Anti-Diabetic Drugs

Siti Farah Md Tohid (PhD)

Diabetes Mellitus • The incidence of diabetes is increasing at an alarming

rate around the world.

• Insulin – β cells secrete due to

high blood glucose levels

– Glucose uptake into tissues increases

• Glucagon– α cells secrete when

blood glucose is low– Glucose is released

from tissues back into blood

Pancreatic axis

• Glucose homeostasis

Figure 26.8

Insulin

Beta cellsof pancreas stimulatedto release insulin intothe blood

Bodycellstake up moreglucose

Blood glucose leveldeclines to a set point;stimulus for insulinrelease diminishes

Liver takesup glucoseand stores it asglycogenHigh blood

glucose level

STIMULUS:Rising blood glucoselevel (e.g., after eatinga carbohydrate-richmeal) Homeostasis: Normal blood glucose level

(about 90 mg/100 mL) STIMULUS:Declining bloodglucose level(e.g., afterskipping a meal)

Alphacells ofpancreas stimulatedto release glucagoninto the blood

Glucagon

Liverbreaks downglycogen and releases glucoseto the blood

Blood glucose levelrises to set point;stimulus for glucagonrelease diminishes

Normal Glucose Control• In the post-absorptive period of a normal individual, low

basal levels of circulating insulin are maintained through constant β cell secretion. This suppresses lipolysis, proteolysis and glycogenolysis. After ingesting a meal a burst of insulin secretion occurs in response to elevated glucose and amino acid levels. When glucose levels return to basal levels, insulin secretion returns to its basal level.

• Type I DM: Lack of functional β-cells prevents mitigation of elevated glucose levels and associated insulin responses. The onset and progression of neuropathy, nephropathy and retinopathy are directly related to episodic hyperglycemia.

• Type II DM: The pancreas retains some β-cell function but effective insulin response is inadequate for the glucose level. Actual insulin levels may be normal or supra-normal but it is ineffective (insulin resistance).

Diabetes mellitus• Type I

– “Childhood” diabetes– Loss of pancreatic β cells– Decreased insulin

• Type II– “Adult” diabetes– Defective signal reception in insulin pathway– In most cases, decreased insulin

• Both cause hyperglycemia, glycosuria, lipid breakdown because tissues are deficient in glucose, ketone bodies

Diabetes Mellitus• This is a disease caused by elevated glucose levels• 2 Types of diabetes:

Type I diabetes (10% of cases)– Develops suddenly, usually before age 15.– Caused by inadequate production of insulin because T

cell-mediated autoimmune response destroys beta cells.– Controlled by insulin injections.

Type II diabetes (90% of cases)– Usually occurs after age 40 and in obese individuals, but

also genetics, aging, and peripheral insulin resistance.– Insulin levels are mostly decreased, sometimes normal/

elevated, but there is either a decrease in number of insulin receptors or the cells cannot take it up.

– Controlled by drugs, dietary changes and regular exercise.

Long term complications

• Diabetes is a heterogeneous group of syndromes characterized by the elevation of glucose levels due to a relative or absolute deficiency of insulin; frequently inadequate insulin release is complicated by excess glucagon release.

Table 24-8. Type 1 Versus Type 2 Diabetes Mellitus (DM) Type 1 DM Type 2 DM Clinical Onset: <20 years Onset: >30 years Normal weight Obese Markedly decreased blood

insulin Increased blood insulin (early);normal to moderate decreased insulin (late)

Anti-islet cell antibodies No anti-islet cell antibodies Ketoacidosis common Ketoacidosis rare;

nonketotic hyperosmolar coma

Genetics 30-70% concordance in twins 50-90% concordance in twins

Linkage to MHC Class II HLA genes

No HLA linkage Linkage to candidate diabetogenic genes (PPARγ, calpain 10)

Pathogenesis Autoimmune destruction of β-cells mediated by T cells and humoral mediators (TNF, IL-1, NO)

Insulin resistance in skeletal muscle, adipose tissue and liver β-cell dysfunction and relative insulin deficiency

Absolute insulin deficiency Islet cells Insulitis early No insulitis Marked atrophy and fibrosis Focal atrophy and amyloid

deposition β-cell depletion Mild β-cell depletion

The long term complications of diabetes may be divided into two large groups:

1. Macrovascular: These complications are associated with pathology of the large and medium-sized vessels; this includes CHD, stroke, Peripheral vascular disease.

2. Microvascular: These complications are due to vascular pathology of the small vessels and include neuropathy, nephropathy, retinopathy

Treatment• Type I: Type 1s depend on exogenous insulin to prevent

hyperglycemia and avoid ketoacidosis. The goal of type 1 therapy is to mimic both the basal and reactive secretion of insulin in response to glucose levels avoiding both hyper- and hypo-glycemic episodes.

• Type II: The goal of treatment is to maintain glucose concentrations within normal limits to prevent long term complications. Weight reduction, exercise (independent of weight reduction) and dietary modification decrease insulin resistance and are essential steps in a treatment regimen. For many this is inadequate to normalize glucose levels, the addition of hypoglycemic agents is often required, often insulin therapy is required.

INSULIN

• Insulin is a peptide hormone synthesized as a precursor (pro-insulin) which undergoes proteolytic cleavage to form a dipeptide; the cleaved polypeptide remnant is termed protein C.

• Both are secreted from the β-cell, normal individuals secrete both insulin and (but much less) pro-insulin.

• Type 2s are found to secrete high levels of pro-insulin (pro-insulin is inactive) measuring the level of C-protein is a more accurate estimation of normal insulin secretion in type 2s.

Insulin• Human insulin consists of 51 aa in

two chains connected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification).

• T1/2 ~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links.

• Bovine insulin differs by 3 aas, pork insulin differs by 1 aa.

• Insulin is stored in a complex with Zn2+ ions.

The Goal of Insulin TherapyAdministration of insulins are arranged to mimic the normal basal, prandial and post-prandial secretion of insulin. Short acting forms are usually combined with longer acting preparations to achieve this effect.

1. Rapid & Ultrashort-acting insulin1. Ultra short /rapid-acting insulin: e.g. Lispro, Aspart & Glulisine preparations -

ultrashort acting forms with onset more rapid than regular insulin and a shorter duration - less often associated with hypoglycemia. Lispro insulin is given 15 minutes prior to a meal and has its peak effect 30-90 minutes after injection (vs. 50-120 minutes for regular insulin). e.g Glulisine can be given anywhere from 15 minutes prior to 20 minutes after beginning a meal.

2. Short-acting insulin• Regular insulin (Humulin R, Novolin R)• short acting, soluble, crystalline zinc insulin is usually given subcutaneously; it

rapidly lowers glucose levels. All regular insulin is now made using genetically engineered bacteria; cow and pig no longer used.

• covers insulin needs during meal• taken about 30 minutes to an hour before a meal to help control blood sugar

levels.• This type of insulin takes effect in about 30 minutes to one hour, and peaks after

two to four hours. Its effects tend to last about five to eight hours.

3. Intermediate –acting Insulin• control blood sugar levels for about

12 hours or longer, so it can be used overnight

• offer baseline insulin coverage and can be used with short-acting or rapid-acting insulin

1. Lente insulin (Humulin N - NPH): an amorphous precipitate of insulin with zinc ion combined with 70% ultralente insulin. Onset is slower but more sustained than regular insulin - cannot be given IV.

2. Isophane insulin (Novolin N – NPH): Neutral protamine insulin - a suspension of crystalline zinc insulin combined with protamine (a polypeptide) - conjugation with protamine delays its onset of action and prolongs it effectiveness.

4. Long-acting insulin 1.Ultralente: a suspension

of zinc insulin forming large particles which dissolve slowly, delaying onset and prolonging duration of action.

2.Insulin Glargine: Precipitation at the injection site extends the duration of action of this preparation.

3. Detemir insulin: has a FA complexed

with insulin resulting in slow dissolution.

Pump vs. Standard Insulin Therapy

• cover insulin needs for a full day. It is often taken at bedtime• provide 24-hour coverage, and have been helpful at achieving good blood sugar control

in type 2 diabetes with just one shot

• Various types of insulin are characterized by their onset and duration of action

5. Insulin Combinations /Pre-mixed insulin• Various premixed combinations

of various preparations of insulin are available to ease administration. Standard combination use should follow establishment of an acceptable regime of individual preparations (not everybody has the same insulin requirements)

• combines intermediate- and short-acting insulin. It is often taken twice a day before meals

• effects last from 10 to 16 hours

Adverse Effects of Insulin1. Hypoglycemia may occur due to insulin overdose,

insufficient caloric intake (missed meal, improper meal content, delayed meal, etc.). Ethanol consumption promotes hypoglycemic response.

2. Hypokalemia: insulin draws K+ into the cell with glucose (hyperglycemia with normal K+).

3. Lipodystrophy at injection site4. Weight gain5. Injection complications

Oral Hypoglycemics• These agents are useful in the treatment of type 2s

who do not respond adequately to non-medical interventions (diet, exercise and weight loss).

• Newly diagnosed Type 2s (less than 5 years) often respond well to oral agents, patients with long standing disease (often diagnosed late) often require a combination of agents with or without insulin.

• The progressive decline in β-cell function often necessitates the addition of insulin at some time in Type II diabetes. Oral agents are never indicated for Type Is.

The goal of management of type 2 diabetes by oral agents

• Increasing pancreatic insulin secretion (secretogogues) with sulfonylureas or meglitinides and/or

• Decreasing hepatic gluconeogenesis with biguanides and/or

• Improving insulin sensitivity in peripheral tissues with thiazolidinediones and/or

• Preventing breakdown of complex carbohydrates into simple sugars with alpha-glucosidase inhibitors.

SulfonylureasPromote the release of insulin from β-

cells (secretogogues); Tolbutamide, Glyburide, Glipizide and Glimepiride.

• Mechanism: – Require functioning β-cells, they stimulate

release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca2+ influx which promotes insulin secretion.

– Also reduce glucagon secretion and increase the binding of insulin to target tissues.

– May also increase the number of insulin receptors

• Pharmacokinetics: bind to plasma proteins - metabolized in the liver and excreted by the liver or kidney. Tolbutamide has the shortest duration of action (6-12 hrs);

the other agents: effective for ~24hrs.

SulfonylureasAdverse Effects: These agents tend to cause

weight gain, hyperinsulinemia and hypoglycemia. Hepatic or renal insufficiency causes accumulation of these agents promoting the risk of hypoglycemia. There are a number of drug-drug interactions. Elderly patients appear particularly susceptible to the toxicities of these agents.

• Tolbutamide is asociated with a 2.5X ↑ in cardiovascular mortality.

Onset and Duration• Short acting: Tolbutamide (Orinase)• Intermediate acting: Tolazamide (Tolinase),

Glipizide (Glucotrol), Glyburide (Diabeta)• Long acting: Chloropropamide, Glimerpiride

Meglitinide analogsThese agents (Repaglinide (Prandin) and Nateglinide (Starlix)) act as

secretogogues.• Mechanism: These agents bind to ATP sensitive K+channels like

sulfonylureas acting in a similar fashion to promote insulin secretion, however their onset and duration of action are much shorter. Particularly effective at mimicking the prandial and post-prandial release of insulin. When used in combination with other oral agents they produce better control than any monotherapy.

• Pharmacokinetics: reach effective plasma levels when taken 10-30 minutes before meals. Metabolized to inactive products by CYP3A4 and excreted in bile.

• Adverse Effects: Less hypoglycemia than sulfonylureas; drugs that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin, etc.) prolong their duration of effect. Drugs that promote CYP3A4 (barbiturates, carbamazepine and rifampin) decrease their effectiveness.

Insulin SensitizersTwo classes of oral hypoglycemics work by improving insulin target cell

response; the biguanides and thiazolidinediones.Biguanides:• Metformin is classified as an insulin sensitizer, it increases glucose

uptake and utilization by target tissues. It requires the presence of insulin to be effective but does not promote insulin secretion. The risk of hypoglycemia is greatly reduced.

• Mechanism: Metformin reduces plasma glucose levels by inhibiting hepatic gluconeogenesis. It also slows the intestinal absorption of sugars. It also reduces hyperlipidemia (↓LDL and VLDL cholesterol and ↑ HDL). Metformin also decreases appetite. It is the only oral hypoglycemic shown to reduce cardiovascular mortality. It can be used in combination with other oral agents and insulin.

• Adverse effects: Hypoglycemia occurs only when combined with other agents. Rarely severe lactic acidosis is associated with metformin use particularly in diabetics with chronic heart failure. Drug interactions with cimetidine, furosemide, nifedipine and others have been identified.

Insulin Sensitizers

Thiazolidinediones (TZD) (Glitazones)

• These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosigglitazone are the two agents of this group.

• In the liver: ↓glucose output• In muscle: ↑glucose uptake• In adipose: ↑glucose uptake , ↓FA release• Only pioglitazone may be used in combination with insulin;

the insulin dose must be modified. Rosiglitazone may be used with other hypoglycemic but severe edema occurs when combined with insulin.

• Pharmacokinetics: Both are extensively bound to albumin. Both undergo extensive P450 metabolism; metabolites are excreted in the urine the primary compound is excrete unchanged in the bile.

• Adverse Effects: Fatal hepatotoxicity has occurred with these agents; hepatic function must be monitored. Oral contraceptives levels are decreased with concomitant administration, this has resulted in some pregnancies.

α-Glucosidase InhibitorsAcarbose and miglitol are two agents of this class used

for type 2 diabetes.Mechanism of action: These agents are oligosaccharide

derivatives taken at the beginning of a meal delay carbohydrate digestion by competitively inhibiting α-glucosidase, a membrane bound enzyme of the intestinal brush border – diminish postprandial hyperglycemia.

Pharmacokinetics: Acarbose is poorly absorbed - remain in the intestinal lumen. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen.

Adverse Effects: flatulence, diarrhea, cramping. Metformin bioavailability is severely decreased when used concomitantly. These agents should not be used in diabetics with intestinal pathology.

α-Glucosidase InhibitorsThis enzyme hydrolyses

oligosaccharides to monosaccharides which are then absorbed. Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucose levels rise modestly and remain slightly elevated for a prolonged period, less of an insulin response is required and hypoglycemia is avoided; use with other agents may result in hypoglycemia. Sucrase is also inhibited by these drugs.

Post Prandial Glucose Regulation