Overview of Pharmacologic Therapy

Introduction

The majority of patients with type 2 diabetes (T2D) have less than ideal metabolic control despite our greater understanding of the underlying pathophysiologic mechanisms of hyperglycemia and the availability of a wide variety of new treatment options. Failure to achieve glycemic goals is related in part to a misconception by patients and caregivers that T2D is a mild disease and not as serious as type 1 diabetes (T1D). In fact, in many respects, T2D may have more severe consequences than T1D because of the multiple cardiovascular (CV) risk factors and accelerated atherosclerosis associated with this form of diabetes.

Insulin resistance is an early and major cause of hyperglycemia and other metabolic abnormalities in people with T2D. Hyperglycemia in T2D often coexists with several other metabolic abnormalities, such as obesity, hypertension, dyslipidemia and a procoagulant state, which themselves require prompt and aggressive diagnosis and treatment. Moreover, prolonged hyperglycemia leads to a worsening of the insulin resistance and endogenous insulin secretory inability (glucose toxicity), thus contributing to the primary and secondary oral-agent failure rate. Aggressive management to reduce the hyperglycemia, which in some cases may require temporary insulin therapy, is necessary to reverse the glucose toxic state.

Pharmacologic therapy with oral antidiabetic agents is required when dietary modification and exercise therapy do not result in normalization or near normalization of metabolic abnormalities. Pharmacologic therapy should always be considered as adjunctive therapy to diet and exercise, and not as a substitute. Although maintaining an optimal diet and exercise regimen is difficult, it is important to emphasize that no pharmacologic therapy can be expected to be successful if the patient is not following some type of dietary and exercise program. Effort should be made to diagnose T2D early in the natural history of the disease when nonpharmacologic therapy tends to be most effective.

Pathophysiologic Basis of Pharmacologic Therapy

The treatment strategies selected for managing T2D are based on understanding the pathophysiology of hyperglycemia and the unique clinical expression of the associated metabolic abnormalities in an individual. T2D is characterized by eight abnormalities (the ominous octet) that contribute to the development of hyperglycemia:

• Peripheral insulin resistance, mainly in the skeletal muscle but also in the liver and adipose tissue
• Excessive glucose production by the liver
• Impaired insulin secretion by the pancreas
• Excessive glucagon secretion
• Increased glucose reabsorption by the kidney
• Neurotransmitter dysfunction
• Accelerated lipolysis in fat cells
• Decreased incretin effect.

Fasting and postprandial hyperglycemia vary considerably among individuals, depending upon the extent, severity and unique expression of each of these metabolic abnormalities, and these differences also play a role in the various responses to the different classes of oral antidiabetic drugs (OADs). Such differences are exemplified by the lean and obese varieties of T2D, which exhibit the same underlying pathophysiology but differ in the extent to which each abnormality contributes to the development of the hyperglycemic state.

In lean patients with T2D, impaired insulin secretion is usually the predominant defect, while insulin resistance tends to be less severe than in the obese variety. Insulin resistance and hyperinsulinemia are the classic abnormalities of obese individuals with T2D, which make up the majority of individuals with this type of diabetes. In obese patients with T2D, the oral antidiabetic agents that do not stimulate insulin secretion tend to be as effective as, but safer than, insulin secretagogues in terms of hypoglycemia when used early in the course of diabetes and when insulin deficiency is not the predominant abnormality. In addition, information is emerging regarding the importance of suppressing glucagon hypersecretion in the management of T2D.

Importance of Controlling Postprandial Hyperglycemia

The evaluation of glycemic control and the response to antidiabetic therapy in T2D has traditionally emphasized monitoring of fasting and preprandial glucose values. However, patients frequently demonstrate normal or near-normal preprandial glucose levels yet have distinctly abnormal postprandial glucose (PPG) values. Postprandial hyperglycemia is often the first clinical abnormality present in those individuals who eventually go on to develop T2D. Although it is not well recognized, postprandial hyperglycemia contributes significantly to elevated glycosylated hemoglobin (A1C) and has been implicated in development of CV and other diabetes complications.

Abnormal PPG values in pregnant diabetic women have also been shown to contribute to perinatal morbidity and mortality and are more significantly correlated with adverse outcomes than fasting glucose levels. Many factors contribute to peak postprandial plasma glucose (e.g., insulin resistance, impaired insulin secretion [especially first phase insulin release], excessive glucagon levels), but up to one third of the variance may be explained by differences in gastric emptying. Many patients with T2D demonstrate abnormally rapid gastric emptying after a high carbohydrate meal, which may contribute to excessive PPG excursions.

The importance of controlling PPG needs to be recognized and treated with modification of diet and use of antidiabetic medication as required. PPG levels are best evaluated 1 to 2 hours after meals by patients using home blood glucose or continuous glucose monitoring devices. American Association of Clinical Endocrinologists (AACE) has published similar stringent, albeit unrealistic for most patients, guidelines for control of PPG with a 2-hour PPG goal of <140 mg/dL. The American Diabetes Association (ADA) has stated that the peak PPG level should be <180 mg/dL, and the International Diabetes Federation (IDF) has set a PPG target of <160 mg/dL (Table 7-1).

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Intensive Therapy in Type 2 Diabetes

Several long-term studies of intensive diabetes management in both type 1 diabetes (T1D) and type 2 diabetes (T2D) have provided clear-cut evidence that near normalization of glycemia can prevent and delay the development and progression of retinopathy, nephropathy and neuropathy. The severity and duration of hyperglycemia have a critical role in the development and progression of microvascular complications, regardless of the etiology of the hyperglycemia. Studies demonstrate not only a reduction in microvascular disease in T2D with improved glycemic control but also reductions in dyslipidemia and coronary artery disease.

The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the benefits of glucose control in >5,000 individuals with newly diagnosed T2D. The subjects were randomized into a conventional-treatment group (nonpharmacologic diet treatment) with the goal to keep the FBG values <270 mg/dL and an intensive-treatment group (sulfonylurea (SFUs), insulin, or metformin (MET)) with the goal to keep the fasting blood glucose (FBG) values <108 mg/dL. The average study duration of subjects was 11 years. Although the UKPDS was not ideally designed or conducted to achieve optimal glycemic control, several important messages have been derived from this study.

Most important, this study demonstrated a highly statistically significant reduction in microvascular disease in the intensive-treatment group on the same order of magnitude as occurred in the Diabetes Control and Complications Trial (DCCT) in T1D (Table 7-2). In the UKPDS, the difference in A1C between the conventional- and intensive-treatment groups was only 0.9% compared with a 2% difference observed in the DCCT.

The natural history of T2D was clearly demonstrated in both treatment groups (ie, there was a definite secondary failure rate [~7% per year] in all subjects) (Figure 7-1). Part of the explanation for the high secondary failure rate may be that subjects were diagnosed relatively late in the natural history of the disease, as they are in the United States: on average, >5 years after onset of hyperglycemia. In this situation, the disease process would be well established and therapeutic interventions less effective to prevent the natural progression of the disease. Another likely possibility is that the mechanism of action of the therapeutic agents utilized did not significantly impact one or more of the major pathophysiologic abnormalities of T2D such as insulin resistance and β-cell dysfunction.

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Intensive Glucose Control and Cardiovascular Risk

In the UKPDS, intensive glucose control with SFU/insulin therapy in patients with newly diagnosed T2D was associated with a reduced risk of clinically evident microvascular complications as well as a nonsignificant (P = 0.052) reduction of 16% in the relative risk of myocardial infarction (MI) compared with patients receiving standard therapy (dietary restrictions). Patients whose body weight was >120% of their ideal weight primarily received MET. In these patients, there were reductions in the risk of MI of 39% (P = 0.01) and of death from any cause of 36% (P = 0.01). The results of long-term follow-up of the original UKPDS trial have been reported. After completion of the primary 5-year trial, 3277 patients of the 4209 initially randomized were followed for an additional 5 years.

Within 1 year of the original study end, the between-group differences in A1C levels disappeared. Nevertheless, the SFU/insulin group had a 15% (P = 0.01) lower risk of MI and a 13% (P = 0.007) lower risk of death from any cause compared with the diet group. The benefits were even greater among overweight patients who received MET, who had a 33% (P = 0.005) lower risk of heart attack and a 27% (P = 0.002) reduced risk of death. These results suggest that it may be very important to initiate early and aggressive treatment to maintain A1C at near-normal levels, possibly translating to long-term beneficial effects on CV disease and mortality (the legacy effect).

The subsequent Steno-2 Trial looked at the cardiac event rate when multiple risk factors were aggressively treated in subjects with T2D when compared with a control group. One hundred and sixty patients with T2D with microalbuminuria (age ~55, body mass index (BMI) ~30, and duration of diabetes ~5.8 years) were randomized to aggressive treatment of their A1C, low-density lipoprotein (LDL), triglycerides and blood pressure levels compared with a control group and then followed for 7.8 years.

Nonpharmacologic interventions in the intensive-therapy group included diet and increased exercise. Pharmacologic interventions included combinations of antihypertensives (angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blocker (ARBs), with thiazides, calcium channel blockers [CCBs] and β-blockers added as needed), vitamin-mineral supplements (e.g., vitamin C, d-α-tocopherol, folic acid, chromium picolinate), aspirin, oral antihyperglycemic agents (MET, gliclazide), insulin (regular, neutral protamine Hagedorn [insulin] (NPH)) and lipid-lowering agents (statins, fibrates). The composite end points were death from CV causes, nonfatal MI, coronary artery bypass grafting, percutaneous coronary intervention, nonfatal stroke, amputation and surgery for peripheral atherosclerotic artery disease. The results were striking in that there was approximately a 50% reduction in the composite end points in <8 years (Figure 7-2).

However, the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and ADVANCE trials have raised questions as to whether CV events can be prevented in patients with T2D by intensive metabolic control alone. In these large, prospective studies, intensive glycemic control resulted in a mean A1C of 6.4% (ACCORD) and 6.5% (ADVANCE) compared with standard control resulting in an A1C of 7.5% and 7.3%, respectively. In neither of these two large studies did the intensively treated group achieve a significantly reduced rate of CV events. In ACCORD, the study with the most ambitious goal (A1C <6%), all-cause mortality and CV mortality was greater in the intensive-treatment group, and the study was terminated early. In the ADVANCE trial, mortality and the incidence of CV events were not statistically different between the two treatment groups, whereas the risk of microvascular complications, especially nephropathy, was significantly decreased in the intensive-treatment group.

In addition, the Veterans Affairs Diabetes Trial (VADT) also showed that intensive glucose control had no significant benefit in terms of decreasing CV complications. Furthermore, any effect on CV risk disappeared with duration of the disease and that the risk of CV events increased in patients with severe hypoglycemic episodes. It is important to note that at baseline, the participants in VADT had an average A1C of 9.5%, 40% had previous CV events, >50% had abnormal lipids, 80% had hypertension and most were obese. In these three studies, the hypoglycemic risk increased in the intensive-control group, which may have contributed to the reduced positive impact of better glucose control on CV complications.

These results from the ACCORD, ADVANCE and VADT trials have raised questions about the benefits of intensive glycemic control on the risk of CV events, as well as what should be an appropriate A1C goal in patients with T2D and CVD. While the ADVANCE study did show benefits of intensive glycemic control in terms of the reduced risk of the combined end point of major macrovascular and microvascular events, this was driven by the significantly reduced risk of microvascular events, since the risk of macrovascular events was not reduced when considered separately. In the ACCORD trial, beginning at approximately 4 years, there was an increasingly favorable, although nonsignificant, separation in the curves for the primary composite end point of nonfatal MI, nonfatal stroke, or death from CV causes (Figure 7-3). One might speculate that this difference may have become significant if the study had gone to completion.

It should also be noted there were differences in the patient populations in the ADVANCE and ACCORD trials. In ADVANCE, the percentages of patients treated with insulin at baseline were 1.5% (intensive group) and 1.4% (standard group), and by study end, the percentages were 40.5% and 24.1%, respectively. In ACCORD, the percentages of patients receiving insulin at baseline were 34.1% and 35.7% and 77% and 55%, respectively, at study end. Thus ACCORD probably included patients with more advanced diabetes that required insulin at baseline, and that insulin was initiated more aggressively in ACCORD than in ADVANCE. Furthermore, the incidence of severe hypoglycemia was much higher in the intensive-treatment groups of ACCORD (10.5%) vs ADVANCE (2.7%) and it has been speculated that a high incidence of severe hypoglycemia may have contributed to the increased total and CV deaths in the intensive-treatment arm of ACCORD.

The results of the VADT clearly indicate that there was no benefit with respect to cardiovascular disease (CVD) from intensive glycemic control, at least in that patient population. However, the VADT was probably underpowered to detect a significant difference among a patient population characterized by long-standing diabetes, poorly controlled hyperglycemia, previous CV events and multiple coexisting CV risk factors. The observed lack of significant CV benefits in the ACCORD and VADT studies and the increased deaths associated with intensive glycemic treatment in ACCORD may not reflect the response of patients with a shorter duration of diabetes and without a strong history of cardiovascular disease (CVD). It remains important to treat early with the goal of maintaining A1C at near normal levels without hypoglycemia.

In light of the above questions and concerns, the ADA currently recommends an A1C target of <7% for nonpregnant adults with the option of more stringent glycemic control in selected individuals where this can be achieved without significant hypoglycemia. Less stringent glycemic control is recommended for other groups, including those who have had severe hypoglycemia and those with a limited life expectancy. In addition, all CV risk factors should be addressed.

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CV Risk Reduction

Five anti-diabetic agents are now available that have been shown to reduce CV events and mortality in patients with T2D and atherosclerotic cardiovascular disease (ASCVD) on metformin. Three sodium glucose cotransporter type 2 (SGLT2) inhibitors (empagliflozin, canagliflozin and dapagliflozin) and two glucagon like peptide 1 (GLP-1) receptors agonists (liraglutide and semaglutide) have demonstrated significant reductions in CV events. In addition, the trials of empagliflozin, liraglutide and semaglutide demonstrated significant reductions in CV death and major adverse CV events, and trials of empagliflozin, canagliflozin, dapagliflozin and ertugliflozin showed that these SGLT2 inhibitors reduce the risk of hospitalization for heart failure. The ADA recommends incorporating a drug with a demonstrated ability to reduce CV events and/or mortality in patients with T2D with or at high risk of ASCVD regardless of baseline A1C, target A1C, or metformin use (see Figure 20-1).

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CKD Progression Risk Reduction

Chronic kidney disease (CKD) is a common comorbidity in patients with T2D and significantly increases the risk of end-stage kidney disease and early death. Three anti-diabetic agents have demonstrated a significantly reduced risk of CKD progression in large clinical trials: the SGLT2 inhibitors canagliflozin (in patients with T2D and diabetic nephropathy with albuminuria) and dapagliflozin (in patients with CKD regardless of T2D), and the mineralocorticoid receptor antagonist finerenone (in patients with T2D and CKD). The ADA recommends incorporating a SGLT2 inhibitor with a proven benefit of reducing CKD progression in patients with T2D and CKD, irrespective of their baseline A1C, individualized A1C target, or metformin use (see Figure 20-1).