Innovative Treatment Modalities for Diabetes

Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. The chronic hyperglycemia is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.¹

This article will describe the types, diagnosis, pathophysiology and treatment options of diabetes, with special attention paid to type 2 diabetes.

Types of Diabetes

There are three primary types of diabetes:

• Type 1 (T1DM): Beta cells of the pancreas slowly get destroyed over time and no longer produce insulin.
• Type 2 (T2DM): Either the body does not produce enough insulin or the insulin does not work properly (a progressive insulin secretory defect on the background of insulin resistance).
• Gestational Diabetes: Diabetes developed during pregnancy (possible diabetes development in the next 10 years).

Other rare types of diabetes are due to genetic defects in beta-cell function or insulin action, e.g., diseases of the exocrine pancreas like CFRD (Cystic Fibrosis Related Diabetes). Others may have diabetes induced by drugs or chemicals [Steroid-induced diabetes or in the treatment of HIV/AIDS or after organ transplantation].¹

Still more rare types of diabetes are genetic forms, namely Latent Autoimmune Diabetes of Adults (LADA) and Maturity Onset Diabetes of the Young (MODY). LADA is the most rare type of diabetes (10% of all cases). It is found in people over 35 years old. This slow-developing autoimmune diabetes has some genetic overlap with both type 1 and type 2 diabetes. A set of criteria for its diagnosis includes: 1) the presence of auto antibodies in the blood, 2) adult age at onset, and 3) no need for insulin treatment in the first six months after diagnosis.² MODY is genetically-linked form of diabetes caused by just a single aberrant gene. MODY is highly heritable. If one parent has a gene that causes MODY, there is a 50% chance it will be passed to a child although not everyone who inherits a MODY gene develops diabetes. MODY accounts for almost 1% to 5% of all diabetes populations.³

Diagnosis of Diabetes¹

Diagnosis of Prediabetes¹

Diagnosis of Gestational Diabetes

Use standard diagnostic criteria to screen for undiagnosed T2DM with risk factors at the first prenatal visit. Screen for GDM (Gestational Diabetes Mellitus) at 24-28 weeks of gestation using a 75-g 2-h oral glucose tolerance test (OGTT) in pregnant women who has no prior h/o diabetes (based on the new revised criteria).

A. OGTT should be performed in the morning after an overnight fast of at least eight hours.
B. GDM diagnosis is made when any of the following plasma glucose values are exceeded: Fasting: 92 mg/dL (5.1 mmol/L), 1 h: 180 mg/dL (10.0 mmol/L) or 2 h: 153 mg/dL (8.5 mmol/L).¹

Normal Glucose Metabolism

Glucose is the premium fuel for the body cells. Insulin is the storage hormone produced by the pancreas β (beta) cells. Insulin production is increased with high blood sugar levels. It stimulates glucose uptake into the liver, muscle, and adipose tissues. Insulin inhibits the breakdown of hepatic glycogen stores and triglyceride reservoirs and also causes less glucagon secretion from the α (alpha) cells. Glucagon is a breakdown hormone produced by the pancreatic α cells. Increased glucagon secretion happens with increased blood sugars. Glucagon and insulin are counter-regulatory hormones. Glucagon stimulates hepatic gluconeogenesis and increases the blood sugar levels. Glucagon injection for severe hypoglycemia will act in this same manner.⁴

Pathophysiology

T1DM accounts for only 5% to 10% of all diabetes cases. It was previously known as insulin-dependent diabetes, type I diabetes, or juvenile-onset diabetes, results from a cellular-mediated autoimmune destruction of the β-cells of the pancreas. Markers of the immune destruction of the β-cell include islet cell autoantibodies, autoantibodies to insulin, autoantibodies to glutamic acid decarboxylase (GAD65), and autoantibodies to the tyrosine phosphatases IA-2 and IA-2β. One and usually more of these autoantibodies are present in 85-90% of individuals when fasting hyperglycemia is detected initially. There is little or no insulin secretion, as manifested by low or undetectable levels of plasma C-peptide. Immune-mediated diabetes commonly occurs in childhood and adolescence, but it can occur at any age, even in the eight and ninth decades of life.⁵

T2DM accounts for 90% to 95% of those with diabetes, previously referred to as non-insulin-dependent diabetes, T2DM, or adult-onset diabetes. These patients are insulin resistant, usually have relative (rather than absolute) insulin deficiency often throughout their lifetime. The insulin secretion is defective in these patients and insufficient to compensate for insulin resistance. These individuals do not need insulin treatment to survive. There are probably many different causes of this form of diabetes. In T2DM autoimmune destruction of β-cells does not occur. Most patients are obese and if they are not obese, they have increased percentage of body fat distributed predominantly in the abdominal region. These patients are at increased risk of developing macrovascular and microvascular complications.⁵

Treatments

Oral Hypoglycemic Agents

Biguanides: For patients with recent-onset T2DM and those with mild hyperglycemia (defined as an A1c <7.5%), initial monotherapy is accomplished with metformin. Metformin is recommended as either initial or monotherapy because of its low risk of hypoglycemia, the likelihood of modest weight loss, the reasonable durability of its antihyperglycemic effects, and its long-term general and cardiovascular safety record. Metformin’s mechanism of action is activation of intracellular adenosine monophosphate-kinase, which reduces hepatic glucose output and secondarily may improve beta-cell function and insulin resistance. Metformin lowers A1c by 1% to 1.5% at maximum or near-maximum doses (dose range, 500 mg/day to 2,550 mg/day). Due to the risk of lactic acidosis, metformin use is contraindicated in patients with impaired renal function (creatinine level >1.5 mg/dL in males and >1.4 mg/dL in females). Metformin should be prescribed with caution in patients with alcoholism or extremes of age and avoid the use if clinical or laboratory evidence of hepatic disease present. Do not use if patient is ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced. vitamin B12 deficiency has been described with metformin.⁶ May restore ovulation in premenopausal anovulatory females. Temporarily discontinue metformin at the time of or prior to intravascular iodinated radio contrast studies and withhold for 48 hours after the procedure. Reinstitute only after renal function has been reevaluated and found to be normal. Discontinue metformin in the presence of cardiovascular collapse. Patients with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia are at increased risk of lactic acidosis.⁷

GLP-1 Receptor Agonists: These stimulate insulin secretion from the beta-cells of the pancreas through a G-protein receptor-mediated process that is regulated by the intracellular glucose level. It is glucose dependent. They also reduce glucagon secretion from the alpha-cells and slow gastric emptying. These are injectables available in three types now. Short-acting exenatide (Byetta) is available in two fixed-dose formulations (5 µg and 10 µg), while long-acting exenatide is injected once weekly at a fixed dose of 2 mg (Bydureon). Liraglutide, with a half-life of eight to 14 hours, is administered once-daily in doses ranging from 0.6 to 1.8 mg and can be titrated to tolerance to achieve the desired glucose-lowering effect. GLP-1 receptor agonists reduce both fasting glucose and postprandial glucose excursions. The weight loss and low hypoglycemia risks are two other advantages. Safety signals were observed for C-cell hyperplasia and malignancy in rodents (liraglutide) and pancreatitis (all) in registries and postmarketing reports, but confirmatory population studies are lacking.⁶

DPP-IV inhibitors: DPP-4 inhibitors increase endogenous GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) by inhibiting the enzyme that breaks down the incretin hormones. The elevated level of GLP-1 increases insulin secretion in a glucose-dependent manner from beta-cells and reduces glucagon secretion from alpha-cells in the pancreas. Four DPP-4 inhibitors are approved for use in the U.S., including sitagliptin (available daily doses, 25 mg, 50 mg, and 100 mg), saxagliptin (2.5 mg and 5 mg), linagliptin (newest one – 5 mg), and alogliptin (6.25 mg, 12.5 mg, and 25 mg. These drugs do not tend to cause weight gain and hypoglycemia.⁶

Alpha Glucosidase Inhibitors (AGI): AGIs lower postprandial glucose by inhibiting the gut enzyme alpha glucosidase that breaks down complex carbohydrates, thus delaying polysaccharide absorption. AGIs lower post prandial sugars. Side effects such as bloating, flatulence, and diarrhea have limited the use of AGIs in the U.S. The AGIs acarbose (available daily doses, 50 mg and 100 mg), miglitol (25 and 50 mg), and vogliobose (0.2 mg and 0.3 mg) must be given before each meal, further limiting their acceptability.⁶ Patient needs to consume quick simple sugars if hypoglycemia occurmg s and no sucrose is ingested when hypoglycemia occurs due to delayed GI absorption. Use not recommended if serum creatinine > 2.0mg/dl. The use of acarbose is contraindicated in the presence of intestinal complications and in patients with cirrhosis. Serum transaminase should be checked every three months during first year of treatment and periodically thereafter.⁷

Thiazolidinediones (TZD): The TZDs reduce insulin resistance in skeletal muscle and other tissues through the downstream effects of peroxisome proliferator activator receptor-gamma (PPARg) activation . Pioglitazone (available daily doses, 15 mg, 30 mg and 45 mg) has many positive attributes, including A1c lowering of 0.7% to 1.2%, low hypoglycemia risk, and possible CVD benefit. Side effects such as weight gain and fluid retention, which may contribute to chronic edema or heart failure, and adverse metabolic effects on bone causing an increased risk of fracture, have limited the use of TZDs. The reported association of pioglitazone and bladder cancer is an unresolved issue.⁶ Rosiglitazone is another drug in this category. It is contraindicated in New York Heart Association Class III and IV heart failure. The drugs in this class have to be used for six to 12 weeks use for the complete effect. Do not initiate in patients with active liver disease or ALT > 2.5 x the upper limit of normal. This class of drugs may restore ovulation in premenopausal anovulatory females. Rosiglitazone not recommended in combination with insulin. Not recommended in symptomatic heart failure.⁷

Sulfonylureas & Glinides: SFUs are the oldest class of noninsulin antihyperglycemic agents. SFUs have relatively potent antihyperglycemic effects, with A1C reductions of 0.4% to 1.2%, but they lack durability and are associated with modest weight gain and hypoglycemia. Evidence-based medicine conclusively demonstrates that the glucose-lowering effect of the sulfonylureas is NOT durable and that loss of glycemic control is associated with progressive beta-cell failure.⁶ SFUs and glinides have the highest hypoglycemia risk of any noninsulin therapy. The second-generation SFUs, which are the most widely utilized, include glipizide (daily dose range, 5 mg to 40 mg), glyburide (1.25 mg to 20 mg), glimepiride (1 mg to 8 mg), and gliclazide (40 mg to 160 mg for short-acting, 30 mg to 120 mg for the modified-release; not available in the U.S.). The secretagogue glinides (repaglinide, 0.5 mg, 1 mg and 2 mg; nateglinide, 60 mg and 120 mg) have a shorter half-life than most SFUs and consequently have both reduced A1C-lowering effects and hypoglycemia risk. They are administered with meals and exert their main glycemic effect in the postprandial period.⁴ Hypoglycemia, hypersensitivity, angioedema, arthralgia, myalgia, and vasculitis have been reported as side effects. May cause hypoglycemia or disulfuram reaction (rare) if used with alcohol. Glyburide not recommended if Clcr <50mL/min. Co-administration of repaglinide with gemfibrozil is contraindicated. Use repaglinide cautiously in hepatic impairment or severe renal impairment.¹

Colesevelam: The bile acid sequestrant (BAS) colesevelam lowers glucose modestly through an unknown mechanism. The A1c drop is generally 0.4% to 0.6%, but it is coupled with a decrease in LDL-C that may be beneficial. The major side effect is GI intolerance, which limits its use. Increased triglyceride levels can be problematic for some patients. Colesevelam does not cause hypoglycemia or increase hypoglycemia risk when used with other agents and thus may be of value as an adjunctive therapy.⁴

Bromocriptine Mesylate: The dopamine receptor agonist bromocriptine mesylate (0.8 mg tablets; daily dose, 1.6 mg to 4.8 mg) has glucose-lowering properties and reduces A1c by about 0.5%

SGLT2 Inhibitors: This is the newest addition of antidiabetes drugs. Canagliflozin (Invokana) (100 mg, 300 mg) has been approved by the U.S. FDA and has been shown to lower A1c by 0.45% to 0.92%. This also is accompanied by a weight loss of 0.7 kg to 3.5 kg. The primary side effects are increased urinary tract and genital infections. An unexplained adverse effect is increased LDL-C. The SGLT2 drugs will likely be used as add-on therapy to two or three other agents, including insulin, in patients who would benefit from weight loss.⁶ The kidneys make an important contribution to balancing blood glucose. As glucose is filtered from the blood into the kidneys, it is reabsorbed back into the bloodstream. An important carrier responsible for this reabsorption is called sodium glucose co-transporter 2 (SGLT2). Invokana selectively inhibits SGLT2, and as a result promotes the loss of glucose in the urine, lowering blood glucose levels in adults with type 2 diabetes.⁸

Exogenous Insulin Therapy

In accordance with ADA guidelines, insulin should be added either as the first agent when clinically indicated or when A1c is not at goal on one to two oral hypoglycemic agents. Most patients with T2DM will eventually require insulin therapy to achieve a goal A1c of < 7% as defined by the American Diabetes Association (ADA) or ≤ 6.5% as defined by the American Association of Clinical Endocrinologists.⁹

Basal Insulin: The pancreas makes a small amount of insulin, termed “basal insulin,” even in the fasting state to suppress catabolism of muscle, fat, and other body tissues and regulate hepatic glucose production. Available long-acting agents include once-daily insulin glargine and once- or twice-daily insulin detemir or twice-daily NPH, an intermediate-acting insulin. Deciding which basal insulin to choose is up to the provider and the patient. Glargine does not have a distinct peak. A starting dose of 0.1 units/kg to 0.2 units/kg is reasonable in patients with an A1c of ≤8.0%, and a dose of 0.2 to 0.3 units/kg is reasonable if the A1c level is between 8% and 10%.⁴ Not to exceed 0.5 units/kg of body weight without first considering adding rapid-acting insulin. Every three days, if the fasting blood glucose is not in the target range of 70-130 mg/dl, the dose of basal insulin can be increased by two units if glucose is relatively close to the fasting target or four units if fasting blood glucose is > 180 mg/dl after three days of monitoring. If hypoglycemia with blood glucose < 70 mg/dl occurs, basal insulin should be decreased by 10% or four units, whichever yields the larger change. If A1c remains elevated ≥ 7% after two to three months on basal insulin, or if prelunch, predinner, or bedtime blood glucose levels are clearly above the goal of 70 mg/dl to 130 mg/dl despite a fasting glucose level at goal, prandial therapy should be instituted.⁹

Bolus Insulin: Insulins available for prandial coverage include regular insulin (defined as short-acting) and the rapid-acting insulin analogs. The rapid-acting analogs, including aspart, lispro, and glulisine, allow a closer approximation of physiological insulin secretion. It is absolutely crucial that patients understand the importance of frequent blood glucose monitoring when adding or adjusting prandial insulin. If prelunch blood glucose is consistently elevated > 130 mg/dl, add rapid-acting insulin at breakfast. If predinner blood glucose is elevated, add rapid-acting insulin at lunch. If bedtime blood glucose is elevated, add rapid-acting insulin at dinner. For each of the doses, one can often begin with four units (in patients with usual insulin sensitivity and renal and hepatic function) and adjust by two units every three days until blood glucose is in range. Insulin-to-carbohydrate (I: C) ratio for inconsistent carbohydrate persons: This requires patients to count the number of carbohydrate consumed at each meal and give a variable amount of insulin according to the determined ratio. For example, patients with an I:C ratio of 1:10 would take one unit of insulin for every 10 grams of carbohydrate consumed.⁹

Types of Insulin⁷

Premixed products:
70% NPH/30% Regular (Novolin 70/30, Humulin70/30), 50%NPH/50% regular (Humulin 50/50)
75% intermediate/25% lispro (Humalog mix 75/25), 50% intermediate/ 50% lispro (Humalog mix 50/50)
70% insulin aspart protamine recombinant; 30% insulin aspart recombinant (Novolog mix 70/30)
50% insulin aspart protamine recombinant; 50% insulin, aspart recombinant (Novolog mix 50/50)

In Summary

There are different types of diabetes and T2DM is the most common. Based on new evidences, obesity and prediabetes as the underlying risk factors for diabetes and associated macrovascular complications and should be treated according to the pathophysiological factors rather than just treating the symptoms. It is now clear that the progressive beta-cell defect that drives the deterioration of metabolic control over time begins early and may be present before the diagnosis of diabetes.⁶ Measures to overcome insulin resistance related to obesity include losing weight, treating prediabetes, healthy meal planning, exercising and taking medications as prescribed, which can control T2DM without causing major macrovascular complications.

References for this article can be accessed here.

Priya M. Mathew is a Chronic Disease Manager, VA North Texas Health Care System, Dallas.