Novel methods of treatment of diabetic patients.

 

The manifestations of diabetes cause considerable human suffering and enormous  economic costs. Both acute and late  diabetic complications are commonly encountered.  Long- term complications represented by cardiovascular diseases, cerebrovascular accidents, end-stage renal disease, retinopathy and neuropathies are already major causes  of morbidity, disability and premature death.

The development of long-term  complications is influenced by hyperglycaernia. Poor  control of diabetes accelerates their progression. Thus, to prevent complications, good  control of diabetes is essential and the management of diabetes should therefore aim to  improve glycaemic control beyond that required to control its symptoms. Intensified therapy and maintaining near-normal blood glucose levels can result in considerable reduction in the risk of development of retinopathy, nephropathy and neuropathy.

People with diabetes must take responsibility for their day-to-day care. This includes monitoring blood glucose levels, dietary management, maintaining physical activity, keeping weight and stress under control, monitoring oral medications and, if required, insulin use via injections or pump.

 

Basic principles

• Correct diagnosis is essential. Thus emphasis should be placed on using appropriate  diagnostic criteria.

• Treatment should not only consider lowering the blood glucose level but also should  focus on the correction of any associated CVD risk factors such as smoking, hyperlipidemias, and obesity as well as monitoring of blood pressure and ~treatment of  hypertension.

• Management of non- insulin- dependent diabetes mellitus (NIDDM) requires teamwork.  The doctor should work closely with the nurse and other members of the diabetes  health care team, whenever available, and with the person with diabetes.

• Self- care is an essential strategy. Education of the person with diabetes and his/her  family is the cornerstone of management. Without appropriate education, the desired  therapy targets are difficult, or even impossible to achieve. People with diabetes should  be encouraged and enabled to participate actively in managing and monitoring their  condition.

 • Good control is important. Self- monitoring  improves the quality and safety of therapy.

 • The health care system should ensure that people with diabetes have access to the basic  requirements essential to practise self- care.

• Record-k eeping is critically needed and sho uld be considered a  basic re quirement for  the management and follow-up of all cases.

• Objectives and priorities of treatment must be tailored to individual needs; therapy  targets should be individually determined for each case

 

General objectives of diabetes management

• To relieve symptoms

• To correct associated health problems and to reduce morbidity, mortality and economic  costs of diabetes

• To prevent as much as possible acute  and long-term complications; to monitor the  development of such complications and  to provide timely intervention

• To improve the quality of life and productivity of the individual with diabetes

 

Glycemic control

Glycemic control is fundamental to the management of diabetes. Prospective randomized clinical trials such as the Diabetes Control and Complications Trial (DCCT) and the U.K. Prospective Diabetes Study (UKPDS) have shown that improved glycemic control is associated with sustained decreased rates of retinopathy, nephropathy, and neuropathy. In these trials, treatment regimens that reduced average A1C to ∼7% (∼1% above the upper limits of normal) were associated with fewer long-term microvascular complications; however, intensive control was found to increase the risk of severe hypoglycemia and weight gain.

Epidemiological studies support the potential of intensive glycemic control in the reduction of CVD . Recommended glycemic goals for nonpregnant individuals are shown in Table .

Table 1. Summary of recommendations for adults with diabetes mellitus

 

 A major limitation to the available data is that they do not identify the optimum level of control for particular patients, as there are individual differences in the risks of hypoglycemia, weight gain, and other adverse effects. Furthermore, with multifactorial interventions, it is unclear how different components (e.g., educational interventions, glycemic targets, lifestyle changes, and pharmacological agents) contribute to the reduction of complications.

Less stringent treatment goals may be appropriate for patients with limited life expectancies, in the very young or older adults, and in individuals with comorbid conditions. Severe or frequent hypoglycemia is an indication for the modification of treatment regimens, including setting higher glycemic goals. More stringent goals can be considered in individual patients based on epidemiological analyses that suggest that there is no lower limit of A1C at which further lowering does not reduce risk of complications. However, the absolute risks and benefits of lower targets are unknown.

HbA1c goals for treatment:

•For all patients: A1c < 7% (old, for reference point)

                  

 

•A1c could be tighter (like < 6.5%) in those with:

1. Short duration of diabetes.

                   2. Long life expectancy.

                   3. No significant cardiovascular disease.

                  

 

•A1c could be higher (like 8%) in those with:

1. History of severe hypoglycemia

                        2. Limited life expectancy.

                        3. Advanced micro-and macro complications.

                        4. long-standing diabetes.

 

Elevated postchallenge (2-h OGTT) glucose values have been associated with increased cardiovascular risk independent of FPG in some epidemiological studies. Postprandial plasma glucose (PPG) levels >140 mg/dl are unusual iondiabetic individuals, although large evening meals can be followed by plasma glucose values up to 180 mg/dl. There are now pharmacological agents that primarily modify PPG and thereby reduce A1C in parallel. Thus, in individuals who have premeal glucose values within target but who are not meeting A1C targets, consideration of monitoring PPG 1–2 h after the start of the meal and treatment aimed at reducing average PPG values <180 mg/dl may lower A1C. However, it should be noted that the effect of these approaches on the microvascular or macrovascular complications has not been studied.

Intercurrent illness

The stress of illness frequently aggravates glycemic control and necessitates more frequent monitoring of blood glucose and urine or blood ketones. A vomiting illness accompanied by ketosis may indicate diabetic ketoacidosis (DKA), a life-threatening condition that requires immediate medical care to prevent complications and death; the possibility of DKA should always be considered. Marked hyperglycemia requires temporary adjustment of the treatment program, and, if accompanied by ketosis, frequent interaction with the diabetes care team. The patient treated with oral glucose-lowering agents or medical nutrition therapy (MNT) alone may temporarily require insulin. Adequate fluid and caloric intake must be assured. Infection or dehydration is more likely to necessitate hospitalization of the person with diabetes than the person without diabetes. The hospitalized patient should be treated by a physician with expertise in the management of diabetes, and recent studies suggest that achieving very stringent glycemic control may reduce mortality in the immediate post–myocardial infarction period. Aggressive glycemic management with insulin may reduce morbidity in patients with severe acute illness.

Treatment of DM has to be individualized and includes:

1.     Diet.

2.     Exercise program.

3.     Education of the patients about the nature of the disease, the importance of its control, all aspects of self-management and routine practices  to minimize the development or severity of the diabetes’ complications. Physician  has to educate, motivate and monitor progress. Patient must understand the importance of differing life-style.

4.     Oral hypoglycemic agents or insulin (indications  for each vary with the type of DM and severity of the disease).

 

DIET

Diet is the keystone of the treatment of the DM.

 

Goals of Diet –therapy that apply to specific situations include the following:

·         For youth with type 1 diabetes, provide adequate energy to ensure normal growth and development; integrate insulin regimens into usual eating and physical activity habits.

·         For youth with type 2 diabetes, facilitate changes in eating and physical activity habits that reduce insulin resistance and improve metabolic status.

·         For pregnant and lactating women, provide adequate energy and nutrients needed for optimal outcomes.

·         For older adults, provide for the nutritional and psychosocial needs of an aging individual.

·         For individuals treated with insulin or insulin secretagogues, provide self-management education for treatment (and prevention) of hypoglycemia, acute illnesses, and exercise-related blood glucose problems.

·         For individuals at risk for diabetes, decrease risk by encouraging physical activity and promoting foods choices that facilitate moderate weight loss or at least prevent weight gain.

 

Picture (b) is more appropriate according to guidelines for diabetic diet (i.e.products with low glycaemic profile).

 

1.     Balanced diet (diet should include physiologic meal components: carbohydrate comprises 50 – 60 % of total calories, fat – 24 – 25 % and protein – 16 – 15 %).

2.     Normal-calorie diet in patients with type I DM (35-50 kcal/kg of ideal weight (weight = height – 100)) and low-calorie diet in obese persons (mostly in patients with type II DM (20 – 25 kcal/kg of ideal weight)). We try to decrease weight in obese patients on 1-2 kg/month by such diet. (Obesity leads to insensitivity of muscle and adipose tissue to insulin, presumable as the result of decreased binding of insulin to its plasma membrane receptor. Hyperglycemia is the face of increased insulin secretion and hyperlipoproteinemia are secondary to this abnormality. The defect in insulin binding and secretion is corrected by weight reduction.)

3.     Regimen has to be consist of 4 – 5 – 6 small feedings a day. (The  most frequent regimen consists of 4 feedings a day, in which breakfast comprises 30 % of total calories, dinner – 40 %, lunch – 10 %, supper – 20 %. Sometimes patients need second breakfast (when they have a tendency to develop hypoglycemia). In such case it comprises15 % of the total calories and we decrease the quantity of calories of the first breakfast and dinner).

4.     Exclusion of high-calorie carbohydrates (sugar, biscuits, white bread, alcohol).

5.     Increasing the quantity of high fiber-containing foods (fruits (exclusion: banana, grapes), vegetables, cereal grains, whole grain flours, bran. Patients need 40 g fibers per day.

6.     Limiting of meat fat, butter, margarine in diet, decrease red and brown meats, increase poultry and fish, encourage skim milk-based cheeses. Should be used skim or low-fat milk, not more than 2 – 3 eggs weekly.

7.     Alcohol should be avoided as much as possible because it constitutes a source of additional calories, it may worsen hyperglycemia, and it may potentiate the hypoglycemic effects of insulin and oral hypoglycemic agents.

Sometimes (mostly in obese diabetics) achievement and maintenance of normal body weight may be enough to eliminate the need for oral hypoglycemic agents or insulin.

So, the diet should be planned in such way that the patient can follow it for the rest of his or her life without starving or becoming malnourished.

 

Exercise program

Exercise is an excellent adjunct to diet therapy, but it is very ineffective when used as the sole weight-reducing modality.

Exercises must be clearly planned and depend on patient’s abilities and the physical condition, exclusion of the competition’s elements.

Before beginning a physical activity program, the patient with diabetes should have a detailed medical evaluation with appropriate diagnostic studies. This examination should screen for the presence of macro- and microvascular complications that may be worsened by the physical activity program. Identification of areas of concern will allow the design of an individualized physical activity plan that can minimize risk to the patient. All levels of physical activity, including leisure activities, recreational sports, and competitive professional performance, can be performed by people with diabetes who do not have complications and have good glycemic control. The ability to adjust the therapeutic regimen (insulin therapy and diet) to allow safe participation is an important management strategy.

 

Exercises may be valuable adjunct to the management of the DM by:

–         lowering blood glucose concentration;

–         decreasing insulin requirements;

–         potentiation the beneficial effects of diet and other therapy.

To prevent hypoglycemia, patients should carefully monitor glucose level and taking of insulin. Mostly they need to reduce the insulin dosage by 20 – 25 % on the day that a strenuous exercise is planned.

 

 

Patient’s education.

Video (link for life)

Patient education is essential to ensure the effectiveness of the prescribed therapy, to recognize indications for seeking immediate medical attention, and to carry out appropriate foot care. On each physician visit, the patient should be assessed for symptoms and signs of complications, including a check of the feet and the pulses and sensation in the feet and legs, and a urine test for albumin. The serum creatinine levels should be assessed regularly (at least yearly) and an ECG and complete ophthalmologic evaluation should be performed at least yearly. Coexistent hypertension and hypercholesterolemia increases the risks for specific late complications and requires special attention and appropriate treatment.

A1C testing should be performed routinely in all patients with diabetes, first to document the degree of glycemic control at initial assessment and then as part of continuing care. Since the A1C test reflects mean glycemia over the preceding 2–3 months, measurement approximately every 3 months is required to determine whether a patient’s metabolic control has been reached and maintained within the target range. Thus, regular performance of the A1C test permits detection of departures from the target (Table.1) in a timely fashion. For any individual patient, the frequency of A1C testing should be dependent on the clinical situation, the treatment regimen used, and the judgment of the clinician.

Glycemic control is best judged by the combination of the results of the patient’s SMBG testing (as performed) and the current A1C result. The A1C should be used not only to assess the patient’s control over the preceding 2–3 months but also as a check on the accuracy of the meter (or the patient’s self-reported results) and the adequacy of the SMBG testing schedule. Table 2 contains the correlation between A1C levels and mean plasma glucose levels based on data from the DCCT.

Table 2. Correlation between A1C level and mean plasma glucose levels

 

 

Principles of education (Video)

1)    the nature of DM and importance of metabolic control;

 

 

2)    the principles and importance of good nutrition and reasonable exercise program;

3)    the principles of adequate foot, dental and skin care;

4)    treatment of DM during the periods of illness;

5)    techniques of insulin administration and measurement of urine and blood glucose level (if taking insulin);

6)    recognition of hypoglycemia, its causes and methods of prevention;

7)    the importance of general and specific measures to minimize in the best possible way diabetic complications and maintain of good overall health.

Video 1

Video 2

                       

 

                        Guidelines for glycaemic control in T2DM

	IDF	AACE	ADA
HbA1c (%)	<6.5	≤6.5	<7.0
Fasting/preprandial glucose (mmol/L / mg/dL)	<6.0 / <110	<6.0 / <110	3.9-7.2 / 70-130
2-h postprandial glucose (mmol/L / mg/dL)	<7.8 / <140	<7.8 / <140	<10.0 / <180*
*ADA recommends that postprandial glucose measurements should be made 1–2 h after the beginning of the meal.

 

Oral hypoglycemic agents

Inadequate control of hyperglycemia by the diet and exercises interventions suggests the need for a good glucose-lowering agent.

Oral hypoglycemic agents are useful only in the chronic management of patients with type II DM. Early initiation of pharmacologic therapy is associated with improved glycemic control and reduced long-term complications in type 2 diabetes.

 

Drug classes used for the treatment of type 2 diabetes include the following:

1.       Biguanides

2.       Sulfonylureas

3.       Meglitinide derivatives (nonsulfonylurea secretagogues)

4. Alpha-glucosidase inhibitors

5. Thiazolidinediones (TZDs)

6. Glucagonlike peptide–1 (GLP-1) agonists

7. Dipeptidyl peptidase IV (DPP-4) inhibitors

8. Insulins

9. Amylinomimetics (Amylin agonist analogues)

10. Bile acid sequestrants

11. Dopamine agonists

 

Principal modes and sites of action of pharmacologic treatment for type 2 diabetes

DESG teaching letter. The use of oral hypoglycaemic agents. November, 2007.

 

Sulfonilureas include:

–         first generation: Tolbutamide, Chlorpropamide, Tolazemide, Acetohexamide (now are not used in treatment of the diabetics);

–         second generation: Glibenclamide (Maninil), Glipizide (Glurenorm), Gliquidone;

 

–         third generation: Glimepiride (Amaryl).

Action:

1)    influence on the pancreatic gland:

–         increasing of the β-cells sensitivity to the glucose and as a result higher secretion of glucose;

–         stimulation of the exocytosis of insulin by insulocytes;

2)    nonpancreatic influence:

–         increasing number of the receptors to insulin;

–         normalization of receptors’ sensitivity to insulin;

–         increasing of  glucose transportation inside muscle cells;

–         stimulation of  glycogen synthesis;

–         decreasing of glycogenolysis and glyconeogenesis;

–         decreasing of glucagon secretion and others.

Indications:

1)    patients with type 2 DM (over the age of 35 – 50 years) who do not suffer severe metabolic abnormalities (hyperglycemia), ketosis or hyperosmolality;

2)    [duration of diabetes less than 15 years.]

Contraindications.

1)    type 1 DM;

2)    blood diseases;

3)    acute infections, heart, cerebral diseases;

4)    trauma, major;

5)    pregnant diabetics or lactation;

6)    III – IV stages of angiopathy (but Glurenorm can be used in patients chronic renal failure, because of gastrointestinal tract excretion);

7)    coma and precoma.

Side effects.

1)    hypoglycemia (hypoglycemic effect of sulfanilureas will be the most obvious in 7 – 12 days from the beginning of the treatment);

2)    allergy;

3)    influence on gastrointestinal tract (nausea and others);

4)    leucopenia (decreasing of the quantity of white blood cells, platelets);

5)    primary or secondary failure. (Primary failure defined as an inadequate response during the first month of treatment with maximum dosage, occurs in approximately 5 % of patients. Secondary failure is defined as a recurrence of hyperglycemia after an initial satisfactory response. Secondary failure may be due to nonadherence to eihter diet or sulfanilurea therapy, to disease progression, or to loss of efficacy of the agent.)

 

Biguanides include:

Metformin (Siofor), Adebit, Buformin.

 

Action:                          Video

1)    inhibition of gastrointestinal glucose absorption;

2)    decreasing of glyconeogenesis, lipogenesis;

3)    enhancing glucose transport into muscle cells;

4)    increasing the quantity of insulin’s receptors;

5)    stimulation of anaerobic and partly aerobic glycolis;

6)    anorrhexogenic effects.

Indications:

Obese patients with type 2 DM, with middle severity of the disease without ketosis.

Contraindications:

1)    heart and lung disease with their insufficiency (chronic heart and lung failure);

2)    status with hypoxemia;

3)    acute and chronic liver and kidney diseases with decreased function;

4)    pregnant diabetics, lactation;

5)    old age;

6)    alcoholism;

7)    coma and precoma.

Side effects.

1)    allergy;

2)    gastrointestinal tract disorders;

3)    lactoacidosis.

 

Alpha-glucosidase inhibitors

Acarbosa.

Action:

1)    inhibition of gastrointestinal tract absorption (blocation of α-glucozidase);

2)    lowering of pastprandial glucose level (postprandial “spikes” in blood glucose are increasingly implicated as a major cause of cardiovascular complications);

3)    partly reducing fasting glucose levels by indirectly stimulating insulin secretion in patients who retain β-cell function (and acarbose has a protective effect on β-cells).

Contraindications:

Chronic gastrointestinal disorders: pancreatitis, colitis, hepatitis.

Side effects:

flatulence, diarrhea.

 

Non-sulfonylureas insulin stimulator

Repaglinide (Novonorm 0,5 mg, 1 mg,2 mg).

(Starting dose is 0,5 mg 15 – 20 min before each meal, maximum dose is 4 mg before each meal (16 mg/d)).

Nateglinide (Starlix 0,06; 0,12; 0,18).

Action:

–         these drugs stimulates insulin production at meal times;

–         very rapidly absorbed from the intestine and metabolized in liver;

–         plasma half0life is less than 1 hour/

Indications:

–         can be used in elderly with type 2 DM (due to short half-life) and in renal impairment (because it is metabolized in liver).

Side effects:

hypoglycemia, transient elevation of liver enzymes, rash and visual disturbances.

 

Thiazolidinediones

Rosiglitazon (Avandia, Rosinorm) Dose in 1 tabl. 0,002;0,004;0,008

Pioglitazon (Actos, Pionorm) Dose in 1 tabl. 0,015; 0,03; 0,045

Action of thiazolidinediones

–         Agonist to the receptors of the nucleus PPARγ of the fat, muscle tissues and the liver;

–         Increasing of the glucose passage to these tissues;

–         Increasing of insulin synthesis in the b-cells;

–         Increasing of the insulas amount;

–         Increasing of glycogen synthesis in the liver;

–         Decreasing of gluconeogenesis;

–         Decreasing of triglycerides;

Indications to thiazolidinediones usage

–         DM type 2, when diet and exercises are no effective;

–         Using with sulfanilureas, biguanides, insulin in case of their insufficient efficacy

Contraindications to thiazolidinediones usage

–         Diabetic coma, precoma, ketoacidosis;

–         Acute and chronic diseases of the liver;

–         Heart failure;

–         Pregnancy, lactation;

–         Children, teenagers;

–         Allergic reactions to the drug.

Side effects of thiazolidinediones

–         Hypoglycemic conditions (rarely);

–         Peripheral edema;

–         Anemia;

–         Obesity.

 

GLP-1

Incretin Physiology

 

Main mechanism of action:

1. Augmentation of pancreas response (i.e. increases insulin secretion) in response to eating meals;

2. Suppression of pancreatic release of glucagon in response to eating;

3. Slowing down gastric emptying;

4. Reducing appetite, promote satiety via hypothalamic receptors;

5. Reducing liver fat content;

 

Exenatide injectable solution (Byetta)

 Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who have not achieved glycemic control with metformin or a sulfonylurea. The solution is administered by subcutaneous injection twice daily.

Liraglutide (Victoza)

 Liraglutide is a once-daily injectable GLP-1 receptor agonist that stimulates G-protein in pancreatic beta cells. It increases intracellular cyclic adenosine monophosphate (cAMP), leading to insulin release in the presence of elevated glucose concentrations. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The drug has not been studied in combination with insulin. Liraglutide is not recommended as first-line pharmacologic therapy, because of potential serious adverse effects. Liraglutide is contraindicated in patients with a history or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, as dose- and duration-dependent thyroid C-cell tumors have occurred in animal studies of liraglutide.

Side effects:

–                   Allergy/Hypersensitivity: injection-site reactions, generalized pruritus and/or urticaria, macular or papular rash, angioedema, anaphylactic reaction

–                   Drug Interactions: International normalized ratio (INR) increased with concomitant warfarin use sometimes associated with bleeding

–                   Gastrointestinal: nausea, vomiting, and/or diarrhea resulting in dehydration; abdominal distension, abdominal pain, eructation, constipation, flatulence, acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death

–                   Neurologic: dysgeusia; somnolence

–                   Renal and Urinary Disorders: altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure or acute renal failure (sometimes requiring hemodialysis), kidney transplant and kidney transplant dysfunction

–                   Skin and Subcutaneous Tissue Disorders: alopecia

 

DPP-4

Mechanism of action:

DPP-4 inhibitors represent an innovative approach to type 2 diabetes treatment with a unique mechanism of action compared to other classes in this therapeutic area.

By binding to the DPP-4 enzyme, they inhibit the breakdown of the two incretin hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). This results in improved β-cell responsiveness to prevailing glucose concentrations and suppression of glucagon secretion in a glucose-dependent manner.

DPP-4 inhibitors increase the GLP-1 plasma concentrations within the physiological range in contrast to injectable GLP-1 mimetics which have supra-physiological plasma levels and are associated with an increased GI side-effect rate, such as nausea and vomiting.

 

Indications:

treatment of type-2 diabetes either as monotherapy or in combination with other anti-diabetic drugs.

 

Drugs belonging to this class are :

• sitagliptin(FDA approved 2006, marketed by Merck & Co. as Januvia),

• vildagliptin (EU approved 2007, marketed in the EU by Novartis as Galvus),

• saxagliptin (FDA approved in 2009, marketed as Onglyza),

• linagliptin (FDA approved in 2011, marketed as Trajenta by Eli Lilly Co and Boehringer Ingelheim),

• dutogliptin (being developed by Phenomix Corporation), Phase III

• gemigliptin (being developed by LG Life Sciences,Korea)

• alogliptin (developed by Takeda Pharmaceutical Company, whose FDA application for the product is currently under review)

 

 CONTRAINDICATIONS

–                  Renal dysfunction, e.g., serum creatinine ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance.

–                  Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.

–                  History of a serious hypersensitivity reaction such as anaphylaxis or angioedema.

 

Adverse effects:

·       acute pancreatitis

·       hypoglycemia in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with DPP-4.

·       hypersensitivity reactions: anaphylaxis, angioedema, and exfoliative skin conditions

·       upper respiratory tract infection, headache, nasopharyngitis

·       urinary tract infection

·       in combination therapy with a thiazolidinedione the incidence of peripheral edema

 

amylinomimetic agent

Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms. Amylin slows gastric emptying (i.e., the rate at which food is released from the stomach to the small intestine) without altering the overall absorption of nutrients. In addition, amylin suppresses glucagon secretion (not normalized by insulin alone), which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally-mediated modulation of appetite. In patients with insulin-using type 2 or type 1 diabetes, the pancreatic beta cells are dysfunctional or damaged, resulting in reduced secretion of both insulin and amylin in response to food.

SYMLIN (pramlintide acetate injection)

Mechanism of action:

1) modulation of gastric emptying;

2) prevention of the postprandial rise in plasma glucagon;

3) satiety leading to decreased caloric intake and potential weight loss.

 

Indications:

üType 1 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.

üType 2 diabetes, as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy, with or without a concurrent sulfonylurea agent and/or metformin.

Side effects:

1.                 Nausea, Vomiting, Abdominal Pain

2.                 Headache

3.                 Anorexia

4.                 Fatigue, Dizziness

5.                 Coughing

6.                 Pharyngitis

Combined medications

Glibomet consists of Maninil 2,5 mg and Siofor 400 mg

 

Novel approach –SGLT2 Inhibitors: Glucuretic Treatment for Type 2 Diabetes

 

Sodium glucose co-transporter-2 (SGLT2) inhibitors (Remogliflozin etabonate, Dapagliflozin) offer a novel approach to treat diabetes by reducing hyperglycaemia via increased glucosuria. This approach reduces renal glucose reabsorption in the proximal renal tubules providing an insulin-independent mechanism to lower blood glucose.

 

Physiology and Pathology of Renal Glucose Transport

In the kidney, glucose is freely filtered at the glomerulus and is reabsorbed via active transport mechanisms in the proximal convoluted tubule. Two sodium-glucose co-transporters are responsible for glucose reabsorption: SGLT1 and SGLT2. SGLT1, which is also found in the gut and other tissues, accounts for about 10% of reabsorption. SGLT2, expressed exclusively in the S1 segment of the proximal tubule, accounts for about 90% of reabsorption (Figure). The concentration gradient that drives the action of these transporters is driven by the Na+/ATPase pump and by transport back into the blood via the GLUT2 glucose transporter. This suggests that the most promising target for drug development is the SGLT2 transporter, both because it is responsible for most glucose reabsorption and because of its exclusive localization to the kidney. SGLP-2 is under investigation in several phase II and III trials.

Figure. Sites of glucose reabsorption in the S1, S2, and S3 segments of proximal tubules.

Treatment algorithm of Type 2 Diabetes

ADA/EASD Consensus Algorithm for the Management of Type 2 Diabetes¹

Reinforce lifestyle interventions at every visit. Check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%.

Summary of the tier 1 and tier 2 algorithms

Tier 1: These interventions represent the best-established and most effective and cost-effective therapeutic strategy for achieving the target glycemic goals.

Step 1: Lifestyle intervention should be initiated as a first step because of the numerous short- and long-term benefits that accrue from exercise and weight loss. Metformin should be initiated concurrently because of its glycemic effects, absence of weight gain or hypoglycemia, tolerability, and low cost.

Step 2: Another medication should be added to achieve glycemic goals if step 1 fails.

Step 3: Insulin therapy should be started or intensified if glycemic goals have not been reached.

Tier 2: In selected clinical settings, the second-tier algorithm may be considered.

When hypoglycemia is particularly undesirable, the addition of a GLP-1 agonist or pioglitazone to step 1 may be considered. If promotion of weight loss is a major consideration and the A1C level is close to target (<8%), a GLP-1 agonist is an option. A sulfonylurea may be added to these interventions if necessary. Further adjustments should be made if A1C target is not achieved.

For more information, read the full ADA/EASD consensus statement for the medical management of hyperglycemia in type 2 diabetes.

 

 

Insulin therapy of diabetes mellitus

Insulin has been available for the treatment of patients with DM since 1921.

History of insulin discovery

In this lab, Banting and Best carried out early experiments which led to the discovery of insulin

 

In 1920, Canadian surgeon Frederick Banting visited the University of Toronto to speak to the newly appointed head of the department of physiology, John J.R. Macleod.. Macleod had studied glucose metabolism and diabetes, and Banting had a new idea on how to find not only the cause but a treatment for the so-called “suga

r disease.”

Frederick Banting (1891 – 1941)

John J.R. Macleod (1876 – 1936)

 

Late in the nineteenth century, scientists had realized there was a connection between the pancreas and diabetes. The connection was further narrowed down to the islets of Langerhans, a part of the pancreas. From 1910 to 1920, Oscar Minkowski and others tried unsuccessfully to find and extract the active ingredient from the islets of Langerhans. While reading a paper on the subject in 1920, Banting had an inspiration. He realized that the pancreas’ digestive juice was destroying the islets of Langerhans hormone before it could be isolated. If he could stop the pancreas from working, but keep the islets of Langerhans going, he should be able to find the stuff! He presented this idea to Macleod, who at first scoffed at it. Banting badgered him until finally Macleod gave him lab space, 10 experimental dogs, and a medical student assistant.

In May, 1921, as Macleod took off for a holiday in his native Scotland, Banting and his assistant Charles Best  began their experiments. By August they had the first conclusive results: when they gave the material extracted from the islets of Langerhans (called “insulin,” from the Latin for “island”) to diabetic dogs, their abnormally high blood sugars were lowered. Macleod, back from holiday, was still skeptical of the results and asked them to repeat the experiment several more times. They did, finding the results the same, but with problems due to the varying purity of their insulin extract.

Charles Best (1899 – 1978)

 

Macleod assigned chemist James Bertram Collip to the group to help with the purification. Within six weeks, he felt confident enough of the insulin he had isolated to try it on a human for the first time: a 14-year-old boy  dying of diabetes. The injection indeed lowered his blood sugar and cleared his urine of sugars and other signs of the disease. Banting and Best published the first paper on their discovery a month later, in February, 1922. In 1923, the Nobel Prize was awarded to Banting and Macleod for the discovery, and each shared their portion of the prize money with the other researchers on the project.

James Bertram Collip

(1893 – 1965)

Leonard Tompson

before and after insulintherapy

 

Ironically, Banting’s original idea wasn’t entirely correct. He and Best later found they could obtain insulin even from an intact pancreas. Improved technology for testing and detecting sugar in the blood and urine provided information that earlier researchers didn’t have, and this encouraged them to pursue a line of thinking that may have looked like a dead end to those working in the decades before them.

The discovery of insulin was one of the most revolutionary moments in medicine. Though it took some time to work out proper dosages and to develop manufacturing processes to make enough insulin of consistent strength and purity, the introduction of insulin seemed literally like a miracle. One year the disease was an automatic death sentence; the next, people — even children — had hopes of living full and productive lives even with the disease. Estimates show there are more than 15 million diabetics living today who would have died at an early age without insulin.

 

For many years, the most commonly used preparations consisted of a combination of pancreatic bovine and porcine insulin. Contamination of small amounts (2 to % percent) of other pancreatic hormones, such as glucagon, proinsulin, C peptide, somatostatin, and pancreatic polypeptide, was the rule. Subsequent purification have yielded purer (almost 100 %) preparations of beef insulin, pork insulin, or combination of two, with a biologic activity of 26 to 28 units/mg as compared to 22 to 24 units/mg for the older preparations.

The most recent development has been the preparation of biosynthetic human insulin. Two procedures have been utilized. In the first, alanine in the 30 position of the B chain of pork insulin is substituted enzymatically by threonine. The resulting “humanized pork” insulin has the amino acid sequence of human insulin (Actrapid, Monotard made by Novo-Nordisk). The second approach involves synthesis by Escherichia coli (E. Coli) or yeast by recombinant DNA technology.

The hormone can be produced by single fermentation in which proinsulin is made first and then cleaved into insulin and C peptide, or by separate fermentation in which A and B peptide are synthesized first and then joined into insulin (Humulin, Lilly).

Synthetic human insulin does not have great advantages over purified pork insulin, except for slightly faster onset of the action. Hypokalemia, C-peptide suppression, and secretion of epinephrine, cortisol, growth hormone and prolactine may be reduced with human insulin. The synthetic hormone has the potential to be less antigenic than the pork insulin. Causes of potential use for human insulin include resistance to exogenous insulin, beef or pork insulin allergy, lipodystrophy, gestation diabetes. Anticipated short-term administration, and newly diagnosed young diabetic patients.

A multitude of insulin preparations are available, and the major difference in their duration of action.

Only short-acting insulins should be given intravenously; all the types can be injected subcutaneously.

 

Insulin preparations.

Indications for insulin therapy

1.     All patients with type I DM.

2.     Some patients with type II DM:

–         uncontrolled diabetes by diet or oral hypoglycemic agents;

–         ketoacidosis, coma;

–         acute and chronic liver and kidneys disease with decreased function;

–         pregnancy and lactation;

–         II – IV stages of angiopathy;

–         infection diseases;

–         acute heart and cerebral diseases;

–         surgery.

Initiation and modification of insulin therapy to achieve diabetic control.

Step 1: Estimate Total Daily Insulin (TDI)

–         on the first year of the disease is 0,3 – 0,5 unite of insulin per kilogram of body weight (0,5 – if the patient with ketosis or DKA);

–         on the next years is 0,6 – 0,8 – 1,0 unite/ kg of body weight.

Total Daily Insulin (TDI) = Insulin Sensitivity Factor X Weight (wt) in Kilograms (kg)

The insulin sensitivity factor is an expression of the patient’s sensitivity to insulin and is affected by type of diabetes, age, body weight, ethnicity, comorbidities, activity level, and a number of other factors. The insulin sensitivity factor may range from 0.4 to 1 or higher. Initial calculations can be based upon the following:

In Insulin Sensitive Patient: TDI = 0.5 X wt (kg) More typical of patients who are young, lean, healthy, and active with type 1 diabetes. Also appropriate for patients with stage 4 or 5 chronic kidney disease.

In Insulin Resistant Patient: TDI = 0.8 X wt (kg) More typical of patients who are older, obese, less healthy, and sedentary with type 2 diabetes.

Examples: A 26 year-old healthy woman with type 1 diabetes weighs 112 lbs (51 kg).

Her TDI is 0.5 X 51 = 25 units of insulin per day.

A 53 year-old man with a body mass index (BMI) of 33, hypertension, and hyperlipidemia whose A1c has climbed to 8.4% despite treatment with metformin and pioglitazone. He weighs 236 lbs (107 kg). His TDI is 0.8 X 107 = 86 units of insulin per day

Step 2: Select Type of Insulin Therapy

–         We can use traditional or multiple component insulin program. The last is better (it is more physiologic). It using three or four shots of short-acting insulin (1/3 of total daily dose) plus intermediate-acting (2/3 of total daily dose) insulin daily is started as soon as possible in an attempt to “rest” the damaged islet cells and help to “induce” a remission (“honeymoon” phase). Other advantages include the following:

–         hypoglycemic reactions may be decreased or prevented because smaller doses of insulin are needed;

–         more physiologic match of insulin to meals is achieved.

 

Intensive Insulin Therapy (Basal + Bolus)

Use: Most complex. Requires frequent self-monitoring of blood sugar and understanding of carbohydrate counting. Risk of hypoglycemia must be considered. Recommend referral to diabetes specialty clinic or Certified Diabetes Educator for initiation and titration of Intensive Insulin Therapy.

 

Basal Insulin:

• NPH in AM and at bedtime OR Once-daily detemir or glargine

Bolus(pre-meal) Insulin:

• R/aspart/lispro/glulisine insulin before each meal

 

Bolus dose includes:

Insulin to cover carbohydrate ingested (Usually start with 1 unit: 15gm carb)

AND

Additional insulin to correct for high SMBG

OR

Utilize sliding scale bolus insulin before meals

 

Starting Dose: 0.3-0.5 units/kg/day (1:1 basal:bolus ratio), or

If current dose >0.5 units/kg/day:

Basal dose = 80% current TDI as NPH dosed AM and bedtime or Once-daily detemir or glargine.

Bolus dose = 80% of basal dose (as calculated) divided between 3 meals.

Scheme: 2/3 of the total daily dose we give before lunch, 1/3 in the evening and then make correction due to the glucose blood level. Insulin doses should be given 30 minutes before meals to allow for adequate absorption of regular insulin.

 

Other commonly used insulin treatment algorithms:

Once Daily Insulin Therapy

Use: Simplest to use and best suited to address fasting hyperglycemia. Use as monotherapy, or in addition to oral agents.

Bedtime: Add 10 units basal insulin: NPH, detemir, or glargine insulin (or 0.2 units per kg).

OR

Before Supper: Add 10 units Premix 70/30 insulin

Achieving Goals with SMBG: Adjust Bedtime or Supper dose based on AM glucose

Titration Schedule: Add 1 unit of insulin each day, or 2 units every 3 days to reach glycemic goals

If glycemic goals not met after 6-12 weeks, consider MDI

 

NPH-Based Multiple-Dose Insulin Therapy (MDI)

Use: Addresses postprandial hyperglycemia. Use of bedtime NPH can minimize nocturnal hypoglycemia and may address dawn phenomenon.

 

2 injections:

• Premix 70/30 before AM and evening meal

OR

• NPH + R/aspart/lispro/glulisine (ratio 2:1) before AM and evening meal; mix insulins in same syringe.

Starting Dose: 0.3-0.5 units/kg/day divided as follows: 2/3 morning, 1/3 evening; before meals

 

3 injections: (especially if high FPG or risk of nocturnal hypoglycemia)

• NPH in AM and at bedtime + R/aspart/lispro before AM and evening meal (ratio 2:1). Mix insulins for AM dose.

OR

• NPH + R/aspart/lispro/glulisine:

If glycemic goals not met after 6-12 weeks, consider Intensive Insulin Management                  Intensive Insulin Therapy (Basal + Bolus)

 

 

Insulin pump (Video) is very useful in achievement of glucemic control.

An insulin pump can help diabetic manage his diabetes. By using an insulin pump, he can match his insulin  to his lifestyle, rather than getting an insulin injection and matching his life to how the insulin is working. When patient works closely with his diabetes care team, insulin pumps can help him keep his blood glucose levels within target ranges.  People of all ages with type 1 diabetes use insulin pumps and people with type 2 diabetes have started to use them as well.

How do insulin pumps work?

Insulin pumps deliver rapid- or short-acting insulin 24 hours a day through a catheter placed under the skin. Your insulin doses are separated into:

• Basal rates

• Bolus doses to cover carbohydrate in meals

• Correction or supplemental doses

Basal insulin is delivered continuously over 24 hours, and keeps the blood glucose levels in range between meals and overnight. Often, diabetic programs different amounts of insulin at different times of the day and night.

When patient east, he use buttons on the insulin pump to give additional insulin called a bolus. He takes a bolus to cover the carbohydrate in each meal or snack. If he eats more than he planned, he can simply program a larger bolus of insulin to cover it.

Patient also takes a bolus to treat high blood glucose levels. If he has high blood glucose levels before he eats, he gives a correction or supplemental bolus of insulin to bring it back to his target range.

Knowing how an insulin pump works is one thing. But patient may be wondering where he is supposed to put it. He can buy a pump case or it can be attached to a waistband, pocket, bra, garter belt, sock, or underwear. He can also tuck any excess tubing into the waistband of your underwear or pants.

When diabetic sleeps, he could try laying the pump next to you on the bed. He could even try wearing it on a waistband, armband, legband, or clip it to the blanket, sheet, pajamas, stuffed toy, or pillow with a belt clip.

Showering and bathing are other instances when patient should know where to put his insulin pump. Although insulin pumps are water resistant, they should not be set directly in the water. Instead, patient can disconnect it. All insulin pumps have a disconnect port for activities, such as swimming, bathing, or showering. Some pumps can be placed on the side of the tub, in a shower caddy, or in a soap tray. There are also special cases you can buy. Diabetic can hang these cases from your neck or from a shower curtain hook.

 

Some words about “honeymoon” stage. It results from a partial recovery of islet-cell function (as measured by C-peptide). It occurs within 1 – 3 month after diagnosis and can last from weeks to a few month during which time insulin requirements fall drastically to less than 0,3 units/kg/day and in some, to no requirement for insulin at all. Insulin administration, however, is not discontinued during this time because of potential development of insulin allergy, as well as the need to reinforce the concept that IDDM is a lifelong illness without potential for true remission.

Some particularities of insulin therapy:

1)    insulin acts faster when is administrated intravenously;

2)    subcutaneous and intramuscular absorption of insulin is decreased in the dehydrated or hypotensive patients;

3)    it is necessary to change the insulin injection site (because the absorption is more rapid from the new sites);

4)    the most rapid absorption from the abdomen;

5)    exercise accelerates insulin absorption (before planned exercise program patient has to decrease insulin dose or take more caloric diet).

Insulin is stable at room temperature, but refrigeration of the vial while not in use is recommended.

Future directions in improving glycemic control:

–         nasal insulin preparations;

Inhaled insulins

Several reports describing research success with pulmonary insulins were presented. Inhaled insulin products in development include:

• Exubera by Inhale Therapeutics, Pfizer, and Aventis

• AERx by Aradigm and Novo Nordisk

• Insulin Technospheres by Mannkind/PDC

• AIR System by Alkermes with Eli Lilly

• Aerodose by Aerogen with Disetronic.

–         pancreatic transplantation;

–         islet replacement therapy;

–         genetically engineered pseudo-beta-cells.

Side effects (complications) of insulin therapy.

1.     Hypoglycemia.

This complication represents insulin excess and it can occur at any time (frequently at night (common symptom: early-morning headache)).

Precipitating factors:

–         irregular ingesting of food;

–         extreme activity;

–         alcohol ingestion;

–         drug interaction;

–         liver or renal disease;

–         hypopituitarism;

–         adrenal insufficiency.

Treatment (preventing coma):

–         to eat candy or to drink sweet orange juice (when the symptoms develop);

–         to receive intravenous glucose;

–         1 mg of glucagon administrated subcutaneously;

–         gradual reduction of insulin dose in future.

Somogyi effect (Somogyi phenomenon, rebound effect).

It is caused by overinsulinization: hyperglycemia proceeded by insulin – induced hypoglycemia. Hypoglycemia causes an increase in the secretion of the counterregulatory hormones (glucagon, epinephrine, cortisol, growth hormone), which inhibit insulin secretion and increase glucose output by the liver (as a result of the stimulation of glucogenolysis and glucogenesis).

Treatment: gradual reduction of insulin dose.

Dawn phenomenon.

Many patients with type I DM demonstrate an early morning (4 – 8 a.m.) rise in glucose levels, because of activation of counterregulatory hormones. It may be confused with the Somogyi phenomenon. Sampling of glucose levels throughout the night might help differentiate the two conditions.

Treatment: some have recommended an earlier injection in the morning (5 – 6 a.m.), and most suggest a late evening (before bedtime) injection of intermediate-acting insulin.

2.     Allergic reactions.

These include burning and itching at the site of insulin injection; skin rash; vasculaties; purpura and anaphylactic reaction.

Treatment:

–         antihistamines;

–         changing of standard insulin to pure pork insulin or to human insulin;

–         in extreme cases – glucocorticoids.

3.     Insulin resistance.

Clinical status characterized by insulin resistance:

–         obesity;

–         therapy with oral contraceptives;

–         glucocorticoid therapy;

–         acromegaly;

–         Cushing’s syndrome;

–         acanthosis nigricans;

–         chronic liver or renal disease.

Non-true insulin resistance may be caused by long-time injections of insulin into the one site.

4.     Lipodystrophy.

 It is atrophy or hypertrophy of the adipose tissue, which occur at the site of insulin injection.

Treatment:

–         changing the site of injection;

–         the usage of human insulin.

 

PREVENTION AND MANAGEMENT OF DIABETES COMPLICATIONS

(Diabetes Care January 2003 vol. 26 no. suppl 1 s33-s50)

 

I. CVD: management of risk factors and screening for coronary artery disease

CVD is the major cause of mortality for persons with diabetes. It is also a major contributor to morbidity and direct and indirect costs of diabetes. Type 2 diabetes is an independent risk factor for macrovascular disease, and its common coexisting conditions (e.g., hypertension and dyslipidemia) are also risk factors. Emphasis should be placed on reducing cardiovascular risk factors, when possible, and clinicians should be alert for signs and symptoms of atherosclerosis.

A. Blood pressure control

Hypertension (blood pressure ≥140/90 mmHg) is a common comorbidity of diabetes, affecting 20–60% of people with diabetes, depending on age, obesity, and ethnicity. Hypertension is also a major risk factor for CVD and microvascular complications such as retinopathy and nephropathy. In type 1 diabetes, hypertension is often the result of underlying nephropathy. In type 2 diabetes, hypertension is likely to be present as part of the metabolic syndrome (i.e., obesity, hyperglycemia, dyslipidemia) that is accompanied by high rates of CVD.

Randomized clinical trials have demonstrated the incontrovertible benefit of lowering blood pressure to <140 mmHg systolic and <80 mmHg diastolic in persons with diabetes. Epidemiologic analyses show that blood pressures >120/80 mmHg are associated with increased cardiovascular event rates and mortality in persons with diabetes. Therefore, a target blood pressure goal of <130/80 mmHg is reasonable if it can be safely achieved.

Although there are no well-controlled studies of diet and exercise in the treatment of hypertension in persons with diabetes, reducing sodium intake and body weight (when indicated), avoiding excessive alcohol consumption, and increasing activity levels have been shown to be effective in reducing blood pressure in nondiabetic individuals. These nonpharmacological strategies may also positively affect glycemia and lipid control.

Lowering of blood pressure with regimens based on antihypertensive drugs, including ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, diuretics, and calcium channel blockers, has been shown to be effective in lowering cardiovascular events. ACE inhibitors have been shown to improve cardiovascular outcomes in high cardiovascular risk patients with or without hypertension. In patients with congestive heart failure, ACE inhibitors are associated with better outcomes when compared to ARBs. ARBs also improve cardiovascular outcomes in the subset of patients with hypertension, diabetes, and end-organ injury. The compelling effect of ACE inhibitors or ARBs in patients with albuminuria or renal insufficiency provide additional rationale for use of these agents.  The α-blocker arm of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was terminated after interim analysis showed that α-blockers were substantially less effective in reducing congestive heart failure than diuretic therapy.

Before beginning treatment, patients with elevated blood pressures should have their blood pressure reexamined within 1 month to confirm the presence of hypertension unless the systolic blood pressure is ≥160 mmHg or the diastolic blood pressure is ≥100 mmHg, in which case treatment should be immediately initiated. Patients with hypertension should be seen as often as needed until adequate blood pressure control is obtained and then seen as necessary. In these patients, other cardiovascular risk factors, including hyperlipidemia, smoking, urinary albumin excretion (assessed before initiation of treatment), and glycemic control, should be carefully assessed and treated. Many patients will require three or more drugs to reach target goals.

Recommendations

·   Blood pressure should be measured at every routine diabetes visit. Patients found to have systolic blood pressure ≥130 or diastolic blood pressure ≥80 mmHg should have blood pressure confirmed on a separate day.

·   Orthostatic measurement of blood pressure should be performed to assess for the presence of autonomic neuropathy.

Goals

·   Patients with diabetes should be treated to a systolic blood pressure <130 mmHg. (B)

·   Patients with diabetes should be treated to a diastolic blood pressure <80 mmHg. (B)

Treatment

·   Patients with a systolic blood pressure of 130–139 mmHg or a diastolic blood pressure of 80–89 mmHg should be given lifestyle and behavioral therapy alone for a maximum of 3 months and then, if targets are not achieved, in addition, should be treated pharmacologically.

·   Patients with hypertension (systolic blood pressure ≥140 or diastolic blood pressure ≥90 mmHg) should receive drug therapy in addition to lifestyle and behavioral therapy.

·   Initial drug therapy may be with any drug class currently indicated for the treatment of hypertension. However, some drug classes (ACE inhibitors) have been repeatedly shown to be particularly beneficial in reducing CVD events during the treatment of uncomplicated hypertension and are therefore preferred agents for initial therapy. If ACE inhibitors are not tolerated, ARBs may be used. Additional drugs may be chosen from these classes or another drug class.

·   If ACE inhibitors or ARBs are used, monitor renal function and serum potassium levels.

·   In patients with type 1 diabetes, with or without hypertension, with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. In patients with type 2 diabetes, hypertension and microalbuminuria (>300 mg/day), nephropathy, or renal insufficiency, an ARB should be strongly considered• ACE inhibitors and ARBs have been shown to delay progression to macroalbuminuria.

·   If one class is not tolerated, the other should be substituted.

·   In patients >55 years of age, with hypertension or without hypertension but with another cardiovascular risk factor (history of CVD, dyslipidemia, microalbuminuria, smoking), an ACE inhibitor (if not contraindicated) should be considered to reduce the risk of cardiovascular events.

·   In patients with microalbuminuria or overt nephropathy, in whom ACE inhibitors or ARBs are not well tolerated, a non-DCCB or β-blocker should be considered.

·   In patients with a recent myocardial infarction, β-blockers, in addition, should be considered to reduce mortality.

·   In elderly hypertensive patients, blood pressure should be lowered gradually to avoid complications.

·   Patients not achieving target blood pressure on three drugs, including a diuretic, and/or patients with significant renal disease (see below) should be referred to a specialist experienced in the care of patients with hypertension.

 

B. Lipid management

Patients with type 2 diabetes have an increased prevalence of lipid abnormalities that contributes to higher rates of CVD. Lipid management aimed at lowering LDL cholesterol, raising HDL cholesterol, and lowering triglycerides has been shown to reduce macrovascular disease and mortality in patients with type 2 diabetes, particularly those who have had prior cardiovascular events.

Diet, increased physical activity, and weight loss should allow some patients to reach these lipid levels. Nutrition intervention should be tailored according to each patient’s age, type of diabetes, pharmacological treatment, lipid levels, and other medical conditions and should focus on the reduction of saturated fat, cholesterol, and transunsaturated fat intake. Glycemic control can also beneficially modify plasma lipid levels. In particular, triglycerides may be significantly reduced with optimal glucose lowering. Target lipid levels are shown in Table 1.

Pharmacological treatment is indicated if there is an inadequate response to lifestyle modifications and improved glucose control. The first priority of pharmacological therapy is to lower LDL cholesterol to a target goal of <100 mg/dl (2.60 mmol/l). For LDL lowering, statins are the drugs of choice. Statins raise HDL modestly, but a greater increase is usually achieved with fibrates.

In patients with LDL between 100 mg/dl (2.60 mmol/l) and 129 mg/dl (3.30 mmol/l), a variety of treatment strategies are available, including more aggressive nutrition intervention and pharmacological treatment with a statin. In addition, if the HDL is <40 mg/dl and the LDL is between 100 and 129 mg/dl, a fibric acid derivative might be used.

Niacin is the most effective drug for raising HDL but can significantly increase blood glucose, particularly at a high dose. More recent studies demonstrate that at modest doses (750–2,000 mg/day), significant benefit with regards to LDL, HDL, and triglyceride levels are accompanied by modest changes in glucose that are generally amenable to adjustment of diabetes therapy.

Combination therapy, with a statin and a fibrate or statin and niacin, may be efficacious for patients needing treatment for all three lipid fractions, but this combination is associated with an increased risk for abnormal transaminase levels, myositis, or rhabdomyolysis.

Recommendations

General recommendations

·   Lowering LDL cholesterol is associated with a reduction in cardiovascular events. (A)

·   Lowering triglycerides and increasing HDL cholesterol are associated with a reduction in cardiovascular events. (B)

Goals

·   Lower LDL cholesterol to <100 mg/dl (2.6 mmol/l) as the primary goal of therapy for adults. (B)

·   Lower triglycerides to <150 mg/dl (1.7 mmol/l) and raise HDL cholesterol to >40 mg/dl (1.15 mmol/l). In women, an HDL goal 10 mg/dl higher may be appropriate. (C)

Screening

·   In adult patients, test for lipid disorders at least annually and more often if needed to achieve goals. In adults with low-risk lipid values (LDL <100 mg/dl, HDL >60 mg/dl, triglycerides <150), repeat lipid assessments every 2 years.

·   In children >2 years of age, perform a lipid profile after diagnosis of diabetes and when glucose control has been established. If values are considered low risk and there is no family history, assessments should be repeated every 5 years.

Treatment

·   Diet  focusing on the reduction of saturated fat and cholesterol intake, weight loss, and increased physical activity has been shown to improve the lipid profile in patients with diabetes. (A)

·   Patients who do not achieve lipid goals with lifestyle modifications require pharmacological therapy. (A)

·   Statins should be used as first-line pharmacologic therapy for LDL lowering. (A)

·   Therapy with fibrates in patients with low HDL has been shown to reduce CVD rates and progression of carotid intimal medial progression. (A)

·   When prescribing fibrates or niacin, in combination therapy with a statin, care is needed to minimize the risk of adverse effects. (E)

 

C. Anti-platelet in diabetes

The use of aspirin in diabetes is reviewed in detail in the ADA technical reviews on aspirin therapy. Aspirin blocks thromboxane synthesis by acetylating platelet cyclo-oxygenase and has been used as a primary and secondary therapy to prevent cardiovascular events in diabetic and nondiabetic individuals. One large meta-analysis and several clinical trials demonstrate the efficacy of using aspirin as a preventive measure for cardiovascular events including stroke and myocardial infarction. Many trials have shown an ∼30% decrease in myocardial infarction and a 20% decrease in stroke in a wide range of patients, including young and middle-aged patients, patients with and without a history of CVD, males and females, and patients with hypertension.

Dosages used in most clinical trials ranged from 75 to 325 mg/day. There is no evidence to support any specific dose, but using the lowest possible dosage and enteric-coated preparations may help reduce side effects. There is no evidence for a specific age at which to start aspirin, but at ages below 30 years, when the risk of CVD is low, there is no evidence of benefit of aspirin for primary prevention.

Clopidogrel has been demonstrated to reduce CVD rates in diabetic individuals. Adjunctive therapy in very high-risk patients or as alternative therapy in aspirin-intolerant patients should be considered.

 

Recommendation

·   Use aspirin therapy (75–325 mg/day) in all adult patients with diabetes and macrovascular disease. (A)

·   Consider beginning aspirin therapy (75–325 mg/day) for primary prevention in patients ≥40 years of age with diabetes and one or more other cardiovascular risk factors. (A)

·   Do not use aspirin in patients <21 years of age because of the increased risk of Reye’s syndrome. (A)

·   Consider aspirin therapy for patients between 30 and 40 years of age with other cardiovascular risk factors. (B)

 

D. Smoking cessation

Issues of smoking in diabetes are reviewed in detail in the ADA technical reviews on smoking cessation. A large body of evidence from epidemiological, case-control, and cohort studies provides convincing documentation of the causal link between cigarette smoking and health risks. Cigarette smoking accounts for one of every five deaths in the U.S. and is the most important modifiable cause of premature death. Much of the prior work documenting the impact of smoking on health did not discuss separately results on subsets of individuals with diabetes, suggesting the identified risks are at least equivalent to those found in the general population. Other studies of individuals with diabetes consistently found a heightened risk of morbidity and premature death associated with the development of macrovascular complications among smokers. Smoking is also related to the premature development of microvascular complications of diabetes and may have a role in the development of type 2 diabetes.

A number of large randomized clinical trials have demonstrated the efficacy and cost-effectiveness of counseling in changing smoking behavior. Such studies, combined with the others specific to individuals with diabetes, suggest that smoking cessation counseling is effective in reducing tobacco use.

The routine and thorough assessment of tobacco use is important as a means of preventing smoking or encouraging cessation. Special considerations should include assessment of level of nicotine dependence, which is associated with difficulty in quitting and relapse.

Recommendations

·   Advise all patients not to smoke. (A)

·   Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care. (B)

 

E. CHD screening and treatment

CHD screening and treatment are reviewed in detail in the ADA consensus statement on CHD in people with diabetes. To identify the presence of CHD in diabetic patients without clear or suggestive symptoms of coronary artery disease (CAD), a risk factor–based approach to the initial diagnostic evaluation and subsequent follow-up is recommended. At least annually, cardiovascular risk factors should be assessed. These risk factors include dyslipidemia, hypertension, smoking, a positive family history of premature coronary disease, and the presence of micro- or macroalbumuninuria. Candidates for screening exercise stress (electrocardiogram [ECG]) testing include those with 1) typical or atypical cardiac symptoms; 2) an abnormal resting ECG; 3) a history of peripheral or carotid occlusive disease; 4) sedentary lifestyle, age >35 years, and plans to begin a vigorous exercise program; or 5) those with two or more risk factors noted above. There is, however, no current evidence that exercise testing in asymptomatic patients with risk factors improves prognosis. Patients with abnormal exercise ECG and patients unable to perform an exercise ECG require additional or alternative testing. Currently, stress nuclear perfusion and stress echocardiography are valuable next-level diagnostic procedures. A consultation with a cardiologist is recommended regarding further work-up.

Recommendations

·   Perform exercise stress testing in asymptomatic diabetic patients based on the criteria outlined above. Consider a risk factor–based strategy for the diagnosis of CAD that might include stress ECG and/or stress echocardiography and/or perfusion imaging. (E)

·   Refer patients with signs and symptoms of CVD or with positive noninvasive test for CAD to a cardiologist for further evaluation. (E)

·   In patients with treated congestive heart failure, metformin use is contraindicated. The thiazolidinediones are associated with fluid retention, and their use can be complicated by the development of congestive heart failure. Caution in prescribing thiazolidinediones in the setting of known congestive heart failure or other heart diseases as well as in patients with preexisting edema or concurrent insulin therapy is required. (E)

 

II. Nephropathy screening and treatment

Diabetic nephropathy occurs in 20–40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD). Persistent albuminuria in the range of 30–299 mg/24 h (microalbuminuria) has been shown to be the earliest stage of diabetic nephropathy in type 1 diabetes and a marker for development of nephropathy in type 2 diabetes. Microalbuminuria is also a well-established marker of increased CVD risk.

Patients with microalbuminuria who progress to macroalbuminuria (≥300 mg/24 h) are likely to progress to ESRD over a period of years. Over the past several years, a number of interventions have been demonstrated to reduce the risk and slow the progression of renal disease. Intensive diabetes management with the goal of achieving near and  control of blood pressure can reduce the development of nephropathy. In addition, large prospective randomized studies in patients with type 1 diabetes have demonstrated that achievement of lower levels of systolic blood pressure (<140 mmHg) achieved with treatment using ACE inhibitors provides a selective benefit over other antihypertensive drug classes in delaying the progression from microalbuminuria to macroalbuminuria and can slow the decline in glomerular filtration rate (GFR) in patients with macroalbuminuria.

In addition, ACE inhibitors have been shown to reduce severe CVD (i.e., myocardial infarction, stroke, death), thus further supporting the use of these agents in patients with microalbuminuria. ARBs have also been shown to reduce the rate of progression from micro- to macroalbuminuria as well as end-stage renal disease in patients with type 2 diabetes. Some evidence suggests that ARBs have a smaller magnitude of rise in potassium compared with ACE inhibitors in people with nephropathy.

While screening for microalbuminuria can be performed by three methods—1) measurement of the albumin-to-creatinine ratio in a random, spot collection; 2) 24-h collection with creatinine, allowing the simultaneous measurement of creatinine clearance; and 3) timed (e.g., 4-h or overnight) collection—the analysis of a spot sample for the albumin-to-creatinine ratio is strongly encouraged. The other two alternatives (24-h collection and a timed specimen) are rarely necessary. At least two of three tests measured within a 6-month period should show elevated levels before a patient is designated as having microalbuminuria. Abnormalities of albumin excretion are defined in Table .

 

Physicians may use the Levey modification of the Cockcroft and Gault equation to calculate estimated GFR (eGFR) from serum creatinine and to stage the patient’s renal disease. The eGFR can easily be calculated by going to www.kidney.org/professionals/dogi/gfr_calculator.cfm.

The role of annual microalbumuria assessment is less clear after diagnosis of microalbuminuria and institution of ACE inhibitor or ARB therapy and blood pressure control. Many experts, however, recommend continued surveillance to assess both response to therapy and progression of disease.

Recommendations

General recommendations

·   To reduce the risk and/or slow the progression of nephropathy, optimize glucose control. (A)

·   To reduce the risk and/or slow the progression of nephropathy, optimize blood pressure control. (A)

Screening

Perform an annual test for the presence of microalbuminuria in type 1 diabetic patients with diabetes duration of ≥5 years and in all type 2 diabetic patients, starting at diagnosis. (E)

Treatment

·   In the treatment of both micro- and macroalbuminuria, either ACE inhibitors or ARBs should be used. (A)

·   In patients with type 1 diabetes, with or without hypertension, with any degree of albuminuria, ACE inhibitors have been shown to delay the progression of nephropathy. (A) In patients with type 2 diabetes, hypertension and microalbuminuria, • ACE inhibitors and ARBs have been shown to delay the  In patients with type 2 progression to macroalbuminuria. (A) • diabetes, hypertension, macroalbuminuria, and renal insufficiency (serum creatinine >1.5 mg/dl), ARBs have been shown to delay the progression of If one class is not nephropathy. (A) • tolerated, the other should be substituted. (E)

·   With presence of nephropathy, initiate protein restriction to ≤0.8 g · kg⁻¹ body wt · day⁻¹ (∼10% of daily calories), the current adult recommended dietary allowance for protein. Further restriction may be useful in slowing the decline of GFR in selected patients. (B)

·   Use of DCCBs are less effective in slowing nephropathy progression compared with ARB therapy in those with diabetes with nephropathy and macroalbuminuria. (B)

·   Consider the use of non-DCCBs or β-blockers in patients unable to tolerate ACE inhibitors and/or ARBs. (E)

·   If ACE inhibitors or ARBs are used, monitor serum potassium levels for the development of hyperkalemia. (B)

·   Consider referral to a physician experienced in the care of diabetic renal disease when the eGFR has fallen to <60 ml · min⁻¹ · 1.73 m⁻² or if difficulties occur in the management of hypertension or hyperkalemia. (B)

 

III. Diabetic retinopathy screening and treatment

Diabetic retinopathy is a highly specific vascular complication of both type 1 and type 2 diabetes. The prevalence of retinopathy is strongly related to the duration of diabetes. Diabetic retinopathy is estimated to be the most frequent cause of new cases of blindness among adults aged 20–74 years.

Intensive diabetes management with the goal of achieving near normoglycemia has been shown in large prospective randomized studies to prevent and/or delay the onset of diabetic retinopathy. In addition to glycemic control, several other factors seem to increase the risk of retinopathy. The presence of nephropathy is associated with retinopathy. High blood pressure is an established risk factor for the development of macular edema and is associated with the presence of proliferative diabetic retinopathy (PDR). Lowering blood pressure, as shown in the UKPDS, has been shown to decrease the progression of retinopathy. Several case series and a controlled prospective study suggest that pregnancy in type 1 diabetic patients may aggravate retinopathy. During pregnancy and 1 year postpartum, retinopathy may be transiently aggravated; laser photocoagulation surgery can minimize this risk. One of the main motivations for screening for diabetic retinopathy is the established efficacy of laser photocoagulation surgery in preventing visual loss.

Recommendations

General recommendations

·   Optimal glycemic control can substantially reduce the risk and progression of diabetic retinopathy. (A)

·   Optimal blood pressure control can reduce the risk and progression of diabetic retinopathy. (A)

·   Aspirin therapy does not prevent retinopathy or increase the risks of hemorrhage. (A)

Screening

·   Patients with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 3–5 years after the onset of diabetes. (B)

·   Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes. (B)

·   Subsequent examinations for type 1 and type 2 diabetic patients should be repeated annually by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing the presence of diabetic retinopathy and is aware of its management. Examinations will be required more frequently if retinopathy is progressing. (B)

·   When planning pregnancy, women with preexisting diabetes should have a comprehensive eye examination and should be counseled on the risk of development and/or progression of diabetic retinopathy. Women with diabetes who become pregnant should have a comprehensive eye examination in the first trimester and close follow-up throughout pregnancy and for 1 year postpartum. This guideline does not apply to women who develop GDM because such individuals are not at increased risk for diabetic retinopathy. (B)

Treatment

·   Laser therapy can reduce the risk of vision loss in patients with HRCs. (A)

·   Promptly refer patients with any level of macular edema, severe NPDR, or any PDR to an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy. (A)

 

IV. Foot care

Amputation and foot ulceration are one of the most common consequences of diabetic neuropathy and a major cause of morbidity and disability in people with diabetes. Early recognition and management of independent risk factors can prevent or delay adverse outcomes.

The risk of ulcers or amputations is increased in people who have had diabetes >10 years, are male, have poor glucose control, or have cardiovascular, retinal, or renal complications. The following foot-related risk conditions are associated with an increased risk of amputation:

·   Peripheral neuropathy with loss of protective sensation.

·   Altered biomechanics (in the presence of neuropathy).

·   Evidence of increased pressure (erythema, hemorrhage under a callus).

·   Bony deformity.

·   Peripheral vascular disease (decreased or absent pedal pulses).

·   A history of ulcers or amputation.

·   Severe nail pathology.

Recommendations

·   A multidisplinary approach is recommended for persons with foot ulcers and high-risk feet, especially those with a history of prior ulcer or amputation. (A)

·   The foot examination can be accomplished in a primary care setting and should include the use of a Semmes-Weinstein monofilament, tuning fork, palpation, and a visual examination. (B)

·   Educate all patients, especially those with risk factors or prior lower-extremity complications, about the risk and prevention of foot problems and reinforce self-care behavior. (B)

·   Refer high-risk patients to foot care specialists for ongoing preventive care and life-long surveillance. (C)

·   Refer patients with significant claudication for further vascular assessment and consider exercise and surgical options.(C)

·   Perform a comprehensive foot examination annually on patients with diabetes to identify risk factors predictive of ulcers and amputations. Perform a visual inspection of patients’ feet at each routine visit. (E)

 

References.

А. Main

1.                 Davidson’s Principles and Practice of Medicine (1st Edition) / Edited by  N. R. Colledge,    B. R. Walker,   S. H. Ralston. – Philadelphia : Churchill Livingstone, 2010. – 1376 p.

2.                 Harrison’s Principles of Internal Medicine (18th edition) / D. Longo, A. Fauci, D. Kasper, S. Hauser, J. Jameson, J. Loscalzo,. – New York : McGraw-Hill Education – Europe, 2011. – 4012 p.

3.                 Kumar and Clark’s Clinical Medicine (8th Revised edition) (With student consult Online Access) / Edited by P. Kumar, M. L. Clark . – London : Elsevier Health Sciences, 2012. – 1304 p.

B. Additional

1. Greenspan’s Basic and Clinical Endocrinology ( 9th Revised edition) / David G. Gardner, Dolores M. Shoback. – New York : McGraw-Hill Education – Europe, 2011. –  880 p.

2. Oxford Textbook of Endocrinology and Diabetes 2nd Revised edition / Edited by John A. H. Wass, Paul Stewart, Stephanie A. Amiel, Melanie J. Davies. – Oxford : Oxford University Press, 2011. – 2160 p.

3. Web-sites:

a)    http://emedicine.medscape.com/endocrinology

b)  https://www.aace.com/

a.    American Association of Clinical Endocrinologists Medical Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan – © 2011

c)   http://care.diabetesjournals.org/

a.    Management of Hyperglycemia in Type 2 Diabetes (2012)