Treatment of type 2 diabetes (T2DM)
- Education of patients is very important
- The importance of diet and exercise should be emphasized
- All patients should be reviewed by a dietitian for appropriate advice
- Measures to induce weight loss (most of these patients are overweight) should be encouraged/implemented
- In the initial phases of the disease, diet and exercise may be enough to maintain good diabetes control
- Patients will eventually need medical intervention with oral hypoglycemic agents or insulin….
Oral hypoglycemic agents
These have proliferated in the past decade or so and we now have a number of different treatment options. These include:
- Biguanides (main agent is metformin)
- The first-line agent in obese T2DM patients
- Metformin lowers blood glucose levels by: reducing hepatic glucose output (decrease in glycogenolysis), reducing glucose absorption and mildly reducing insulin resistance
- Effective, cheap and safe
- Use of this agent is associated with weight loss, which is welcome in subjects with diabetes
- Side-effects are mainly gastrointestinal (nausea, bloating) and these are minimized by a gradual increase in drug dose or use of long-acting preparations
- Contraindications include: renal failure – if creatinine is >150 μmol/L, the drug should be discontinued (or not started) due to fears of inducing lactic acidosis; advanced heart or liver failure – again there is a risk of inducing lactic acidosis. Use of metformin in mild heart failure or minor derangement of liver function is perfectly safe.
- Insulin secretagogues
- Sulphonylureas: gliclazide, glibenclamide and glimepiride are probably the most widely used agents in the UK. These agents lower blood glucose by stimulating pancreatic insulin secretion. Side-effects include hypoglycemia and weight gain.
- Meglitinides: natiglinide and repaglinide are the most widely used agents. These increase insulin secretion by the pancreas, an effect that is more pronounced after a meal. They are less commonly associated with hypoglycemia and weight gain compared with sulphonylureas. In practice, they are often less effective at reducing glucose levels compared with sulphonylureas.
- Insulin sensitizers
- Thiazolidinediones (also known as glitazones), pioglitazone and rosiglitazone, are stimulators of the peroxisome proliferators nuclear receptor (PPAR)-y, which results in improvement in insulin resistance and decrease in blood sugar.
- These agents have cardiovascular protective features
- Recent analysis, however, indicates that rosiglitazone has a neutral effect on cardiovascular events, whereas pioglitazone may reduce the risk
- These agents can cause fluid retention and, therefore, they are contraindicated in subjects with heart failure
- These agents induce weight gain
- Drugs that interfere with glucose absorption
- a-Glucosidase inhibitors (acarbose is perhaps the most widely used agent in this group)
- Use of these agents in the UK is limited due to a modest blood glucose lowering effect and gastrointestinal side effects, mainly bloating, which are very common
- Agents working on the glucagon-like peptide-1 (GLP-1) system
- GLP-1 is a natural hormone secreted by the gastrointestinal tract in response to meals
- GLP-1 stimulates insulin secretion by the pancreas and inhibits glucagon production, thereby lowering plasma glucose levels
- GLP-1 has a very short half-life as it is metabolized by dipeptidyl peptidase (DPP)-4 enzymes and quickly cleared from the circulation
- GLP-1 analogues (exenatide)
- Work similarly to native GLP-1 but are slowly metabolized by DPP-4 enzymes, resulting in a longer half-life in the circulation
- Injected s.c. twice a day resulting in a reduction in blood sugar levels and weight loss. Side effects including gastrointestinal symptoms in relatively large number of patients (around one-fifth), which may improve with continued use of the drug
- DPP-4 inhibitors (sitagliptin/vildagliptin)
- Inhibition of DPP-4 results in slower breakdown of ‘native’ GLP-1 and consequently an increase in plasma levels
- These agents are less effective at reducing blood glucose levels compared with GLP-1 analogues
- DPP-4 inhibitors are weight neutral
- They have advantages over GLP-1 analogues in that they are given orally (no injections are needed) and side effects are minimal
Table 21 summarizes the main characteristics of GLP-1 analogues and DPP-4 inhibitors.
When do we need to move patients from oral hypoglycemic treatment to insulin?
- Failure of oral hypoglycemic agents to maintain adequate glucose levels (metformin is usually continued with insulin treatment)
- Pregnancy: insulin is safe to use during pregnancy and, therefore, pregnant women with diabetes are usually treated with insulin only
- Severe illness or operation requiring hospital admission: oral hypoglycemic agents are temporarily stopped
Management of diabetic complications
- A medical emergency with a death rate of 3-5%
- Is due to the lack of insulin and subsequent switch from glucose to fatty acid metabolism, which results in the production of ketone bodies:
- Acetoacetic acid
- Hydoxybutyric acid
- Acetone (giving DKA patients acetone-smelling breath)
- Subjects with DKA have three fundamental abnormalities
- Metabolic acidosis, which causes abdominal pain and vomiting, and compensatory hyperventilation (Kussmaul respiration): blowing off CO2 results in respiratory alkalosis, trying to compensate for the metabolic acidosis
- Dehydration, secondary to osmotic diuresis (high glucose levels) and vomiting
- Electrolyte imbalance, including hyperkalaemia, secondary to metabolic acidosis, hyponatremia and ‘relative’ hypokalemia due to vomiting
- Causes of DKA:
- New diagnosis of T1DM in 20% of cases
- In a known diabetic patient, DKA can be due to: infection in 35% of cases, non-compliance with insulin injection in 30%, and errors in insulin administration and dose calculation in 15%. In older patients, DKA may be precipitated by an ischemic event such as myocardial infarction.
DKA subjects can present with a variety of symptoms:
- Abdominal pain
- Generally feeling unwell
- Coma in advanced cases
- In those with known diabetes, DKA should be suspected in anyone who is not feeling or looking well
- In subjects with suspected DKA who are not known to have diabetes, a proper history is paramount to make the correct diagnosis
- Confirm the diagnosis
- Raised glucose levels: glucose can be only slightly elevated
- Reduced plasma bicarbonate levels with or without low pH (bicarbonate <15 mmol/L confirm the diagnosis of DKA)
- Presence of ketonuria
- Rule out precipitating cause:
- Chest X-ray (infection)
- Check urine for the possibility of infection
- ECG (myocardial infarction)
- Take blood and urine samples for culture
- Note that a high white cell count may occur in subjects with DKA in the absence of infection
This should be promptly started and consists of fluid and insulin replacement as well as management of electrolyte imbalance. In addition, treatment should be directed to the precipitating cause (if any). Monitoring of patients after initial treatment is very important and local hospital guidelines for the management of these patients should be strictly followed.
- Fluid replacement usually starts with normal saline (0.9%): 1 L over the first h, 1 L over 2 h, then 1 L every 4–6 h, with careful monitoring of the patient and adjustment of fluid replacement accordingly. Normal saline should be substituted with 5% dextrose infusion once plasma glucose drops below 12–15 mmol/L (different protocols use different cut-offs)
- Failure to replace potassium can result in severe hypokalamia, which may cause cardiac arrhythmias, potentially resulting in death. Serum potassium is usually elevated on initial presentation due to the presence of acidosis, despite low total body potassium. Potassium levels quickly drop after initiation of DKA treatment, as both insulin replacement and correction of acidosis shift the potassium from the extracellular space into the cells. As a rough guide, 20 mmol/L potassium should be added to the fluid in patients with normokalamia, 40 mmol/L to those with hypokalamia and no potassium should be given to those with hyperkalamia. Monitoring potassium levels (every 2–4 h) during treatment is extremely important
- Insulin is started as an i.v. infusion at around 0.1 u/kg/h and adjusted according to a sliding scale insulin (see Table 24). Capillary glucose should be checked hourly and i.v. insulin should only be stopped once the urine is ketone-free and the patient is clinically well
- This is very rarely given; only in cases of severe acidosis not responding to conventional treatment. Bicarbonate administration should only be done in an intensive care setting and after the involvement of a senior colleague with expertise in DKA management
- Precipitating cause(s)
- Around two-thirds of DKA cases are due to newly diagnosed type 1 diabetes or compliance problems/errors in insulin administration in known diabetic patients. In around one-third, DKA is due to other causes such as infection or myocardial infarction and these conditions should be treated appropriately.
- Other measures
- Some recommend low-dose heparin to prevent thromboembolism, but there is no clear evidence to support this practice, which is perhaps unnecessary unless other risk factors exist (prolonged immobility)
- A nasogastric tube may need to be inserted in those with severe vomiting or in those with impaired conscious level
- Capillary glucose should be checked hourly and blood samples should be taken every 2-4 h for U&Es, bicarbonate and venous glucose. The clinical condition of the patient should be regularly assessed. The management of DKA is summarized in Fig. 37.
Hyperosmolar non-ketotic hyperglycemia (HONK)
- This is characterized by the gradual development of hyperglycemia
- Mortality is very high approaching 50% in these patients
- Causes include:
- Omission of oral hypoglycemic agents or insulin (rarely it can be the first presentation of T2DM)
- Vascular events such as myocardial infarction and stroke
- Insidious onset of symptoms with ill health for weeks
- History of osmotic symptoms
- Symptoms of precipitating cause
- Glucose levels: these are usually very high
- U&Es, this usually shows high urea and creatinine levels, with a relatively larger impairment in urea (prerenal renal failure)
- There is no acidosis in these patients (unless it is due to the precipitating cause)
- Investigations for causes of HONK are mandatory (CXR, ECG, urinalysis, CT head if necessary)
- Blood and urine cultures should be requested in all patients with HONK
Treatment of HONK is broadly similar to that of DKA, but with some differences:
- Fluid replacement should be more gentle in HONK compared with DKA as these are older patients, who are more prone to heart failure with aggressive fluid replacement. In difficult cases, a central line should be inserted to help guide the appropriate fluid replacement.
- In uncomplicated HONK, potassium levels do not drop particularly quickly due to the absence of acidosis, but this should still be carefully monitored.
- Despite the very high glucose levels in these patients, insulin requirements in HONK are modest and, therefore, insulin should be given at 0.5–2 units/h aiming for a gradual drop in blood sugar (around 5 mmol/L/h).
- This is not needed in uncomplicated hyperosmolar hyperglycemia as the patient is not usually acidotic.
- Precipitating cause(s)
- Infection is the most common precipitating cause and, therefore, antibiotic cover must be started after appropriate cultures.
- Other measures
- Due to high osmolarity and dehydration, thrombotic complications are very common and, therefore, all patients should be covered with prophylactic unfractionated heparin.
- This should be done regularly with blood samples taken every 2 h in the first 6–8 hours to assess response to treatment.
- Hypoglycemia in diabetes patients may be secondary to oral hypoglycemic agents (usually sulphonylurea) or insulin
- All patients with diabetes should be warned regarding hypoglycemic symptoms:
- Tremor and sweating
- Patients with hypoglycemic symptoms should have their capillary glucose checked to confirm the diagnosis before initiating treatment
- Patients with frequent hypoglycemic episodes may lose their warning symptoms, in which case plasma glucose should be kept slightly elevated for 2–3 weeks in order to regain the hypoglycemic symptoms
- Patient conscious:
- Oral glucose or sucrose (any fluid high in sugar content would do, such as Lucozade)
- Patient unconscious
- Intravenous glucose
- Intramuscular or s.c. glucagons (this loses its effect with repeated dosing)
Investigations for chronic complications have been discussed above and only treatment is covered here.
Treatment of microvascular disease
- Ensure good glucose control
- Ensure good blood pressure control
- Laser therapy in advanced stages
- Early nephropathy (microalbuminuria): angiotensin converting enzyme inhibitors or angiotensin receptor blockers (sometimes a combination of the two) can be used to delay/prevent further deterioration in renal function. Also, need to ensure good glycemia and blood pressure control
- Advanced nephropathy (macroalbuminuria or raised creatinine): similar measures to those above can be used. Potassium and renal function should be frequently monitored and referral to a renal physician considered
- End-stage renal disease: dialysis and renal transplant
- Painless peripheral neuropathy: repeated foot examination by patient and/or cohabiting relative and regular chiropody
- Charcot’s arthropathy: immobilization of the joint is important to prevent further damage, and bisphosphonate may be of help
- Painful peripheral neuropathy: difficult to treat and most only have a partial response. Some of the agents used include: tricyclic antidepressants, capsaicin, anticonvulsants (phenytoin, gabapentin) and opiates
- Autonomic neuropathy: postural drop in blood pressure can be treated with mechanical measures (wearing support stockings, sleeping with the head elevated) and fludrocortisone (monitor for hypertension and hypernatremia). Gastrointestinal symptoms such as vomiting can be treated with metoclopramide, domperidone and erythromycin, and diarrhea with loperamide
- Sexual dysfunction: rule out an endocrine cause. Phosphodiesterase inhibitors, such as sildenafil, may help. Ensure good diabetes and blood pressure control.
Treatment of macrovascular complications
- The majority of patients with diabetes die of cardiovascular disease
- The risk of myocardial infarction in subjects with T2DM diabetes is similar to those without diabetes and a previous cardiac event
- Patients with diabetes and established cardiovascular disease are treated similarly to high risk non-diabetic individuals with known cardiovascular disease
- Diabetes patients should, therefore, be treated with:
- Lipid lowering agents such as statins (simvastatin, atorvastatin, rosuvastatin) to lower cholesterol levels and reduce cardiovascular events.
- Other agents can also be used such as ezetimibe, which inhibits cholesterol absorption in the gut, and fibrates, which lower cholesterol levels but their main effect is on triglycerides
- Angiotensin converting enzyme inhibitors (ACEI)
- Antiplatelet agents (aspirin or clopidogrel)
- Agents to maintain strict blood pressure control
- Treat microalbuminuria, which is a cardiovascular risk
Ramzi Ajjan, MRCP, Med Sci, PhD, Senior Lecturer and Honorary Consultant in Diabetes and Endocrinology, Department of Health Clinician Scientist, The LIGHT Laboratories, University of Leeds, Leeds, UK
A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.
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