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Studies into Diabetes Treatments

INTRODUCTION

The word Diabetes is derived from the Greek language which means ” to run through ” which refers to the excessive urination (polyuria) which is a classical symptom of the condition.

The word Mellitus is derived from the latin language and means “honey” because urine from an untreated patient is sweet due to the presence of sugar.

By definition, Diabetes is a chronic metabolic disorder characterised by elevated levels of glucose ensuing from defects in secretion of insulin or insulin action or both of them. It is one amongst the foremost common metabolic diseases with intricate complex etiology and has wide-ranging biochemical and clinical manifestations.

The long term elevation in blood glucose levels of patient with diabetes is linked to secondary pathophysiologic changes, chronic damage, dysfunction and malfunctioning of varied organs notably the eyes, heart, nerves, blood vessels and also the kidneys.

PREVALENCE

The overall predominance of DM has grown dramatically over the  past 2  decades, from a measurable 108 million cases in 1980 to 422 million out of 2014. In perspective of current patterns, the International diabetes Federation predicts that 592 million individuals can have diabetes by the year 2035. In spite of the fact that the the prevalence of type 2 DM is rising far more quickly, presumptively as a result of increasing obesity, reduced activity levels due to industrialization of countries and also the ageing of the population.

Statistics depicts the countries with the maximum prevalence of diabetes worldwide in 2017 and the Marshall Islands was the country with the highest prevalence of diabetes, with some 33 % of its population aged between 20 and 79 affected by the disease. in this same year, just about 13 % of adults within the USA had diabetes, whereas solely 7.7 % of those in Japan had the disease.The other countries with the greatest range of people with diabetes are China, India, Brazil and the Russia. Up to 80 % of people with diabetes live in low-income or medium-income countries.

As per the statistics of diabetes UK from November 2017 there are virtually 3.7 million people who are diagnosed with diabetes in the United Kingdom, within which England alone have 3,116,399 patients with diabetes.

PATHOPHYSIOLOGY

The pancreas is an glandular organ of our body that anatomically sits behind the stomach and releases hormones into the gastrointestinal system. Within the healthy human body, once glucose levels gets too high, special cells in the pancreas (called beta cells) release insulin. Insulin is a secretion and it causes cells to take in sugar to use as energy or to store as fat. This causes blood sugar levels to go back down.

Type 1 diabetes occurs when our body’s  defense mechanism mistakenly attacks and kills the beta cells of the pancreas. Nil, or very minimal, insulin is released into the body. As a result, sugar builds up in the blood instead of being used as energy. About five to 10 per cent of people with diabetes have type 1 diabetes. Type 1 diabetes usually develops in childhood or adolescence, but can develop in adulthood.

The etiology of type 1 diabetes is multifaceted and may be divided into genetic and environmental etiology and possible gene environment interaction

The etio- pathophysiology of type 1 diabetes may be divided into  three distinct stages namely Stage 1 in which there is beta cell autoimmunity but patient is in normal glycemic state, Stage 2 in which there is loss of beta-cell secretary functions in autoantibody positive individual and leads to dysglycemia but still not symptomatic and in 3rd Stage there is a loss of beta cell secretary capacity to the extent that there is dysglycemia and the patient is symptomatic with symptom of diabetes.

It is well established. HLA associated beginning of beta cell autoimmunity and sharing of environmental factors contributes to beta cell autoimmunity and type 1 diabetes mellitus or both especially in families of type 1 diabetes HLA risk haplotypes.

The main putative environmental risk factors are gestational infections, viral infections, dietary factors such as vitamin D deficiency, short duration of breastfeeding psychological stress and toxic substances which directly damages beta cells.

So extensive advances has been made in comprehension of etiology   of type 1 diabetes mellitus as it relates to the appearance of beta cell autoimmunity before the clinical onset of the disease.

Studies such as TEDDY i.e. The environmental determinants of diabetes in the Young are needed to understand better environmental factors which may be responsible for triggering beta cell autoimmunity.

Type 1 diabetes also incorporates latent autoimmune diabetes in adults (LADA), the term used to potray the small number of patients with apparent type 2 diabetes who appear to have immune-mediated loss of pancreatic beta cells.

Type 1 diabetes is always managed with insulin. Meal planning also helps with keeping blood sugar levels within the range.

Type 2 diabetes happens when the body can’t properly utilize the insulin that’s released (called insulin insensitivity) or doesn’t build enough insulin. As a result, sugar builds up within the blood rather than getting utilized as source of energy. About 90% of individuals with diabetes have type 2 diabetes. Type 2 diabetes more usually develops in adults, however children may be affected.

Insulin resistance is a major factor in pathogenesis of type 2 diabetes but it can also be seen in some patients with type 1 diabetes.

Insulin resistance occurs in sequential pattern inserting into certain insulin responsive issues such as skeletal muscle, liver and the adipose tissue.

The major factors anticipating type 1 diabetes mellitus are male sex increasing age, low levels of physical exercise, junk food diet, overweight and obesity.

Insulin resistance is more commonly seen in persons with Metabolic syndrome which in addition to visceral obesity comprises of dyslipidemia, hypertension and dysglycemia.

For estimation of insulin resistance a homeostasis model assessment (HOMA) estimate of steady-state beta-cell function ( HOMA B)and insulin sensitivity (HOMA S) as percentages of normal is used for population estimation purposes. It mainly shows that Insulin resistance as an early abnormality is compensated by adding on of beta cell functioning much before insulin-glucose feedback  loop fails. It not only predicts type 2 diabetes mellitus but also co-relates with cardiovascular diseases and outcomes.

The association between obesity, ectopic fat accumulation and insulin resistance makes it very difficult to identify the tissue involved as the primary cause of insulin resistance.

Insulin resistance is likely the initial event preceeding in type 2 diabetes mellitus but it has always been a debate whether insulin resistance or beta-cell dysfunction is the primary essential defect and which one goes before the other.

Depending on the severity of type 2 diabetes, it’s going to be managed through physical activity and meal planning, or may additionally need medications and/or insulin to regulate glucose a lot effectively.

Gestational diabetes, is a temporary condition that occurs during pregnancy. It affects approximately two to four per cent of all pregnancies and involves an increased risk of developing diabetes for both mother and child.

MODY is a very uncommon kind of diabetes that is completely different from each type 1 and type 2 diabetes, and runs strongly in families. MODY is caused by a mutation (or change) in a single gene. If a parent has this hereditary change in gene, any child they have, contains a fifty per cent likelihood of acquiring it from them.

 

 

Other types of uncommon diabetes includes  :

 

  • Type 3 diabetes
  • Type 1.5 diabetes
  • Diabetes insipidus
  • Diabetes LADA
  • Diabetes MODY
  • Alström syndrome
  • Brittle diabetes
  • Cystic fibrosis related diabetes
  • Double diabetes
  • Drug induced diabetes
  • Glucagonoma
  • Hemochromatosis
  • Neonatal diabetes
  • Secondary diabetes
  • Steroid induced diabetes
  • Wolfram syndrome (DIDMOAD

 

 

 

 

Diagnosis of Diabetes-

The guidelines for diagnosing and classifying diabetes came into the effect in the United Kingdom in June 2000

The guidelines set up by the world Health Organisation are jointly adopted by the Royal College of Physicians, Royal College of General Practitioners and the Royal College of Nursing as well as Association of Clinical biochemists in consultation with Diabetes UK.

Diabetes mellitus is easily diagnosed on the basis of classical  symptoms such as polyuria, thirst and weight loss and blood glucose concentrations.

Guidelines states that patient have diabetes mellitus if patient is symptomatic and :

● Fasting glucose >_ 7.0 mmol/l

● Random glucose >_ 11.1 mmol/l

If the patient is asymptomatic the above criteria applies but must be demonstrated on two separate occasions.

Impaired fasting glucose (IFG) – Fasting glucose 6.1 to 7 mmol/l implies IFG.

 

Impaired glucose tolerance (IGT) – It is fasting plasma glucose < 7.0 and  Oral glucose tolerance test (OGTT)

2-hour between 7.8 – 11.1 .

About 50% off individuals with IGT reverts back to normal glucose tolerance within 10 years through weight loss and exercise. Some of them remains glucose tolerant and some of them develops type 2 diabetes mellitus. In these individuals

Risk factors for cardiovascular ailments are often elevated and should be treated appropriately.

 MANAGEMENT 

Like any other chronic illnesses diabetes mellitus causes a wide range of issues for patients and their family members. It is also associated with numerous acute and chronic complications which effects almost every major part of our body.

Multiple problems may occur if diabetes is not cared for.

In diabetes the blood sugar level gets high so to counteract or delay the complications the fundamental emphasis is on keeping the glucose levels under normal range.

The primary targets of treatment of diabetes mellitus are :

● Avoidance of hypoglycemia/hyperglycaemic symptoms

● Maintaining body weight

● Delay or prevent the onset of complication of diabetes

● Identify and treat any psychosocial issues associated with diabetes

In type 1 diabetes mellitus the hallmark is insulin deficiency due to the destruction of beta cells, so pillar of treatment is starting patients on Insulin based treatment.

Insulin treatment for type 1 diabetes expects to lower glucose level in blood as near to the normal as possible without causing significant hypoglycemia. Surgical procedures such as pancreatic transplantation and Islet cell transplantation are likewise accesible.

Management of type 2 diabetes requires consideration of various aspects of patients health so emphasis ought to be made on individual basis as each patient will be having different levels of diabetic complications and cardiovascular risk so care should be tailored according to the individual needs. Management of type 2 diabetes includes lifestyle modifications, dietary changes, drug treatment and even insulin based treatment.

Agents used in diabetes therapy includes biguanides, sulfonylureas, meglitinide derivatives, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, selective sodium glucose transporter 2 inhibitors, insulins, amylinomimetics, bile acid sequestrants, dopamine agonists.

Similarly, each type of diabetes requires distinctive level of approach to manage it to avoid long term complications.

TREATMENT THERAPIES

 

BIGUANIDES –

It actually means two guadino groups. The names of drugs in this class are Phenformin, Buformin and Metformin etc.

Phenformin and Buformin became known in 1950’s yet they were connected to a fatal condition called lactic acidosis which implies production of lactate exceeding its utilization. Along these lines Metformin hydrochloride was acquainted in 1980 due to lesser incidence of lactic acidosis with a mindful approach in view of particular acceptable range of serum creatinine which was diverse for males and females . It was affirmed in the year 1994 and advertised in 1995.

It acts by preventing the production of glucose in the liver and improving the sensitivity of our body towards insulin and the amount of sugar absorbed by the intestines.

It had additional benefits of reducing serum LDL concentration and not causing hypoglycemia or weight gain.

Adverse effects include lactic acidosis , diarrhea, vitamin B12 defiecency and abdominal discomfort.

THIAZOLIDINEDIONES –

 

These are also known as TZD’s or glitazones and they act by increasing the sensitivity of specific fat cells such as adipose tissue , liver and skeletal muscle to the insulin and therefore decreasing insulin resistance.

There are two medications in this class which are pioglitazone and rosiglitazone.

They acts by stimulation of PPARy receptors.

In a study in 2007, Rosiglitazone was found to be associated with increased risk of myocardial infarction and death which led to its usage decreasing dramatically.

They are contraindicated in Class III and class IV heart failure and is at increased risk of heart failure due to fluid retention.

 

 

GLUCAGON-LIKE PEPTIDE-1 AGONISTS –

 

GLP-1 stimulates the release of insulin from pancreatic beta cells and inhibits gluconeogenesis and glycogenolysis.

It slows gastric emptying and increases satiety after meals.

The drugs in this class are lixisenatide, liraglutide, semaglutide and exenatide.

Victoza (Liraglutide) is a once daily GLP-1 whose efficacy was checked in LEAD trial and it’s effectiveness was tested in comparison with exenatide in LEAD 6 trial which showed greater reduction of Hba1c with liraglutide.

The cardiovascular outcome trials of GLP-1 receptor antagonists are namely Elixa trial , Leader trial and Sustain 6 trial.

 

 

DIPEPTIDYL PEPTIDASE-4 INHIBITORS –

 

Dpp-4 inhibitors are also known as gliptins. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which annihilates the hormone incretin. Incretins enable the body to deliver more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed. These hormones are released throughout the day and levels are increased especially during meal times.

The drugs in this class are Saxagliptin, Alogliptin, Sitagliptin and Linagliptin.

Along with lowering the glucose level in our body gliptins help in reducing the appetite so have an additional benefit for those who are overweight and require to lose weight.

Adverse effects includes flu like symptoms , nausea and stomach pains.

They have been associated with risk of having pancreatitis.

Cardiovascular outcome trials of gliptins are SAVOR- TIMI 53 trial, EXAMINE and TECOS trial.

 

 

SELECTIVE SODIUM GLUCOSE TRANSPORTER 2 INHIBITORS –

 

SGLT2 inhibitors offers a different mechanism of action from the other antidiabetic drugs.

They acts directly on blood glucose by reducing the reabsorption of glucose from the renal tubules into the bloodstream leading to urinary glucose excretion and works independently of beta cell function and insulin resistance.

The drugs in this class are Empagliflozin, Canagliflozin etc.

Advantages are weight loss and reduction in blood pressure.

Adverse effects includes genitourinary infections, dehydration and increased risk of bladder cancer.

Cardiovascular outcome trials of this class of antidiabetic drugs are EMPA-REG trial and CANVAS trial.

 

INSULIN BASED TREATMENT –

Insulin is a hormone in our body which is produced by pancreas whose main action is to lower the level of blood sugar in our body.

It allows the cell to absorb the glucose and stores sugar in specialised tissues and muscles. It converts the additional glucose into fat and helps and absorption of amino acids and potassium. It also retain sodium in our body. Deficiency or resistance to insulin leads to classical diabetes.

In patient with diabetes depending on type and management strategy, Insulin is given subcutaneously.

There are two main groups of insulin used in treatment of diabetes i.e. Human insulins and analogues.

Analogues are made by recombinant DNA technology.

There are four categories of insulin namely very rapid acting insulin, rapid acting insulin, intermediate acting insulin and long acting insulin.

There are also mixed insulins available to provide both short and long acting effect.

Insulins are used in both type 1 and type 2 diabetes. It is very important to give patient education about insulin to ensure proper technique when injecting insulin each time. With insulin it is very important to keep a check on blood sugar levels by monitoring to avoid any complications such as hypoglycemia.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

COMPLICATIONS OF DIABETES –

Patients with diagnosis of diabetes are approximately  twice at risk of death each year in contarst  to people without diabetes. Mortality rate is about 6.1 deaths per 1000 patients as per the latest data and their life expectancy is reduced by an average span of 5 to 10 years.

The complication of diabetes are generally divided into acute and chronic complications.

Acute metabolic complications of diabetes are diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS).

However most of the morbidity and mortality inferable with diabetes                      mellitus is attributable to its chronic complications.

It is essential to comprehend that all patient with diabetes are at risk of developing complications indeed many patients with type 2 diabetes are asymptomatic and complications maybe the presenting signs.

Chronic complications are divided into micro and macrovascular complications.

Macrovascular complications of diabetes includes the heart disease cerebrovascular disease stroke and peripheral vascular disease.

Coronary heart disease death rates are several times higher in people with diabetes. Cardiovascular disease death rate in diabetes is 2.3 deaths per 1000 patients which have come down in recent years from 5.8

Microvascular complications includes retinopathy, nephropathy and neuropathy. These complications occurs either alone or in combination with each other.

 

 

 

 

 

Aims and objectives

 

The Aim of the review is :

To determine the long term cardiovascular outcomes with drug treatment versus placebo in patients with type 2 diabetes and cardiovascular disease receiving standard care regimen.

 

The objective of the review is :

To comprehend whether the drugs used in management of diabetes demonstrates cardiovascular safety and efficacy along with action of glucose lowering.

To evaluate the clinical trials and analyse the adequacy of their outcomes.

Methodology

A systematic review is a research article that identifies studies , appraises their qualities and summarises their result using a scientific method.  It tries to recognize, acknowledge, select and create all top quality evidence relevant to the questions.

The systematic review summarizes the literature relevant to the question asked in the research. The systematic review uses the transparent approach for research synthesis, thus minimizes the chances of bias.

Aim of a systematic review

A single question is focused on a systematic review and evidence-based high-quality research material is used to direct a systematic review. Each study is assessed on the basis of a defined criteria. [11]

Search Strategy

The relevant studies were identified by using HOWIS website which had OVIDSP as their search interface which includes around around 14 databases. Examples of the databases included in the search are Medline, Embase, Pubmed, Proquest, CINAHL and Cochrane etc.

An advanced search was done using subject headings such as “Diabetes”,  “Type 2 diabetes”, “Outcome studies on oral hypoglycaemic drugs” , “Cardiovascular outcome trials ” , “antidiabetic medications”, “Placebo versus drugs in diabetes”.

Boolean expressions “and” & “or” were used to to provide more articles.

The search was refined using Explode box which potentially expanded the search related to the subject headings and by using Focus box to restrict search only to relevant data when all the subject headings were combined.

 

 

 

 

 

 

 

 

 

 

 

 

 

LITERATURE  REVIEW

 

PAPER 1

This study was done by Eugene Braunwald et.al starting in year 2010 and completed in year 2013.The aim of the study was to investigate whether addition of saxagliptin to the background therapy of diabetes and/or cardiovascular disease  would be non-inferior to the placebo for the composite endpoint of cardiovascular death ,nonfatal M.I. or non-fatal ischaemic stroke. And if non inferiority were met to decide whether saxagliptin would be better than placebo. While, Non-inferiority was defined as hazard ratio (HR) of < 1.3 for the upper bound of 95% confidence interval (CI), Superiority could be claimed if the upper boundary of 95% confidence interval is found to be < 1.0 in a subsequent statistical analysis. [12]It was a multi – centre, randomized, double-blind, placebo-controlled,  phase 4 trial.The trial was conducted at 788 sites in 26 countries.[13] The participant configuration included 16,492 patients with type 2 diabetes and cardiovascular illness or cardiovascular illness risk.Inclusion criteria was a documented diagnosis of type 2 diabetes mellitus and all of the following that is age >/ 40 years and a document  HbA1c level of >/6.5% in the previous 6 months and high risk of a cardiovascular event with established cardiovascular disease or multiple risk factors. Eligible patients were randomly assigned in a 1:1 ratio to receive saxagliptin at a dose of 5mg by day or alternatively 2.5 mg by day in patients with an egfr of under 50 ml /min or matching placebo. Randomisation was performed by means of a central computerised telecommunication or web based framework in blocks of four with classification according to the documented cardiovascular disease state and kidney function.The sample size was 8280 vs 8212 for saxagliptin and placebo respectively. In terms of study conduct for saxagliptin and placebo the percentage of population that withdrew the consent was 2.3% vs 2.4%, percentage in which the study drug was prematurely discontinued in 18.4% vs 20.8%, and patients lost to follow up in this study was 0.2% and and those who did not receive the treatment was 0.5% for both saxagliptin and placebo respectively. Functional vital status was checked in 99.1% of patients.Median follow up of the study was 2.1 years.Primary composite CV endpoint was as mentioned above. The secondary composite endpoint was cardiovascular death, non-fatal MI , non fatal ischemic stroke, hospitalization for heart failure, coronary revascularization or unstable angina. Saxagliptin or Placebo was administered in a blinded fashion until the end of the follow up period.The primary safety and efficacy analysis were performed according to the intention to treat principle on data from all patients when they went randomisation with use of a Cox proportional hazard model.The end point HbA1c of the saxagliptin arm was 7.7% +/ – 1.4% (p <0.001 vs placebo) while placebo had 7.9% +/ – 1.5%.The cardiovascular outcome showed primary hazard ratio of 1.00 and secondary hazard ratio of 1.02.Outcomes showed saxagliptin met the criteria for non-inferiority as compared to placebo by showing that it neither reduces no increases the risk of primary composite endpoint of cardiovascular death, myocardial infarction or ischemic stroke when added to the standard of care in patients at high risk for cardiovascular events. It confirmed appreciably improved glycemic control and reduced development and progression of microalbuminuria. However it was associated with elevated risk for hospitalization for heart failure and chances of low blood sugar incidents.

 

 

 

 

 

 

STUDY 2

 

This study was done by Jennifer B. Green et.al starting in December 2008 and completion in March 2015.

The aim of the trial was to evaluate the cardiovascular safety after treatment with sitagliptin as compared to usual care in patients with type 2 diabetes mellitus and inadequate glycaemic control.

While, Non-inferiority was defined as hazard ratio (HR) of < 1.3 for the upper bound of 95% confidence interval (CI),Superiority could be claimed if the upper boundary of 95% confidence interval is found to be < 1.0 in a subsequent statistical analysis. [12] It was a multicenter trial in which trial took place at 673 sites in 38 countries.It was double blinded i.e. masking of both participant as well as investigator. It was randomized and placebo controlled i.e. outcome was compared with placebo.The study was designed and run by Oxford University Diabetes Trial Unit and the Duke Clinical Research Institute in collaboration with the industry sponsor.14671 participants with type 2 diabetes mellitus and established cardiovascular disease were actually enrolled.Inclusion criteria was a documented diagnosis of type 2 diabetes mellitus and CVD and atleast age of 50 years with HbA1c level of 6.5 to 8% when treated on standard care. The exclusion criteria was if the patient has taken dipeptidyl peptidase-4 inhibitor, glp-1 agonist or thiazolidinedione during the preceding three months or if they had more than 2 episodes of severe hypoglycemia during the preceding one year or if egfr was <30 ml per minute or history of type 1 diabetes mellitus or ketoacidosis and is not able to take sitagliptin.The sample size for Sitagliptin was 7332 while that of placebo was 7339.95.1% patient in the sitagliptin group and 94.1% patients in the placebo group completed this study. Vitals were obtain for 97.5% of patients.Median follow-up period was 3 years.The primary  endpoint was to demonstrate non-inferiority as it relates to the composite of cardiovascular death, nonfatal MI, nonfatal stroke and hospitalization for unstable angina.The secondary end point included the individual components of the primary cardiovascular outcome and  additionally hospitalization for heart failure, changes in HbA1c level and the eGFR and starting of any additional glucose lowering medication.Results showed that overall in the intention to treat the population the primary composite outcome in the sitgliptin group was 11.4% as compared to placebo group which was 11.6 %. There was no significant difference between the drug and placebo group in terms of primary and secondary composite cardiovascular outcome which showed non – inferiority. In TECOS trial there was no significant difference in the rate of hospitalization for heart failure, incidence of infections ,cancer ,site reported renal failure or severe hypoglycemia. In conclusion it was observed that on addition of sitagliptin to the usual care among patients with diabetes it did not affect the rate of major atherosclerotic cardiovascular events.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

STUDY 3

 

 

The study was done by Bernard Zinman et.al started in year 2010 and completed in year 2015.

The aim of the trial was to examine the effects of empagliflozin on cardiovascular mortality and morbidity as compared with placebo in patients with type 2 diabetes who are on standard care and at a high risk of cardiovascular events.The sample of participant population was 7064 patients.It was a phase III, randomised double-blinded , cardiovascular safety trial. It was a multicenter trial in which patients participated at 590 sites of 42 countries. This trial was done as there were concerns that intensive lowering of blood glucose levels or the use of some specific antihyperglycemic drugs may be associated with adverse cardiovascular outcomes. It was a non-inferiority study in which prespecified hazard ratio margin was 1.3 for primary endpoint. Median follow-up period was 3.1 years. While, Non-inferiority was defined as hazard ratio (HR) of < 1.3 for the upper bound of 95% confidence interval (CI), Superiority could be claimed if the upper boundary of 95% confidence interval is found to be < 1.0 in a subsequent statistical analysis. [12]Primary endpoint was a composition of cardiovascular death, nonfatal MI, excluding silent MI or non fatal stroke.Secondary endpoint was composite of non-fatal MI, non fatal stroke , cardiovascular death and hospitalization for unstable angina. The dose of empagliflozin was either 10 mg or 25 mg once daily. Inclusion criteria was diagnosis of type 2 diabetes mellitus in adults over 18 years with HbA1c between 7 to 10% and established cardiovascular disease. Eligible patients underwent a two week placebo run-in ,  in which background glucose lowering medications were not changed. After that randomisation was done in a ratio of 1:1:1 to receive either 10 mg or 25 mg of empagliflozin or placebo once daily. Background therapy was not changed for first 12 weeks but after that investigators were advice to adjust the glucose lowering therapy and cardiovascular risk factors at their discretion as per necessity. Patients were advised to attend the clinics on site at the pre mentioned timings which included visit in a period of 30 days after the end of treatment. Data were analysed under the Haybittle-Peto rule in which a two-sided p value of 0.0498 or less than that was considered to indicate statistical significance. Non-inferiority for the primary outcome was determined if the upper boundary of the two-sided 95.02% confidence interval was found to be less than 1.3. Overall 97.0% of patients completed the study and final vital status was checked for 99.2% of patients.  Results showed that the primary outcome occurred in a significantly less percentage of patients in the empagliflozin group that is 490 out of 4687 patients which accounts for 10.5% as compared to placebo group in which the outcome occurred into 282 out of 2333 patients which accounted for 12.1%. Hazard ratio in the empagliflozin group was found to be 0.86 , p less than 0.001 for non-inferiority and value of p equal to 0.04 for superiority. Individual dose effects for non significant because of the smaller number of outcome events in the individual groups is the hazard ratio for primary end point was 0.85 in 10 mg dose of empagliflozin as compared to Placebo and 0.86 for 25 mg dose of empagliflozin vs placebo. A higher percentage of patients in the placebo group received additional antihyperglycemic drugs and antihypertensive medicines and anticoagulants during the trial as compared to the study drug. There was no enormous difference between the groups in the key secondary outcome in which p was kept equal to 0.08 for demonstration of superiority. Results showed that on addition of empagliflozin to the standard care in the patients with type 2 diabetes and established cardiovascular disease there were lower rate of the primary composite cardiovascular outcome.

 

 

STUDY 4

The study was done by Steven P Marso et. al initiated in year 2010 and primarily completed in year 2015. The aim of the trial was to evaluate the cardiovascular effect of liraglutide when added to standard care in patients with type 2 diabetes. It was a double blind, parallel  and placebo controlled trial.  So both the investigators and the patient had no idea of allocated treatment and compared with addition of placebo to standard care. It was a multicenter study which was done at 410 sites in 32 countries. The trial was done because the benefits of blood glucose lowering in the patients with diabetes in reducing the risk of microvascular complications of diabetes is known but the macrovascular benefits were less known. It was a non-inferiority study in which prespecified margin was kept at less than 1.3 for upper bound of 95% CI for primary endpoint. . Superiority could be claimed if the upper boundary of 95% confidence interval is found to be < 1.0 in a subsequent statistical analysis. [12]

The primary endpoint was the first occurrence of death due to cardiovascular disease , non-fatal MI  including silent MI or non fatal stroke.

The secondary endpoint was composite of cardiovascular death, non-fatal MI  including silent MI or non fatal stroke, coronary revascularization and hospitalization for unstable angina or heart failure. Inclusion criteria was diagnosis of type 2 diabetes mellitus, HbA1c of >/ 7.0% and age of >/50 years and cardiovascular disease or age of >/60 years and cardiovascular risk factors. Exclusion criteria was diagnosis of type 1 diabetes,  if the patient is on glp-1 receptor agonist, dpp-4 inhibitors or rapidly acting insulin , a family or personal history of multiple endocrine neoplasia type 2 or any acute coronary of cerebral vascular disease within two weeks before screening and randomisation.The sample size was 9340 patients who were eligible with type 2 diabetes and high cardiovascular risk out of which 4672 patients received liraglutide while 4668 patients received placebo. A Placebo run in was done for 14 days to check the adherence and then randomisation was done in ratio of when is 1:1 to receive 1.8 mg of liraglutide or matching placebo once daily subcutaneously on top of standard care that the patients were receiving before the trial. Patients were asked to follow up at an interval of 13 and 6 months and then every 6 months after that. Median follow up period was 3.8 years. Cox proportional hazard model was used to analyse time to event outcomes. Cumulative incidence of estimated with the use of Kaplan – Meier method . All the patients who underwent randomization were included in primary analysis and entire population whoever completed the study or discontinued without having an outcome were analysed from the day of their last visit. Throughout  the trial , 2-sided p values were presented. Functional vital status was assessed in 99.7% of the sample size and 96.8% of the patient completed the trial. The primary outcome was seen in less number of patients in the study drug group i.e 608 out of 4668 patients accounting for 13% as compared to placebo in which it occurred in 694 patients out of 4672 accounting for 14.9%. So the results showed that liraglutide have lower rates of all-cause death and cardiovascular death demonstrating both non inferiority as well as superiority. It also showed significant mortality benefits. But the analysis also showed the increase rate of gastrointestinal events in liraglutide treated patients and fuel incidence of pancreatitis as well which were not statistically significant.

 

 

 

 

 

 

 

STUDY 5

 

The study was done by Steven P Marso et. al initiated in year 2013 and primarily completed in year 2016. The aim of the trial was to evaluate the cardiovascular  safety of semaglutide, a glp-1 agonist as compared to placebo when added to usual care in patients with type 2 diabetes. It was a double blinded, parallel grouped and placebo controlled trial.  It was a International study, multicentred which was done at  230 sites in 20 countries. The trial was done because it was mandatory for any drug to be approved for marketing to undergo a cardiovascular safety trial and prove its safety. While, Non-inferiority was defined as hazard ratio (HR) of < 1.3 for the upper bound of 95% confidence interval (CI), Superiority could be claimed if the upper boundary of 95% confidence interval is found to be < 1.0 in a subsequent statistical analysis.[12]  The primary endpoint was the first occurrence of death due to cardiovascular disease , non-fatal MI  including silent MI or non fatal stroke.

The secondary endpoint was composite of cardiovascular death, non-fatal MI  including silent MI or non fatal stroke, coronary revascularization , hospitalization for unstable angina or heart failure, retinopathy and new or worsening nephropathy.The inclusion criteria was a diagnosis of type 2 diabetes with HbA1c level of 7% or more with age of >/ 50 year with the diagnosis of cardiovascular disease or the chronic kidney disease of >/ stage 3 or age of >/  60 years with minimum of one cardiovascular risk factor. Exclusion criteria was treatment with dpp 4 inhibitor within 1 month or use of glp-1 receptor analogue or insulin  on any coronary or cerebrovascular accident within 90 days before the starting of the screening process. 3297 participants were enrolled in this double trial. Among all the participants 1648 patients received semaglutide and 1649 patients received placebo. Stratification and randomisation was done according to the cardiovascular disease status, eGFR levels and insulin treatment. A study dose maximizing process was followed with the initial dose of 0.25 mg a month that escalated to 0.25 mg for another month until the maintenance dose of 0.5 mg or 1.0 mg was attained. No changes after that in either of study drug or placebo was permitted. Median follow-up was 2.1 year. Study was planned for period of 109 weeks for each patient in which first 104 week were taken as treatment period and rest five weeks were taken as follow up.Cox proportional hazards model was used calculate the hazard ratio which was pre specified at the margin of less than 1.8 for upper bound of 95% CI to demonstrate non-inferiority. All p-values  were 2 – sided with the level of 0.05 to show statistical significance. Out of all those patients who underwent randomisation 98% of the patients attended follow up visits, or were in contact with telecommunication or died during the study. Last mission was seen on March 15th of year 2016. Vital status was known for 99.6% of the patients. Results showed that the primary composite outcome garden 108 patients out of 1648 accounting to 6.6% in the semaglutide group whereas primary outcome was seen in 146 patients out of 1649 patients in the placebo pool accounting for 8.9%. Hazard ratio 4 primary endpoint was calculated as 0.74 of 95% confidence interval. Hazard ratio for revascularisation, retinopathy complications and new or worsening nephropathy was found to be 0.65, 1.76 and 0.64 respectively. Serious adverse events were seen in 33.6% of patients who received semaglutide whereas 36.1% patient in placebo group had a serious adverse event. Gastrointestinal disorders such as diarrhoea nausea and vomiting well seen in 52.3% of patients receiving semaglutide as compared to only 35.2% in patients receiving placebo. The study concluded that semaglutide is non-inferior to placebo in terms of cardiovascular outcome and was associated with significant and sustained reduction in glycated hemoglobin level when compared with placebo demonstrating its safety and efficacy.

 

 

 

 

 

 

 

 

STUDY 6

 

This study compose of two trials CANVAS and CANVAS- R done by Bruce Neal et.al initiated in year 2009 and completed by year 2017.The aim of the study was to investigate whether addition of Canagliflozin to the background therapy of diabetes and/or cardiovascular disease  would be non-inferior to the placebo. And if non inferiority were met to decide whether Canagliflozin would be better than placebo. While, Non-inferiority was defined as hazard ratio (HR) of < 1.3 for the upper bound of 95% of CI [12]It was a multi – centre, randomized,  placebo-controlled, study.The trials were conducted at 667 sites in 30 countries.The participant configuration included 4330 patients with type 2 diabetes and cardiovascular illness or cardiovascular illness risk. Masking was quadruple that is neither participant, care provider , investigator  or the outcome assessor had any idea  of the allocated treatment. Key criteria were similar in both trials. Inclusion criteria was a documented diagnosis of type 2 diabetes mellitus and all of the following that is age >/ 30 years and a document  HbA1c level of >/7.5% upto 10.5% but history of atherosclerotic cardiovascular illness or age of >/ 50 years with two or more cardiovascular risk factors participant must have an egfr of more than 30 ml/min/1.73 square metre. Eligible patients had a two weeks placebo run in period and then they were randomly assigned in a 1:1:1 ratio to receive canagliflozin at the doors of 100mg, 300mg or matching placebo in CANVAS trial while participants in Canvas are were randomly assigned in one’s to one ratio to deceive 100mg daily dose of canagliflozin with an option to increase it up till 300mg from week 13 onwards and matching placebo. Randomisation was performed by means of a central computerised telecommunication or web based framework in permutable blocks. Post randomisation  the follow-up was  planned as 3 visits during the first year and 6 months interval after that  with telephone communication in between . In CANVAS trial albumin to creatinine ratio was measured annual whereas in CANVAS – R it was checked at week 12 and then every 26 weeks.

Primary composite CV endpoint was as death from cardiovascular causes, non-fatal MI or non fatal stroke. The secondary composite endpoint was cardiovascular death, non-fatal MI , non fatal ischemic stroke, hospitalization for heart failure and progression of albuminuria. The progression of albumin in urine was stated as a more than thirty percent increase in the albuminuria.

The sample size was 5795 vs 4347 for Canagliflozin and placebo respectively. 96% of the patients completed the trial. Functional vital status was checked in 99.6% of patients. The length of follow-up was 295.9 weeks in CANVAS trial whereas it was 108 weeks in CANVAS-R trial. Median follow up of the study was 126.1 weeks. 71.4% of patients in CANVAS- R trial had the dose of study drug increased up to 300 mg.

Results showed that less number of participants in the canagliflozin group had primary outcome as compared to placebo with the ratio of 26.9 vs 31.5 participants with an event per 1000 patient years. Hazard ratio was calculated as 0.86 for the primary outcome. Progression of albumin urea occurred less frequently in patients receiving canagliflozin then placebo with the ratio of 89.4 vs 128 .7 participant with an event per thousand patient years leading to a hazard ratio of 0.73. Serious adverse events well less common in canagliflozin group as compared to placebo with a hazard ratio of 0.93. But there was a higher risk of amputation of toes, feet and legs in canagliflozin group as compared to placebo with estimate of 6.3 vs 3.4 participants with amputation per 1000 patient years respectively.

Therefore canagliflozin was able to demonstrate it’s non-inferiority as compared to placebo in primary cardiovascular outcome.

 

 

 

 

 

 

 

 

 

 

 

 

CRITICAL ANALYSIS

 

PAPER 1

In this study the problem statement have been clearly introduced i.e correlation of type 2 diabetes mellitus with cardiovascular complications.

Literature review apprises the facts known about the topic and are relevant to the topic. Literature review describes that the study drug saxagliptin belongs to the class of selective dipeptidyl peptidase-4 inhibitor.

The research question is clearly defined.In the methods section of study it clearly describes that as it was a multicenter study which was conducted at 788 sites in 26 countries, it was approved by the relevant ethical communities of all the participating centres. In the study population the inclusion and exclusion criteria is clearly mentioned and it asserts that informed written consent was taken from all the participants. Sample size of 16492 patients is ample for the study. Research design is appropriate.The process of randomization is well explicated in the study with good description of the stratification process but however data collection process in this study remains speculative. The administration procedure of both saxagliptin and placebo in a blinded pattern is well enunciated. Study deciphers that all other diabetes treatment were as per the discretion of treating Physician/ Endocrinologist whilst the cardiovascular management was as per the treating Physician/ Cardiologist. Dates(in the year) for trial are clearly mentioned.The primary efficacy and the secondary efficacy composite endpoints are nicely illustrated. The statistical analysis is pertinent and the use of cox proportional hazards model to analyse the statistic data is explained.Tables and figures are clearly labelled. Outcomes were adjudicated by Cardiologists and Gastroenterologists who were not aware of the study‐group allocation. Therefore the assessment of methodological quality of this review was acceptable as it met most of the pre specified criteria by FDA. Results have affirmed that saxagliptin met the criteria for non inferiority as compared to placebo but does not meet the criteria for superiority.Duration of 2.1 years as a follow up may be apt to measure glycaemic control but it is a short follow up to measure any macrovascular outcome. Per protocol analysis was incomplete as initially designed for a  superiority trial.  Analysis of intention to treat results in a bias towards “no difference”, per protocol analysis is usually recommended when the design is for demonstration of non‐inferiority Overall, this trial did meet its “primary safety objective of non-inferiority” vs placebo, but was not able to demonstrate superiority of the drug over placebo in decreasing cardiovascular composite end point of cardiovascular death, nonfatal MI, or nonfatal ischemic stroke with raised concerns about hospitalization for heart failure. Less number of participants in the saxagliptin group as compared to  placebo needed an increase in the dose of diabetes medications or starting of insulin therapy for more than 3 months

 

PAPER 2

In this study the problem statement have been explained that is the role of a good control of blood glucose levels among patient having type 2 diabetes linked to reduction of diabetes related cardiovascular complications.Literature review clearly describes that Sitagliptin is an orally taken dpp-4 inhibitor and it help to  prolong action of hormones called incretin including glp-1 and glucose dependent insulinotropic polypeptide by suppressing glucagon level and increasing endogenous insulin secretion.The study also mentions about the limitations of the previous trials of same class of drug and their findings which raised concerns about the increased risk of hospitalisation due to heart failure.In this study the research question is clearly defined. The study is an interventional clinical trial which is double blinded and controlled by placebo. It indicates that it was a multicenter trial and the event-driven study took place at 673 sites in 38 countries. It also declares that the protocol was agreed and approved by the Ethical committies of each site where the trial took place. Dates(in the year) for trial are clearly mentioned. Study had the longest duration of follow-up for a DPP4-inhibitor CV outcome trials. with median follow up of 3.0 years. The information provided regarding the randomization and blinding process is suitable. Cox proportional hazards model to measure the hazard ratio and two-sided 95% confidence interval have been well chosen for this type of study. All the data were analysed using modified SAS software. Primary composite endpoint was homogeneous among subgroups. Figures in this study are well labelled. 26.1% of all sitagliptin patients and 27.5% of all placebo patients  discontinued study medication and no reason documented for the same. Data of all of pre-specified outcomes (e.g., change in weight) and some serious adverse events were not  reported leading to reporting bias .Overall, Sitagliptin therapy showed non-inferiority as compared to placebo in terms of cardiovascular safety and no increased risk of heart failure or related adverse outcome but it was not able to meet the criteria for superiority. Study infers that sitagliptin therapy can be safely used in type 2 diabetes mellitus patient without the concern for worsening heart failure.

 

 

 

 

PAPER 3

In the study the problem statement that is type 2 diabetes as a major risk factor for development of macrovascular outcomes such as cardiovascular disease is introduced. Research question is clearly mentioned. Literature review explains about the information which is known about the topic and the rationale behind doing the trial. Mechanism of action of empagliflozin which is a selective inhibitor of sodium glucose cotransporter and acts by decreasing the renal glucose reabsorption and thereby elevating the glucose excretion in urine have been explained in this article. This study was a phase III ,International ,multicenter , parallel group , double-blind cardiovascular safety study. Study have clearly mentioned about blind treatment. Research protocol were approved by ethics committee call institutional review board at each site. Two clinical event committees arbitrated cardiovascular outcome and cardiovascular deaths prospectively. The trial was conducted according to the principal of International conference on harmonisation good clinical practice guidelines and Declaration of Helenski. The inclusion and exclusion criteria is clearly mentioned. Randomisation process of 1:1:1 ratio of 10 milligram and 25 milligram dose of empagliflozin to placebo with the computer generated random sequence and interactive voice system is stated. Baseline demographics were kept equivocal and distinct between placebo and study drug groups. The primary outcome and the secondary outcome are emphasized in the hypothesis.The assessment of safety on the basis of adverse events was properly coded with the use of medical dictionary for regulatory activities version 18.0.Primary hypothesis state that the non-inferiority for  primary outcome with empagliflozin versus placebo with HR in a margin of 1.3. Cox proportional hazards model was used to analyse the data and primary analysis was performed using a modified intention to treat approach if the patients had received at least one dose of empagliflozin. The assessment of methodological quality of this review was acceptable because it met most of the criteria as set up by FDA.The ratio of serious adverse event in empagliflozin pool vs placebo was 38.2 vs 42.3% respectively. But the study also showed the increased rates of genital infection in empagliflozin treated patients with the ratio of 5.0 vs 1.5 in males and 10.0 vs 2.6 in females in empagliflozin pool versus placebo respectively. A dose response curve for difference between both the doses of empagliflozin was missing in the study as both the doses virtually provided the same analysis. Empagliflozin also lowered the blood pressure and weight as compared to placebo group.Overall, empagliflozin when compared with placebo resulted in significant lower risk of death from cardiovascular causes and hospitalization for heart failure and met the criteria for non-inferiority.

 

 

PAPER 4

In this study the problem statement that is raised concerns about the cardiovascular safety of therapies               for management of diabetes have been mentioned. Research question was clearly mentioned and focussed throughout. Literature review clearly describes that Liraglutide which is the study drug is an analogue of human glucagon-like peptide-1 and is used in management of type 2 diabetes. The study is a double blinded, control trial  and was conducted out at 410 sites in 32 countries.  Data was analysed by both sponsor and an multidisciplinary team expert in biostatistics called Statogen Consulting. The protocol of the study trial was approved by the institutional review board in all of the participating sites. The inclusion and exclusion criteria is elucidated. The safety surveillance was done by an independent safety monitoring committee who had access to all the data in an unblinded pattern. The process of randomisation is described but instrument used for randomisation is not indicated in the study. Cox proportional hazard model has been used to calculate the hazard ratio.All the outcomes were adjudicated by external team of experts. Dates(in the year) for trial are clearly mentioned.

Results showed that both the primary composite outcome and the secondary or expanded composite outcome was less in the liraglutide pool as compared to placebo. But the analysis was not pre specified in events of myocardial infarction, stroke and transient ischaemic attack. Participants who completed or discontinued the study without having an outcome were censored after their last visit, and events occurring after that visit were not included in the study, which could have led to missing of some key events.

Though Liraglutide also resulted in an additional approximately 2.3kg  loss of weight as compared to the placebo group, and also affected heart rate and  BP (SBP↓1.2 mmHg). It also showed lesser incidences of transient ischaemic attack, coronary revascularization, hospitalization for unstable angina and hospitalization for heart failure in the liraglutide group as compared with the patients who received placebo. Therefore Liraglutide is the first drug of its class (GLP1‐A) to demonstrate positive cardiovascular outcomes in a randomized control trial.

PAPER 5

In this study the problem statement have been explained that is regulatory guidance specifies that all the new drugs developed post  year 2008 have to undergo a safety trial to establish its cardiovascular safety.

Literature review clearly describes that  Semaglutide is a newly developed GLP-1 analogue and have an extended half life of approximately one week. The study also mentions about the the previous trials of same class of drug as well as other classes of antidiabetes drugs and their findings which is relevant to the study.In this study the research question is clearly defined. The study is an interventional clinical trial which is double blinded and controlled by placebo. It indicates that it was a multicenter trial and the event-driven study took place at 230 sites in 20 countries. It also declares that the protocol was agreed and approved by the Institutional review boards and equivalent of each site where the trial took place. Dates(in the year) for trial are clearly mentioned. Inclusion and exclusion criteria is well explained. Though information provided regarding the randomization and blinding process is inadequate. Duration of follow up i.e.109 weeks and its division into treatment and follow up period is clearly stated. Cox proportional hazards model was used to measure the hazard ratio and two-sided 95% confidence interval have been well chosen for this type of study. All the data were analysed on intention to treat pattern. Figures in this study are well labelled and easy to follow. Overall, results have affirmed that Semaglutide met the criteria for non inferiority and demonstrated superiority as compared to placebo driven by a significant reduction of risk of stroke.

PAPER 6

 

In this study the problem statement i.e. association of type 2 diabetes mellitus with the risk of double up in cardiovascular and renal disease and regulations set up for new drugs for treatment of diabetes developed to undergo a safety trial to establish its cardiovascular safety have been well explained. The CANVAS study composed of data from two sister trials namely CANVAS and CANVAS-R.

Mechanism of action of cangliflozin which is a selective inhibitor of sodium glucose cotransporter and acts by decreasing the renal glucose reabsorption and thereby elevating the glucose excretion in urine have been explained in this article. This study was International ,multisite , parallel group ,cardiovascular safety study. Masking was quadrupled in the study. Study have clearly mentioned about blind treatment. Research protocol were approved by institutional review board at each site.

The inclusion and exclusion criteria is clearly mentioned. Randomisation process of dose of canagliflozin to placebo with the computer generated random sequence and interactive voice system is stated. The primary outcome and the secondary outcome are emphasized in the hypothesis.The assessment of safety on the basis of adverse events was properly coded with the use of medical dictionary for regulatory activities (MedDRA). Primary hypothesis state that the non-inferiority for  primary outcome with cangliflozin versus placebo with HR in a prespecfied margin of 1.3. Cox proportional hazards model was used to analyse the data.The assessment of methodological quality of this review was acceptable because it met most of the criteria as set up by FDA. Homogeneity of treatment in both the contributing trials were assessed. Analyses were performed with the use of SAS software version 9.2 and SAS Enterprise guide version 7.11. Overall , there were lesser incidences of primary outcome in canagliflozin group as compared to placebo with a hazard ratio of 0.86 but only 2/3 of population in the study had established cardiovascular disease as compared to other trial of same class of drug.  Data also suggest a potential renoprotective effect of canagliflozin treatment in patients with type 2 diabetes at high CV risk due to positive outcome by holding the progression of albuminuria and showing regression of albuminuria.Thus, Canagliflozin therapy had shown non-inferiority as compared to placebo in terms of cardiovascular safety for marketing as a drug for treatment of diabetes.



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