Diabetes Mellitus – Diagnosis and Treatment

Diabetes mellitus (DM) is a very prevalent disease (median prevalence ~ 8% in USA) that leads to significant morbidity and mortality. DM can be classified in 2 types: Type 1 (due to beta cell destruction that leads to absolute insulin deficiency) or Type 2 (insulin resistance that may or may not be accompanied by relative insulin deficiency). Type 2 DM is the most common (90%) type in USA.

The risk factors for type 2 diabetes include: age (>=45 years), overweight, DM in a first-degree relative, sedentary lifestyle, history of gestational DM, dyslipidemia, impaired glucose tolerance, polycystic ovary syndrome and history of vascular disease.

CLINICAL SIGNS AND SYMPTOMS:

Acutely, hyperglycemia due to uncontrolled diabetes can be life threatening when it presents as diabetic ketoacidosis or hyperosmolar hyperglycemic state (both discussed in another article).

Most individuals, however, can be hyperglycemic and fairly asymptomatic for a long time, which may delay the diagnosis of DM. The symptomatic patients may complain of fatigue, nocturia, polyuria, polydipsia and sometimes weight loss. Late in the disease course, patients may present with symptoms due to chronic complications of DM like neuropathy, foot ulcers, visual problems or macrovascular complications (CAD among others).

DIAGNOSIS:

Any of the following is diagnostic of diabetes:

Hemoglobin A1C ≥6.5
Fasting plasma glucose (FPG) ≥126mg/dL (7mmol/L) (fasting 8hr)
Two-hour plasma glucose ≥200mg/dL (11.1mmol/L) during a 75g oral glucose tolerance test (OGTT).
A patient with symptoms of hyperglycemia or with DKA/HHS with a random plasma glucose ≥200mg/dL

If the patient does not have symptoms and does not have high blood glucose when examined, it may be relevant to repeat tests 1-3 before establishing the diagnosis of DM.

Some patients are at increased risk of cardiovascular complications even before they meet criteria for DM. Such patients include people with FPG between 100 and 125mg/dL [impaired fasting glucose (IFG)], with a 2hour 75g OGTT between 140-199mg/dL [impaired glucose tolerance (IPG)], and patients with hemoglobin A1C between 5.7 and 6.5.

In addition to glucose tests and hemoglobin A1C, it is important to order the following tests for recently diagnosed diabetic patients:

Fasting lipid profile
Liver function tests
Kidney function tests
Urine albumin excretion
TSH (in type 1 DM)

CHRONIC COMPLICATIONS OF DIABETES MELLITUS:

DM is not problematic only because of its acute complications, but mostly because of its chronic and often incapacitating complications. These complications are:

Eye complications:

Diabetic retinopathy can occur. It may be visible as early as 3 years after DM, with 80% of patients being affected after 20 years of DM. Untreated, it can lead to blindness. Cataracts and glaucoma are also more prevalent in patients with DM.

Nephropathy:

Diabetic nephropathy can manifest as albuminuria, hematuria or chronic kidney disease. The major histologic changes in the glomeruli include mesangial expansion, glomerular basement membrane thickening, podocyte injury, and glomerular sclerosis.

An increase in urinary protein is the earliest clinical manifestation of diabetic nephropathy. Albuminuria between 30mg/day and 300mg/day is called moderately increased albuminuria (previously known as microalbuminuria) and it is, by itself, a risk for cardiovascular disease and may indicate diabetic nephropathy. Albuminuria values over 300mg/day, known as severely increased albuminuria (previously known as macroalbuminuria) is only present when diabetic nephropathy is already stablished. Moderately increased albuminuria starts to develop after 5 to 15 years of DM and can affect up to 50% of patients after 30 years. Severely increased albuminuria is usually seen after 10 years of disease.

Since 24h urine often cannot be obtained properly in order to measure the total albuminuria/day, the urine albumin to creatinine ratio (UATC) can be obtained. An UATC value from 30mg/g to 300mg/g of creatinine corresponds to 30mg to 300mg/day of albuminuria.

Patients should have their UATC ratio measured yearly.

Despite the high prevalence of albuminuria, the degree of albuminuria is not necessarily linked to disease progression (GFR decrease) in patients with diabetic nephropathy.

It is also important to point that most patients with diabetic nephropathy will already show signs of diabetic retinopathy.

Neuropathy:

The prevalence of neuropathy is ~ 40% after 10 years of DM. The neuropathy can manifest in many ways: symmetric polyneuropathy, autonomic neuropathy, radiculopathy, mononeuropathies, and mononeuropathy multiplex. The most common peripheral manifestation is a distal symmetrical sensory polyneuropathy. Some patients have only sensory loss, but many also have pain and paresthesias. Reduced or absent ankle reflexes are usually present.

The diabetic autonomic neuropathy of the GI tract is also very prevalent and can present as GERD, gastroparesis or diabetic diarrhea. Gastroparesis is the most common condition that the patients complain about because it causes bloating, nausea, vomiting, and pain. Scintigraphic gastric emptying can be used to confirm the diagnosis.

Foot ulcers:

Due to neuropathy and vasculopathy, patients are more likely to develop diabetic foot ulcers which can cause significant morbidity and even mortality since they are prone to infection/

Macrovascular complications, mainly atherosclerosis can affect, among other arteries, the aorta, carotids, coronary arteries and arteries of the inferior limbs.

TREATMENT:

The treatment of acute diabetes complications (DKA and HHS) is discussed in another article.

Regarding the chronic management, the role of lifestyle intervention is vital. Lifestyle intervention consists of dietary modification, exercise and weight reduction, and can reduce glucose levels.

For most patients pharmacological therapy should be initiated together with the lifestyle modifications. Patients with hemoglobin A1C higher than 9-9.5% should be started on insulin right away. For the others, there is a wide variety of medications that can be used for type 2 DM (type 1 DM should use insulin since the beginning of treatment).

Metformin is the first choice agent that has to be started (500mg qDay or BID with meals, can be increased slowly –a tablet per week, to up to 850mg TID). It inhibits gluconeogenesis in the liver and increases insulin-mediated glucose utilization in peripheral tissues. Can be used in patients with mild CKD but it is contraindicated in those with GFR <30mL/min. It may cause lactic acidosis, particularly in prone individuals (those with liver disease, kidney disease, hypoperfusion/shock). It may also cause vitamin B12 deficiency.

If metformin is not successful alone [cannot reach, after at least three months of treatment, A1C <7% (that relates to a FPG between 80-130mg/dL or postprandial glucose less than 180mg/dL)], a second oral or injectable agent can be added.

Sulfonylureas (such as glipizide 2.5 to 10mg PO before breakfast or before breakfast and evening meal, start with low dose) can be used. They act by directly stimulating insulin secretion and, therefore, have a higher risk of causing hypoglycemia (particularly in patients with CKD). They also often cause weight gain.

Meglitinides (such as repaglinide – PRANDIN – 0.5 to 2mg PO before each meal, start with low dose) can be used in patients that cannot tolerate metformin or sulfonylureas for any reason. They also increase insulin secretion. They often cause weight gain.

Thiazolidinediones (such as pioglitazone – ACTOS – 15 to 45mg PO qDay, start with low dose) can also be considered for patients that do not tolerate metformin and sulfonylureas or meglitinides. They act on the peroxisome proliferator-activated receptors (PPARs) of cells and increase the sensitivity to insulin of adipose tissues, muscle and liver. The main issues with this drug are: weight gain, fluid retention, risk of heart failure, decreased bone density and increased risk of bladder cancer.

GLP-1 receptor agonists (such as liraglutide – VICTOZA – 0.6mg SC qDay for one week that can be increased to 1.2mg qDay after 1 week and 1.8mg qDay after another week if needed) may be useful in patients that need extra weight loss, that have a prior history of infarction or stroke, that are prone to hypoglycemia and for whom cost is not an issue. GLP-1 receptor agonists can be even used in patients taking 2 other oral drugs if they are already close to the treatment goal. They act as incretines by stimulating glucose-dependent insulin release in the pancreatic islets. Gastrointestinal effects may occur. An increased risk of pancreatitis may be present.

DPP4-inhibitors (such as sitagliptin – JANUVIA – 100mg PO qDay) act by inhibiting the enzyme that deactivates the GLP-1, therefore affecting glucose regulation. They may be considered as monotherapy in patients with type 2 diabetes who are intolerant or have contraindications to metformin, sulfonylureas, or thiazolidinediones, despite their lower effect in glucose reduction, or as a second or third agent. Dose adjustments may be required in patients with CKD (except for linagliptin). A higher risk of heart failure may be present.

SGLT-2 inhibitors (such as empagliflozin – JARDIANCE – 10 to 25mg PO qDay, start with low dose) act in the kidneys` proximal tubule, blocking the reabsorption of glucose and stimulating glycosuria. They may be useful as a third agent in patients that cannot take GLP-1 agonists or as a second agent in patients that do not want injections. Patients with eGFR <30 mL/minute/1.73 m2 should not use this class of medication. They may also be beneficial for patients with cardiovascular disease. Candida infections and hypotension are possible side effects.

Alpha-glucosidase inhibitors (such as acarbose – PRECOSE – 25-100mg PO with every meal) slow the absorption of glucose, reducing postprandial glycemia. Their efficacy is lower than most of the other agents mentioned above and their main side effect is diarrhea.

Pramlintide (SYMLIN, dose: 15mcg prior major meals that may be increased every 3 days in 15mcg increments until total of 60mcg/meal) is an amylin analogue that slows gastric emptying, therefore reducing postprandial rises in blood glucose. It is approved for patients that are also taking prandial insulin. It promotes weight loss, but it is inconvenient due to the need of three injections every day. It is also still expensive.

Patients that do not respond to one, two or even three of the above mentioned drugs will need insulin.

Below you find a flowchart (from American Diabetes Association: STANDARDS OF MEDICAL CARE IN DIABETES—2017. Diabetes Care. January 2017 Volume 40, Supplement 1.)

Reproduction of: American Diabetes Association: STANDARDS OF MEDICAL CARE IN DIABETES—2017. Diabetes Care. January 2017 Volume 40, Supplement 1.

INSULIN THERAPY:

All patients with type 1 DM should be started on insulin. The details about insulin treatment in type 1 diabetes will be discussed at the end.

For type 2 DM patients, insulin should be considered on patients with:

Hemoglobin A1C >9.5 percent (80.3 mmol/mol)
FPG >250mg/dL (13.9mmol/L)
Random glucose >=300mg/dL
Ketonuria
Weight loss
Dual or Triple oral or SC agent therapy that is not reaching the target goal
ESRD on Hemodialysis

Insulin regimen for type 2 DM (with or without oral agents): Start with 10U (or 0.2U/kg) of intermediate or long acting insulin at night (NPH or detemir) or long-acting insulin in the morning (glargine). FBG should be measured every day, and if it is above 130 mg/dL the insulin should be increased by 2-4U every 3 days until the target glucose range is reached (80-130mg/dL).

The goal of the treatment is to reach normal or near-normal glycemia (A1C value of ≤7.0% in general, with lower values -<6.5 or 6.0% for younger patients and <8.0% for older patients). The hemoglobin A1C should be checked at least twice a year.

If after 3 months hemoglobin A1C is >= 7%, additional glucose monitoring done before lunch, dinner and bed becomes relevant. The patient may need bolus of short or rapid acting insulin according to the glucose measured. If the pre-lunch glucose is too high, bolus of rapid-acting insulin (4-6U) should be added at breakfast. If the pre-dinner glucose is high, intermediate-acting insulin should be added at breakfast or rapid acting insulin at lunch.

Insulin dosing for type 1 DM is a little more complex and has to include basal insulin once or twice a day OR continuous rapid insulin via pump PLUS preprandial boluses of short or rapid acting insulin. Most patients can be started with a total daily dose of 0.2 to 0.4 units of insulin/kg/day. This dose may be increased and most patients will need 0.7U/kg/day for proper control. Half of this total daily dose should be given as basal insulin (2/3 NPH at the morning and 1/3 at night OR long-acting insulin in a single dose – glargine or detemir – at morning or night) and the other half should be given as short or rapid action insulin before meals.

If possible, patients receiving insulin therapy should be managed by an endocrinologist.

MANAGEMENT OF ASSOCIATED CONDITIONS:

Ophthalmological complications:

All DM patients should have ophthalmologic examination every two years or every year if retinopathy is already present.

Kidney complications:

Patients with moderately increased albuminuria should be monitored. If the values start to increase they should receive ACE inhibitors or ARBs to reduce the risk of progression. Control of glucose and BP is also important to prevent progression. Patients should have their UATC ratio measured yearly.

Cardiovascular and Macrovascular risks:

Patients with high risk of cardiovascular disease or established CVD should receive aspirin for primary and secondary prevention, respectively. Managing hypertension, smoking and dyslipidemia when present is also very important to reduce the cardiovascular risk of the patient. Assessing the peripheral arteries with ABI or Doppler and carotid arteries with Doppler may be necessary depending on the case and individual risk.

Neuropathy:

Patients should be screened [pinprick, temperature, vibration (128Hz tuning fork) and pressure (10g monofilament] at the time of diagnosis (type 2 DM) or 5 years after diagnosis (type 1 DM). Oral drugs for painful diabetic neuropathy include pregabalin (LYRICA – 50mg PO q12hr to 100mg q8hr), tricyclic antidepressants, duloxetine, venlafaxine, and valproate. Capsaicin cream (0.075% QID) can also be used.

Gastroparesis can be managed with glycemic control, dietary modification (small, frequent meals), hydration and prokinetics (metoclopramide, domperidone, erythromycin and cisapride). In patients with severe symptoms that do not respond to dietary modifications and pharmacological therapy, decompressive gastrostomy may be needed.

Diabetic foot:

Perform a comprehensive foot examination annually, including inspection of the skin and palpation of joints and pulses. Test the sensation using a monofilament. Give preventive advice to the patient: smoking cessation, avoid walking barefoot, careful control of water temperatures, do not use tight shoes, look at the feet daily.

As you can see, the chronic management of diabetes and its complications is complex and can involve multiple professionals such as primary care doctors, neurologists, endocrinologists, nephrologists, vascular surgeons and podiatrists.

REFERENCES & FURTHER READINGS: