Tratment of Diabetes Mellitus includes Injectables (Insulins & non-insulins) and Oral Hypoglycemic Agents (OHA). OHA are discussed here.
Insulin secretagogues - agents that affect the ATP-sensitive K+ Channel
Insulin secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell, therefore used in type 2 DM of relatively recent onset (<5 years) who have residual endogenous insulin production.
- Sulfonylureas: Weight gain because of increased insulin levels and improvement in glycemic control.
- First generation sulfonylureas include acetohexamide, carbutamide, chlorpropamide, glycyclamide (tolhexamide), metahexamide, tolazamide and tolbutamide.
- Second generation drugs: glibenclamide (glyburide), glibornuride, gliclazide, glipizide, gliquidone, glisoxepide and glyclopyramide
- Third generation drugs include glimepiride, although it is sometimes considered second-generation
- Non-sulfonylureas Insulin secretagogues: Repaglinide, nateglinide, and mitiglinide are not sulfonylureas but also interact with the ATP-sensitive potassium channel. Because of their short half-life, these agents are given with each meal or immediately before meal.
Insulin secretagogues that enhance GLP-1 receptor signaling
- Glucagon-like peptide (GLP-1) analogues: Also known as Incretins. They heighten glucose-dependent insulin secretion, reduce glucagon secretion, promote weight loss, slow gastric emptying, decrease appetite, and promote beta-cell regeneration. For details,
- DPP-IV inhibitors (Gliptins): They inhibit degradation of native GLP-1 and thus enhance the incretin effect. No hypoglycemia or wt. gain. Preferred for PP-Hyperglycemia. Inhibit the breakdown of glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP) leading to an increase in plasma concentrations of the same.
- Sitagliptin Brand: Januvia (Merck) 100mg Tab: Absorption is unaffected by food. For moderate renal impairment (creatinine clearance 30 to 50 mL/min) the dose is 50 mg/day and for severe renal impairment (creatinine clearance is <30 mL/min) the dose is 25 mg/day. For hepatic impairment Child grade C Sitagliptin use in not recommended.
- Vildagliptin Brands: Galvus (Novartis), Jalra (USV) 50mg BD: Absorption is unaffected by food. No dosage adjustment in liver disease although caution in Child-C. In patients with renal impairment no dose adjustment is required for mild renal insufficiency ,for moderate renal insufficiency dose is 50 mg OD.
- Saxagliptin Brand: Onglyza (AstraZeneca) 5mg, 2.5mg OD: Absorption is unaffected by food. Approximately 75% of the total dose of Saxagliptin is renally excreted, while 22% is eliminated in the feces. No dose adjustment in mild RF, while One-half the usual dose i.e. 2.5 mg OD is recommended for moderate to severe renal failure (CrCl <50 mL/min).
- Linagliptin Brand: Trajenta (Boehringer Ingelheim) 5mg OD: Linagliptin is predominantly excreted by the enterohepatic system (84%), and only 5% eliminated by urine. Therefore safe in renal failure. It improves in wound re-epithelialization.
- Teneligliptin 20mg OD, Brands: Tendia, Teniva, Tenlimac, Tenginow.
- Gemigliptin Brand: Zemiglo 50mg (Sanofi India)
- Anagliptin (approved in Japan in 2012)
- Alogliptin (FDA approved 2013)
- Trelagliptin (approved for use in Japan in 2015)
- Omarigliptin 25mg: Approved in Japan in 2015,developed by Merck, research showed that omarigliptin can be used as once-weekly treatment and generally well-tolerated throughout the base and extension studies.
- Evogliptin (approved for use in South Korea)
- Gosogliptin (approved for use in Russia)
- Dutogliptin (being developed by Phenomix Corporation), Phase III
Alfa-Glucosidase inhibitors
Alfa-Glucosidase inhibitors reduce postprandial hyperglycemia by delaying glucose absorption. They do not affect glucose utilization or insulin secretion. Should not be used in IBD, gastroparesis, or a serum creatinine >2 mg/dL. Reduces the postprandial glucose rise even in individuals with type 1 DM.
Thiazolidinediones
Thiazolidinediones reduce insulin resistance by binding to the PPAR-gamma (peroxisome proliferator activated receptor - Gamma) nuclear receptor (which forms a heterodimer with the retinoid X receptor). Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance. They are associated with weight gain (2-3 kg), mild increase in plasma volume. Peripheral edema and CHF are more common with these agents. These agents are contraindicated in liver disease or CHF (class III or IV).
- Rosiglitazone raises LDL, HDL and triglycerides slightly.
- Pioglitazone raises HDL to a greater degree and LDL a lesser degree but lowers triglycerides.
Dual PPAR agonists
Inhibition of PPAR alfa-agonists (Fibrates) lowers plasma triglycerides and VLDL particles and increases HDL cholesterol while PPAR gamma-agonists (thiazolidinediones) influence free fatty acid flux and reduce insulin resistance and blood glucose levels. The PPAR (alfa/gamma) dual agonism addresses both insulin resistance (the inability of tissues to utilize insulin efficiently for the uptake of glucose) and key aspects of the dyslipidemia that contribute to the high risk of cardiovascular disease (CVD) in diabetics.
Aleglitazar, a new balanced dual PPAR agonist, reduces hyperglycemia and improves the levels of HbA1C, HDL-C, LDL, and triglycerides with minimal PPAR-related adverse effects.
Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors
They act by increasing urinary glucose excretion by inhibiting SGLT2 co-transporter in Proximal Convoluted Tubules of kidneys. Glucose-lowering effect is insulin independent and not related to changes in insulin sensitivity or secretion. Brand: Canagliflozin (Invokana 100)
Glucokinase activators
Glucokinase (also called hexokinase IV or D) owing to its glucose sensor role in pancreatic beta-cells and being the rate-controlling enzyme for hepatic glucose clearance and glycogen synthesis is known to have an exceptionally high impact on glucose homeostasis. Drug: Piragliatin
Dopamine-2 receptor agonist
Bromocriptine (centrally-acting dopamine D2 receptor agonist) is believed to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients. Bromocriptine is approved by the FDA for the treatment of type 2 DM.
Monoclonal antibodies
Otelixizumab, an anti-CD3 monoclonal antibody, is known to stimulate C-peptide levels and reduce insulin requirement in type 1 diabetes. Another drug is Teplizumab.