MEDICINE UPDATE FOR ALL DOCTORS

DIABETES MELLITUS

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DR DINESH MITTAL DR SONALEE MITTAL

DRISHTI EYE HOSP VIJAYNAGAR INDORE

•Diabetes is a disease with increasing global incidence, affecting more than 371 million people and causing 4.8 million deaths in 2012• India has the world’s second largest population of people with diabetes, affecting about 63 million people with about a half of them still undiagnosed

DIABETES•The prevalence of diabetes mellitus in the United States is estimated to be as high as 8%. Obesity is a major contributing factor and continues to increase in prevalence yearly•Moderate exercise and weight loss can prevent the onset of type 2 diabetes mellitus in patients at risk for development of the disease .

•The risk of hyperglycemia is 2 times as great in individuals who are 20% above ideal body weight, compared with those at ideal body weight; the risk is 4 times, 8 times, 16 times, and 32 times as great in those 40%, 60%, 80%, and 100% above ideal body weight, respectively.

Basics of Glucose Metabolism• The plasma glucose level is reduced by a single hormone,

insulin. In contrast, 6 hormones increase the plasma glucose level: somatotropin, adrenocorticotropin, cortisol, epinephrine, glucagon, and thyroxine. All of these hormones are secreted as needed to maintain normal serum glucose levels in the face of extremely variable degrees of glucose intake and utilization. In the fed state, anabolism is initiated by increased secretion of insulin and growth hormone. This leads to conversion of glucose to glycogen for storage in the liver and muscles, synthesis of protein from amino acids, and combination of fatty acid and glucose in adipose tissue to form triglycerides.

Basics of Glucose Metabolism• In the fasting state, catabolism results from the increased

secretion of hormones that are antagonistic to insulin. In this setting, glycogen is reduced to glucose in the liver and muscles, proteins are broken down into amino acids in muscles and other tissues and transported to the liver for conversion to glucose or ketoacids, and triglycerides are degraded into fatty acids and glycerol in adipose tissue for transport to the liver for conversion to ketoacids and glucose (or for transport to muscle for use as an energy source).

Basics of Glucose Metabolism• A lean adult without diabetes secretes approximately 33 units

of insulin per day. If pancreatic β- cell mass is reduced (as in type 1 diabetes), then catabolic hormones results in fasting hyperglycemia, and persistent catabolism may lead to fatal diabetic ketoacidosis if insulin therapy is not started. Thus, insulin-dependent diabetic patients require a continuous baseline dose of insulin, even in the fasting state: some level of insulin is needed to offset the effect of all the other hormones .

Basics of Glucose Metabolism• In an obese adult, insulin secretion can increase almost

fourfold, to 120 units per day. In this state, the plasma glucose level may rise only slightly, but pancreatic β-cell mass increases. When serum insulin levels are elevated, number of insulin receptors on surface of insulin-responsive cells actually decreases, and formerly insulin-sensitive tissues become resistant to the glucose-lowering effects of both endogenous and exogenous insulin. This condition may progress to fasting hyperglycemia and type 2 diabetes .

Prediabetic disorders• Impaired glucose tolerance (IGT) is the diagnosis when a standard

75-g OGTT yields a 2-hour plasma glucose level of ≥140 mg/dL to <200 mg/dL. A separate category, impaired fasting glucose (IFG), requires a fasting plasma glucose level of ≥110 mg/dL to <126 mg/dL. Both conditions can be considered early stages of type 2 diabetes and are often called prediabetic states. For instance, type 2 diabetes develops in 30%–50% of patients with IGT within 10 years of diagnosis. Although there is a great deal of overlap, IGT and IFG are not identical states. An HbA1c value of at least 6.0% but below 6.5% also denotes prediabetes.

• Patients with these conditions have an elevated risk of macrovascular disease compared with persons with normal glucose tolerance. Accumulating evidence also suggests an increased risk of microvascular disease, including nephropathy and retinopathy.

Metabolic syndrome

• Closely associated with type 2 diabetes, metabolic syndrome is not a disease but a collection of disorders. The clinical syndrome includes obesity, lipid abnormalities, hypertension, and some type of glucose intolerance , risk factors common to both diabetes and cardiovascular disease. Men with a majority of metabolic syndrome features have roughly 4 times the risk of coronary heart disease and 25 times the risk of diabetes as those without these abnormalities. Metabolic syndrome represents a profound public health risk, and treatment of the syndrome may have a significant impact on preventing diabetes and cardiovascular diseases.

Clinical Presentation of Diabetes• The classic symptoms of diabetes mellitus are polyuria,

polydipsia, and polyphagia. Type 1 diabetes tends to present more acutely than type 2, and the diagnosis is usually made based on the presence of these classic symptoms in association with an elevated plasma glucose level. The diagnosis of type 2 diabetes often depends more on laboratory testing, as patients may have abnormal glucose metabolism long before overt symptoms develop. Other important historical findings that suggest the diagnosis of diabetes include complications during pregnancy or birth of large babies, reactive hypoglycemia, family history, advanced vascular disease, impotence, leg claudication, and neuropathy symptoms.

Clinical Presentation of Diabetes• Physical findings, particularly in type 2 diabetes, may

include obesity, hypertension, arteriopathy, neuropathy, genitourinary tract abnormalities (especially recurrent Candida infections or bacterial bladder or kidney infections), periodontal disease, foot abnormalities, skin abnormalities, and unusual susceptibility to infections.

Definition, Diagnosis• The ADA recommends a diagnosis of diabetes mellitus• when 1 of the following 4 criteria are met and confirmed

with retesting on a subsequent day:• HbA1c ≥6.5% (<5.7% = normal)• FPG level ≥126 mg/dL (7.0 mmol/L)• 2-hour plasma glucose level ≥200 mg/dL (11.1 mmol/L)

with 75-g OGTT• random plasma glucose level ≥200 mg/dL (11.1 mmol/L) in

a patient with classic symptoms of hyperglycemia, including polyphagia, polyuria, and polydipsia

The importance of glucose control

OVERALL GOALS• The goals of therapy for type 1 or type 2 diabetes mellitus

(DM) are to• ( 1 ) eliminate symptoms related to hyperglycemia ， • (2) reduce or eliminate the long-term microvascular and

macrovascular complications of DM and• (3) allow the patient to achieve as normal a lifestyle as

possible. • Symptoms of diabetes usually resolve when the plasma

glucose is < 1 1 . 1 mmol/L (200 mg/dL) ， and thus most DM treatment focuses on achieving second and third goals.

Type 1 diabetes•Type 1 diabetes was previously called insulin-dependent diabetes mellitus or juvenile-onset diabetes. Although incidence peaks around the time of puberty, approximately 25% of cases present after 35 years of age. This form of diabetes is due to a deficiency in endogenous insulin secretion secondary to destruction of insulin-producing β-cells in the pancreas.

Type 2 diabetes• Type 2 diabetes was formerly known as non–insulin-dependent

or adult-onset diabetes mellitus. Patients with type 2 diabetes are usually, but not always, older than 40 years at presentation. Obesity is a frequent finding and, in the United States, is present in 80%–90% of these patients. Other risk factors for type 2 diabetes include hypertension, a history of gestational diabetes, physical inactivity, and low socioeconomic status. This form of diabetes mellitus is frequently undiagnosed for years because hyperglycemia develops slowly and patients are often asymptomatic. Despite minimal symptoms, these patients are at increased risk for microvascular and macrovascular complications.

CHOICE OF INITIAL GLUCOSE-LOWERING AGENT

• The level of hyperglycemia and the patient's individualized goal should influence the initial choice of therapy. • Assuming that maximal benefit of MNT and increased physical

activity has been realized ， patients with mild to moderate hyperglycemia (FPG < 200-250 mg/dL ) often respond well to a single ， oral glucose-lowering agent. Patients with more severe hyperglycemia (FPG > 250 mg/dL ) may respond partially but are unlikely to achieve normoglycemia with oral monotherapy.• A stepwise approach that starts with a single agent and adds

a second agent to achieve the glycemic target can be used.

Risk Factors for Type 2 Diabetes Mellitus

Prevention of Diabetes Mellitus• the risk of progression from IGT to type 2 diabetes can

be markedly reduced (by approximately 50% over several years) with lifestyle modifications such as a combination of diet and exercise therapy. The amount of weight loss and exercise required to achieve this result is surprisingly modest. For instance, in the Diabetes Prevention Program, patients who were asked to perform only 150 minutes of brisk walking a week (a little over 20 minutes a day) lost only about 12 pounds of weight on average but reduced their risk of diabetes development by 50%.

Treatment Goals for Adults with Diabetesa

Pharmacologic Comparisons between Oral Hypoglycemic Drug Classes

Pharmacologic Comparisons between Oral Hypoglycemic Drug Classes

First line•The majority of patients and certainly those who are overweight should start METFORMIN first line. This should be started at 500 mg once or twice a day and the dose increased after 5–7 days . Increasing the dose gradually may offset the gastrointestinal side effects that many patients fail to tolerate .

Metformin• Metformin has a number of beneficial actions in diabetes. It

reduces hepatic gluconeogenesis, increases insulin sensitivity and reduces carbohydrate absorption from the gastrointestinal tract. It also improves circulating free fatty acids and VLDL levels. The UKPDS study suggested that metformin improves cardiovascular risk independently of its effect on blood glucose levels. Very occasionally, metformin causes reduction in vitamin B12 absorption, and serum B12 levels should be checked in patients taking metformin who develop peripheral neuropathy.

First line• Non-obese patients may be insulin-deficient (particularly if

they have actually lost weight) and could start a sulphonylurea first rather than metformin, but metformin has other benefits and so could be co-prescribed from the start in this situation. The sulphonylurea is titrated upwards according to fasting blood glucose levels if available, or HbA1c .

Second line• If the HbA1c is still not in target after 2–3 months, offer a

second agent. This could either be a sulphonylurea, a glitazone, or a gliptin . Glitazones should be avoided in those with, or at risk of heart failure. If the patient is unwell or actually losing weight then insulin should be started without delay. This may also be appropriate if the HbA1c is still very high (e.g. over 9% ).

Third line• ‘Triple therapy’ using metformin, a sulphonylurea and

either a glitazone or sitagliptin is licensed, but many patients using this combination are candidates for insulin, and this should always be considered before starting a third oral drug. Patients starting insulin can continue their oral medication, but an intensive insulin therapy regimen may be simpler if sulphonylurea is withdrawn, as the insulin is providing a similar effect exogenously.

INSULIN• insulin treatment for T2DM is usually started when the initial

oral therapy, in double or triple combination and at the maximum tolerated doses fails to achieve optimal glycaemic control. recent guidelines recommend initiation of insulin early in the course of disease, especially in patients with HbA1c > 9% as it is unlikely to achieve glycaemic targets with the use of oral agents alone .

Starting insulin in general practice

• Insulin can be started in most type 2 patients in general practice. the usual preferred regimen is a twice daily dose of premixed insulin such as Novomix 30 or Mixtard 30 given before breakfast and before the evening meal. It is usual to start at 6–8 u twice a day with home blood glucose monitoring. The monitoring technique should be taught prior to commencing (and not at the same time as) the insulin.

insulin• The insulin dose can be titrated upwards according to

blood glucose levels, usually in increments of 2–4 units,. An alternative is to start with a long-acting analogue such as glargine or detemir at 8 units in the evening, titrating upwards according to fasting glucose levels. Conversion to a more flexible regimen can be achieved later on, either through the addition of short- or rapid-acting insulins with meals to create a basal-bolus regimen, or by changing over to a premixed insulin twice or three times a day

• long-acting insulins (NPH ， glargine ， or detemir) supply basal insulin ， whereas regular ， insulin aspart ， glulisine ， or lispro insulin provides prandial insulin. Short-acting insulin analogues should be Injected just before (< 10 min) or just after a meal; regular insulin is given 30-45 min prior to a meal.

Multiple-component insulin regimen

• . A multiple-component insulin regimen consisting of long-acting insulinA glargine or detemir may be required each day to provide basal insulin coverage and three shots of glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal.

• . B. The injection of two shots of long-acting insulin (NPH) and short-acting insulin [glulisine, lispro, insulin aspart (solid red line), or regular (green dashed line)]. Only one formulation of short-acting insulin is used.

• C. Insulin administration by insulin infusion device is shown with the basal insulin and a bolus injection at each meal. The basal insulin rate is decreased during the evening and increased slightly prior to the patient awakening in the morning. Glulisine, lispro, or insulin aspart is used in the insulin pump.

• In general ， individuals with type 1 DM require 0 . 5 - 1 U/kg per day of insulin divided into multiple doses ， with -50% of the insulin given as basal insulin. one commonly used regimen consisted of twice-daily Injections of NPH mixed with a short-acting insulin before the morning and evening meals (Fig. 4 1 8 - 1B). Such regimens usually prescribe two-thirds of the total daily insulin dose in the morning (with about two-thirds given as long-acting insulin and one-third as short-acting) and one-third before the evening meal (with approximately one half given as long-acting insulin and one-half as short-acting) .

Insulin Therapy• OVERVIEW• • Patients presenting with type 1 diabetes require

insulin without delay to avoid ketoacidosis• • An increasing proportion of type 2 patients will require

insulin to achieve modern glycaemic control targets• • The majority of type 2 patients requiring insulin can

have this treatment initiated in primary care

1. Introduction• Insulin replacement therapy is essential for a patient with type

1 diabetes and is needed to achieve good glycaemic control in many patients with type 2 diabetes once other agents are no longer able to achieve this effectively. For patients with previously poor glycaemic control insulin has dramatic effects and can enhance wellbeing in a way that other therapies cannot match. Despite these obvious benefits, many patients who have previously taken tablets resist going onto insulin therapy, principally because it is an injectable preparation.• Insulin therapy also requires much more active involvement by

the patient to adjust the doses.

Insulin regimens Starting insulin in type 1 diabetes

• Many type 1 patients can start treatment with a twice-daily biphasic regimen, usually about 8 units twice a day and then the dose is optimised. However, in younger patients in particular, a more flexible method is the basal-bolus regime where a long-acting insulin is given at bedtime and meals are covered by soluble insulin or a very short-acting analogue.

Basal-bolus regime• an intermediate- or long-acting acting insulin is used at bedtime

and meals are covered using a short-acting insulin or a rapid-acting insulin analogue. A long-acting insulin analogue such as insulin glargine or insulin detemir is often used in the UK now as the basal insulin. The timing of the rapid-acting insulin can vary according to the timing of meals. This is convenient for those at work or at college.

Twice or three times a day biphasic regimen• Some patients opt to have twice-daily biphasic mixtures

taken at breakfast and with an evening meal. This can be increased by adding in a lunch time dose if using a biphasic with a rapid acting component, but there may in some cases be a risk of overlap between the lunchtime and evening doses. Occasionally such patients may require a short-acting or rapid-acting insulin with lunch instead of the biphasic.

Starting insulin in type 2 diabetes

• For some type 2 patients where symptom control is main aim of therapy, it may be appropriate to provide once-daily insulin injection with a long-acting insulin analogue. For most patients, however, pre-mixed insulin or insulin analogue is preferred. Many patients with type 2 diabetes also elect to go on a basal bolus regimen, which involves four or more injections a day because of the flexibility it offers. For most patients with type 2 diabetes, however, a twice or three times a day regimen of pre-mixed analogues is useful. Maintaining glycaemic control in a patient with type 2 diabetes represents more of a challenge as their needs will change along with disease progression

Starting insulin in type 2 diabetes• The doses are increased usually in increments of 2 or 4

units with each dose until glucose control is satisfactory, taking care to avoid hypoglycaemia.• This is important to explain to the patient and also to

alter insulin doses and the regime as requirements increase. Patients should also be warned about weight gain, particularly in those with type 2 diabetes and concomitant attention to control of obesity is valuable in mitigating this.

Final recommendations• 1. EXERCISE• 2 . WEIGHT REDUCTION• 3 . METFORMIN• 4. SULFONYL UREA• 5. POIGLITAZONE• 6. ADD MIXTARD INSULIN PEN . START BEDTIME DOSE

OF 8 UNITS AND INCREASE ACCORDING TO BLOOD GLUCOSE MONITORING .

THANK YOU

DR DINESHDR SONALEE