new treatment for diabetes mellitus and drugs to treat hypoglycemia

New Treatment For Diabetes MellitusDrugs To Treat Hypoglycemia

Faraza JavedMphil Pharmacology

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.caCopyright © 2013 Canadian Diabetes Association

Diabetes Mellitus

Diabetes mellitus is a

group of metabolic

diseases characterized

by hyperglycemia

resulting from defects

in insulin secretion,

insulin action, or both.


Treatment Synthetic Amylin Analog Incretin Mimetics Oral Agents

Insulin Sectretagogues

Alpha Glucosidase Inhibitors

Dipeptidyl Peptidase IV Inhibitors

Insulin Sensitizers


Synthetic Amylin Analog

• Pramlintide, a synthetic analogue of amylin, is an injectible antihyperglycemic agents that modulates postprandial glucose levels and is approved for postprandial use for persons with type 1 and type 2 diabetes.

• Pramlintide lowers glucagon during a meal, slows food emptying from the stomach and curbs the appetite.


• It is administered in addition to insulin who are unable to achieve their target postprandial blood sugar level.

• Major adverse effects are hypoglycemia and GI symptoms including nausea, vomiting and anorexia.


Glucagon like Polypeptide- 1 Receptors Agonists

• Incretins are intestinal factors that are released in response to nutrients, contributing to blood glucose lowering.

• In type 2 Diabetes, the release of glucagon like polypepide is diminished postprandially, which leads to inadequate glucagon suppression and excessive hepatic glucose output.


• Two synthetic analogues of glucagon likepolypeptide Exenatide and Liraglutide are commercially available to help restore GLP-1 activity.

• Exenatide and Liraglutide, along with DPP-4 inhibitors, are currently available to treat patients with T2DM by addressing decreased concentrations of GLP-1.


Insulin Pump

Insulin pumps are small computerized devices that deliver insulin in two ways:

• In a steady measured and continuous dose (the "basal" insulin)• As a surge ("bolus") dose, at your direction, around mealtime.

This FDA Approved Insulin delivery system most closely mimics the body's normal release of insulin.


Combination Therapy• GLP-1 (Glucagon like Polypeptide) Receptor agonist

with Insulin Secretagogue or with Insulin.

• DPP-4 (Dipeptidyl Peptidase IV) Inhibitor Sitagliptin or Vidagliptin (Glavusmet) in combination with metformin.

• Pramlintide in combination with Insulin, Metformin or Sulphonylurea.


Modern Advancement in DM Treatment

The current classes of medications are effective initially, but glucose-lowering effects are not typically sustained long term as beta cell dysfunction progresses. Several new classes of medications are currently in development, as well as a new long-acting insulin.


There are two organizations that are reviewing the DM therapy treatment and encouraging new reasearches:

• American Diabetes Association (ADA) • International Diabetes Federation (IDF)


Sodium Glucose Cotransporter 2 Inhibitors (SGLT-2)

SGLT-2, a low-affinity but high-capacity transporter found in the brush border of the proximal tubule, is a mediator of glucose reabsorption in the kidneys. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, which in turn contributes to chronic glycemic burden and the risk of microvascular consequences.


• SGLT-2 inhibitors exert their effects by causing the kidneys to excrete glucose into the urine. The effects are also independent of insulin secretion.

• These proposed mechanisms make SGLT-2 a viable target to help combat hyperglycemia in patients with T2DM. These agents decreased A1C anywhere from 0.5 to 1.5%, and demonstrated low incidences of hypoglycemia with minimal side effects.


SGLT-2 Inhibitors (Phase III) include:

• Canagliflozin • Empagliflozin • Dapagliflozin


Long Acting Basal Insulin Analogue

LY2605541 is a long-acting basal insulin analogue that is currently being evaluated in phase III studies in T2DM patients. The primary aim of insulin therapy is to replace endogenous insulin secretion in patients with type 1 or type 2 diabetes in a physiologic manner, mimicking normal secretion patterns to adequately regulate glucose metabolism.


• The currently available human insulins for basal therapy - neutral protamine Hagedorn (NPH), - and analogs such as insulin glargine, differ in pharmacokinetic properties.

• Clinical trial data indicate that insulin glargine may satisfy basal insulin requirements, with an improved safety profile relative to other available insulins used for basal supplementation.


11-β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors (11-β-HSD1)

11-β-Hydroxysteroid Dehydrogenase or cortison reductase convert cortison to cortisol. Overexpression of this enzyme can lead to obesity insulin resistance.


Preclinical evidence indicates that 11-β-HSD1 has a function in both obesity and metabolic disease in rodents, which suggests that inhibiting this catalyst in liver and adipose tissues may lead to enhanced hepatic and peripheral insulin sensitivity, thus improving overall glucose levels and possibly decreasing overall macrovascular risk.


Vitamin D In DMRecent studies have found that deficiency of Vitamin

D results in reduction in insulin secretion and thus in hyperglycemia. Both insulin secretion and sensitivity depends upon intracellular calcium concentration also and Vitamin D is one of the hormone which has been found to regulate calcium flux within the cells. In both observational and case-control studies, an inverse relationship has been reported with level of 25(OH)Vit D and degree of glycemic control.


Stem Cell TherapyA newly created method of

placing stem cell-derived

pancreatic cells in capsules

under the skin to replace

insulin is tested in diabetic

disease models. The method is successful without producing likely complications. The study confirms the viability of combining stem cells and 'encapsulation' technology to treat insulin-dependent diabetes.


Betatrophin

Scientists at Harvard Stem Cell Institute (HSCI) found that a hormone called betatrophin plays a significant role in enhancing the production of insulin by beta cells in mice.

If the study also shows similar results in humans, it will be a huge leap forward in the treatment of diabetes.


Islet Cell TransplantationIn islet cell

transplantation,

beta cells are

removed from

a donor's pancreas

and transferred

into a person

with diabetes.


• Beta cells are found in the islets of the pancreas and produce insulin, which regulates blood sugar levels. Once transplanted, the donor islets begin to make and release insulin.

• As with all organ and tissue transplants, rejection of the donor cells is the greatest challenge.


Brown Fat Transplant May Aid in Diabetes Management

There are at least two types of adipose (fat) tissue.

• White adipose tissue is the more common type that lies below the skin, stores excess fat in the body, and expands with weight gain.

• Brown adipose tissue, on the other hand, is derived from muscle and is highly thermogenic. In other words, it burns energy to produce heat and maintain body temperature in warm-blooded organisms.


• Unlike white adipose tissue, the quantity of brown fat in the body is inversely proportional to body mass index (BMI), meaning that lean people tend to store more of this type of fat than people that are overweight , leading to the characterization of brown fat as “good” fat.


• Researchers find out that brown fat transplant had significantly lower body weight, reduced white fat mass, show better sensitivity to insulin, and improved glucose metabolism in labourtary animals.

• Now researchers are trying to collect data on humans to evaluate either the study also shows similar results in humans or not.


The Use of Vanadium Complexesin Diabetes Mellitus

Recent researches found that vanadyl ion and its complexes are effective not only in treating or relieving both types of DM but also in preventing the onset of DM. Exact mechanism is still unknown.


Gastric Stimulator

DIAMOND, made by

the Israeli medical

device company

MetaCure, is an

implantable gastric

stimulator with

electrodes attached to the

outer stomach muscles.


• Its original purpose was to treat obesity But its developers discovered that in the hundreds of people implanted with DIAMOND worldwide, the device also effectively controls blood glucose levels as well as, or better than, synthetic insulin and other diabetes medications. It also helped improve diabetes-associated conditions such as high blood pressure, cholesterol and triglycerides.


The Dead Sea

The mineral-rich Dead Sea

has long been known

as a natural treatment

for skin, rheumatic and

respiratory diseases.

According to a study by health sciences researchers

at Ben-Gurion University, the salty water also help lower blood glucose levels and could improve the medical conditions of diabetics.


• After soaking in a pool filled with Dead Sea water for 20 minutes, there was a considerable decrease – up to 13 percent in some cases – in the blood glucose levels.

• It’s still a bit early to draw conclusions, but further testing will determine if one day a Dead Sea dunk could be prescribed as a way to lessen the dose of insulin needed.


Hypoglycemia

Hypoglycemia is a condition characterized by abnormally low blood glucose (blood sugar) levels, usually less than 70 mg/dl.

• Hypoglycemia is not a disease itself – it is the result of an underlying issue or combination of them.


Causes

• Drugs e.g. Insulin, Sulphonylurea• Endocrinopathies (Glucagon Deficiency)• Tumor of B cells• Poisoning (ethanol inhibits gluconeogenesis)• Renal Failure


Mild Symptoms• Trembling/shakiness• Sweating• Anxiety• Irritability• Pallor• Palpitations• Headache


Severe Symptoms• Concentration problems• Confusion• Irrational and disorderly behavior • Seizures • Loss of consciousness


Treatment ProtocolInitially• Glucose 10-20 g is given by mouth, either in liquid

form or as granulated sugar (2 teaspoons) or sugar lumps.

• GlucoGel® - formerly known as Hypostop® Gel - may be used.

• Repeat capillary blood glucose after 10-15 minutes; if the patient is still hypoglycaemic then the above can be repeated (probably up to 1-3 times).


Recommendation 1

1. Mild to moderate hypoglycemia should be

treated by oral ingestion of 15 g carbohydrate;

glucose or sucrose crystals/ solutions are

preferable to orange juice and glucose gels.

Patients should retest blood sugar in 15 minutes

and retreat with another 15 g of carbohydrates if

BG remains <70mg/dl


Recommendation 2

2. Severe hypoglycemia in a conscious person

should be treated by oral ingestion of 20 g of

carbohydrate, preferable as glucose tablets or

equivalent.

Blood sugar should be retested in 15 minutes,

and then retreated with a further 15 g of glucose

if BG remains <70 mg/dl.


Recommendation 3

3. Severe hypoglycemia in an unconscious individual:

– No IV access: 1 mg of glucagon should be

administered subcutaneously or intramuscularly.

– Hypoglycemic effects (specially due to drugs) may

persist for 12-24 hours and ongoing glucose

infusion or other therapies such as octreotide may

be required.


• With IV access: 10-25 g (20-50 cc of D50W) of glucose should be given intravenously over 1-3 minutes.

• Retest in 15 minutes to ensure the BG >70mg/dl and retreat with a further 15 g of carbohydrate if needed.

• Once conscious, eat usual snack or meal due at that time of day or a snack with 15 g carbohydrate plus protein.


Recommendation 4

Prolonged Hypoglycemic Coma:

Use IV mannitol and dexamethasone with constant glucose monitoring and IV glucose to keep serum level at 70-80mg/dl until either consciousness has been restored or permanent brain damage is diagnosed.


3. Once the patient is more alert, carbohydrate should be given, e.g. toast, or a normal meal. For inpatients, an infusion of 10% glucose may be administered if required.


Recommendation 5

• Patients receiving antihyperglycemic agents that may cause hypoglycemia should be counseled about strategies for prevention, recognition and treatment of hypoglycemia.


ReferencesKatzung Pharmacology, 11th Edition

www.idf.org

SGC2I in DM Treatmet, Jcem. (2010) vol.95(1)

NIDDK, NIH Review (2014)

www.diabetes.org.uk

CDA clinical practice guidelines

ND Cohen, JE Shaw - Internal medicine journal, 2007.

C Kelly, NH McClenaghan - Stem cells international, 2011.

www.guidelines.diabetes.ca

Alexander, G Caleb. (2008). Trends in DM treatment. Archives of internal medicine. 168(19):2088-2094.

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new treatment for diabetes mellitus and drugs to treat hypoglycemia

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