Dr. M Yeolekar shares expert insights on the ever-changing scenario of therapeutics in Diabetes with a special emphasis on SGLT2.

Dr. M Yeolekar, an eminent physician with a rich experience shares his valuable thoughts as he takes us through the significance of normoglycaemia, value of postprandial glucose and the concept of metabolic memory. He highlights the the intricate association of diabetes mellitus and coronary artery disease/cardiac failure, the cardiorenal links and clinical implications. 

Finally, the therapeutics of diabetes is discussed and the latest development of the remarkable results of DECLARE are welcomed as game changers. 

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Times have changed significantly in the understanding and management of diabetes over the last couple of decades. The magnitude of the problem is huge (expectedly feared to cross 100 million by 2030) demanding attention not just from the clinical community but from the government authorities as a part of strategy in dealing with Non-Communicable Diseases (NCD). 

Ever since the notable landmark UKPDS study, the importance of maintaining ‘Euglycaemia’ was emphasised in preventing/delaying many (microvascular) though not all vascular complications. Two main drug groups sulfonylureas and biguanides had ruled the roost for a substantial period of time.

Emphasis then was laid on control of fasting blood glucose (FPG) and/or glycosylated haemoglobin (Hb A1C). Attention had somehow, unknowingly not been drawn to control postprandial glucose levels (PPG). Soon, it was realised that many studies documented the precise relationship between 2-hour postprandial glucose (PPG) and cardiovascular disease amongst diabetics. Furthermore, some studies documented 2-hour PPG and not fasting blood sugar FPG levels significantly related to renal changes involvement amongst diabetics.                                            

It is worthwhile to understand the importance of PPG in normal individuals (non-diabetics) plasma glucose concentrations reaches peak sixty minutes after the commencement of the meal, rarely exceeds 140 mg% and returns to preprandial levels within two to three hours.

Measurement of glucose 2 hours after the start of  a meal tends to approximate peak value in diabetics. The PPG is contributed by:

• carbohydrate absorption
• insulin and glucagon secretion
• their coordinated effects on the glucose metabolism in the liver and peripheral tissues

The focus now changed- as cardiovascular disease is the major cause of morbidity and mortality in patients with diabetes, treatments directed at specifically lowering PPG is crucial. Two hour PPG is a very sensitive index of diagnosis; several epidemiological and interventional studies have demonstrated that postprandial hyperglycaemia is a 'direct' and 'independent' risk factor for cardiovascular disease.

Large epidemiologic studies have shown a 'continuous graded direct' relation between the level of post glucose challenge glycaemia and risk for events including coronary heart disease, cerebrovascular stroke, sudden cardiac death, and peripheral arterial disease.                   

The concept of 'metabolic memory' is important to understand because of its vascular implications. Legacy effects, metabolic imprint, glycaemic memory, hyperglycaemic memory are some related terms implying some similarities and overlap.

The phenomenon of ongoing beneficial effects on diabetic complications after a period of improved glycaemic control even if followed by a return of usually poorer metabolic control has been described as representing ‘metabolic memory' by the DCCT investigators and as a ‘legacy effect‘ by UKPDS investigators.                               

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Coronary Artery Disease and Diabetes

It is sufficiently well recognised that there exists a ‘cluster‘ of risk factors such as diabetes mellitus, hypertension, and hyperlipidaemia and tobacco/sedentariness adding to the composite and cumulative cardiovascular risk. Diabetes accelerates the tempo of atherosclerotic process. Cardiovascular disease is the leading cause of death among people with type1 and type 2 diabetes

Coronary artery disease is the cause of death in more than half of all diabetic patients. Patients with diabetes but  without other conventional risk factors for atherosclerosis have a risk of death from CAD 2-4 times that of age matched controls. Prevalence of diabetes in patients with CAD is upto 50% in many countries and individuals with diabetes and CAD fare worse than do other patients with CAD. Those who present with myocardial infarction are at increased risk of dying from the event or at developing heart failure

Inflammation plays an important role in atherosclerosis. Inflammation activation in type 2 diabetes may result from obesity and insulin resistance, in which an acute phase reaction can occur and a large number of inflammatory and proinflammatory cytokines are released from adipose tissue.

Endothelial dysfunction occurs because of low levels of nitric oxide. Enhanced thrombus formation tends to occur in diabetics because of enhanced platelet activity and blood coagulability. Healthy endothelium regulates blood vessel tone, platelet activation, leukocyte adhesion, thrombogenesis and inflammation. When these processes are defective, atherosclerosis is accelerated.

Both insulin deficiency and insulin resistance promote dyslipidaemia accompanied by increased oxidation, glycosylation, triglyceride enrichment of lipoproteins; added with endothelial dysfunction, all these factors contribute to enhanced atherogenicity and thus the macrovascular disease in diabetics. 

Diabetes contributes to defects in the autonomic nervous system, the endothelium and local metabolism all of which can result in microvascular disease. Capillary basement membrane thickening associated with prolonged hyperglycaemia is a structural hallmark of diabetic microvascular disease. The increase in cardiovascular morbidity and mortality in diabetics is thus multifactorial and is related to a combination of both macrovascular and microvascular dysfunction. Coronnary artery disease in Indian diabetics tends to be premature, diffuse and extensive and therefore demands all measures towards cardioprotection at all levels of prevention.                                                                     

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Chronic Heart Failure

It can arise in a diabetic from myocardial damage resulting from an ischaemic, thombotic  event. There can however be a non-thrombotic aetiology namely diabetic cardiomyopathy, defined as myocardial disease in patients with diabetes that cannot be attributed to hypertension or coronary artery disease.

Microvascular damage in the diabetic heart can lead to myocardial injury, fibrosis, hypertrophy found in diabetic cardiomyopathy. It is no wonder then that abnormal glucose homeostasis and cardiac disease- both coronary artery disease and cardiac failure of cardiomyopathy calls for research and clinical trials on drugs that could address these clinical problems- SGLT2 inhibitor as an example.  

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Nephroprotection

The kidney is important in the context of diabetes mellitus because it is involved in glucose homeostasis and furthermore because it is one of the most important end organs to be involved in diabetic complications. Glomeruli are the meeting point of both microvascular or renal and macrovascular or cardiovascular.

Around a million glomeruli of each kidney receive their blood supply from afferent arterioles, and exit into high-resistance efferent arterioles. The pressure gradient creates a hydrostatic force which facilitates ultrafiltration and allows excretion of waste products. The glomerular filtration rate is an important measure of renal function.

Glomeruli are also the site of intense endocrine activity: the afferent arteriole walls synthesise renin, and juxtaglomerular cells play host to the renin-angiotensin systems. These regulate blood volume and blood pressure by multiple mechanisms. Damage to glomerulus may alter its permeability and allow excretion of albumin in urine. The phenomena of microalbuminuria and macroalbuminuria are markers of diabetic nephropathy and cardiovascular disease.

Maintenance and improvement of glomerular health is an important strategy as well as target in metabolic and diabetes care. Glucose-lowering drugs such as glucagon-like peptide 1 receptor agonists (GLP1RA) and sodium glucose co-transport 2 inhibitors (SGLT2) have been demonstrated to attenuate albuminuria.

This pharmaco-physiological effect is postulated to contribute to their cardiovascular benefit. Diabetic nephropathy is the foremost cause of CKD in India. Staging of CKD is based on three parameters: cause, albuminuria, and GFR.

Early chronic kidney disease (CKD) has no signs or symptoms and patients  may therefore not seek timely help. Loss of 70 to 90% of function may be associated with only minimal clinical manifestations. The initial symptoms are non-specific. Therefore the diagnosis of CKD based on signs and symptoms is always late. Renal symptoms of CKD  include frothy urine, milky urine, graveluria, haematuria, oliguria, anuria, polyuria, facial puffiness, urinary frequency, nocturia, flank pain, and mass.

Anaemia, metabolic bone disease, pulmonary oedema, polyuria convey pathogenetic basis of presentation. Progressive loss of kidney function, which manifests as chronic kidney disease (CKD) is characterised by relentless and self-perpetuating fibrosis of renal parenchyma and loss of nephrons. The cardiorenal interrelationships are now better understood and no issue in cardio-diabetology can be duly assessed without evaluating renal status and function.

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Therapy for diabetes 

Lifestyle modifications including right diet, oral hypoglycaemic agents and insulins- conventional and newer ones have been the mainstay of treatment. Furthermore, management of complications- neuropathy, nephropathy, and retinopathy form the extended spectrum of care. 

1. Metformin continues to remain the initial fulcrum used in doses upto 1.5 to 2 g daily in divided doses, also in combination most commonly with glipizide, gliclazide, and glimepride useful in the initial years.
2. Pioglitazone in 7.5 to 15 mg may be useful agent but for oedema and weight gain.
3. Amongst DPP4, the Indian version Tenaligliptin 20 mg modest in price is employed individually and in combination with metformin.
4. Linagliptin  considered useful as nephroprotective and sitagliptin have now been used adequately, cost, gastrointestinal side effects and apprehension of pancreatitis being notable concerns.

Despite profound utility, because of physician and patient inertia insulinisation occurs twelve to fifteen years after onset. Better basal/bolus insulins are available, but premixed tend to used maximally. With this background, the latest arrival was SGLT2 inhibitors, much discussed and debated and focused on individual agents— empa, kana, dapa with huge trial evidence forthcoming.

It must be stated, this group aroused and churned up the diabetic therapeutic scenario with hopes and promises for the patients that sound realistic. The latest-- DECLARE TIMI 58 (DAPAGLIFOZIN  effect on cardiovascular events) was a multinational randomised, double blind, placebo-controlled, phase III B cardiovascular outcomes trial with a perfect study design and claimed the largest with over 17000 patients, longest, running over 4.5 years and the broadest including 60% patients with >1 multiple risk factors, and importantly 40% patients with established CVD.

The salient features included:

1. Primary efficacy end-points: MACE, composite of CV death and hospitalisation for heart failure.
2. Primary safety end points: Composite of CV death, non-fatal myocardial infarction, or non-fatal ischemic stroke (MACE).
3. Secondary end points: RENAL composite endpoint (sustained 0% decrease in eGFR to GFR <60 ml/min/1.73m² and/or ESRD and/or renal or CV death) and all cause mortality.

The results stand out against the earlier CANVAS programme and EMPA-REG outcome. The results are so impressive, assuring and resounding – the SGLT2 inhibitors and Dapaglifozin juggernaut will carry profound influence on diabetes therapeutics.

Disclaimer-The information and views set out in this article are those of the author(s) and do not necessarily reflect the official opinion of M3 India. Neither M3 India nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein.