DIABETES

DIABETES

 

I am not a 'Diabetologist'.  Don't rush to me for treatment.  --  T. Rama Prasad

                           

BLUE  CIRCLE  is the 'Universal Symbol' for  Diabetes

                                                                                             

DIABETES  and  COVID-19  -- October 2020 /  2022 /  2023

            The impact of the COVID-19 pandemic on diabetes brought to the fore the research on this formidable duo.  The evidence base is still a moving target even three years  after the entry of the Corona.  There is growing evidence that diabetics are at a higher risk of severe complications of COVID-19, and that the pandemic has substantially increased the diabetes burden on its own for unclear reasons ( Rama Prasad. T., The Long COVID.  The Antiseptic, 2022 October; Vol. 119; No. 10; P: 12-19; Indexed in IndMED – www.antiseptic.in 

A brief introduction to the writer, in the context of his writings on COVID & DIABETES :

Dr. T. Rama Prasad is the WORLD RECORD holder of authoring  28 articles related to COVID-19 in 30 months, published in a medical journal (The Antiseptic – www.theantiseptic.in -- Indexed in IndMED), and reporting in the same journal the WORLD’s FIRST CASE of ‘Yellow Nail Syndrome’ associated with COVID-19, PT & DM (https://drtramaprasad.blogspot.com/2017/04/yellow-nail syndrome_28.html  ;  The significance of the association with DIABETES in this case is not known.)  He wrote his first article in the premier journal, The Antiseptic, four decades ago.  Many of his articles written over half-a-century may be accessed at https://drtramaprasad.blogspot.com/2017/04/dr-t-rama-prasad.html  &  https://drtramaprasad.blogspot.com/2017/04/my-in-newspapers_28.html   &  https://drtramaprasad.blogspot.com  . )

        It is well known that hyperglycaemia impairs defences and promotes infections.  The interplay between diabetes and COVID-19 entails a complex pathophysiology which may lead to acute metabolic complications such as  uncontrollable diabetic ketoacidosis and uncontrollable hyperglycaemia.  To date, the mechanisms underlying the "conspiracy of this duo" are unclear.  Nevertheless, it may be presumed that involvement of the Angiotensin Converting Enzyme 2 (ACE 2) receptors, a binding site for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is responsible.  The ACE 2 is expressed in the key metabolic organ of diabetes, the pancreas --   especially the beta cells.  This results in impairment in insulin secretion.  

        The virus may also precipitate Type 1 diabetes.  In many of the cases of COVID-19, diabetic status got worsened, and in some cases diabetes had set in as a new problem.  And, some patients on regular oral hypoglycaemic agents went out of control and had to be given insulin,  without obvious history of contracting the virus.  Were these cases infected with the virus and had the pancreas damaged, but didn't have any significant symptoms of Covid (many normal people are infected without the manifestation of any Covid symptoms)  ?  At present, there is no answer. To know more about this, look into my article :  Rama Prasad. T., The Long COVID.  The Antiseptic, 2022 October; Vol. 119; No. 10; P: 12-19;

                Indexed in IndMED – www.antiseptic.in

STRESS

        The ominous and looming Corona and the trail of economic destruction it left in its wake has imposed a worldwide stress of humongous proportions.  The resultant stress, anxiety, tension and depression is causing enormous morbidity and mortality across the world.  Diabetes may be one of the diseases affected through neurohormonal influences of stress.

BAD  LIFESTYLE

        Owing to increasing bad lifestyle habits,  diabetes has grown by leaps and bounds during the previous half-a-century.  It remains to be seen as to how much more it would grow aided by SARS-CoV-2.  Human physiology and pathology is a highly complex one, interlinked with all the systems in the body.  Often, diabetics think that their problem is linked only to 'blood sugar'.  In the same way, people diagnosed with many other diseases or disorders focus only on things related to those systems.  Often, it's a combination of many abnormalities which may or may not show up as symptoms.  

        Anyway, some common things may be taken care of -- glycated haemoglobin (HbA1c) to be around 6.5 %; blood pressure around 130/80 mm/Hg; LDL cholesterol around 50 mg/dl.  Generally, a good lifestyle (healthy diet, adequate exercise and sleep, & low stress) ensures normalcy of these three parameters without medicines.  These four  things of 'good lifestyle' takes care of not only diabetes but also of several other metabolic diseases.  Of course, it's easier said than done in this 'MODERN WORLD' !!!

Diabetes mellitus, commonly known as diabetes, is a metabolic disease that causes high blood sugar. The hormone, insulin moves sugar from the blood into the body cells to be stored or used for energy. With diabetes, the body either doesn't make enough insulin or can't effectively use the insulin it does produce.

About 422 million people worldwide have diabetes, the majority living in low-and middle-income countries, and 1.6 million deaths are directly attributed to diabetes each year. Both the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades. 

OLD is GOLD !!!   Up to 1980s,  we used to test blood sugar after giving a drink of glucose solution (Oral Glucose Tolerance Test or OGTT) to detect diabetes or predict the risk of developing diabetes.  Later we have been using FPG, PPPG, HbA1c, MBG, etc. for that purpose, giving up the OGTT.   Now, in 2024, the International Diabetes Federation (IDF) has recommended 1-h PG test (blood sugar one hour after a drink of 75 gm of glucose solution) to identify the risk of developing diabetes -- Intermediate Hyperglycaemia (IH or Pre-diabetes or Impaired Glucose Tolerance - IGT) and Type 2 Diabetes (T2D) , setting aside HbA1c, FPG and PPPG of 2-hours.  A level below 155 mg/dL is considered as normal, and a level above 209 as indicative of T2D.  A level in between these two is IH or IGT or Pre-diabetes.  With the implementation of this recommendation, more "normal" people would come into the net of "diabetics", to the joy of some pharmaceutical and medical establishments !!!  Some details of the recommendation are in the report below:

The 1-h PG test may be used to detect "future diabetics" with just one prick.  The tests that are conventionally being used now for control of diabetes and detection of diabetes may continue to be employed.

In those days, we used to monitor diabetics mostly by doing Benedict's Test (heating Benedict's reagent mixed with urine over an open flame).  It's almost forgotten now.

With the country having the highest number of diabetic patients in the world, the disease is posing an enormous health problem to our country today. Often known as the diabetes capital of the world, India has been witnessing an alarming rise in incidence of diabetes (more than 50 million) according to the International Journal of Diabetes in Developing Countries. According to a World Health Organization (WHO)'s fact sheet on diabetes, an estimated 3.4 million deaths are caused due to high blood sugar.

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DIABETES  NOW (2020s)

---------  India had 64.5 million diabetics in 2015  compared to 11.9 million in 1980 (study by The Lancet released in 2016) and 101 million (ICMR-INDIAB study) in 2020s.  Nearly half of them were women.  And, there are 136 million people with 'pre-diabetes' in India now.  A recent (2023) ICMR-INDIAB study published in The Lancet found that 11.4% of Indians had diabetes while 35.5% were hypertensive, 39.5% had abdominal obesity and 32.1%had hypertriglyceridemia.

----------  In Tamil Nadu, 10% of the adults in rural areas,  15% in urban areas and 25% in Chennai city are diabetics.  And, double this number are 'pre-diabetics'.

---------  It is obvious that the alarming difference in the figures is due to 'BAD LIFESTYLE'  --  insufficient exercise,  excessive consumption of 'bad' foods,  etc.  -- read about them under the heading 'Food, exercise & sleep' on this blog.   Most of the "fashion foods" of the day which are considered as "normal" by the "modern folk" contain excessive amounts of the deadly "FSS (fat, sugar & salt) ... processed and semi-processed foods, sweetened soft drinks, colas, pizzas, burgers, noodles, chips, etc.

                                                        --  Dr. T. Rama Prasad

"Look, I am human.  It's hard to be fair sometimes.   We don't always feel the right thing, do the right thing."  --  Stephenie Meyer

In my experience of over half-a-century in medical profession, not many diabetics strictly followed diet or life-style advice.  That's because they are 'HUMANS' as in the quote above !  It may be obvious that humans can't kill their tastes for the rest of the life !

REVERSAL of DIABETES

Sometimes, people are needlessly scared by showing statistics (true / false) or comforted by the very recent concept of 'REVERSAL' or 'REMISSION' of diabetes  (this is now being debated).

Around 2023,  the Internet is falloff promises to "reverse" diabetes, especially by using "Continuous Glucose Monitoring (CGM)" devices.  These devices consist of a patch on the skin of arm which upon scanning shows instant level of blood glucose.  It is without a needle prick and a glucometer.  Otherwise it's the same mechanism used by the 'glucose strips'.  As it is painless and very easy, it's more acceptable to the people to frequently monitor and adjust diet, exercise and medicines which may lead to better control.  But, misleading ads and claims are made to reverse diabetes.  One should be vary of the commercial gimmicks to sell CGMs and subscription plans for 'diabetes reversal'.   Of course, in some milder forms of diabetes, there may be periods of "remission" (good control without medicines), not "reversal".  This usually occurs following 'life-style' modification.

The latest & the futuristic 

Emerging Role of AI in Diabetology

Diabetes accounts for an estimated 1.6 million deaths each year globally.

But there’s hope! Advances in diabetes management and healthcare have significantly improved mortality rates. 

Artificial Intelligence (AI) is revolutionizing diabetes management through continuous glucose monitoring devices, offering real-time data to patients and healthcare providers, helping with immediate adjustments to insulin, and modifying dietary intake for better glycemic control. These proactive measures can improve diabetes management significantly.

          To date, the advanced form of 'insulin injection' delivery is through an "open-loop" system made of electronics likened to 'artificial pancreas'.

           Now, a "Smart Gel" is in the pipeline.  This is a new user-friendly, electronics-free insulin delivery device that works like 'artificial pancreas' to distribute insulin in response to changing glucose concentrations.  Researchers from the Tokyo Medical and Dental University have tested this design in mice.  This "Smart Gel" uses a glucose-sensitive gel to deliver the appropriate amount of insulin through a catheter via a "closed-loop" approach.  When the blood glucose levels are high, the gel becomes more permeable and releases more insulin, and when the glucose level is low, the gel develops a less permeable, skin-like layer to decrease insulin supply (Science Advances).

          We have developed a number of drugs and devices to control diabetes, but we couldn't find the exact cause which makes one a diabetic, except blaming the imperfect lifestyle or the genes.  Perhaps, multiple factors are involved -- some known and some unknown ... even the toothpaste may be the one !  Researchers from the University of Texas found (2018) that crystalline particles of titanium dioxide were found in pancreas specimens from Type 2 diabetics.  Titanium dioxide has become the commonly used white pigment in paints, food items, toothpaste, cosmetics, plastics and paper.

On  09.07.2017  at a 'Diabetes Symposium'

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 DIABETES   DECADES   AGO

Dr. T. Rama Prasad

               It was in 1967 .. half-a-century ago.  I entered  'Perundurai Sanatorium'  to join as a 'Medical Officer'.   The first patient I saw was a case of 'Diabetic Foot' with 'Pulmonary Tuberculosis'.   At that time, there were no 'Diabetologists' here around .. and there were not many diabetics .. we used to walk or cycle .. not much junk food .. a different lifestyle.  During the 'Roman Empire' era, Galen, the Roman physician observed that he saw only two cases of diabetes in his entire career !  Lifestyle has changed a lot since then.  This patient had to undergo amputation of the foot and also 'Thoracoplasty'.  Patients were reluctant to have 'Insulin Injections', and doctors were also hesitant to prescribe the injections.  Perhaps, 'modern therapy' could have saved his foot and the ribs. 

         Even in those days, I used to 'scribble' something for publication.  Hereunder are a few reprints of the published writings which are of 'archaic knowledge and of historical interest' at this point of time -- 2017 - 2024.  They may hardly have any relevance to the present scenario.

                                        --  T. Rama Prasad

June 1980 issue of the journal ANTISEPTIC.   HIGHLY PURIFIED INSULINS -- an assessment.  Author :  Dr. T. Rama Prasad  (more than 40 years ago when I used to type the articles on a manual typewriter and send them by 'Registered Post' ! )

Sept/Oct 1981issue of the journal THE MEDICINE & SURGERY.                                           DIABETES and TUBERCULOSIS.

Sept/Oct 1981issue of the journal THE MEDICINE & SURGERY.                             DIABETES and TUBERCULOSIS.

January 14, 1983 issue of THE HINDU -- a comment on Prof. Ramdas's observation

NEW DRUGS in DIABETES in 1998

FB id: T Rama Prasad                                                                   Reprinted from the FACEBOOK

                DIABETES – new drugs … February 21, 2017

We just had a meeting of ‘Continuous Medical Education’ programme.  I would not have posted this on FB as this is more of a pharmacological subject.  But the home truths and the snide remarks about our drugs may be thought-provoking to the public and the doctor friends as well.

In my little talk at the meeting, I said something like the following:

            “ … It is a refreshing experience to learn more about the age-old and important problem of ‘Diabetic Foot’. Thank you very much Dr. E. Thangavelu for enlightening us.  This subject takes me down memory lane kindling nostalgic thoughts.  It was half-a-century ago ( in 1967 -- most of you who are here now were yet to be born at that point of time ! ) when I  joined as a Medical Officer at the ‘Perundurai Sanatorium’,  and the first case I saw was a patient with ‘diabetic foot’ with gangrene and lung TB.  There were no big corporate hospitals or diabetologists here around and there were not many alternative drugs to diabetes or TB.  And today we are talking about ‘new’ anti-diabetic drugs while the incidence of diabetes and TB has been increasing enormously over the decades.

The world is currently having a great hope on the novel treatment of Type 2 diabetes by DPP-4 inhibitors. The status and the concern about the cardio-vascular safety of this new class of drugs is well-articulated by Dr. S.P. Hemanand. Thank you very much Dr. Hemanand for lucidly and comprehensively presenting the subject.

              There are many DPP-4 inhibitors;  some are in various stages of clinical development.  The first approved DPP-4 was sitagliptin in 2006.  Later, vildagliptin, saxagliptin, alogliptine, linagliptine, anagliptin and teneligliptin were introduced. Phase III studies are in progress with regard to more gliptins like denagliptin.  The incretin agents (GLP-1 receptor agonists and the DPP-4 inhibitors) belong to a unique class of anti-diabetic agents.

There is a huge body of evidence of the goodness of DPP-4 inhibitors,  beyond their hypoglycaemic effect. They have pleiotropic properties which improve b-cell function;  reduce postprandial lipemia;  lower blood pressure;  improve myocardial contractility and endothelial function;  and have potential neuroprotective, neurotrophic, and bone resorptive effects.  These benefits of the incretins, if confirmed in long-term studies, have the potential to favourably influence the course of the disease process and its complications in patients with type 2 diabetes.

As the DPP-4 enzyme is involved not only in the regulation of glucose but also several substrates like BNP, brain natriuretic peptide; SDF-1, type 1 stromal derived factor; NPY, neuropeptide; PYY, peptide YY, DPP 4 inhibitors may have cardio-protective benefits and immune-modulating actions. Thus, they favourably modify myocardial contractility, blood pressure, cardiac output, etc. ALL THIS IS MUSIC TO THE MANUFACTURERS.

Now, let us turn to the flip side of the issue. These new drugs are ‘validated regarding surrogate outcomes’ but not about ‘real-world outcomes’. Sometimes, adverse evidence comes a bit late, often due to vested interests. Often, the “pro-industry ‘paid’ cacophony” overshadows reports of adverse reactions. Some drugs once considered to be ‘most effective and least toxic’ are now banned. Evidence is now growing to list some statins as dangerous drugs. We don’t know about the durability or long-term safety of the DPP 4 inhibitors. The jury is still out on DPP-4 inhibitors. Let us wait and see.  AND, THIS IS A BITTER PILL TO THE BIG BUSINESS BARONS.

All said and done, the world is running on money, including research.  The big business barons go to any extent,  laughing all the way to the bank. These days, scientific evidence may be genuine or fabricated, what with all the talk about “paid research.”  The evidence is too much to ignore.  This reminds me of a scientific flip-flop in India. The diabetic drug, pioglitazone was ‘banned’ in India in 2013.  And the government made a ‘U-turn’ and the ‘ban’ was revoked within weeks.  Can any one of you tell me why such a laughable lapse occurred ? It was alleged that a DPP-4 inhibitor drug was behind the ban of pioglitazone ! There were allegations in the media and medical circles that the reason behind the ‘ban’ was based on adverse reports (bladder cancer) on pioglitazone from a diabetes research institution in India which received funds from a medical company whose new diabetes drug sitagliptin stands to gain if pioglitazone was banned. Do you think that there are genuine and scientific reasons behind the decisions ? You bet not. Lies, damned lies and drugs !

I wrote about many of such murky deals in my article titled “MODERN MEDICINE – how good is it in India ?” You may get that article by writing to me over my E-mail.  It was published in the ‘Co-Chamber Journal (The Indian Chamber of Commerce and Industry)’. … ” 

“Unless the thief decides to transform himself,
it is never possible to eradicate stealing.”     (“ thirudanai parthu thirunthavital thirutai olika mudiyathu.”)

                    -- Pattukottai Kalyanasundaram

Dr. T. Rama Prasad,
drtramaprasad@gmail.com, 'PAY WHAT YOU CAN’ Clinic, Perundurai, Erode Dt., TN, India., Former Medical Superintendent (Special), RTS & IRT Perundurai Medical College and Research Centre.

    

Reprinted from the FACEBOOK

DIABETIC FOOT     July 9, 2017

I have just returned from a Symposium on the above subject.  Many people pay 'low' attention to their feet, perhaps, as they are 'low down' ! Diabetics should pay adequate attention to their feet (more than the face which is 'high up').  Otherwise, even a minor injury may make the feet end in complications.  Foot has a low status in human minds. We profusely apologise when accidentally our foot just touches any part of anybody, even their foot .. but not when our hand touches.  What a partiality !  Foot does more strenuous work than the hand .. hence, we have “Diabetic Foot” (disease), but not “Diabetic Hand” !  But, paradoxically, we touch the feet of somebody to express our reverence and respect,  and to seek blessings ! A conundrum !  Anyway, please respect the foot.  You may read about 'new' drugs in diabetes on my blog - Dr. T. Rama Prasad's Scribblings  --  https://drtramaprasad.blogspot.com. – under the title ‘DIABETES’.

I had asked one of the speakers, in a lighter vein, as to whether diabetic foot problems are more in the right foot or the left. He couldn't cite any data. Traditionally, we are advised to put the right foot first, while entering a house or going up the steps. I was wondering whether the practice of always 'starting off on the right foot' makes the right foot more vulnerable to injuries and   infection ! 

Feet have long been the subject of superstition. A mole on the sole of the left foot is said to be inauspicious. When the right foot itches, a happy travel is predicted. The right foot is associated with a positive vibe.

The tennis star, Rafael Nadal was always found to put his right foot first while leaving or entering a tennis court without touching the lines. See the video -- file:///Users/ramaprasadtata/Pictures/Tennis.html.

Dr. T. Rama Prasad, Perundurai.

SUGAR  STRENGHTHENS  !!!

So, diabetics must be stronger !!!

COMMENTS

Raghu Rangaswamy Hi Dr. I do accept your comments. It’s sad to say many drugs which are banned abroad citing various proven evidences are still marketed in India, which clearly indicates money can do anything in this country. I have no idea who will tie the bell to these mafias. I appreciate the recent Govt's action on bringing down the cardiac stent prices by 80% lower, the same thing should be brought on medicines too. Being in medical research I would say every medicine you take is a chemical and it’s not going to give you miracle. They bind to certain receptors which are responsible for a disease, but one can't assure the same chemical will not bind to other receptors and block the natural body function. The reason is body produces few chemicals which interacts with many receptors. For example ATP binds to nearly 300+ kinases which are involved in different body functions, when you design a kinase inhibitor even though your molecule binds to your desired kinase but it will also bind to other kinases because of the protein structural similarity. The best way one should do is to have  control on the food, to change life style and to prefer  natural remedies. Being in modern medicine profession, I will still give my vote to ayurveda and naturopathy. I still vouch that our ancestors were more knowledgeable than today’s technologically advanced scientists. I wonder how they identified certain herbs and plants for diseases.

Like · Reply · 3 · 11 hrs

Sivaraman Subramanian What a wonderful article sir ! ...Great depth of knowledge, in-depth understanding of the real situation...Great eye-opener sir.. Thanks Sir.

Like · Reply · 1 · 10 hrs

Solaiappathevar Narayanan Thank you Dr. T. Rama Prasad garu for your thought- provoking article.
Now, can we hope to get the desired results through stem cell therapy enhancing Beta cells of Islets of Langerhans which produce chiefly insulin. This can help overcome insulin resistance.
Our native herbal medicines should be encouraged on scientific lines.

Like · Reply · 9 hrs

Damarla Nalini Useful Article Uncle

Like · Reply · 
9 hrs

Like · Reply · 9 hrs

Nazarmohamad Nazar dr very useful article sir and also an eye opener.

Like · Reply · 9 hrs

DrThangavel TA 100% Truth about false tall claims...TR💐

Like · Reply · 9 hrs

Saminathan Rozario Money can do anything in this country.   

Like · Reply · 9 hrs

Anbhu Selvan Ips Good one sir very useful article and thoughtful sir

Like · Reply · 8 hrs

Muthu Raja sir,i still remember the visual aid and detailing talk about tolbutamide in the year 1978.the drug metformin which is widley in use today launched after long delay in 1974.sir,you are the only doctor who has the guts to write about the real reason behind the ban of pioglitazone.  All the formulations are sold with doctors prescription.  Pattukottaiyar rightly said thirudanai parthu thirunthavital thirutai olika mudiyathu..

Like · Reply · 2 hrs

Sridhar Vatyamkumaraswami Having been in pharma marketing for about 30 years,I concur with you.Today's medico marketing is one sided.They have been bothered about converting or convincing some opinion builders,  a small section of Doctors whose prescriptions are followed.

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http://www.iosrphr.org/papers/v3i3/M0331081085.pdf

            Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.

Acts when sugar increases after a meal, increases insulin levels (help lower blood sugar) and decreases glucagon (a hormone that raises blood sugar) Linagliptin (Trajenta™), Saxagliptin (Onglyza®), Sitagliptin (Januvia®) Combination agents: Linagliptin/metformin (Jentadueto®), Saxagliptin/metformin (Komboglyze™), Sitagliptin/metformin (Janumet®)  In the future further gliptins (alogliptin, linagliptin, denagliptin) may be marketed, with which Phase III studies are in progress or the results have already been published. . At present, there seems to be little to distinguish between the different inhibitors in terms of their efficacy as antidiabetic agents and their safety. Long-term accumulated clinical experience will reveal whether compoundrelated characteristics lead to any clinically relevant differences.

P 1 analogues; incretins I. INTRODUCTION DPP 4 (dipeptidyl peptidase-4) inhibitors are the recently developed and approved chemical for the treatment of the diabetes mellitus. They act mainly on pancreas via inhibition of degradation of the incretin hormones such as type 1 glucagon like peptide (GLP-1), and GIP. The Incretin hormones are release from the intestine in response to oral glucose ingestion and stimulate insulin release from β-cells of pancreas (so called incretin effect), and also suppress glucagon release from α-cells of pancreas. DPP-4 inhibitors are approved for the treatment in Type 2 diabetes either as monotherapy or as add-on therapy with other oral hypoglycemic agents like metformin. There are numerous DPP4 inhibitors; some are in various stages of clinical development. The first approved DPP4 was sitagliptin in 2006. Then vildagliptin, saxagliptin, alogliptine, linagliptine, anagliptin and teneligliptin were introduced.

es like Parkinson’s disease and alzeimer disease. IX. CONCLUSION The incretin agents (GLP-1 receptor agonists and the DPP-4 inhibitors) belong to a unique class of antidiabetic agents. These agents have pleiotropic effects that extend beyond their known ability to lower glucose. These include effects to improve b-cell function and mediation of trophic effects on the b-cell (in animal and in vitro models); effects to reduce postprandial lipemia; effects to lower blood pressure; effects to improve myocardial contractility and endothelial function; and potential neuroprotective, neurotrophic, and bone resorptive effects (seen only in animal models). These beneficial effects of the incretins (if confirmed in longterm studies) have the potential to favorably influence the course of the disease process and its complications in patients with type 2 diabetes. 

DPP 4 (dipeptidyl peptidase-4) inhibitors: beyond glycemic control 83 III. CARDIOVASCULAR PROTECTION Effect on Myocardial function Heart failure, myocardial infarction, cardiac hypertrophy and coronary artery disease is often associated with diabetes and metabolic syndrome. As the DPP-4 enzyme is involved not only in the regulation of glucose but also several substrates (like BNP,brain natriuretic peptide; SDF-1, type 1 stromal derived factor; NPY, neuropeptide; PYY, peptide YY) known to have cardiovascular, renal and immune-modulating actions. Thus long-term DPP-4 inhibition may have clinical benefits and/or consequences including cardioprotective actions. Effects on contractility, blood pressure, cardiac output and cardioprotection appear to be independent of diabetes [12-19] . A few studies have been published on cardioprotective effect of GLP-1 analogues and DPP 4 inhibitors. In studies done on mice genetically lacking the DPP-4 receptors that were treated with sitagliptin, the investigators induced acute myocardial infarction by left anterior descending coronary artery ligation (20). In these mice, an upregulation of cardio-protective genes and their protein products was shown. In another study in mice, it was shown that treatment with sitagliptin can reduce the infarct area and the protective effect of sitagliptin was protein kinase A dependent (21) . In diabetic patients who suffer from ischemic heart disease, it was demonstrated that treatment with sitagliptin improved their heart function and coronary artery perfusion, as observed in echodebutamin tests (22) . IV. EFFECT ON BLOOD PRESSURE The effect of DPP 4 inhibitors on blood pressure is contradictory. In diabetic rats, sitagliptin was associated with a significant normalization of blood pressure in diabetic rats with elevated blood pressure (versus non-diabetic rats)(23) , whereas vildagliptin showed no influence on blood pressure in hypertensive fatty rats (24). Recently, a study by Marney et al.(25), in metabolic syndrome patients, showed that during placebo and low-dose ACE inhibition (5 mg enalapril), sitagliptin lowered blood pressure. However, this trend was reversed during higher-dose acute ACE inhibition (10 mg enalapril). They hypothesized that the combination of sitagliptin and high-dose ACE inhibition causes activation of the sympathetic tone, hence attenuating blood pressure reduction. Marney et al. suggested that high levels of substance P, because of the double blockade of ACE and DPP-4, caused the activation of the sympathetic system. V. ENDOTHELIAL FUNCTION Endothelia dysfunction is an independent predictor for cardiovascular events in patients with type 2 diabetes. In some studies it was found that GLP-1 has some vasodilatory action and Sitagliptin significantly improved endothelial function and inflammatory state in patients with coronary artery disease and uncontrolled diabetes mellitus. VI. LIPID METABOLISM DPP 4 inhibitors found to decrease the postprandial surge in lipid levels. Matikainen et al.(26) in his study found that treatment with vildagliptin for 4 weeks improves postprandial plasma triglyceride and apolipoprotein B-48–containing triglyceride-rich lipoprotein particle metabolism after a fat-rich meal in drugnaive patients with type 2diabetes. Hsieh et al. (27) also suggested that DPP 4 inhibitors augment the level of GLP-1receptors thus reduce secretion of tryglycerol, cholesterol, and apolipoprotein B-40 from intestine. Antiatherosclerotic effect has been found in some model by reducing media-intima ratio in carotid artery of rat in dose dependent manner. 

ulature. 3.4 Cardiovascular effects Although it summarized the results of studies with non-cardiovascular endpoints, a metaanalysis investigating the safety of sitagliptin (100mg/day) showed no substantial differences as compared to the control group in relation to coronary artery disease (0.2 vs. 0.4 event per 100 patient-years), myocardial ischemia (0.0 vs. 0.2 event per 100 patient-years) and acute myocardial infarction (0.1 vs. 0.2 event per 100 patient-years) respectively (Williams-Herman, Engel et al. 2010). A post hoc metaanalysis of saxagliptin’s effect on major cardiovascular events (CV death, non-fatal MI, non-fatal stroke) showed no increase of CV risk in the treated patients (Wolf, Friedrich et al. 2009). Recently, a large outcome trial with sitagliptin (A randomized placebo controlled clinical Trial to Evaluate Cardiovascular Outcomes after treatment with Sitagliptin in patients with type 2 diabetes mellitus and inadequate glycaemic control on mono or dual combination oral antihyperglycaemic therapy, TECOS) and with saxagliptin (Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus, SAVOR-TIMI 53) has been started. GLP-1 receptors can be found in cardiac muscle cells and vascular endothelial cells as well (Nauck and Smith 2009; Nikolaidis, Mankad et al. 2004). The beneficial effect of GLP-1 has been demonstrated also in coronary ischemia and left ventricular failure both in animal experiments and in human studies (Nikolaidis, Mankad et al. 2004; Bose, Mocanu et al. 2005; Nikolaidis, Elahi et al. 2004). In rats, myocardial necrosis developed in a smaller area when they received GLP-1 infusion (Bose, Mocanu et al. 2005). Following intravenous infusion of GLP-1, less wall motion disorder and better left ventricular function developed in patients with and without type 2 diabetes who had undergone angioplasty after acute myocardial infarction (Nikolaidis, Mankad et al. 2004). Based on these, a beneficial effect of DPP-4 inhibitors on cardiovascular disease may be presumed, however further long-term clinical studies with a high number of patients are required for an exact elucidation. www.intechopen.com 

In addition to severe joint pain, other possible side effects of DPP-4 inhibitors include inflammation of the pancreas, low blood sugar when this class of medicines is combined with other prescription medicines used to treat diabetes, and allergic reactions.
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