THE EPIDEMIC OF DIABETES

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1 THE EPIDEMIC OF DIABETES

2 TYPE 1 AND TYPE 2 DIABETES DIFFER IN INSULIN PRODUCTION AND FUNCTION

3 IN TYPE 2 DIABETES DEFECTS IN INSULIN FUNCTION LEAD TO HYPERINSULINEMIA

4 NATURAL HYSTORY OF TYPE 2 DIABETES Insulin resistance Genetics Weight gain Hypertension Dyslipidemia IGT IFG Early diabetes Late diabetes Macrovascular complications Advancing age Microvascular complications In diabetic patients, pharmacological treatment aims to - reduce risks associated to the disease - control the clinical outcome and the disease course - ameliorate patients quality of life

5 DIABETES AND ITS COMPLICATIONS Morbidity and mortality (mainly related to cardiovascular events) in diabetes is strictly associated to impaired glucose tolerance, evolving from glucose intolerance to open diabetes (hyperglycemia). However, even before glucotoxicity, it is important to consider the deleterious effects of high insulin levels (hyperinsulinemia) as a compensatory mechanism to initial insulin resistance

6 DIABETIC DRUGS TARGET HYPERGLYCEMIA WITH SEVERAL DISTINCT MECHANISMS

7 INSULIN Insulin is a tiny protein. It moves quickly through the blood and is easily captured by receptors on cell surfaces, delivering its message. Small proteins pose a challenge to cells: it is difficult to make a small protein that will fold into a stable structure. Pancreatic beta cells solve this problem by synthesizing a longer protein chain, which folds into the proper structure. Then, the extra piece is clipped away, leaving two small chains (Chain A and Chain B) in the mature form. The structure is further stabilized by three disulfide bridges.

8 PANCREATIC INSULIN SECRETION Insulin secretion from beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter, the glycolytic phosphorylation of glucose cause a raise in the ATP:ADP ratio This raise inactivates the K channels that depolarizes the membrane, causing Ca channels to open up allowing Ca ions to flow inward. The ensuing raise in Ca levels leads to the exocytotic release of insulin from its storage granules

9 INSULIN METABOLIC EFFECTS on GLUCOSE UPTAKE One of the many physiologic actions of insulin is to promote glucose uptake in skeletal muscle, heart, and adipose tissue. The effect of insulin on glucose uptake in these tissues is a direct result of the recruitment of the GLUT4 facilitative glucose transporter from an intracellular vesicle pool to the plasma membrane. GLUT4 was first implicated as the major insulin-responsive glucose transporter when it was shown to be the predominant isoform expressed in tissues exhibiting insulinstimulated glucose uptake

10 SIGNALING PATHWAYS ACTIVATED BY INSULIN Insulin receptor Insulin Endocrine Reviews 28, 463, 2007 PIP2 PIP3 SHC P GRB2 P SOS P IRS P P P PI3-K RAS PDK P RAF MEK P Akt P P apkc P FOXO1 P MAPK P enos P GSK3 P Glucose uptake Gene transcription Endothelin-1 NO Gluconeogenesis Glycogen synthesis Protein synthesis Cell growth Differentiation Vascular constriction Endothelium Vascular relaxation Skeletal muscle Adipose tissue Liver

11 INSULIN Young surgeon Frederick Banting began his research about insulin on May 19, 11, with J92ohn Macleod as formal supervisor and Charles Best as his assistant. In August of 1921 after numerous failures, Banting and Best prepared a new extract from the atrophied pancreas of one of the dogs. They then isolated two other dogs with diabetes, administering the extract to one and leaved the second untreated. Four days later, the untreated dog died of severe diabetes. The dog that received the extract lived for three more weeks, dying only when the extract was used up In 1923, Frederick Banting e John MacLeod won the Nobel Prize for Medicine in recognition of their studies on insulin effects and extraction methods Insulin has been the first human recombinant protein to be approved on the market under the brand Humulin. It was initially developed by Genentech and marketed by Eli Lilly in This was a massive step forward to replace pig insulin and improve the life of diabetics worldwide. Since then, the recombinant insulin never stopped being improved.

12 NORMAL INSULIN SECRETION: the BASAL/BOLUS INSULIN CONCEPT Glucose-stimulated insulin secretion typically follows a biphasic time course. Shortly after elevation of the glucose concentration, a transient stimulation of insulin secretion is observed, referred to as first phase secretion (occurring within the first 10 minutes) which at later times is followed by a gradually developing secondary stimulation, second phase secretion (that reaches plateau in 2-3 hours)

13 INSULIN THERAPY SHOULD MIMIC PHYSIOLOGICAL PATTERN INSULIN AND INSULIN ANALOGS

14 REGULAR INSULIN Rapid effect Regular human insulin is crystalline zinc insulin dissolved in a clear solution. It is the only insulin that can be administered by any parenteral route: subcutaneous, intramuscular, or intravenous. hexamers dimers monomers Minimal diffusion Limited diffusion Rapid diffusion Capillary barrier Onset of action is approximately at min, peak effect at 1-2 hours, and duration of action up to 6-8 hours

15 NPH INSULIN Intermediate effect NPH, which stands for Neutral Protamine Hagedorn, was created in 1936 by Hans Christian Hagedorn and B. Norman Jensen. These scientists discovered that the effects of subcutaneously injected insulin could be prolonged by the addition of protamine, a protein that they obtained from the "milt" or semen of river trout. NPH insulin is categorized as an intermediate-acting insulin, whose onset of action is approximately 2 hours, peak effect at 6-14 hours, and duration of action up to 24 hours (depending on the size of the dose). Intermediate-acting insulins can serve as basal insulin and/or prandial insulin depending on time of administration. NPH insulin is available in various combinations with either regular insulin or short-acting insulins

16 INSULIN ANALOGS Protein engineering has been used to produce variant forms of insulin, known as insulin analogues, with modified amino-acid sequences and improved pharmacokinetic properties. A number of insulin analogues have now been licensed for treatment, including rapid-acting forms for use at meal times and long-acting insulins for basal requirements.

17 RAPID-ACTING INSULIN ANALOGS Insulin Lispro (Humalog) Insulin lispro [Lys (B28), Pro (B29)] was approved in The B28 (proline), B29 (lysine) amino acid sequence of the insulin molecule is reversed resulting in a rapid absorption, within 15 minutes. Because it is absorbed more rapidly, its onset and peak are sooner (and duration shorter) compared to regular insulin. Insulin lispro can be more effective in lowering postprandial blood glucose levels and has a reduced risk of hypoglycemia Insulin Aspart (Novolog) Insulin aspart was approved in The B28 amino acid proline is substituted with aspartic acid resulting in a rapid onset of activity. Insulin aspart should be injected 5-10 minutes before the meal. Advantages for insulin lispro and aspart are the same. Insulin Glulisine (Apidra) Insulin glulisine has been available in USA since Insulin glulisine differs from human insulin in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid.

18 LONG-ACTING INSULIN ANALOGS Insulin Glargine (Lantus) Glargine was approved in 2000 and presents 2 modifications: two arginines added to the C-terminus of the B chain shift the isoelectric point from a ph 5.4 to 6.7, making the insulin more soluble at an acidic ph (glargine is formulated at ph 4.0). In addition, asparagine is replaced by glycine at the A21 position, preventing deamidation and dimerisation that would occur with acid-sensitive asparagine. When glargine is injected into subcutaneous tissue (physiologic ph), the acidic solution is neutralized. Microprecipitates are formed, from which small amounts of insulin are released throughout a 24-hour period, resulting in a low level of insulin throughout the day. Insulin glargine has been shown to have less nocturnal hypoglycemia when used at bedtime compared with NPH insulin. Insulin Detemir (Levemir) Insulin detemir is a long-acting human insulin analog in which the B30 amino acid is omitted and a C14 fatty acid chain (myristic acid) is bound to the B29 lysine amino acid. Insulin detemir is slowly absorbed due to its strong association with albumin in the subq tissue and when it reaches the bloodstream it again binds to albumin delaying its distribution to the peripheral tissues.

19 INSULIN STORAGE and ADMINISTRATION INSULIN STORAGE Insulin should not be allowed to freeze, nor be heated above room temperature. Insulin should be stored in the refrigerator until opened, then may be stored at room temperature until gone. At sustained temperatures above room temperature, insulins lose potency rapidly. Excess agitation should be avoided to prevent loss of potency, clumping or precipitation. All insulins except Regular, Lispro and Aspart should be gently rolled in the palms to resuspend solution. (Do not shake) INSULIN ADMINISTRATION Because of its proteic nature, insulin cannot be taken by oral administration. Therefore, all insulin and insulin analogs must be injected. It is most commonly given as a subcutaneous injection or, in some cases, intravenously (only certain types). Insulin can be supplied in different ways. These options include an insulin PUMP, an insulin PEN, or an insulin VIAL.

20 INSULIN INJECTION SITES Rotating sites is very important because: - It can be painful to inject in the same site frequently. - Injecting in the same site can cause the skin tissue to become very hard. - Injecting in the same site can cause increase in fat tissue at that site. The fat tissue alters the body's ability to absorb the insulin.

21 Hypoglycemia (glicemia < mg/dl) (dose changes, diet variations, modified time of administration, surrenalic failure, physic exercise, fever) Allergic reactions and cutaneous reactions Lipohypertrophy or Lipoatrophy (direct or self Ab-mediated effect) Weight gain, edema (increased Na+ retention and vascular permeability, increased glucose utilization) Reactive hyperglycemia (Somogyi effect) (night hypoglycemic state not diagnosed) ADVERSE EFFECTS of INSULIN Interaction with IGF-1 Receptors INSULIN ANALOGS ADDITIONAL RISK Decreased dissociation from Insulin R mitogenic activity increased risk of cancer? increased teratogenic risk?

22 OVERVIEW OF INSULIN PRODUCTS Afrezza is a rapid-acting inhaled insulin that has been FDA-approved in Currently, it is the only inhaled insulin on the market, as an earlier product was discontinued. Spirometry testing is required prior to the initiation of therapy due to the risk of acute bronchospasm. The most common adverse effects include hypoglycemia, cough, throat pain or irritation, and headache

23 MAIN CLASSES OF DRUGS FOR THE TREATMENT OF TYPE 2 DIABETES INSULINS SULFONYLUREAS GLINIDES INCRETINS GLIPTINS α-glucosidase INHIBITORS Adipose tissue pancreas bowel THIAZOLIDINEDIONES HYPERGLYCEMIA liver BIGUANIDES THIAZOLIDINEDIONES kidney SGLT-2 INHIBITORS muscle

24 SULFONYLUREAS (SU) Sulfonylureas are likely to bind to ATP-sensitive Potassium Channel Receptors on pancreatic cell surface, reducing potassium conductance and causing membrane depolarization. Therefore, they are able to enhance insulin release disregarding the ATP:ADP ratio.

25 SULFONYLUREAS (SU) PK of FIRST GENERATION MOLECULES

26 SULFONYLUREAS (SU) PK of SECOND GENERATION MOLECULES

27 KEY SIDE EFFECTS PRECAUTIONS AND ADVERSE REACTIONS POTENTIAL: MAY THEY INTERFERE WITH CARDIAC FUCTION? POTENTIAL: MAY THEY PROMOTE BETA CELL APOPTOSIS?

28 DRUG INTERACTIONS

29 MEGLITINIDES Metiglinide analogues are insulin secretagogues that are structurally unrelated to the sulfonylureas, but share a similar mechanism of action. These compounds are named for the initial, prototype molecule, metiglinide, found to have a sulfonylurea-like effect in stimulating the pancreatic beta cell to secret insulin. Metiglinides have been found to improve postprandial hyperglycemia in diabetic patients and to improve glycemic control and hemoglobin A1c levels. Two metiglinides have been approved for use in the United States: repaglinide in 1997 and nateglinide in REPAGLINIDE GLINIDES NATEGLINIDE Beta pancreatic cell

30 -GLUCOSIDASE INHIBITORS Alpha-Glucosidase is one of the enzymes responsible for breaking down carbohydrates to smaller sugar particles like glucose, in order for the carbohydrates to be absorbed. Alpha-Glucosidase inhibitors work by competitive and reversible inhibition of these intestinal enzymes. They slow the digestion of carbohydrates and delay glucose absorption. This results in a smaller and slower rise in blood glucose levels following meals, and effectively throughout the day. ACARBOSE

31 -GLUCOSIDASE INHIBITORS

32 BIGUANIDES BUFORMIN withdrawn PHENFORMIN withdrawn Galega officinalis METFORMIN Drugs originally isolated from Galega officinalis. Metformin is the only drug of this class available on the market.

33 METFORMIN mechanism of action Metformin decreases blood glucose levels by decreasing hepatic glucose production, decreasing intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization. These effects seem mediated by the activation of liver AMP-Kinase (AMPK).

34 MAIN PK FEATURES OF METFORMIN BIOAVAILABILITY PLASMA PROTEIN BINDING METABOLISM HALF-LIFE ELIMINATION 50-60% at fasting state 20% none 6.2 h Active tubular excretion by OCT2 OCT2 = Organic Cation Transporter

35 ADVANTAGES, SIDE EFFECTS AND ADVERSE REACTIONS KEY SIDE EFFECTS Loss of appetite Bloating Heartburn Gas Nausea Vomiting RARE (SEVERE) SIDE EFFECTS Lactic acidosis RISK FACTORS FOR LACTIC ACIDOSIS ADVANTAGES No weight gain No hypoglycemia Cheap

36 PROPOSED CITOSTATIC EFFECTS OF METFORMIN A fundamental action of the drug is to reduce mitochondrial oxidative phosphorylation, and this metformininduced energy stress inhibits hepatic gluconeogenesis, which represents the export of energy (as glucose) from the liver. This ameliorates the energetic stress of the hepatocyte but also lowers circulating glucose levels, causing a fall in insulin levels (provided insulin is elevated at baseline, which is often the case in type II diabetes or obesity). This can have a cytostatic effect on the subset of tumors that thrive in a high-insulin environment. Normal cells and some transformed cells are able to cope with the modest degree of energy stress induced by metformin, in part by reducing, in an AMPK-dependent fashion, energy-consuming biosynthetic functions such as protein synthesis (via AMPK-dependent mtor inhibition) and lipid synthesis (via AMPK-dependent FAS inhibition). This relieves the energetic stress but obliges the cell to adopt the restrictions of a low-energy lifestyle, leading to a cytostatic effect. In contrast, certain tumors have defects that make them incapable of compensating for the energetic stress induced by metformin, leading to a cytotoxic effect on the tumor, with no important effect on the host and a favorable therapeutic index.

37 THIAZOLIDINEDIONES Thiazolidinediones also called glitazones, are insulin sensitizers that act as agonists of the peroxisome proliferator-activated receptors-gamma (PPARgamma) CIGLITAZONE withdrawn TROGLITAZONE withdrawn PIOGLITAZONE ROSIGLITAZONE Withdrawn in EU in 2010 Still available in US

38 INSULIN-SENSITIZING EFFECTS of THIAZOLIDINEDIONES

39 THIAZOLIDINEDIONES

40 DRUGS ACTING ON INCRETIN SYSTEM Incretins are gut hormones that are secreted from enteroendocrine cells into the blood within minutes after eating. One of their many physiological roles is to regulate the amount of insulin that is secreted after eating. In this manner, they aid in disposal of the products of digestion. There are two incretins, known as glucose-dependent insulinotropic peptide (GIP) and glucagonlike peptide-1 (GLP- 1), that share many common actions in the pancreas but have distinct actions outside of the pancreas. Both incretins are rapidly deactivated by an enzyme called dipeptidyl peptidase 4 (DPP4)

41 GLP-1 ANALOGS (MIMETICS) The glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of injected drugs that mimic the action of GLP-1 and increase the incretin effect in patients with type 2 diabetes, stimulating the release of insulin. They have additional effects in reducing glucagon, slowing gastric emptying, and inducing satiety. In clinical practice they are associated with significant reductions in glycosylated haemoglobin (HbA 1c ), weight loss and a low risk of hypoglycaemia. Beneficial effects have also been observed on blood pressure and lipids.

42 GLP-1 ANALOGS (MIMETICS)

43 DPP-IV INHIBITORS The first dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin was approved in The second DPP-4 inhibitor, saxagliptin, was approved in the U.S. It was approved both as monotherapy as well as in combination with metformin, sulfonylurea, or thiazolidinedione. The use of a DPP-4 inhibitor called vildagliptin was approved in Europe and Latin America also as a combination with metformin, sulfonylurea, or thiazolidinedione. Two other DPP-4 inhibitors are also available (linagliptin and alogliptin). The different DPP-4 inhibitors are distinctive in their metabolism (saxagliptin and vildagliptin are metabolized in the liver and sitagliptin is not), their excretion, their recommended dosage, and the daily dosage that is required for effective treatment. They are similar, however, when comparing their efficacy regarding lowering HbA 1c levels, safety profile, and patient tolerance.

44 CLINICAL PROFILE OF GLP-1 AGONISTS and DPP-IV INHIBITORS Comparative trials show that there are important differences between and among the glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors with respect to glycemic lowering, weight effects, and effects on systolic blood pressure and the lipid profile. Nausea, diarrhea, headaches, and dizziness are common with both of the available GLP-1 receptor agonists. Upper respiratory tract infections, nasopharyngitis, and headaches are common with the DPP-4 inhibitors. Ongoing safety evaluations should provide a clear picture regarding long-term safety.

45 DRUGS INHIBITING KIDNEY GLUCOSE REABSORPTION SGLT2 is a low-affinity, high capacity glucose transporter located in the proximal tubule in the kidneys. It is responsible for 90% of glucose reabsorption. Inhibition of SGLT2 leads to the decrease in blood glucose due to the increase in renal glucose excretion. The mechanism of action of this new class of drugs also offers further glucose control by allowing increased insulin sensitivity and uptake of glucose in the muscle cells, decreased gluconeogenesis and improved first phase insulin release from the beta cells. SGLT2 INHIBITORS

46 DRUGS INHIBITING KIDNEY GLUCOSE REABSORPTION Drugs in the SGLT2 inhibitors class include empagliflozin, canagliflozin, dapagliflozin, ipragliflozin. SGLT2 inhibitors are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. They are available as single-ingredient products and also in combination with other diabetes medicines such as metformin. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine. The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.

47 DRUGS INHIBITING KIDNEY GLUCOSE REABSORPTION ADVERSE EFFECTS

48 Active principle Generic name Trade name Drugs enhancing insulin sensitivity (euglycemic drugs) Drugs enhancing pancreatic secretion of insulin (hypoglycemic drugs) Drugs acting on the incretin system Drugs inhibiting renal glucose reabsorption Biguanides Metformin Glocophage, Metforal, Metfonorm, Zuglimet, -glucosidase inhibitors Acarbose Glucobay Glicobase Glitazones Sulfonylureas Glinides GLP-1 analogs DPP-4 inhibitors SGLT-2 inhibitors Pioglitazone Pioglitazone + Metformin Glibenclamide Glibenclamide + Metformin Glipizide Glimepiride Glicazide Repaglinide Nateglinide Exenatide Liraglutide Sitagliptin Sitagliptin + Metformin Vildagliptin Vildagliptin + Metformin Saxagliptin Canagliflozin Dapagliflozin Actos Competact Gliben, Daonil, Euglucon, Gliboral Glibomet, Gliconorm, Glicorest, Minidiab Amaryl, Solosa Diabrezide, Diamicron, Dramion Novonorm Starlix Byetta Vyctoza Januvia, Xelevia, Tesavel Janumet, Efficib Galvus Eucreas Ongliza Invokana Forxiga