Pharmacological treatment of hyperglycemia in type 2 diabetes

Abstract

Diabetes mellitus is a major public health problem, affecting about 10% of the population. Pharmacotherapy aims to protect against microvascular complications, including blindness, end-stage kidney disease, and amputations. Landmark clinical trials have demonstrated that intensive glycemic control slows progression of microvascular complications (retinopathy, nephropathy, and neuropathy). Long-term follow-up has demonstrated that intensive glycemic control also decreases risk of macrovascular disease, albeit rigorous evidence of macrovascular benefit did not emerge for over a decade. The US FDA's recent requirement for dedicated cardiovascular outcome trials ushered in a golden age for understanding the clinical profiles of new type 2 diabetes drugs. Some clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP1) receptor agonists reported data demonstrating cardiovascular benefit (decreased risk of major adverse cardiovascular events and hospitalization for heart failure) and slower progression of diabetic kidney disease. This Review discusses current guidelines for use of the 12 classes of drugs approved to promote glycemic control in patients with type 2 diabetes. The Review also anticipates future developments with potential to improve the standard of care: availability of generic dipeptidylpeptidase-4 (DPP4) inhibitors and SGLT2 inhibitors; precision medicine to identify the best drugs for individual patients; and new therapies to protect against chronic complications of diabetes.

Figure 1. Mechanisms of action for drugs approved for glycemic control in patients with T2D.

Seven classes of FDA-approved T2D drugs are widely used: Biguanides. Several hypotheses have been proposed for metformin’s mechanism of action: (i) activation of AMPK (102, 103); (ii) inhibition of hepatic adenylyl cyclase (104); (iii) inhibition of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) (105); (iv) increasing levels of GDF15 (106, 107); and (v) alteration of intracellular protein-bound iron levels (108). Metformin decreases hepatic glucose production (109). Its action may be exerted in the gut independent of absorption into the circulation (110). Sulfonylureas bind to sulfonylurea receptor-1 (SUR-1) in pancreatic β cells, leading to closure of the ATP-inhibitable K⁺ channel K_ir6.1, thereby initiating electrophysiological changes that trigger insulin secretion (111). Thiazolidinediones (TZDs) activate PPARγ, an adipose tissue transcription factor (112). TZDs promote triglyceride storage in adipose tissue while decreasing deposition of triglycerides in liver and muscle, thereby increasing insulin sensitivity (113, 114). GLP1RAs bind to the GLP1 receptor on pancreatic β cells, augmenting glucose-stimulated insulin secretion. GLP1RAs also delay gastric emptying, decrease glucagon levels, and decrease food intake (115). DPP4is protect GLP1 from degradation, thereby potentiating endogenous GLP1 activity. SGLT2is promote glucosuria and natriuresis by inhibiting proximal tubular glucose reabsorption. Glucosuria decreases HbA1c levels and promotes weight loss. Natriuresis decreases blood pressure, and may also protect against congestive heart failure (41). Insulin binds to its receptor in liver, skeletal muscle, and adipose tissue, triggering intracellular signaling pathways that mediate the various biological actions of insulin — including increased glucose transport into skeletal muscle and adipocytes, regulation of several key metabolic enzymes, and regulation of gene expression (116). Five other classes of approved drugs are less widely used: meglitinides, α-glucosidase inhibitors, amylinomimetics, bile acid sequestrants, and bromocriptine (a D2/D3 dopaminergic agonist).

Figure 2. Overview of ADA/EASD guidelines.

The ADA and EASD provided detailed guidance about pharmacological approaches to treat hyperglycemia in diabetic patients (55). The figure illustrates a simplified version of these guidelines. Initiation of therapy: Guidelines advocate simultaneous initiation of metformin and lifestyle modification (i.e., promoting weight loss in patients who are overweight or obese). Guidelines also suggest consideration of an option to initiate two-drug combination therapy if the patient’s HbA1c is more than 1.5%–2.0% above the HbA1c target (e.g., patients with HbA1c >8.5%–9.0% if the HbA1c target is 7.0%). Addition of second drug: Many patients experience secondary failure as T2D progresses, and require addition of a second drug. ADA/EASD guidelines recommend one of four drug classes for second-line therapy: DPP4is, GLP1RAs, SGLT2is, or TZDs. Low-cost generic sulfonylureas represent a fifth option if cost considerations are the major concern. Third- and fourth-line drug. If necessary, three- and four-drug combinations can be constructed with additional drugs from among DPP4is, GLP1RAs, SGLT2is, and TZDs in combination with metformin. Many patients will eventually experience severe β cell failure and transition to insulin-dependent physiology requiring therapy with basal insulin. With one important exception, guidance from the ACC, ESC, and AHA resembles that from the ADA/EASD (–58). Both the ACC and the ESC have advocated for monotherapy with either GLP1RAs or SGLT2is in patients at high risk for atherosclerotic heart disease. However, it is important to emphasize that there is relatively little evidence to support this recommendation as more than 80% of patients in CVOTs with SGLT2is or GLP1RAs were receiving metformin as part of their therapeutic regimens. The ADA/EASD guidelines provide an inclusive list of options allowing physicians and patients considerable freedom to select whichever drug(s) they prefer. Many physicians may want simpler guidelines offering fewer options, such as we propose in Figure 3.

Figure 3. Algorithm to guide selection of HbA1c-lowering drugs for T2D patients.

DP-0: lifestyle modification. Although lifestyle modification may sufficiently improve glucose levels to avoid the need for drugs, pharmacotherapy and lifestyle modification are most often initiated simultaneously. DP-1: which drug(s) to initiate. As recommended by the ADA/EASD, metformin should ordinarily serve as the foundation for pharmacotherapy. Nevertheless, the fact that patients will often benefit from intensive therapy early in the natural history of T2D (60) favors the ADA/EASD guidelines’ option to initiate two drugs simultaneously. DPP4is and GLP1RAs have favorable safety profiles without increasing risk of serious hypoglycemia in this setting. Driving to lower HbA1c levels diminishes risk of microvascular complications (12). Although addition of a second drug increases cost, this will become less of an issue after DPP4is become generic. DP-2: which third drug to add? Many patients experience secondary failure, requiring intensification of therapy. Achievement of ambitious HbA1c targets favors the objective of minimizing risk of microvascular complications (12, 60). SGLT2is are an attractive component of three-drug regimens (e.g., metformin+DPP4i+SGLT2i or metformin+GLP1RA+SGLT2i), especially because of lowering of blood pressure, weight loss, renoprotection, and reported cardiovascular benefits. The “all-oral” three-drug option is available as convenient fixed-dose combination tablets (metformin+DPP4i+SGLT2i), which will be more affordable when DPP4is and SGLT2is become generic. We deprioritize pioglitazone despite its attractive efficacy profile (117) because of safety concerns with TZDs (17). If secondary failure occurs in patients receiving metformin+DPP4i, the regimen can be intensified by substitution of a GLP1RA in place of a DPP4i. DP-3: whether to initiate insulin. Insulin is often the best option for patients experiencing secondary failure on a three-drug regimen. Nevertheless, some patients may be manageable with a four-drug regimen that does not include hypoglycemia-inducing drugs such as insulin. Metformin+DPP4i+SGLT2i+pioglitazone and metformin+GLP1RA+SGLT2i+pioglitazone stand out as the most attractive among these regimens.