NIDM Vs. NIDDM CURRENT THERAPEUTIC APPROACH TO TYPE2DM

DR.RISHIKESAN K.VSPECIALIST PHYSICIAN

VENNIYIL MEDICAL CENTRESHARJAH,UAE

A HUGE PROBLEM DIABETES IS A HUGE

PROBLEM WORLDWIDE 371 MILLION

INDIVIDUALS LIVE WITH TYPE 2 DIABETES

THE MOST RECENT NHANES REPORT INDICATES THAT LESS THAN 50% AMERICANS WITH DIABETES ACHIEVE A HbA1C GOAL LESS THAN 7%

PREVALENCE OF DIABETES THERE IS A DRAMATIC

INCREASE IN THE PREVALENCE OF DIABETES GLOBALLY

MANY PEOPLE WITH DIABETES FAIL TO MEET GLYCAEMIC TARGETS

A JOINT STATEMENT BY ADA , AHA , & ACC URGES A TARGET HbA1C LEVEL OF < 7%

COMMON BARRIERS

COMMON BARRIERS TO THE ACHIEVEMENT OF TARGET HbA1C ARE SIDE EFFECTS WITH CURRENTLYAVAILABLE DRUGS PARTICULARLYHYPOGLYCAEMIA ANDWEIGHT GAIN

AN UNMET NEED…. REMAINS FOR IMPROVED GLYCAEMIC CONTROL IN PATIENTS WITH TYPE 2 DM

CURRENT APPROACHES ARE ASSOCIATED WITH LIMITATIONS

NEW THERAPIES WOULD BE OF VALUE

PATHOPHYSIOLOGY IN T2DMTHERE IS A BUNCH OF DEFECTS AND DIFFERENT MECHANISMS OF ACTION IN DIABETIC INDIVIDUAL AS SUGGESTED IN THE FAMOUS OMINOUS OCTET MODEL BY PROF. DE FRONZO.WE HAVE TO APPRECIATE THAT ALL OF THESE ORGANS COMMUNICATE WITH EACH OTHER.WHAT WE DO TO TREAT 1 ORGAN MAY HAVE EFFECTS ON THE RESPONSE OF OTHER TARGET TISSUES

The increasing prevalence of T2DM, in combination with limitations of current therapies, has led to the search for newer alternatives. SGLT2 inhibitors represent a novel 'glucuretic' therapeutic strategy for the treatment of T2DMs.

PROS AND CONSExisting therapies focus on

*Reducing insulin resistance, *Increasing insulin secretion, *Slowing CHO digestion, Restraining glucagon production, and *Supplying exogenous insulin.LIMITATIONS OF TRADITIONAL AGENTS : (metformin, SUs and insulin) GI side effects, wt. gain and hypoglycaemia.TZDs : CV safety concerns, wt. gain, increased fractures and fluid retention.DPP-4 inhibitors well tolerated, but merely weight neutral. GLP-1analogues result in moderate wt. loss, are injectables and their use is limited by GI side effects

NEW TREATMENT OPTIONS

RENAL GLUCOSE TRANSPORT MAY PRESENT A RATIONAL TARGET

FILTRATION AND REABSORPTION

MOST OF US HAVE A GFR OF ~ 180L/DAY AND OUR GLUCOSE IS 90-100 MG/D .WE FILTER ABOUT 160GM. PER DAY90% OF THIS IS REABSORBED IN THE S1 SEG. OF PCT BY SGLT2THE REMAINING 10% BY SGLT1 OF S3 SEGMENTSGLT1 ALSO PRESENT IN THE GUTBLOCKING SGLT1 LEADS TO DIARRHOEA

GLUCOSE TRANSPORTERS

SGLTs 4-6 ROLES NOT YET DETERMINED

A CLOSER VIEWSGLT2 TRANSPORTS GLUCOSE IN CONCERT WITH Na+Na+ IS PUMPED OUT BY Na+ K+ ATP- ase GLUT2 , ANOTHER TRANSPORTER GETS THE GLUCOSE FROM THE CELL BACK INTO THE BLOOD STREAM

A DRUG THAT SEEMS TO BE SO FAR REMOVED FROM OUR CONCPEPTS ABOUT THE CORE DEFECTS IN T2DM, CAN CORRECT THE CORE DEFECT

We have a drug that will work in those who have good renal function, causing glycosuria, with weight loss and a low risk of hypoglycemia. That is a very attractive class.

INSULIN RESISTANCEIN INDIVIDUALS WITH T2DM INSULIN RESISTANCE IS MAXIMALLY ESTABLISHED AND > 50% OF BETA CELL FUNCTION HAS BEEN LOST AT THE TIME OF DIAGNOSIS

AS GLUCOTOXICITY IS REVERSED…

GLUCOSE TRANSPORT SYSTEM IN THE MUSCLE IS IMPROVEDMORE OF ACTIVATED GLUT4 TRANSPORT PROTEIN ARE TRANSLOCATED TO THE CELL MEMBRANE

THERE IS ENHANCEMENT OF INSULIN-SIGNALING TRANSDUCTOR SYSTEM

G 6 PHOSPHATASE, THE RATE LIMITING ENZYME IS INHIBITED SO THAT LESSER AMOUNT OF GLUCOSE GET OUT OF THE LIVERHEPATIC GLUCOSE PRODUCTION IS MODULATED.

THERE IS DECREASE IN THE CRITICAL ENZYMES OF GLUCONEOGENESIS

INSULIN SENSITIVITYWith the use of SGLT2 inhibitor , glucose reabsorption is inhibited from the renal tubules. Approx.70 g of glucose a day is now excreted in the urine, independent of insulin sensitivity, and serum insulin levels.FBS goes down , overall glucose tolerance improves with a reduction in A1C, and some wt loss . In doing so, there may be some improvement in peripheral insulin sensitivity.The reduced insulin secretory demand by lowering ambient glucose, may help conserve beta cell function.

A DELICATE AND WELL BALANCED SYSTEM OF GLUCOSE INPUT AND UTILISATION

GLUCOSE HOMEOSTASIS & KIDNEY

The total glucose stored in the body is 450g. The brain and the rest of the body use almost same (125+125=250g) amount of glucose. Glucose prodn. is 70 g.Typical western diet contains 180g. glucoseThe kidney filters and reabsorbs 140 -180 g/d .

Glucose Production(Gluconeogenesis Glycogenolysis) -70g/d

KIDNEY,ANDNEOGLUCOG-ENESIS

Glucose production happens in the renal cortex. The renal medulla as an obligate consumer affects glucose utilization. FFA -the main energy source of renal cortex gluconeogenesis . 20-25% of the total body glucose is released by kidney.

KIDNEYS IN T2DM

*Increased baseline gluconeogenesis,*Insulin resistance , and *Increased FFA in diabetes stimulate gluconeogenesis in the kidney.The liver down-regulates, there is a reduction in hepatic glucose release.

However the kidney has an increase in glucose release. These different organs have different responses to diabetes.

KIDNEY’S CONTRIBUTIONGlucose control is altered in people with T2DM. Gluconeogenesis is increased in the postprandial and post absorptive state. There exists the renal contribution to hyper- glycemia with a 3-fold increase relative to patients without diabetes.

TRANSPORT MAXIMUM :T max

As the glucose level rises in the blood more glucose is filtered but much of it is reabsorbed. However as we reach T max. tubule can’t reabsorb more. Once we cross that point we start excreting more and more glucose. That level is 180-200 mg/ dlThe magic number is approx.180 mg/d L.

THE PATHOPHYSIOLOGY

The magic number is approx.180 mg/d L.However, normally resorption levels off and more and more filtered glucose is excreted when levels exceed 180 mg/d L .In pts. with diabetes, T Max for Glucose changes, because these SGLT2 receptors change.

THE ABILITY OF THE DIABETIC KIDNEYTO CONSERVE GLUCOSEMAY BE AUGMENTED IN ABSOLUTE TERMS BY AN INCREASE IN THE RENAL Tm FOR GLUCOSE

GLUCOSE TRANSPORT IN DIABETES IN EVERY ANIMAL MODEL OF TYPE 1

AND TYPE 2 DIABETES THERE IS AN INCREASE IN THE Tm FOR GLUCOSE.

WE HAVE PTs. WITH FBS 180 MG.THEY EAT A MEAL , IT GOES TO 300 MG; STILL THEY HAVE NO GLUCOSE IN THE URINE

THIS IS BASICALLY TELLING THAT THEIR Tm IS SET UPWARDS

HIGHER SGLT2 mRNA / GLUT2 EXPRESSION…

SGLT2 LEVELS IN T2DM

There is increased SGLT2 expression and activity in the renal epithelial cells of the proximal tubule.This proves that the renal SGLT2 levels, are increased in patients with type 2 diabetes

SGLTs2 types : the SGLT2s and the SGLT1s. The SGLT2s are found almost exclusively in the kidney. These low affinity but high capacity glucose transporters are the ones that are doing the majority of the work in the kidney.The SGLT1s are mostly found in the intestine. They handle glucose or galactose. They have high affinity and low capacity for glucose, in contrast to the SGLT2s. These co transporters work together in PCTs

The kidney is very dynamic and produces a large number of sensors. It is so important in the homeostatic mechanisms of the body . There are many SGLTs -- many of which are sensors,

CHANGE THE MINDSET

We need to change our mind set regarding the adversarial relationship clinicians have with the kidney. The kidney is actually an ally in managing T2DM We as clinicians should understand and actually utilize , the KIDNEY.KIDNEY has the ability to handle glucose and help the patients to achieve glycemic control.

The kidney is actually an ally in managing T2DM

By reducing the activity of these transporters – (SGLT2 ) by around 30%, we are able to flush out approx.60-70 gm. of glucose out into the urine/day. This, of course, not only reduces hyperglycemia, but it also reduces calories therefore, assists weight loss via a non-insulin dependent mechanism, so it is not associated with hypoglycemia.

GENETIC MODEL OF SGLT2 INHIBITION

NATURE HAS PROVIDED US WITH A BEAUTIFUL GENETIC MODEL OF SGLT2 INHIBITION THAT TELLS US FOR SURE THAT THE APPROACH OF BLOCKING THE SGLT2 TRANSPORTER WILL WORK EFFICIENTLY TO DUMP OUT EXCESS GLUCOSE

AR DEFICIENCY OF THE SGLT2 TRANSPORTER

ABSOLUTELY ASYMPTOMATIC

RENAL GLUCOSURIC PERSONS ARE ASYMPTOMATIC , DON’T BECOME HYPOVOLEMIC AND DEHYDRATED, DON’T DEVELOP HYPOGLYCAEMIARENAL Bx. HAVE BEEN DONE : THEY HAVE NORMAL RENAL HISTOLOGY , NO INCREASED INCIDENCE OF CRF, UTI OR DIABETES AND THEY ARE NEVER OBESE

WE HAVE MULTIPLE GENERATIONS OF HUMAN DEFECT. WE CANNOT GET BETTER TOXICOLOGY

WE HAVE MULTIPLE GENERATIONS OF HUMAN DEFECT. WE CANNOT GET BETTER TOXICOLOGY

PHLORIZINThis is the molecule called Phlorizin , the prototype of an SGLT inhibitor.It is toxic to humans , was first described in the mid-19th century. It is isolated from the root of the bark of the apple tree and is utilized for exploration of SGLT function.

PHLORIZIN IN RATS

Here is the representation .They work by blocking the transporter –SGLT2.Those dots in the middle of what is supposed to be a proximal tubule represent glucose. As the transporters are blocked, very little glucose comes back to the body . The glucose reabsorption is decreased and the majority of the glucose is excreted in the urine. Glucose levels fall.Calories are lost, Less insulin is required.Sugar levels improve

OPEN THE SPIGOT

WE ARE JUST GOING TO OPEN THE SPIGOT IN THE KIDNEY AND LET THE GLUCOSE FLOW OUT.

This alleviates glucotoxicity by dumping the excess in the urine.

NOW WE SHOULD FEEL COMFORTABLE WITH THIS APPROACH OF SGLT2 INHIBITION

SMART MOLECULES..When SGLT2 inhibitors reduce the amount of glucose that is coming back into the body the signals to the kidney suggest that the SGLT2 receptors now have less glucose to handle . As a result they readjust ; and the TM for glucose falls.It does not fall to 20 or 30 mg/dL and induce hypoglycemia, but it falls to levels of approx. 70 mg/d L.

SMART MOLECULES.THEY READJUST THEMSELVES TO A T MAX.OF APPROX. 70MG/DL.

There are 2 SGLT2 inhibitors that are approved in the United States and Europe: canagliflozin and dapagliflozin. There is one on the horizon, empagliflozin, which may be available within the next year, and there are others in development.

POTENTIAL CLINICAL BENEFITS OSMOTIC DIURESIS LEADS TO

INITIAL WEIGHT LOSS LOSS OF EXCESS CALORIES IN THE

URINE LEADS TO SUSTAINED WEIGHT LOSS

GLUCOSE LOWERING WITH A LOW RISK OF HYPOGLYCAEMIA

NON INSULIN DEPENDENT MECHANISM (NIDM CHALLENGES NIDDM)

EFFICACY AND TOLERABILITY

CANAGLIFLOZIN MONOTHERAPY

CANAGLIFLOZIN USED AS MONOTHERAPY IN T2DM WHO ARE INADEQUATELY CONTROLLED WITH DIET AND EXERCISE , AGAIN OVER A PERIOD OF 52 WEEKS.THERE IS A DOSE RESPONSE REDUCTION OF HbA1C APPROXIMATELY .8% WITH 100MG AND 1.1% WITH 3OOMG .MORE THAN 50% PTS. REACHING HbA1C LESS THAN 7%.BODY WEIGHT CHANGES BY 3-4KG

COMBINATION WITH SU & METFORMIN

The changes in hemoglobin A1c, are consistent and durable over a period of 52 weeks. There is a dose response whereby the average drop in A1C was in the order of 0.7%, with the lower dose of canagliflozin and 0.9% with the higher dose of canagliflozin.

We have data from different compounds of this new class. It shows that it is

beneficial to add an SGLT2 inhibitor even with a long, 15-years’ duration of diabetes, where the patient has been on 70-90 units/day of insulin for 6 years.

This causes an HbA1c reduction from a baseline of 8.5% down to 7.4% .

A reduction of 25% insulin use and good effect on weight.

The study showed that at week 26 a greater proportion of patients with T2D who had received canagliflozin achieved an HbA1c of <7% or an HbA1c of ≤6.5%, SBP <140 mm Hg, body weight reduction 4%, with canagliflozin 100 and 300 mg compared with placebo.

Wilding J, et al. EASD 2013 Poster 946

The diastolic blood pressure, likewise, drops between 2 -3 mm Hg. The BP effects are thought to be related to the osmotic diuretic effect and very mild natriuresis. SGLT2 Inhibitors may affect nitric oxide, and it is currently under investigation.

Clinically meaningful drop in SBP were seen with canagliflozin over 26 weeks 25

NATRIURESIS

The effect on BP is in all likelihood the combined result of the reduction in body weight but also the loss of sodium through the urine.

The natriuretic effect-because the compounds block, the sodium glucose cotransport at the level of the tubular nephron.

LIPIDS AND SGLT2 INHIBITORS

The proportion of patients with LDL-C <100 mg/dL at week 26 was modestly lower with both canagliflozin doses compared with placebo

SAFETY & EFFICACYIncreased urination has been reported particularly in women, but also in men. Women are likely to get vulvo vaginal infections. The people who tend to get those infections are ones that had the infections before the drugs were given in the first place

EFFICACY AND SAFETY in ELDERLY T2D TREATED OVER 2 YEARSEmerging Role of SGLT2 Inhibitors: Updates From ADA 2014 CME

Ages 55 to 80 yrs. Canagliflozin 100 mg or 300 mg vs placebo. HbA1c decrease as being relatively modest.

UTIs : 10%(placebo ), 15% in 100 mg and 17% in the 300 mg group . The osmotic diuresis symptoms 6% (placebo) , 100 mg had 9%, and 300 mg was 12%. The AE of dizziness , hypotension , was mainly seen in the 300-mg group at 2%-4% . The SBP decreased significantly at 5 to 7 mm Hg vs placebo. There are always mycotic infections in this population. No Hypoglycemia in the canagliflozin arm.

Caution should be exercised in elderly patients, with renal impairment. These are patients with an estimated GFR between 45 and 60. Dapagliflozin is not indicated in those patients and Canagliflozin is.

There are at least 3 major studies running right now. We will have the results by 2017 and 2018. Then we will have much more information regarding long-term safety, efficacy, and possible effects on both macro/ microvascular outcomes.

GU INFECTIONSThe extensive clinical program with this class of agents has shown that:There is a clear signal regarding the increase of genital infections, occurring in 4-10% of patients; mostly in elderly, female patients. Generally, these infections are easy to treat with standard methods. There is a low rate of recurrence, and very rarely are discontinued the treatment. Discontinuation of therapy occurred at a frequency of about 1 in 500 in the clinical development program

REFRESHER COURSE FOR PATIENTSWomen should have proper hygiene and keep the area dry and clean. Circumcised males do not have any significant issues. Non circumcised males need to keep the area clean because balanitis has been reported in men with these agents.The side effects are rare ;generally well tolerated if they are properly educated

SGLT2 INHIBITORS… SUMMARYA NOVEL NON INSULIN DEPENDENT MECHANISM .

They can be used at any stage in the natural history of T2DM. They can be used as monotherapy or in combination with insulin, metformin , DPP4inh.Treatment is associated with mean weight loss , small reduction in BP, which may also be beneficial to patients with co-existing CVD. Trials regarding long-term cardiovascular outcomes are ongoing. 

BOTTOM LINEBy the very mechanism of action, these drugs can also potentially be used in type 1 diabetes, because they do not depend on the presence of endogenous insulin or beta cell function. Therefore, in association with insulin, obviously, they might find a place in the treatment of type 1 diabetes #To stabilize the glucose swing.#To limit the weight gain that occurs with satisfactory insulin treatment in type 1 DM. This application is being actively investigated.

KEY TAKEAWAYSThe kidney contributes to gluconeogenesis and hyperglycemia in patients with type 2 diabetes. SGLT2 inhibitors act by a novel mechanism and are useful in patients to achieve goal HbA1c

SGLT2 inhibitors lower HbA1c levels They have the benefit of wt. reduction in pts with T2DM

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