Diabetes Risk Factors
- Physical inactivity.
- First-degree relative with diabetes.
- Women who delivered a baby >9 lb or were diagnosed with GDM.
- High-risk race/ethnicity.
- A1C ≥5.7%, Impaired Glucose Tolerance (IGT), or Impaired Fasting Glucose (IFG) on previous testing.
- Hypertension (≥140/90 mm Hg or on therapy).
- HDL-C <35 mg/dL ± TG >250 mg/dL.
Initial therapy in most patients with type 2 diabetes should begin with diet, weight reduction, exercise, and metformin unless contraindications exist. The benefits of metformin include its ability to lower A1C by 1–2% and Fasting Plasma Glucose (FPG) by 60–70 mg/dl. Other advantages of metformin over other oral agents include no hypoglycemia when used as monotherapy, no weight gain, possible modest weight loss, and availability as a generic agent, providing a cost advantage.
If patients still are not at a goal A1C of < 7% after maximal metformin (2550mg) and lifestyle changes for 3 months, further agents can be added to metformin include sulfonylureas, meglitinides, thiazolidinediones (TZDs), acarbose, GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors.
- Sulfonylureas have been in existence since the 1950s. They are usually considered as second-line therapy after metformin because they are effective, can lower A1C by 1–2%. Sulfonylureas can cause hypoglycemia, especially in patients who are elderly or have renal insufficiency. They also result in weight gain of 3 kg on average over 3–4 years, and their efficacy decreases over time. Glipizide (Minidiab) is the sulfonylurea of choice because it has a shorter duration of action and inactive metabolites, making hypoglycemia less likely, especially in the setting of renal insufficiency.
- Meglitinides (Novonorm, Starlix): If hypoglycemia is a concern, however, especially in elderly patients or those who have renal insufficiency, meglitinides (repaglinide and nateglinide) are an option. Meglitinides are nonsulfonylurea insulin secretagogues. The advantages of meglitinides are that they are shorter acting, with a half-life of about 1 hour, thus lowering the risk of hypoglycemia. These medications are taken from 0 to 30 minutes before meals and act mainly to reduce first-phase insulin secretion and postprandial glucose (PPG) levels. The disadvantages of these medications are their frequent dosing (three times daily) and their limited efficacy. These drugs mainly lower only PPG and lower A1C by only 0.5–1% compared to A1C-lowering of 1–2% with metformin or the sulfonylureas. Therefore, these drugs may play a role in the treatment of type 2 diabetes in patients who are at high risk for hypoglycemia, have renal insufficiency, and have only mildly elevated A1C.
- Thiazolidinedione (Pioglitazone: Actos) is another agent that could be used in conjunction with metformin or other oral therapies to achieve a goal A1C of < 7%. This drug is a selective agonist for peroxisome proliferator–activated receptor-γ, a superfamily of nuclear receptors that function as ligand-activated transcription factors. It modulates the transcription of the insulin-sensitive genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues; increases the expense of insulin-dependent glucose; decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated hemoglobin in the bloodstream. Because it acts on gene expression at the nuclear level, onset of action may not occur for 4–12 weeks.
TZDs decrease insulin resistance, FPG, insulin, and free fatty acids. TZDs can lower A1C by 1–1.5% and do not result in any hypoglycemia when used as monotherapy. Pioglitazone has an added benefit on HDL cholesterol and triglyceride levels.
Despite these beneficial effects, TZDs have fallen out of favor recently for several reasons. Aside from the known side effects of weight gain of 2–20 lb, edema, and potential elevation of transaminases, concerns regarding increased cardiovascular risk and cancer have surfaced.
Pioglitazone has been found to be associated with bladder tumors and has been withdrawn in some countries.
DPP-4 inhibitors can be considered as monotherapy in patients who are intolerant of or have contraindications to metformin, sulfonylureas, or thiazolidinediones, such as patients with chronic kidney disease or who are at particularly high risk for hypoglycemia.
 Anti-diabetic Medication
|Diabetes (Antidiabetic drugs)|
|Insulin Secretagogues (drugs that increase insulin release from pancreas)||Sulfonylureas||Chlorpropamide (Diabinese) • Glibenclamide or Glyburide (Diabeta, Micronase, Glynase, Daonil, Euglycon) • Gliclazide (Diamicron) • Glimepiride (Amaryl, Solosa) • Glipizide (Glucotrol, Minidiab, Glibenese) • Gliquidone (Glurenorm)|
|Meglitinides||Repaglinide (Prandin, Novonorm) • Nateglinide (Starlix)|
|Dipeptidyl peptidase-4 inhibitors||Linagliptin (Trajenta) • Saxagliptin (Onglyza) • Sitagliptin (Januvia) • Vildagliptin (Galvus)|
|Incretin mimetics (GLP-1 agonists and analogs)||Exenatide (Byetta) • Liraglutide (Victoza) • Lixisenatide (Lyxumia) • Dulaglutide (Trulicity)|
|Insulin Sensitizers (drugs that decrease insulin resistance)|
|Drugs that retard the digestion and absorption of carbohydrates in the small intestine|
|Alpha-glucosidase inhibitors||Acarbose (Glucobay, Precose)|
|Drugs that reduce glucose absorption in the kidney and increase glucose excretion in the urine|
|Sodium glucose cotransporter 2 (SGLT2) inhibitors||Canagliflozin (Invokana) • Dapagliflozin (Farxiga) • Empagliflozin (Jardiance, Glyxambi, Synjardi)|
|Insulin and insulin analogs|
|Intermediate acting insulins||Insulin lispro protamine (Humalog BASAL) • Isophane human insulin : Human insulin protamine (NPH) (Humulin I, Protaphane)|
|Long-acting insulins||Insulin detemir (Levemir) • Insulin glargine (Lantus)|
|Fast-acting insulins||Regular insulin : Insulin (Human recombinant) (Actrapid, Humulin R)|
|Ultra-rapid-acting insulins||Insulin aspart (Novorapid) • Insulin glulisine (Apidra) • Insulin lispro (Humalog)|
|Premixed insulin (ultra-rapid-acting + intermediate acting||Insulin aspart / Insulin aspart protamine (Novomix) • Insulin lispro / Insulin lispro protamine (Humalog Mix)|
|Sulfonylurea + Metformin||Glibenclamide / Metformin (Bieuglicon M, Diaglimet, Glibomet, Gliconorm, Glicorest, Suguan M)|
|Thiazolidinedione + Metformin||Pioglitazone / Metformin (Competact, Glubrava)|
|Thiazolidinedione + Sulfonylurea||Pioglitazone / Glimepiride (Tandemact)|
|Dipeptidyl peptidase-4 inhibitors + Metformin||Linagliptin / Metformin (Jentadueto) • Sitagliptin / Metformin (Efficib, Janumet, Velmetia) • Vildagliptin / Metformin (Eucreas)|