Medical Treatment of Diabetes Mellitus

Self-monitoring of blood glucose

For patients with type 1 DM and patients with insulin-dependent type 2 DM, self-monitoring of blood glucose allows patients to adjust insulin dosing to prevent hypoglycemia and hyperglycemia.^2,5–7 The American Diabetes Association (ADA) guidelines recommend that patients with type 1 DM self-monitor their glucose:

• Before eating

• At bedtime

• Before exercise

• If hypoglycemia is suspected

• Until hypoglycemia is corrected

• Postprandially upon occasion

• And before critical tasks (ie, driving).⁸

Patients should be educated about how to use real-time blood glucose values to adjust their food intake and medical therapy.

It is commonly recommended that patients with type 2 DM self-monitor their blood glucose levels, but the evidence to support the effectiveness of this practice is inconclusive. Initial studies showed reductions in HbA1c with self-monitoring; however, the inclusion of beneficial health behaviors such as diet and exercise in the analyses makes it difficult to assess the effectiveness of self-monitor blood glucose alone.^2,9

The ADA recommends that nonpregnant adults maintain blood glucose levels of 80 mg/dL to 130 mg/dL preprandial and less than 180 mg/dL postprandial.⁸ The blood glucose goals for patients with gestational diabetes are 95 mg/dL or less pre-prandial and either 140 mg/dL or less 1-hour postprandial or 120 mg/dL or less 2-hours postprandial.

HbA1c

HbA1c tests reflect the mean blood glucose values over a 3-month period and can predict patients’ risk of microvascular complications.^10,11 The ADA recommends that patients with stable glycemic control have an HbA1c test at least twice a year. Quarterly HbA1c testing is suggested for patients with a recent change in therapy or for patients not meeting their glycemic goals.⁸

Measurement of HbA1c is influenced by the red blood cell turnover rate; therefore, anemia, transfusions, and hemoglobinopathies can cause inaccurate test values. The ADA recommends that nonpregnant adults maintain HbA1c levels near 7%. For patients with diabetes who become pregnant, the goal is HbA1c levels less than 6.0%.⁸ The ADA also recommends that select patients, especially those with a long life expectancy and little comorbidity, adopt glycemic targets near normal levels (HbA1c < 6.5%), providing the target can be achieved without significant hypoglycemia.⁸

Insulin sensitizers

Insulin secretagogues

Insulin secretagogues such as sulfonylureas and glinides stimulate secretion of insulin from the pancreas regardless of the ambient glucose concentration.

Alpha-glucosidase inhibitors

Alpha-glucosidase inhibitors such as acarbose, miglitol, and voglibose block the enzyme alpha-glucosidase in the cells of the brush border of the small intestine, which delays absorption of carbohydrates. Alpha-glucosidase inhibitors primarily affect postprandial hyperglycemia without causing hypoglycemia. Abdominal cramps, bloating, flatulence, and diarrhea are the most common side effects. Use of alpha-glucosidase inhibitors should be avoided in patients with severe hepatic or renal impairment. Dosing is prior to carbohydrate-containing meals.^8,20

Incretin-based therapies

Therapies that target the incretin hormones to increase insulin production include glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors.

SLGT-2 inhibitors

SGLT-2 inhibitors include canagliflozin, dapagliflozin, and empagliflozin and are the newest group of antidiabetic medications. These medications inhibit glucose reabsorption in proximal tubule of the kidney leading to glycosuria, which lowers the blood glucose concentration, lowers blood pressure, and leads to some weight loss. Empagliflozin was shown to be cardioprotective in some patients.²³

SGLT-2 inhibitors are given once a day in the morning and the primary side effects are polyuria and genital yeast infections. These medications are contraindicated in patients with severe end-stage renal disease and those who are on dialysis.^8,24

Pramlintide (amylinomimetics)

Pramlintide, an amylinomimetic, is a synthetic drug that acts like amylin, a hormone secreted by beta cells that suppresses glucagon secretion, slows gastric emptying, and suppresses appetite through central pathways. Pramlintide acts primarily on postprandial blood glucose levels.

The side effects of pramlintide are gastrointestinal complaints, especially nausea. Currently, pramlintide is approved only as an adjunctive therapy with insulin, and it can be used in patients with type 1 DM or type 2 DM. The dose for type 1 DM is 15 μg before each meal subcutaneously, and for type 2 DM it is generally 60 μg before meals.²⁵

Insulin

Insulin and insulin analogues remain the most direct method of reducing hyperglycemia. There is no upper limit in dosing for therapeutic effect, so it can be used to bring any HbA1c down to near-normal levels. Other benefits of insulin include reducing triglyceride levels and increasing high-density lipoprotein cholesterol.

Hypoglycemia is a concern with use of insulin, and studies have shown that episodes for which the patient required assistance due to the hypoglycemia occurred between 1 and 3 times per 100 patient-years.¹³ Weight gain can occur after initiation of insulin therapy, and patients typically gain 2 kg to 4 kg.⁸

Basal-bolus therapy

The basal-bolus regimen combines a long-acting agent for basal-insulin needs that is used once or twice daily and a rapid-acting agent for prandial coverage. Traditionally, 50% of the total daily dose is given as basal insulin (detemir, glargine, degludec) and the remaining dose as prandial insulin divided equally before meals (regular, lispro, glulisine, or aspart).

The meal dose of insulin can be fixed, but it is better to determine the dose based on the carbohydrate content of the meal. To do so, patients should be educated about carbohydrate counting and the dose of insulin required to cover the carbohydrate content of the meal. Consultation with a diabetes educator is needed for patients to effectively dose insulin based on the carbohydrate content of meals. Patients are also provided with a sliding scale of supplemental insulin to use as a third component of therapy when the blood glucose level is higher than desired.

The starting total daily insulin dose is typically 0.3 U/kg for patients with type 1 DM and 0.5 U/kg for patients with type 2 DM if no other medications are used. The ADA recommends adding basal insulin at 0.1 to 0.2 U/kg for patients with type 2 DM once they need it. The key to good glycemic control is self-monitoring of blood glucose by the patient and frequent adjustment of the regimen until control is achieved.⁸

Insulin-pump therapy

The insulin pump allows the use of different basal insulin rates at different periods of the day for greater flexibility with daily dosing. The insulin pump also allows administration of the meal bolus as a single discrete bolus or as an extended bolus (square bolus) over a certain period of time, which allows a better match between insulin delivery and glucose absorption from the meal in patients with abnormalities of gastric emptying. Use of an insulin pump should be considered in the following patients:

• Patients unable to achieve target goals with basal-bolus regimens

• Patients with frequent hypoglycemia, dawn phenomenon, or brittle diabetes

• Pregnant patients

• Patients with insulin sensitivity or those requiring more intense monitoring due to complications.

Recently, continuous glucose monitors have been developed that measure interstitial glucose levels. Continuous glucose monitoring has been shown to lower HbA1c in adult patients with type 1 DM.²⁹

Gestational diabetes

In patients with gestational diabetes, insulin therapy is indicated when exercise and nutritional therapy are ineffective in controlling prandial and fasting blood glucose levels. Basal therapy alone may be sufficient, but a basal-bolus regimen is often required.⁸