kalra
(2014)

ABSTRACT
Diabetes mellitus is a major health problem in our country, andthe prevalence is on the increase. Cardiovascular complicationsare the commonest causes of mortality and morbidity in patientswith type II diabetes mellitus. Diabetes may not be a coronaryartery disease (CAD) equivalent, but it certainly carries a highrisk for atherosclerotic cardiovascular disease (CVD). There areeffective drugs to treat hyperglycemia, and these drugs may behaving adverse effects or advantageous outcomes on CVD, orthey may be neutral. While developing antidiabetic drugs, it hasbecome necessary to study their effect on CVD and outcome.
Among the newer antidiabetic drugs, sodium glucosecotransporter 2 (SGLT2) inhibitors have exhibited impressivecardiovascular benefits. Various mechanisms have beenproposed to explain their improved cardiovascular outcome.They are not without adverse effects. There are a numberof SGLT2 inhibitor preparations, and it is debatable whetherthis cardiovascular benefit is a class effect or individual drugspecific. These newer antidiabetic drugs are looking beyondblood sugar control.
Keywords: Cardioprotective antidiabetic drugs, Heart anddiabetes, Sodium glucose cotransporter 2 inhibitors.
How to cite this article: Iyengar SS. Cardiovascular ProtectiveActions of Sodium Glucose Cotransporter 2 Inhibitors.Hypertens J 2017;3(3):161-165.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

In a highly informative article with a catchy phraseembedded in the title, "Nations within a nation," providingestimates of 333 diseases and 84 risk factors fromdifferent states of India, covering the period from 1990to 2016, it has been reported that CVD and diabetesaccounted for 15.9 and 8.9% of the disability-adjusted lifeyears respectively.1
 
Diabetes is highly prevalent and is potentially anepidemic in India with more than 62 million individualsdiagnosed to have type II diabetes.2,3

Diabetic state poses serious problems with microvascularand macrovascular complications. There is astrong relationship between CVD and diabetes, CVDaccounting for most of the mortality and morbidityamong type II diabetic patients. Adults with diabetes aretwo to four times more likely to die from heart diseasethan adults without diabetes. At least 68% of the diabeticpeople in the age group 65 years or older die of heartdisease and 16% die of stroke.4 Haffner et al5 stated thatpatients with type II diabetes without a previous historyof myocardial infarction have the same risk of CADas nondiabetic subjects with a history of myocardialinfarction. However, this claim has been challengedby subsequent studies. A systematic review and metaanalysisshowed that patients with diabetes without priormyocardial infarction have a 43% lower risk of CAD ascompared with patients without diabetes with previousmyocardial infarction.6 A population-based prospectivecohort analysis concluded that all diabetics should notbe considered to be at a risk equivalent to that of patientshaving prior CAD.7

The increased risk of CVD in diabetics is thought tobe due to hyperglycemia and the consequent intracellularmetabolic changes resulting in oxidative stress, low-gradeinflammation, and endothelial dysfunction. Generally,diabetics have associated comorbidities like obesity,hypertension, and dyslipidemia, which contribute to anincreased risk for CVD.8

The benefit of lowering blood sugar levels in diabeticshas been well established in the UK Prospective DiabetesStudy trial.9 With a number of antidiabetic drugs availablenow, it has become necessary that cardiologists getthemselves familiar with antidiabetic drug classes thathave cardiovascular benefits.10

In view of this complex issue of diabetic treatmentand cardiovascular risk, regulatory agencies have madeit mandatory to produce evidence based on adjudicatedoutcomes from clinical trials that there is cardiovascularbenefit or that the risk of cardiovascular harm is lowfor all new glucose-lowering therapies before a drug ismade available, and usually also require a postmarketingcardiovascular safety trial.

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Shamanna S Iyengar

SODIUM GLUCOSE COTRANSPORTER
2 INHIBITORS


The SGLT2 inhibitors have brought in some encouragingnews, brightening up the field of the depressive reportsof antidiabetic drugs in the past. Other drugs that haveshown cardiovascular benefits are metformin, pioglitazone,and glucagon-like peptide-1 receptor agonists. TheSGLT2 inhibitors are unique antidiabetic drugs, and byinhibiting SGLT2 in the proximal convoluted tubuleprevent re-absorption of glucose and facilitate its excretionin urine. As glucose is excreted, its plasma levels fallleading to an improvement in all glycemic parameters,and this action is independent of the actions of insulin.Thus, the hypoglycemia risk is minimal.

Other effects of SGLT2 inhibitors are as follows11-16 (Fig. 1):
  • Sodium glucose cotransporter 2 inhibitor usageresults in a reduction of body weight, and it is usuallythe visceral fat that is lost.
  • Sodium glucose cotransporter 2 inhibitors reduce bothsystolic and diastolic blood pressure.
  • Sodium glucose cotransporter 2 inhibitors increasehigh-density lipoprotein (HDL) by about 7 to 10%,low-density lipoprotein (LDL) by 7%, and reducetriglycerides by 2%.
  • Uric acid levels are reduced by SGLT2 inhibitors.
  • Sodium glucose cotransporter 2 is one of the determinantsof glomerular hyperfiltration and SGLT2inhibition offers nephroprotective action.

CLINICAL TRIALS OF SGLT2 INHIBITORS
EMPA-REG Outcome17


In this study, 7,020 diabetic patients were randomized toreceive 10 or 25 mg of empagliflozin or placebo once dailyand were followed up for 3.1 years, for primary outcome ofcomposite of death from cardiovascular causes, nonfatalmyocardial infarction, or nonfatal stroke, and secondary outcome of primary outcome plus hospitalization forheart failure.
 
More than 90% of patients had established CVD [myocardialinfarction, cerebrovascular accident, peripheralarterial disease (PAD)], and they were on appropriatetreatment for hypertension and dyslipidemia.

There was a statistically significant 14% reduction inprimary endpoint, 38% reduction in cardiovascular death,35% reduction in hospitalization for heart failure, and32% reduction in death from any cause. The differencebetween empagliflozin and placebo was mainly drivenby a significant reduction in death from cardiovascularcauses, there being no significant difference in the risk ofmyocardial infarction or stroke. The cardiovascular benefitswere seen early in the trial, and continued throughout.

One notable adverse event was an increased rate ofgenital infection with empagliflozin.

Empagliflozin reduced HbA1c significantly and wasalso seen to result in small reductions in body weight,waist circumference, uric acid level, and systolic anddiastolic blood pressure with no increase in heart rateand small increases in both LDL and HDL cholesterol.The investigators of this study are of the opinion thatcardiovascular benefits of empagliflozin are multidimensional.Apart from their effects on blood sugar, bodyweight, central adiposity, and blood pressure, they probablyinduce favorable changes in arterial stiffness, cardiacfunction, cardiac oxygen demand, cardiorenal effects,reduction in albuminuria, and reduction in uric acid.

EMPA-REG Outcome Substudy18

In this substudy, 982 patients who had PAD treated withempagliflozin were compared with 479 patients of PADreceiving placebo. Those receiving empagliflozin hadsignificant reduction in mortality, hospitalization forheart failure, and progression of renal disease and therewas no increase in the risk of lower limb amputation.

Cardiovascular Protective Actions of Sodium GlucoseCotransporter 2 Inhibitors
Fig. 1: Possible mechanisms to explain CV benefits of SGLT2 inhibitors (Modified fromInzucchi et al. Diabetes Vasc Dis Res 2015;12:90-100)
 
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Cardiovascular Protective Actions of Sodium Glucose Cotransporter 2 Inhibitors

CANVAS Trial19

This study had 10,142 participants with type II diabetes andhigh cardiovascular risk. Nearly 65% of them had CVD andwere randomized to receive canagliflozin or placebo. Theywere followed up for a mean of 188.2 weeks. The primaryoutcome was a composite of death from cardiovascularcauses, nonfatal myocardial infarction, or nonfatal stroke.Secondary outcomes studied were death from any cause,death from cardiovascular causes, progression of albuminuria,and the composite of death from cardiovascularcauses and hospitalization for heart failure. The primaryendpoint was reduced by a significant 14% in the canagliflozinarm. It also reduced the risk of the progression ofalbuminuria, the need for renal-replacement therapy, anddeath from renal causes. The points of concern were anincreased risk of amputation, though primarily of toe ormetatatrsal, and an increased risk of fractures.

The authors proposed that improved glycemic control,lowering of blood pressure, decrease in intraglomerularpressure, reduction in albuminuria, and amelioration ofvolume overload offered by canagliflozin are probablythe mechanisms responsible for cardiovascular and renalprotection.

Results from the CANVAS Program20

In this study, the efficacy and safety of canagliflozin wereanalyzed separately for the primary and secondary preventioncohorts enrolled in the CANVAS Program. There were3,486 primary prevention participants and 6,658 secondaryprevention participants. Canagliflozin reduced cardiovascularand renal outcomes in both the primary and secondaryprevention groups, though authors cautioned aboutthe use of canagliflozin in patients at risk for amputations.

Dapagliflozin21

Dapagliflozin, like other SGLT2 inhibitors, has low risk forhypoglycemia, lowers blood pressure, decreases weightand waist circumference, and decreases albuminuria andserum uric acid levels.

A meta-analysis of 9,339 patients with type II diabetesand increased cardiovascular risk and received dapagliflozinhad the following results. Overall population hada 23% lower risk of major adverse cardiovascular event(MACE) and patients with history of CVD had 20% lowerrisk of MACE.

Meta-analysis of SGLT2 Inhibitors22

In a meta-analysis of 37,525 patients who received one ofthe seven SGLT2 inhibitors (canagliflozin, dapagliflozin,empagliflozin, ipragliflozin, luseogliflozin, tofogliflozin,and ertugliflozin), the study looked at the primary outcome of MACE: CV death, nonfatal myocardial infarction, andnonfatal stroke.

 
The key conclusions were:
  • Sodium glucose cotransporter 2 inhibitors significantlydecreased MACE, cardiovascular death, andall-cause mortality.
  • The risk of heart failure also decreased, but data wereavailable only for empagliflozin.
  • Sodium glucose cotransporter 2 inhibitor use waslinked to significantly increased risk of nonfatal stroke.
  • Cardiovascular results were driven largely by outcomesfrom empagliflozin reported from a singlestudy, and more studies are needed to confirm thesefindings across the drug class

Sodium Glucose Cotransporter 2 Inhibitors-
Class Effect?


To date, three such drugs-canagliflozin, dapagliflozin,and empagliflozin-have been approved by internationalregulatory agencies for the treatment of type II diabetes.Impact on hospitalization for heart failure was similarin both CANVAS (with canagliflozin) and EMPA-REGOUTCOME (with empagliflozin) trials. This suggeststheir similarity in hemodynamic effects.

If one looks at the individual components of endpoints in the two trials, there are some differences. Therewas an increase in amputations in the CANVAS trial withcanagliflozin, which is not fully explained, and it is notedthat the European Medicines Agency has urged cautionto be exercised for the class (in particular canagliflozin) inpatients with previous foot complications. In EMPA-REGOUTCOME (with empagliflozin) trial, there was a statisticallynonsignificant increase in nonfatal stroke rate.

The SGLT2 inhibitors do share some common features,but there could be some minor differences. Ongoing trialswill probably clarify the picture.

SUMMARY

The effects of SGLT2 may be summarized as below:

Adverse Effects
  • Urogenital tract infections are the most frequentlynoticed adverse events in subjects on SGLT2 inhibitors.
  • The osmotic diuresis associated with SGLT2 inhibitoruse also has the potential to cause volume depletionand orthostatic hypotension.
  • The SGLT2 inhibitor use leads to a slight reduction inbone formation, and a rise in bone resorption markers.
  • The SGLT2 inhibitors should not be used in patientswith type I diabetes where its use is limited to clinicalresearch studies. The Food and Drug Administrationissued a warning about the risk of ketoacidosis occurring in the absence of significant hyperglycemia(euglycemic diabetic ketoacidosis) in patients withtypes I and II diabetes treated with SGLT2 inhibitors.

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Glucose Lowering Effect

The SGLT2 inhidresults in further HbA1c reduction, lower insulin doserequirement, and greater weight loss, and there is noworsening of hypoglycemia. The SGLT 2 inhibitorsusually reduce HbA1c by 0.7 to 1.0%.

Nonglycemic Effects of SGLT2 Inhibitor23
  • Elevations in HDL cholesterol and reduction in triglycerideconcentrations along with a minor elevation ofLDL cholesterol should not cause concern over CVDrisk. The EMPA-REG OUTCOME trial has refutedthis concern, along with the fact that SGLT2 inhibitorswitches metabolism from carbohydrate toward lipidutilization, which moderately increases ketogenesisand low-density lipoprotein concentrations despitenet lipid metabolic utilization.
  • Blood pressure lowering: several factors are likely to beinvolved including changes in plasma volume andreduced arterial stiffness.
  • Reduction in body weight induced by SGLT2 inhibitors:the effect is seen mainly on visceral obesity. TheSGLT2 inhibitors have neutral effects on the sympatheticnervous system. The SGLT2 inhibition doesnot increase heart rate despite the plasma volumereduction associated with the class.
  • The SGLT2 inhibitor-mediated reductions in hyperfiltrationwould suppress markers of inflammation andfibrosis.
  • Dapagliflozin has been shown to reduce C-reactiveprotein.
  • Renal hemodynamic function and albuminuria: SGLT2inhibitors reduce albuminuria by 30 to 40%, possiblybased on reductions in intraglomerular hypertension.
  • Uric acid: The SGLT2 inhibitor class of drugs has beenassociated with a 10 to 15% reduction in plasma uricacid levels.

Beneficial effects seem to outweigh a small number ofadverse actions of SGLT2 inhibitors. The glycemic andnonglycemic effects of SGLT2 inhibitors enumeratedabove probably explain the cardiovascular benefitsimparted by these agents.

RECOMMENDATIONS

The American Diabetes Association24 has recommendedthe following:
"In patients with long-standing suboptimally controlledtype II diabetes and established atherosclerotic CVD, empagliflozin or liraglutide should be consideredas they have been shown to reduce cardiovascularand all-cause mortality when added to standard care.Ongoing studies are investigating the cardiovascularbenefits of other agents in these drug classes."

 
CONCLUSION

Now that there are antidiabetic agents that offer glycemiccontrol and, in addition, reduce cardiovascular events,the physician or endocrinologist or cardiologist has aresponsibility to consider the use of these and avoid drugsthat are likely to harm or offer no benefit.

It is probably appropriate to conclude
"Current management of diabetes is characterized byopportunities and options, and not obstacles."

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