I was always told by our MEA chaps that the best protocol in the business was the American state department. I had first knowledge of their clock work precision, they ensured VIP movement by the second and I mean by the second. The secret service was not to be outdone by any means; I was a part of the delegation of the Indian president in the mid nineties that was travelling to Brazil. We had a stopover in New York city. The entire Indian delegation was put up in the Waldorf with the president, who by any standards was a terrific human being; erudite, sophisticated and spectacularly down to earth. It was therefore a pleasure and privilege to accompany Mr Narayanan in his foreign travels. I have let me confess a poor traveller. But during the Waldorf stay I desperately wanted to trace a child hood mate. Satindar Sood had played for the Indian school boys cricket team, and had been a kind of chaperone when I was a kid. He tried his best to make me take up cricket but my heart form the beginning was always in long distance running, but I did not mind playing for the school cricket team. I do know a little about cricket, but have always tried keep my eyes on the ball, be it a doosra or a googly, that are thrown at you by the dozens each day in current India. That evening in the Waldorf all I remembered was Satindar’s residence, which I provided those big secret service guys. True to form one big guy got back to me in less than 15 minutes with confirmation that my mate was rocking in New Jersey along with his telephone number. I most certainly was impressed by the secret service dude who probably had some inflated impression of my status, Look I was merely Mr Narayan’s cardiologist. I mention this incident because I have witnessed the precision of American protocol, to be a part of the motorcade from the Waldorf to the airport without a single hitch cannot be described, let me underline that unlike the Delhi police there was not a single road block, and yet the motorcade arrived on the tarmac on time without a second’s delay. Why do I remember those times? It’s because of Mr Imran Khan’ visit to the US this week. I am a full blooded Indian without any emotional baggage for Pakistan whatsoever. Yet I am filled with a tinge of sorrow that the prime minister of a sovereign nation travelled to the US as an ordinary passenger in a foreign airline only to be welcomed by not a single US state department official. From the aircraft the honourable prime minister was compelled to take a shuttle till the airport building. Thats taking matters to an unimpressive extreme. Obviously the Donald is more than annoyed with our neighbour, He has already blocked the billion dollar annual military aid, and now this. While Mr Trump in his unrehearsed speech declared he would if he wanted decimate the entire region of Afghanistan in a mere 10 days, an almost shrunken Mr Imran Khan sat in stoic silence. He almost looked both terrified and exceedingly helpless because he basically had come for some badly financial aid. He dis not then in Mr Trump’s presence or any time later till today expressed any discomfort.But then he primarily gone for some badly needed financial assistance. Pakistan is an a dire state of affairs, but yet Mr Khan had to have his “Something Stupid “. Originally a song best known by Frank and Nancy Sinatra. Its a great song that I strongly recommend you listen to. However Mr Khan’s “something stupid “ moment was not that “ I love you” but that incorrigible “K” word in public. Yes the retired cricketer could not refrain from Kashmir. Here he is almost pleading for money from any and every quarter but the bedrock of all his country’s woes is Kashmir. 50% of Pakistani children are stunted, polio stays endemic but all that Mr Khan can focus on is Kashmir and building a champion cricket team for the next world cup. It is obvious that his excellency is missing the wood for the trees, our rather for the fiscal bailout. Whats with these cricketers active or retired?
Coronary stenting has revolutionised the treatment of heart disease. Lakhs of patients destined for CABG surgery are now tackled with a percutaneous technique that does not need general anaesthesia, almost completely does the job of rectifying ischemia, with the patient being discharged next day or even the same day in selected cases. No amount of praise for the pioneer researchers can be enough. We have a device that cuts mortality apart from providing excellent symptomatic relief. Chest pain and breathlessness become complaints of the past as if by magic, by the insertion of a thin catheter from the wrist or the groin. The stent is a metallic mesh tube that is lined by a plastic polymer laced by a medicine that prevents restenosis of the coronary artery.We now have second generation stents that are markedly thin in size. The procedure is reasonably simple for the experienced operator. Experts in the field do not hesitate to treat complex lesions that would surely have been managed by bypass surgery in the past.
The job however is not complete with insertion of the stent. Stenting procedure has to be followed by months of anti platelet therapy, which consists of pills. The pills are invariably tablet aspirin accompanied with a P2Y12 inhibitor. The P2Y12 receptors on the surface of platelets are the glue that binds them to form a clot. There are 3 P2Y12 inhibitors in the market; clopidogrel, prasugrel and ticagrelor, all available in the Indian market.
In cricketing analogy ,once the base has been set in a one day game, someone has to consolidate the score by launching himself in the death overs. Bairstow and Roy have been laying down superb foundations for the English, while Stokes and Buttler do the demolition job towards the end. Dhoni has been a stunning finisher all these years, in fact he has been regarded as the best in the business. But it is becoming obvious that he no longer possesses that prowess. The ongoing World Cup has exposed his inability to ratchet up the strike rate , a strike rate of 100% or less in a World Cup semifinal would just not good enough. Good work done by Sharma and Kohli at the top has to be bolstered by a strike rate around 140-150% later on, the strike rate of course should fetch some handsome runs too.
I distinctly remember Mr Imran Khan stating more than once that the solution to the Kashmir problem should be a cricket match. If India were to win ,Kashmir would be hers, but in case Pakistan were the victors then ‘paradise on earth’ would be rightfully their territory. Those were the days when the Pakistani cricket team more or less had an edge on India. Pakistani batting then was not only rock solid but buttressed by arguably the finest pace attack on the planet. Mr Imran Khan, no minnow with the bat , was a terrific fast bowler. Somewhere down the line he mastered the reverse swing too. It would be interesting to know of his personal opinion in current times, bearing in mind that now its the Indian cricket team that bats deep with one of the most potent pace attack. Mr Imran Khan understandably refrains from attaching any form of cricket to Kashmir. Not test, not one day cricket nor the T20 form. To his credit Mr Imran Khan was right up there as one of the best all rounders in the world. So it comes as some surprise that such a fine cricketing brain is now batting in the murky world of Pakistani politics. I personally preferred him when he made those frank promulgations that smacked of simplicity in a man who played with a straight bat.
I am compelled to recollect those artless days; we also believed that saturated fat was a killer. The equation was simple, eat meat particularly red meat and you would kick up your cholesterol level. The spike in cholesterol in turn would clog your arteries, resulting in heart attacks and stroke. There was the famous “seven countries” data that set up the high cholesterol diet equals heart attack hypothesis. It was only much later we all found that that the “seven countries” data was full of holes. I have elaborated on the flaws in the past. Every randomised study on saturated fats has failed to show reduction in heart attacks by having a diet with reduced saturated fats. The Women’s Health Initiative followed 49,000m postmenopausal women for 8 years who had been on a low fat diet, but could not record reduction in the risk of death, heart attack or diabetes. The conclusion was no different when saturated fat was replaced by a vegetable oil (polyunsaturated fat). There were more heart attack and death in the intervention group. There have been 2 such randomised trials, both concluded that replacement with a vegetable oil somehow did not lower clinical events.
An interesting article recently published dilates on the fact that a drug backed by solid evidence in the past may be found ineffective some years later. Beta blockers considered indispensable subsequent to an acute myocardial infarction are now not recommended in post MI patients with normal left ventricle function. A beta blocker does not improve clinical outcomes in a post MI patient who does not have an impaired left ventricle. Another drug seems to be fizzling out as a prophylaxis against cardiovascular events. Three randomised trials have shown little or no benefit in clinical outcomes with prophylactic aspirin. In fact prophylactic aspirin is almost always associated with increased bleeds, which can be a serious advert effect. Some years ago however aspirin had consistently demonstrated good efficacy as a prophylactic in middle aged people. Prophylactic aspirin was backed by reasonably good evidence of better clinical outcomes. Why does the same medicine at the same dosage not work any longer? The explanation is simple; over the years population has altered, people are more health conscious now with much better lifestyle application. Also there is much greater emphasis on control of high blood pressure and management of lipids with statins. The net result is that the marginal albeit clinically significant prophylactic advantage has evaporated. Evidence based medicine is not forever, there can be an expiry date.
Treating a patient with shock can be an extremely daunting task for any clinician. Shock is a common reason for admission into an intensive care unit. Shock is accompanied with low blood pressure that is invariably raised by vasopressors and inotropes. Two thirds of patients entering an intensive care unit septic shock, which is a distributive type of shock. Other albeit uncommon causes of distributive shock are drug/toxin induced, anaphylactic shock, endocrine shock (Addison crisis) and neurogenic shock. Every protocol on spec shock mandates administration of norepinephrine at 0.2 mcg/kg/min (recommneded first line) and if need be vasopressin at 0.3 units /min. Norepinephrine can be combined with epinephrine, both having combined vasopressor and inotropic effects. The latest vasopressor to be found effective is angiotensin II. Angiotensin II acts by Gq protein stimulation in vascular smooth muscle. The ATHOS -3 (N Engl J Med 2017;377:419-30) randomised trial comparing angiotensin II with placebo in 344 patients with vasodilatory shock (80% had sepsis), showed that significantly more patients had their mean blood pressure raised more than 75 mm Hg at 3 hours with angiotensin II than placebo against background conventional vasopressor therapy ( 70% versus 23%). It must be noted that all these patients were suffering from vasodilatory shock defined as cardiac index greater than 2.3 litresb per minute per square meter or as central venous oxygen saturation greater than 70% coupled with central venous pressure more than 8 mm Hg, with mean arterial pressure between 55 and 70 mm Hg.
Cardiologists on the other hand are confronted with cariogenic shock where low blood pressure is a result not of dilated peripheral arteries but inability of the heart to pump adequately. Poor pumping of the heart is usually due to acute myocardial infarction, and in other instances due to mechanical failure (valvular dysfunction, ventricular septal defect, atrial myxoma), and arrhthmias. Initial treatment includes inotropic support with dobutamine and vasopressor support with norepinephrine. Vasodilatory shock by itself is very difficult to treat, but cariogenic shock is even more so because of the fact that too much vasopressor administration can be detrimental to the already struggling heart. No sweet spot has so far been determined for vasopressor/inotrope dosage, and hence patients of cariogenic shock will need supportive treatment consisting of the intraaortic balloon pump (IABP), Impella, or extracorporeal membrane oxygenation (ECMO).
It has become impossible to get a happy story on diabetes. Every succeeding story is grimmer than the preceding one. We yet again learn that Asian patients with diabetes are exquisitely vulnerable to the disease. More than 230 million people in Asia suffer from type 2 diabetes, which is more than half of the world population. A recent study on Asian patients with diabetes has established that in a follow up of 12.6 years 148,868 participants died. The study included more than a million (10 lacs) individuals from China, Japan, India, Bangladesh and South Korea. Individuals with diabetes had twice the number of deaths as compared to those without diabetes. The risk of relative mortality far exceeded that seen in Western populations. The researchers concluded that Asian people with diabetes were at increased risk of dearth due to a variety of causes. You just cannot take diabetes lightly (JAMA Netw 0pen 2019:2(4):e192696). Therefore the recommendation for urgent need for Asia-centric diabetes management strategies. It is against this background of a looming diabetes epidemic that one needs to become aware of newer more effective medicines to tackle diabetes; albeit they will be outside the reach of most Indian patients.
Type 2 diabetes is a complex problem with multiple underlying pathophysiological mechanisms. It therefore makes sense to administer combined therapy. Treatment with an SGLT2 inhibitor may increase production of glycogen even as it reduces glucose level via the kidney. Semaglutide a GLP 1 receptor agonist on there other hand not only kick starts insulin production by the pancreatic islet cells but also tone down glycogen delivery. The recently published SUSTAIN 9 trial ( Lancet Diabetes Endocrinol 2019;7:356-67 ) employed addition of once weekly injection of semaglutide in addition to daily ingestion of an SGLT 2 inhibitor in patients of type 2 diabetes. The primary outcome of this trial was change in HbA1C at 30 weeks while the secondary outcome was change in weight.
Patients with an HbA1c ranging from 7% – 10% despite 3 months of an SGLT2 inhibitor were randomised to subcutaneous 1 mg of semaglutide or placebo once weekly. Semaglutide dose was gradually increased from O.25 mg to 0.5 mg to eventually 1 mg per week. Apart from randomised medication and SGLT2 inhibitor, 70% patients were on metformin and about 13% were taking a sulfonylurea. SUSTAIN 9 showed that addition of semaglutide to existing therapy with SGLT2 inhibitor resulted in significantly greater reduction in HbA1C and fasting glucose levels. Moreover almost 80% of patients got their HbA1C level down to less than 7%.
The WOEST trial ( Lancet 2013; 381:1107-15) was the first randomised study to show that a combination of a vitamin K antagonist (VKA) and a P2Y12 inhibitor when employed inn a patient of atrial fibrillation undergoing PCI resulted in significantly less bleeds than a triple combination of VKA, aspirin and a P2Y12 inhibitor. The study however randomised less than 600 patients. At the end of a year major bleeds were reduced from 45% in the triple therapy group to 20% in the double therapy group; p<0.0001). The conclusion was that use of clopidogrel minus aspirin was associated with a significant reduction in bleeding complications, without an increase in thrombotic events. The study was not powered to assess changes in ischemic events or mortality.
Atrial fibrillation (AF)s the commonest arrhythmia in adults and therefore more than 10% of patients suffering from acute coronary syndrome are found to be in AF. The aim is to prevent ischemic events such as myocardial infarction or stent thrombosis, and also simultaneously prevent thromboembolism because of AF. Ischemic events can be avoided by dual anti platelet therapy (DAPT) while embolism (stroke) is prevented by an oral antocaogulant (OAC). The problem is that combining DAPT with an OAC increases the risk of major bleeding considerably. Choosing antithrombotic treatment for an AF patient suffering also from acute coronary syndrome becomes quite a challenge.
Apart from WOEST, 2 more randomised trials comparing a new oral anticoagulant (NOAC) plus a P2Y12 inhibitor with triple therapy consisting of VKA, aspirin and P2Y12 inhibitor showed a lower incidence of bleeding with double regimen therapy without aspirin. These 2 rials were not powered to assess whether lower bleeds were due to avoidance of aspirin or due to use of a NOAC.
All said and done the promise of ultra thin strut stents with biodegradable polymer to cut down the incidence of stent thrombosis and neoatheroscelrosis remains to be fulfilled. Drug eluting stents (DES) have indeed reduced restenosis but have been hampered by development of late stent thrombosis and neoatherosclerosis. In order to improve clinical results ultra thin stents were developed in which strut size is a mere 60 microns. These stents are made of the allow cobalt chromium and are covered by a polymer that is only 5 microns in thickness. Moreover the polymer is biodegradable, which means that it melts away in a few months to a year, having done its job of preventing smooth muscle proliferation or restenosis. Crucially the stent left behind behaves like a bare metal stent that is incapable of inducing inflammation in the coronary artery wall. The situation that we have currently is that every ultra thin strut stent in the market carries biodegradable polymer (BP). All randomised studies done with the ultrathin strut stent have compared them with the durable polymer (DP) everolimus eluting stent ( or the Xience stent). The Xience stent has a strut thickness of 80 microns, which is also quite thin. The Xience stent and other thin strut stents with a durable polymer have provided excellent clinical outcomes compared to earlier generation drug eluting stents, but results have flattened. Second generation DP-DES have a lower risk of stent thrombosis, restenosis, myocardial infarction and death in comparison with bare metal stents. The latest ultra thin strut BP-DES also provide clinical outcomes comparable to second generation BP-DES but no randomised trial has shown superiority.
The latest trial comparing BP-DES with DP-DES ( the TALENT trial) reported similar outcomes by 12 months (Lancet 2019,393:987-97). TALENT studied 1435 patients and the primary endpoint was a composite of death, myocardial infarction or clinically indicated target vessel revascularization. At the end of one year both groups had an incidence of about 5%. Participating centres were from Europe.
Trans catheter aortic valve replacement (TAVR) is an established technique that has been found to be a viable alternative to surgical valve replacement (SAVR) in patients of severe aortic stenosis (AS) at high risk or moderate risk for death following SAVR. Severe AS includes patients of AS who have a valve area equal or less than 1cm2 ( equal or less than 0.6 cm2 per square meter of body surface area) or mean gradient greater than 40 mm Hg or Doppler flow across the aortic valve exceeding 4 meter per second, assessed by 2D echo performed at rest.
Aortic stenosis can become as life threatening condition once symptoms develop. The aortic valve becomes narrowed, obstruction blood flow from the heart to the rest of the body. Patients develop breathlessness, chest pain and can even faint. Open heart surgery in which a mechanical valve with solid carbon leaflets is inserted has been the mainstay of treatment for the last half century. The mechanical valve however requires life long anticoagulation or blood thinners. Biological valves made from cow and pig heart tissue are also implanted when anticoagulation is undesirable, such as in patients who are old (more than 65 to 70 years, pregnant women, and in those who are incapable of takin blood thinners for life).
It was inevitable that the next target would be patients of severe AS at low risk defined as predicted 3% risk of death by 30 days. We now have 2 large studies that have taken the interventional cardiology world by a storm. In fact the entire audience at the latest American College of Cardiology Meeting was left breathless the presentation of these 2 studies; both studies were published simultaneously by the New England Journal of Medicine.
The first trial to be discussed used a self expanding valve in more than 1400 severe AS patients (N Engl J Med March 17). The researchers compared outcomes of SAVR ( in which the chest and heart are opened in the operation room) versus the far less invasive procedure of TAVR, in which the aortic valve is inserted via the groin. All patients were considered ow risk ( predicted death less than 3% at 30 days); 65% were male while mean age was 74 years.
The introduction of first generation drugs eluting stents ( 1G- DES) sub substantially reduced rates of in stent restenosis (ISR) as seen with bare metal stents (BMS). Bare metal stents had significantly cut down plain balloon angioplasty complications such as emergency coronary artery bypass grafting surgery and restensis, but were associated with stent thrombosis (ST). ST is a dreaded complication of coronary stenting that apart from killing a patient, invariably results in a large myocardial infarction. Improved anti platelet therapy in the form of dual anti platelet therapy (DAPT) and improved stent technology with better implantation techniques did reduce early ST events (less than 30 days). In stent restenosis with BMS was due to neo intimal hyperplasia, and this pathological phenomenon paved way for the entry of the IG-DES. The IG-DES significantly reduced in stent restenosis but became associated with late ST (30 days to 1 year), and with very late ST (later than 1 year) ST. Late ST necessitated development pf more powerful anti platelet medication, administered for prolonged duration, which in turn brought in the spectre of increased bleeding.
Delay in re-endotheliazation is considered the primary substrate for late and very late ST. Optical coherence tomography (OCT) has revealed that stent malapposition and rupture of a neoatherosclerotic plaque are nearly always associated with late and very late stent thrombosis. In a few cases uncovered struts are the cause. Delayed re-endotheliazation is due to the anti proliferative effect of the drugs released by the 1G-DES.
Another phenomenon to explain late ST was a chronic inflammatory reaction induced by the polymer attached to the stent struts, and even the stent struts themselves. The stent itself essentially has 3 components, the metallic platform, the polymer (drug carrier) and the pharmacological agent.
Let us consider randomized trials comparing paclitaxel eluting stents (PES) with the newer generation everolimus eluting stent ( EES); the COMPARE trial randomized PES to EES in 1800 patients to report that the composite of death, MI and target vessel revascularisation by the end of 1 year was significantly better with the newer generation EES ( Lancet 2010;375:201-9). By 2 years the difference was almost 5 % ( 13.7% versus 9%); with stent thrombosis lower by 77% and MI reduced by 45%( 7.5% versus 3.9%) ( J Am Coll Cardiol 2011;58:11-18). The SPIRIT IV trial ( N Engl J Med 2010;362:1663-74) too found that the composite of death, MI and target lesion revascularisation was significantly less with EES as compared to PES in 3687 randomized patients, at one year follow up.
The ENDEAVOUR III trial, albeit randomized only 436 symptomatic patients with single vessel disease to zotarolimus eluting stent ( ZES) versus sirolimus eluting stent ( SES); at the end of 5 years death/ MI was significantly less with ZES than with SES ( 1.3% versus 6.5%). The simple conclusion was that death/ MI was less with ZES than with SES ( JACC Cardiovasc Inter 2011;4: 453-50).
The message is clear, earlier generation stents are inferior to the newer generation stents where clinical outcomes are concerned. The newer stents with much thinner struts induce less inflammation of vessel walls, and therefore are clinically more durable.
The FREEDOM Follow On trial with a median 7.5 years follow up should be assessed against the above backdrop. FREEDOM randomised 1900 patients ( mean age 63 years) with diabetes to either CABG or PCI. Eighty three percent had 3 vessel disease with SYNTAX score of 26; but 33% of patients had a high SYNTAX score greater than 33. About 35% of patients had a low SYNTAX score of less than 22. It should be noted that the majority of patients studied had a high or intermediate score; all guidelines proscribe PCI in such patients of multivessel disease with intermediate and high SYNTAX scores.The extended follow up of FREEDOM at reports significantly less death in the CABG cohort as compared to PCI ( 18% versus 24%, p=0.01). An absolute decrease of 6% and a relative decrease of 25%. CABG showed better results in every subgroup and crucially provided better results in younger patients (JACC 10.1016/j.jacc.2018.11.001).
The FREEDOM trial however must be carefully analysed. The number of patients available for following by the researchers were a mere half of the original groups, a substantial mitigation in the number studied.
There are almost 10 million new cases of tuberculosis (TB) in a calendar year with around 1.7 million deaths. Worse we now have more than half a million patients of multi drug resistant TB ( MDR TB) ,with 10% of these being extensively drug resistant TB ( XDR TB). The definition of MDR TB is drug resistance of TB bacilli to rifampicin and isoniazid, while XDR TB constitutes added resistance to quinolones and second line injectables like amikacin and capreomycin. Successful treatment of MDR TB is quite difficult with an average success rate of less than 50%. Treatment is of long duration and extends for at least 20 months. Mercifully, WHO has come out with a revised simpler protocol for managing MDR-TB.Medicines have been regrouped based on latest clinical evidence.
Group A : medicines to be prioritised , Levofloxacin, bedaquiline, linezolid.
Group B: medicines to be added next: cycloserine, terizodone, clofazimine.
Group C: medicines to complete regimen or when drugs from groups A and B cannot be used; ethambutol, pyrazinamide, delamanid, ethionamide, prothionamide, PAS, streptomycin, meropenam, imipenam.
Kanamycin and capreomycin are no longer recommended because of relapse, toxicity and treatment failure.
A shorter regimen lasting 9 to 12 months has been observed to have similar efficacy as with the longer schedule, but with a higher chance of relapse. Quinolone, bedaquiline and linezilod have become top priority drugs while the injectables have been downgraded if not removed entirely from the list. Delamanid comes in group C because of limited data regarding its efficacy. Read More…
The advantages of an arterial graft during coronary artery bypass graft operation is well recognised; largely because of the fact that an internal mammary graft will remain patent as long as 20 or more years. It has been known for decades that more than 90% single internal mammary artery graft (SIMA) are patent into the third decade post CABG, while more than two thirds of venous grafts get blocked by 10 years. A systematic review and meta analysis had previously documented significantly reduced mortality with bilateral internal mammary grafting (BIMA) as opposed to SIMA accompanied by venous grafts, albeit this included observational studies that had a collective cohort of more than 15,000 BIMA patients. The mean follow-up was around 4 years only. It was explained that the reduced mortality was a consequence of greater patency associated with BIMA ( N Engl J Med 2016;375: 2540-46).
Despite the promise of prolonged survival associated with BIMA less than 5% North American cardiac surgeons use bilateral internal mammary graft technique, the statistic from Europe being marginally better, around 10% surgeons employ BIMA ( Circulation 2014;130:539-45).A meta analysis with a 10 year follow up also demonstrated reduced mortality when BIMA is used as opposed to SIMA, but surgeons continued to be hesitant. The reasons for their reluctance were largely that BIMA was far more challenging and the incidence of sternal infection was markedly increased. Also there was little or no randomised data.
Another meta-analysis of 29 observational studies including almost 90,000 patients noted that overall the BIMA group had significantly better long term survival than the SIMA cohort (HR 0.78; p< 0.00001). The BIMA group also had significantly lower in hospital mortality, cerebrovascular accidents, and requirement for revascularization. However the incidence of deep sternal wound infection was significantly more in the BIMA cohort ( 1.8% vs. 1.4%, p = 0.0008), (Heart 2017;103:1419-26).
Patients of type 2 diabetes will be relieved and even downright happy to learn that finally a double blind randomized trial using an oral insulin preparation has been published. The researchers report that an oral insulin preparation developed by the company funding the trial was found to be as defective as an injection of basal insulin in reducing fasting glucose level. Insulin was developed more than a century ago, the big downside despite saving lives was the needle prick. The early injections must have been an ordeal, but over the years we have pen filled insulin preparations with very fine needles that are almost not felt. Yet a needle prick once or twice a day every day for years is not a prospect one looks forward to, and there are lakhs and lakhs of patients with diabetes.
The latest Lancet endocrinology issue carries the first randomized trial on oral insulin ( Lancet Diabetes Endocrinol ; published online Jan 21, 2019;) and also an editorial applauding the effort of the researchers. Fifty patients of type 2 diabetes who were insulin naive but not controlled adequately on metformin or other oral anti diabetic medication were randomized to injection insulin glargine or a basal oral insulin preparation ( I338). Twenty five patients got the oral insulin once a day only and a dummy subcutaneous injection while the remainder received insulin glargine injection plus a once a day dummy oral preparation. At the end of 2 months fasting glucose had dropped to a similar extent in both groups (43 mg% and 47 mg %) . There was also no differences in the drop in HbA1C level in both groups (0.75% with oral insulin and 1.05% with injection.
Rightly or wrongly it is being suggested that cardiologists begin managing patients with diabetes with the realisation that 2 new classes of drugs have a beneficial effect on cardiovascular outcomes. Albeit oral hypoglycaemic agents have been used for decades in the treatment of diabetic patients no clear signal indicating salutatory cardiovascular effects has ever been recorded. The United Kingdom Prospective Diabetes Study (UKPDS) studied metformin versus diet control ( only) in overweight diabetics ( > 120% of ideal body weight)and came to the conclusion that metformin significantly reduced mortality as compared to diet alone therapy. Metformin also reduced mortality when compared to a sulfonylurea or insulin. But when metformin was added to sulfonylurea treatment there was increased mortality.
Metformin has been considered all these years as the go to therapy in patients with diabetes, especially because it induces less hypoglycaemia and less increase in weight. The problem with the UKPDS study is that only 342 patients got studied on metformin, this number would be considered a pittance in contemporary clinical research.
One should be wary of metformin in patients with diabetes having impaired kidney function. American guidelines proscribe use of metformin when creatinine is greater than 1.5 mg%, while British guidelines urge caution with metformin once GFR is less than 45 ml/ min/ 1.73 m2. It should be noted that insulin also requires reduction in dosage when GFR gets below 50ml/ min. Similarly most if not all sulfonylureas should be avoided in the presence of impaired renal function. Glimeride is not to be used if the GFR <60 ml/min, as also glibeclamide and glyburide are contraindicated with GFR <60 ml/min.The only sulfonylurea to be used safely in diabetics with impaired kidney function is glipizide as it is largely eliminated by the liver (Clinics 2016:71: 47-53).